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"abstract": "Pulmonary artery pseudoaneurysm is an uncommon yet fatal clinical entity. Its presentation can mimic a number of common diseases and can be easily missed. As pseudoaneurysm is associated with a number of fatal complications, clinicians should be aware of imaging features which distinguishes pseudoaneurysms from its close differentials. Early recognition and treatment of pseudoaneurysm can prevent fatal outcomes including hemothorax, rupture, or death.",
"affiliations": "Department of Internal Medicine, Albert Einstein Medical Center Philadelphia, Pennsylvania.;Department of Internal Medicine, Albert Einstein Medical Center Philadelphia, Pennsylvania.;Department of Hematology and Oncology, MOHA Cancer Center, Albert Einstein Medical Center Philadelphia, Pennsylvania.",
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"fulltext": "\n==== Front\nClin Case RepClin Case Repccr3Clinical Case Reports2050-09042050-0904John Wiley & Sons, Ltd Chichester, UK 10.1002/ccr3.363Case ReportsPseudoaneurysm of pulmonary artery: rare complication of systemic chemotherapy Garg Shivani 1King Gentry 1Varadi Gabor 21 Department of Internal Medicine, Albert Einstein Medical CenterPhiladelphia, Pennsylvania2 Department of Hematology and Oncology, MOHA Cancer Center, Albert Einstein Medical CenterPhiladelphia, PennsylvaniaCorrespondence Shivani Garg, Department of Internal Medicine, Albert Einstein Medical Center, Philadelphia, PA. Tel: 2404000889; Fax: 4047271300; E-mail: shivanigarg88@yahoo.co.inFunding Information No sources of funding were declared for this study\n\n10 2015 02 9 2015 3 10 845 848 21 4 2015 17 6 2015 30 6 2015 © 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.2015This is an open access article 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.Key Clinical Message\nPulmonary artery pseudoaneurysm is an uncommon yet fatal clinical entity. Its presentation can mimic a number of common diseases and can be easily missed. As pseudoaneurysm is associated with a number of fatal complications, clinicians should be aware of imaging features which distinguishes pseudoaneurysms from its close differentials. Early recognition and treatment of pseudoaneurysm can prevent fatal outcomes including hemothorax, rupture, or death.\n\nChemotherapycoil embolizationpseudoaneurysm\n==== Body\nIntroduction\nAcquired pseudoaneurysm is uncommon finding and is extremely rare after systemic chemotherapy 1,2. Focal dilatation of pulmonary artery can be seen in tuberculosis, pulmonary vascular infections, trauma, and vasculitis. It can also be observed after intra-arterial chemotherapy and Swan–Ganz catheter placement 7. There is some evidence that erosion of vessel wall by tumor can result in a pseudoaneurysm of branches of the pulmonary artery. Rarely pulmonary artery pseudoaneurysms are seen as complication of systemic chemotherapy.\n\nCase Report\nAbout 47-year-old female was recently diagnosed synovial sarcoma of thigh with metastasis to lung with tumor invading the left pulmonary artery (Fig.1). Patient was on systemic chemotherapy with adriamycin and ifosfamide and had completed four cycles of chemotherapy so far. She presented with sudden onset of pleuritic chest pain with subjective fevers. No other positive indicators were found on review of systems. On examination, her vitals were stable, afebrile, and spO2 was 94% on room air. Rest physical examination revealed no focal findings with a benign chest examination. Her laboratory workup revealed anemia (hemoglobin 10 g/dL) and leukopenia. As patient had neutropenia with subjective fevers and recently received a course of chemotherapy, a computerized tomography of chest was done to rule out infection, consolidation, infarct/embolism, or progression of cancer. Computed tomography with contrast revealed 10-mm round isodense enhancement at the base of left main pulmonary artery consistent with pseudoaneurysm and an 8-mm big similar round isodense enhancement was noticed at the base of the subsegmental branches of right pulmonary artery (Fig.2). On further comparison with previous images (imaging done at the time of diagnosis of the metastatic synovial sarcoma), we found that pseudoaneurysm to be a new finding and the site of pseudoaneurysm was same as the site of tumor invasion into pulmonary vasculature. As one of the major vessel had the pseudoaneurysm with a higher chances of rupture resulting in unfavorable outcomes like hemothorax/intraparenchymal hemorrhage or intrabronchiolar hemorrhage, patient underwent angiography and stenting of the pseudoaneurysm. Postprocedure imaging revealed stabilization of the size of pseudoaneurysm and no bleed/leak of the pseudoaneurysm. On follow-up, patient was stable with no progression or new pulmonary artery pseudoaneurysm (Fig.3).\n\nFigure 1 CT of chest which shows synovial sarcoma invading pulmonary artery.\n\nFigure 2 CT showing resolution od cancer invasion after chemotherapy but the same site of invasion now shows a pulmonary artery pseudoaneurysm.\n\nFigure 3 CT chest showing resolution of pulmonary artery pseudoaneurysm post procedure.\n\nDiscussion\nPulmonary artery aneurysms and pseudoaneurysms are uncommon but important to recognize because of the associated morbidity. By definition, an aneurysm is focal dilatation of a blood vessel that involves all three layers of vessel wall. A pseudoaneurysm does not involve all layers of the arterial wall and is therefore at higher risk of rupture. Pseudoaneurysm is commonly described in hepatic artery accounting for more than 65% of all pseudoaneurysms reported in the literature 1,2. Pseudoaneurysm of pulmonary vasculature is infrequently described in the literature and usually remains clinically silent or present with subtle symptoms 1. Because of higher tendency of getting ruptured, on rare occasions these present with hemorrhages and other catastrophic events like intrapulmonary hemorrhage, hemothorax, or intrabronchiolar hemorrhage. Idiopathic pulmonary artery pseudoaneurysm is more commonly found in elderly females, besides that no other demographic event has been attributed to pseudoaneurysm formation in pulmonary vasculature 7. Pulmonary artery pseudoaneurysm are seen either after traumatic event, tuberculosis, pneumonia, vasculitis (few common ones: Behcet's syndrome and Hughes–Stovin syndrome which is characterized by recurrent thrombophlebitis and pulmonary artery aneurysm) or congestive heart failure. There are a handful of cases with invasive cancer presenting with pseudoaneurysm of pulmonary vasculature which resolve after the treatment of cancer with systemic chemotherapy 1,2,4,5. Few case reports mention the occurrence of pseudoaneurysm of pulmonary vasculature after local invasive procedures like placement of Swan–Ganz catheter or after sessions of local chemotherapy 3,7,8. Few cases mention adriamycin as the most commonly associated chemotherapy agent with pseudoaneurysm especially in patients undergoing transarterial chemoemobilzation (TACE) for hepatocellular carcinoma 6–8,10. As pseudoaneurysm is usually a consequence of local procedures involving mechanical trauma to vessel wall or local effect to chemotherapy, it is not clearly mentioned whether adriamycin is the sole culprit 9,10. But development of pseudoaneurysm of pulmonary artery after systemic chemotherapy has not been documented so far in medical literature.\n\nPseudoaneurysm can present as chest pain, hemoptysis, and shortness of breath. As a number of diseases like pulmonary thromboembolic disease, pulmonary infections, bronchogenic cancer, or pulmonary metastasis can mimic above so it is important for clinicians to know the diagnostic features of pseudoaneurysm on imaging. On a plain radiography image pulmonary artery aneurysm can present as hilar enlargement or lung nodule 12. Computerized tomography with contrast enhancement has high sensitivity of diagnosing pseudoaneurysm and also it gives a precise location of aneurysm for deciding the modality of treatment required. The common presentations on contrast enhanced computerized tomography (CECT) are round enhancement isodense with central pulmonary artery, with central enhancement and no precontrast enhancement are diagnostic of pulmonary artery pseudoaneurysm 1,7. The upper limit of normal diameter of the main pulmonary artery on CT is 29 mm and of the right interlobar artery is 17 mm 11. Aneurysm is defined as focal dilatation of a pulmonary artery beyond its maximal normal caliber, whereas outpocketing from the vessel wall depicts a pseudoaneurysm. MRI also can show arterial wall thickening in connective tissue disease and provide information regarding blood flow direction in cases of poststenotic dilatation due to disease of the pulmonary valve. Besides confirming the diagnosis of pulmonary vasculature pseudoaneurysm, it is also very important to find out the underlying etiology (e.g., tuberculosis-related pseudoaneurysm, mycotic pseudoaneurysm, autoimmune pathology vs. malignant process) of this clinical entity as treatment might vary according to the underlying etiology.\n\nTreatment of pseudoaneurysm is debatable and depends on size of pseudoaneurysm and location of pseudoaneurysm. Because of unpredictable course of pseudoaneurysm, early and rapid treatment is recommended with angiography and coiling/stenting of aneurysm. Other therapeutic options are chemoembolization or surgical procedures like lobectomy which have higher side effects like infections, adhesions, or infarction 9,10. Our case is unique as our patient presented with pseudoaneurysm as a complication of systemic chemotherapy. Early recognition and treatment of pseudoaneurysm prevented mortality and fatal outcomes requiring surgical intervention.\n\nConclusion\nPulmonary vascular aneurysms and pseudoaneurysms are uncommon entities. It is a potentially life-threatening complication that physicians should be aware of when they evaluate a patient for hemoptysis or chest pain after chemotherapy. Appropriate diagnostic imaging followed by treatment can prevent massive hemorrhage into lungs or mediastinum. Stenting of the involved segment of the pulmonary artery is an option in the management of pseudoaneurysms.\n\nThis case was presented as a challenging case in scientific community of American Thoracic Society International Conference Abstracts, 2014.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\nKim S-Y Kim H-R Song J-S Hwang K-E Pseudoaneurysm due to squamous cell carcinoma of the lung: two cases of spontaneous resolution after chemotherapy Cancer Res. Treat 2009 41 237 241 20057971 \nMarkowitz DM Hughes SH Shaw C Denny DF Wilkinson LA White RI Transcatheter detachable balloon embolotherapy for catheter-induced pulmonary artery pseudoaneurysm J. Thorac. Imaging 1991 6 75 78 1856906 \nCamargo JdeJ Camargo SM Machuca TN Bello RM Large pulmonary artery pseudoaneurysm due to lung carcinoma: pulmonary artery pseudoaneurysm J. Thorac. Imaging 2010 25 W4 W5 20160588 \nOz K Demirhan R Onan B Sancakli I Pulmonary artery pseudoaneurysm after a vascular access port catheter implantation Ann. Thorac. Surg 2009 87 295 297 19101317 \nBartter T Irwin RS Phillips DA Benotti JR Worthington-Kirsch RL Pulmonary artery pseudoaneurysm. A potential complication of pulmonary artery catheterization Arch. Intern. Med 1988 148 471 473 3341843 \nSakurai J Mimura H Gobara H Hiraki T Kanazawa S Pulmonary artery pseudoaneurysm related to radiofrequency ablation of lung tumor Cardiovasc. Intervent. Radiol 2010 33 413 416 19449071 \nBao M Zhou Y Jiang G Chen C Pulmonary artery pseudoaneurysm after a left upper sleeve lobectomy World J. Surg. Oncol 2013 11 272 24119497 \nShin TB Yoon SK Lee KN Choi JS Kim YH Sung CG The role of pulmonary ct angiography and selective pulmonary angiography in endovascular management of pulmonary artery pseudoaneurysms associated with infectious lung diseases J. Vasc. Interv. Radiol 2007 18 882 887 17609448 \nKhan AA Bauer TL Garcia MJ Panasuk DB Davies AL Angiographic embolization of a traumatic pulmonary pseudoaneurysm Ann. Thorac. Surg 2005 79 2136 2138 15919328 \nDimarakis I Thorpe JAC Papagiannopoulos K Successful treatment of a posttraumatic pulmonary artery pseudoaneurysm with coil embolization Ann. Thorac. Surg 2005 79 2134 2136 15919327 \nNguyen ET Silva CIS Seely JM Chong S Lee KS Müller NL Pulmonary artery aneurysms and pseudoaneurysms in adults: findings at CT and radiography Am. J. Roentgenol 2007 188 W126 W134 17242217 \nPulmonary arterial aneurysm. Dr Ahmed Abd Rabou and Dr Yuranga Weerakkody. Radiopedia.org\n\n",
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{
"abstract": "Heparin-induced thrombocytopenia type II (HIT type II) can have devastating consequences in cardiac surgical patients. We report two cases of massive left atrial thrombus after mitral valve replacement and endocardial cryoablation in patients with HIT type II.",
"affiliations": "Department of Cardiac Surgery, Klinikum Passau, Passau, Germany.;Department of Cardiac Surgery, Klinikum Passau, Passau, Germany.;Department of Cardiac Surgery, Klinikum Passau, Passau, Germany.;Department for Laboratory Medicine, Klinikum Passau, Passau, Germany.;Department for Laboratory Medicine, Klinikum Passau, Passau, Germany.;Department of Cardiac Surgery, Klinikum Passau, Passau, Germany.",
"authors": "Mandryk|Yuriy|Y|;Czesla|Markus|M|;Mogilansky|Christian|C|;Stefkova|Kristina|K|;Drees|Aloys|A|;Massoudy|Parwis|P|",
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"fulltext": "\n==== Front\nTH OpenTH Open10.1055/s-00033990TH Open: Companion Journal to Thrombosis and Haemostasis2567-34592512-9465Georg Thieme Verlag KG Stuttgart · New York 10.1055/s-0038-1672188180005Case ReportMassive Left Atrial Thrombus in Two Patients with Heparin-Induced Thrombocytopenia Type II after Cardiac Surgery Mandryk Yuriy 1Czesla Markus 1Mogilansky Christian 1Stefkova Kristina 2Drees Aloys 2Massoudy Parwis 11 Department of Cardiac Surgery, Klinikum Passau, Passau, Germany2 Department for Laboratory Medicine, Klinikum Passau, Passau, GermanyAddress for correspondence Yuriy Mandryk, MD Klinik für Herzchirugie, Klinikum PassauInnstrasse 76, 94032 PassauGermanyyuriy.mandryk@klinikum-passau.de7 2018 26 9 2018 2 3 e334 e337 11 1 2018 16 8 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is properly cited.Heparin-induced thrombocytopenia type II (HIT type II) can have devastating consequences in cardiac surgical patients. We report two cases of massive left atrial thrombus after mitral valve replacement and endocardial cryoablation in patients with HIT type II.\n\nKeywords\nheparin-induced thrombocytopeniaargatrobanmitral valve replacementendocardial cryoablation\n==== Body\nClinical Summary\n\nTwo patients underwent mitral valve replacement (MVR) and endocardial cryoablation of the left atrium (CryoICE, AtriCure). Patient A was 58 years old and patient B was 61 years old. Both were male. Patient A had combined mitral valve stenosis and regurgitation, and patient B had mitral valve endocarditis. Both had chronic atrial fibrillation and enlarged left atria. Left ventricular ejection fraction was slightly reduced in patient A and preserved in patient B. Thromboembolic prophylaxis with intravenous unfractioned heparin was started in both patients on the day of hospital admission and continued until surgery with a target activated partial thromboplastin time of 60 to 80 seconds because of underlying atrial fibrillation (\nFigs. 1\nand\n2\n).\n\n\nFig. 1 \nThrombocyte count (y-axis) in patient A with early left atrial thrombus formation 10 days after surgery. x-axis represents time line. Unfractioned heparin was started on the day of hospital admission as an intravenous application, because of atrial fibrillation. In the preoperative period, target partial thromboplastin time (PTT) was 60–80 seconds; intraoperatively, target ACT was 400 seconds; and postoperatively, target PTT was again 60–80 seconds. Time of PF4-H IgG-specific ELISA and HIPA tests and time of redo-MVR surgery are indicated by arrows. Result for ELISA was 2.09 OD, for HIPA 4 of 4 cells (details in Clinical Summary). Argatroban infusion was started on day 13 after MVR surgery, with a target value of 1.0 ng/mL.\n\n\nFig. 2 \nThrombocyte count (y-axis) in patient B with delayed left atrial thrombus formation 5 weeks after surgery. x-axis represents timeline. Unfractioned heparin was started on the day of hospital admission as an intravenous application, because of atrial fibrillation. In the preoperative period, target PTT was 60–80 seconds; intraoperatively, target ACT was 400 seconds; and postoperatively, target PTT was again 60–80 seconds. Time of PF4-H IgG-specific ELISA and HIPA tests and time of redo-MVR surgery are indicated by arrows. Result for ELISA was 2.04 OD, for HIPA 4 of 4 cells (details in Clinical Summary). Argatroban infusion was started on day 9 after MVR surgery, with a target value of 1.0 ng/mL. For redo surgery, heparin was administered because of negative HIT tests. For this period, argatroban was discontinued and thereafter resumed.\n\n\nIn both patients, intraoperative repair of the mitral valve was not successful; therefore, a bioprosthesis was implanted. Patient A had concomitant coronary artery bypass grafting, and patient B had concomitant closure of a patent foramen ovale over a minimally invasive approach. Anticoagulation for cardiopulmonary bypass (CPB) during the operation was achieved using intravenous heparin. Treatment was started with an initial dose of 30 IU/kg with a target activated clotting time (ACT) of over 400 seconds.\n\nAfter surgery, patient A could be weaned from the respirator within 15 hours and was transferred to the regular ward on postoperative day 6. In patient B, postoperative lung function was severely compromised and percutaneous tracheostomy was performed 2 weeks after surgery. Thereafter, weaning from the respirator was initiated but failed due to aspiration. The patient had to be sedated again and ventilated in a controlled manner. In both patients, postoperative thromboembolic prophylaxis was initially continued with unfractioned intravenous heparin.\n\n\nA significant drop in platelet count was observed on day 14 (patient A) and day 9 (patient B) after the initial intravenous heparin exposure (\nFigs. 1\nand\n2\n). Directly thereafter, heparin was replaced by argatroban (with an initial infusion rate of 0.5 µg/kg/min), using therapeutic drug monitoring with a target range in blood serum of 1.0 µg/mL. An antiplatelet factor 4-heparin (anti-PF4-H) antibody test, based on a chemiluminescent assay (ACL, AcuStar), revealed positive results for both patients (2.44 U/mL in patient A, and 4.6 U/mL in patient B, cut-off value: ≥1.0 U/mL). The chemiluminescence test is specifically designed for the detection of very low concentrations of analytes. Having a quick turnaround time of approximately 30 minutes, it has superior range and sensitivity qualities compared with enzyme-linked immunosorbent assays (ELISA) or immunoturbidimetric assays.\n1\nWith chemiluminescent assays, the tracer binds specifically to the target of the assay, emitting light when an oxidizer and a catalyst are added. The light detector in the ACL AcuStar is highly sensitive and detects extremely low levels of light, significantly increasing the linearity (or working range) versus typical colorimetric assays.\n2\n\n\n\nThe results were confirmed by two further assays, performed in the Institute for Immunology and Transfusion Medicine in Greifswald, which constitutes our reference laboratory. The tests used were a PF4-H IgG-specific ELISA\n3\nand a heparin-induced platelet aggregation (HIPA) test.\n4\nThe optical density (OD) value in the ELISA test was 2.09 OD in patient A and 2.04 OD in patient B (cut-off: >1.0 OD). The HIPA test was also positive in both patients (4 of 4 cells).\n\n\n\nIn parallel to the typical serological configuration of heparin-induced thrombocytopenia type II (HIT type II), thrombotic complications and a clinical deterioration with acute hemodynamic and respiratory instability were observed for 10 days (patient A) and 5 weeks (patient B) after surgery. Therefore, patient A was an example for an early thrombotic complication in association with an HIT type II, whereas the thrombotic complication occurred late in patient B. In patient B, although heparin had been discontinued for more than 4 weeks, the thrombotic complication impressed similar to the acute reaction, which is usually observed closer to the serological diagnosis of an HIT type II or may even proceed it.\n5\n\n\n\nIn both patients, echocardiography showed massive thrombus formation in the left atrium, obstructing opening of the bioprosthetic valves (\nFig. 3A\n). On day 46 after initial heparin exposure, patient B was screened again for PF4-H IgG antibodies, revealing only weak positive result (OD 0.81, cut-off: > 1.0 OD) in the ELISA assay and a negative result in the HIPA test.\n\n\nFig. 3 \n(\nA\n) Massive thrombus formation (\narrow\n) in the left atrium in transesophageal echocardiographic view. (\nB\n) Intraoperative view of thrombus sticking to imprints of lines (\narrow\n) drawn with the cryoablation probe in the left atrium.\n\n\nBoth patients underwent urgent redo surgery, which could not be postponed due to the instable cardiorespiratory situation. During CPB, anticoagulation was performed with argatroban (initial infusion rate of 2 µg/kg/min), with a target ACT of over 400 seconds in patient A, and heparin (initial dose of 30 IE/kg), with a target ACT of over 400 seconds in patient B, because the HIPA test was negative in the meantime. However, after surgery, he was again treated with argatroban.\n\n\nIn patient A, the bioprosthesis was immured by thrombus, extending into all four pulmonary veins. Thrombus sticking to left atrial wall showed imprints of lines drawn with the cryoablation probe (\nFig. 3B\n). All thrombus material was removed and the bioprosthesis was cleaned and could be left in place.\n\n\nIn patient B, thrombus did not only almost completely fill the left atrium but also extend into the left ventricle. The bioprosthesis had to be replaced and the left ventricle was evacuated from thrombus via the aortic valve.\n\nPatient A developed fulminant liver failure which affected argatroban metabolization; the patient died due to uncontrolled bleeding the day after surgery. Patient B died 5 days after redo surgery of multiorgan failure. Although it was only applied perioperatively, heparin may have reactivated antibodies and triggered multiorgan failure in association with the HIT type II.\n\nThus, both patients died of HIT-associated complications.\n\nDiscussion\n\nVenous and arterial thrombus formation are well-known complications of HIT type II,\n6\nbut reports about atrial or ventricular thrombus and prosthetic valve thrombosis after cardiac surgery are scarce.\n7\n8\n9\nAbout 25 to 50% of patients after cardiac surgery reveal antibodies to PF4-H complexes in peripheral blood, but only 1 to 3% develop clinical signs of HIT type II.\n10\nIt is well known that MVR alone can result in thrombus formation in the left atrium in up to 26% of patients with otherwise uneventful postoperative courses. In the majority of patients, thrombus will regress spontaneously or under anticoagulation therapy.\n11\nEndocardial cryoablation itself carries the risk of thrombus formation,\n12\nand an increased left atrial volume, among others, is recognized as risk factor for atrial thrombus formation.\n13\nHIT type II has been described to trigger multiorgan failure in a cardiac surgical patient.\n14\n\n\nWe conclude that an HIT type II triggered massive intracardial thrombus formation in two patients who had undergone MVR and endocardial cryoablation. In one patient, it occurred early at day 17, and in another one it occurred late at day 46 after initial heparin exposure. Both patients died from the HIT type II–associated complications of redo surgery.\n\nConflicts of Interest None declared.\n==== Refs\nReferences\n1 Althaus K Hron G Strobel U Evaluation of automated immunoassays in the diagnosis of heparin induced thrombocytopenia Thromb Res 2013 131 03 e85 e90 23351665 \n2 Legnani C Cini M Pili C Boggian O Frascaro M Palareti G Evaluation of a new automated panel of assays for the detection of anti-PF4/heparin antibodies in patients suspected of having heparin-induced thrombocytopenia Thromb Haemost 2010 104 02 402 409 20539902 \n3 Juhl D Eichler P Lubenow N Strobel U Wessel A Greinacher A Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia Eur J Haematol 2006 76 05 420 426 16466367 \n4 Greinacher A Michels I Kiefel V Mueller-Eckhardt C A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia Thromb Haemost 1991 66 06 734 736 1796420 \n5 Greinacher A Heparin-induced thrombocytopenia J Thromb Haemost 2009 7 01 019 12 19630757 \n6 Vazquez-Jimenez J F Janssens U Sellhaus B Thrombosis of a mitral valve prosthesis in a patient with heparin-induced thrombocytopenia type II J Thorac Cardiovasc Surg 1999 118 04 751 753 10504646 \n7 Campisi S Fuzellier J F Vola M Favre J P Giant left ventricular thrombus formation associated with heparin-induced thrombocytopenia Ann Thorac Surg 2014 98 06 e143 e145 25468127 \n8 Kuhl T Wendt S Langebartels G Kröner A Wahlers T Recurrent left atrial and left ventricular thrombosis due to heparin-induced thrombocytopenia: case report and short review Thorac Cardiovasc Surg 2013 61 06 537 540 23424064 \n9 Sidhu M Goel P Singh H P Chopra A K Arora R Sidhu S Acute bioprosthetic mitral valve stenosis in a patient with HITS J Card Surg 2011 26 04 369 371 21554391 \n10 Warkentin T E Levine M N Hirsh J Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin N Engl J Med 1995 332 20 1330 1335 7715641 \n11 Take A Yamaguchi T Horimi H Kato M Hasegawa T Left atrial thrombus in the early postoperative period after mitral valve replacement [in Japanese] Nippon Kyobu Geka Gakkai Zasshi 1991 39 07 1039 1048 1894986 \n12 Mack C A Milla F Ko W Surgical treatment of atrial fibrillation using argon-based cryoablation during concomitant cardiac procedures Circulation 2005 112 (9, Suppl):I1 I6 16159799 \n13 Tanaka K Aso K Kumate M Aoyagi S Kosuga K Ohishi K Left atrial thrombosis after mitral valve replacement [in Japanese] Kyobu Geka 1990 43 04 291 295 2352393 \n14 Barth K Hanke C Nakamura L Zieger B Arnold R Stiller B Heparin induzierte Thrombozytopenie II (HIT II) bei 6-jährigem Jungen nach Herzoperation Paper presented at: Jahrestagung der Süddeutschen Gesellschaft für Kinderheilkunde und Jugendmedizin gemeinsam mit der Süddeutschen Gesellschaft für Kinderchirugie; May 15, 2009; Karlsruhe, Germany\n\n",
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"issn_linking": "2512-9465",
"issue": "2(3)",
"journal": "TH open : companion journal to thrombosis and haemostasis",
"keywords": "argatroban; endocardial cryoablation; heparin-induced thrombocytopenia; mitral valve replacement",
"medline_ta": "TH Open",
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"pmid": "31249958",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports",
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"title": "Massive Left Atrial Thrombus in Two Patients with Heparin-Induced Thrombocytopenia Type II after Cardiac Surgery.",
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"abstract": "BACKGROUND\nBehçet disease (BD) is a recurrent vasculitis characterized by oral and genital mucous membrane ulcers, uveitis, and skin lesions but only rarely leg ulcers. To our knowledge, no efficacious therapy has been described for BD patients with complicating, destructive leg ulcers.\nHere, We report the case of a 55-year-old woman with generalized erythema nodosum-like, papulopustular lesions, recurrent oral and genital ulcers accompanied with recurrent leg ulcers and trouble walking.\nBased upon the patient's clinical feature and positive pathergy test , BD was confirmed.\n\n\nMETHODS\nConventional immunosuppressive therapy and anti-tumor necrosis factor inhibitors, adalimumab and etanercept, had no demonstrable clinical effect. Mesenchymal stem cell (MSC) injection combined with low-dose prednisone and thalidomide, however, completely ameliorated the ulcers on one leg, significantly improved ulcers on the other leg, and returned normal function to both legs.\n\n\nRESULTS\nThe ulcerative lesions remained in remission, and the affected leg functioned normally after 34 months' follow-up.\n\n\nCONCLUSIONS\nOur experience suggests that MSC infusion might be a potentially successful therapy for intractable drug-resistant BD patients with concomitant leg ulcer.",
"affiliations": "Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China Department of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN.",
"authors": "Li|Yanhong|Y|;Wang|Zhongming|Z|;Zhao|Yi|Y|;Luo|Yubin|Y|;Xu|Wangdong|W|;Marion|Tony N|TN|;Liu|Yi|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D013792:Thalidomide; D000068879:Adalimumab; D000068800:Etanercept; D011241:Prednisone",
"country": "United States",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29668637MD-D-17-0794110.1097/MD.0000000000010515005156900Research ArticleClinical Case ReportSuccessful mesenchymal stem cell treatment of leg ulcers complicated by Behcet disease A case report and literature reviewLi Yanhong MD, PhDaWang Zhongming MDaZhao Yi MD, PhDaLuo Yubin MD, PhDaXu Wangdong MD, PhDaMarion Tony N. MD, PhDbLiu Yi MD, PhDa∗NA. a Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR Chinab Department of Microbiology, Immunology, and Biochemistry, The University of Tennessee Health Science Center, Memphis, TN.∗ Correspondence: Yi Liu, Department of Rheumatology, West China Hospital, Sichuan University, 37 Guoxue Xiang, Chengdu, Sichuan 610041, PR China (e-mail: yi2006liu@163.com).4 2018 20 4 2018 97 16 e051521 12 2017 27 2 2018 20 3 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nBehçet disease (BD) is a recurrent vasculitis characterized by oral and genital mucous membrane ulcers, uveitis, and skin lesions but only rarely leg ulcers. To our knowledge, no efficacious therapy has been described for BD patients with complicating, destructive leg ulcers.\n\nPatient concerns:\nHere, We report the case of a 55-year-old woman with generalized erythema nodosum-like, papulopustular lesions, recurrent oral and genital ulcers accompanied with recurrent leg ulcers and trouble walking.\n\nDiagnoses:\nBased upon the patient's clinical feature and positive pathergy test , BD was confirmed.\n\nInterventions:\nConventional immunosuppressive therapy and anti-tumor necrosis factor inhibitors, adalimumab and etanercept, had no demonstrable clinical effect. Mesenchymal stem cell (MSC) injection combined with low-dose prednisone and thalidomide, however, completely ameliorated the ulcers on one leg, significantly improved ulcers on the other leg, and returned normal function to both legs.\n\nOutcomes:\nThe ulcerative lesions remained in remission, and the affected leg functioned normally after 34 months’ follow-up.\n\nLessons:\nOur experience suggests that MSC infusion might be a potentially successful therapy for intractable drug-resistant BD patients with concomitant leg ulcer.\n\nKeywords\nBehçet diseaseleg ulcermesenchymal stem cell transplantationtherapyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nBehçet disease (BD) is a systemic vasculitis characterized by recurrent oral and/or genital aphthosis, uveitis, retinal vasculitis, and variable skin lesions.[1] The etiology of BD remains unknown, and its treatment depends upon clinical presentation and organ involvement.[2,3] Jung et al[4] reported that leg ulcers are rare in BD patients, generally associated with vasculitis or deep vein thrombosis, and are refractory to conventional immunosuppressive therapy. To date, available evidence has suggested that tumor necrosis factor (TNF) inhibitors may be effective for treatment of leg ulcers.[5,6] Mesenchymal stem cells (MSCs), mainly isolated from bone marrow and some other sources such as umbilical cord blood, possess unlimited self-renewal and pluripotential capacity.[7] Several studies have documented the immunosuppressive and anti-inflammatory effect that MSC may exhibit in different diseases.[8,9] For example, MSC treatment has been reported to be a new, effective therapeutic strategy for severe, refractory autoimmune diseases including systemic lupus erythematosus (SLE),[10] rheumatoid arthritis (RA),[11] and systemic sclerosis (SSc).[12–14] In the present case report, we describe a BD patient with leg ulcers who did not respond to anti-TNF-α or conventional immunosuppressive therapy, but did achieve sustained, successful therapeutic response when MSC injection was used in combination with low-dose conventional immunosuppression. To our knowledge, this case report is the first documented evidence for the potential benefit of MSC transplantation in the treatment of leg ulcers associated with BD.\n\n2 Case report\nA 47-year-old woman with generalized erythema nodosum-like, papulopustular lesions, recurrent oral and genital ulcers, and positive pathergy test was diagnosed with BD (Table 1). The diagnosis was consistent with International Study Group (ISG) recommendations,[1] and the recently developed International Criteria for Behçet Disease (ICBD)[15]; the patient's ICBD score would have been 7 at the time of diagnosis. An ICBD score of 4 is sufficient for BD diagnosis. The patient was initially treated with oral prednisone (35 mg qd), cyclosporine A (75 mg bid), colchicine (0.5 mg qd), and thalidomide (100 mg qn). Symptoms including oral and genital ulcers were partially improved (Table 2). One year later, the patient developed multiple painful and destructive leg ulcers with biopsy confirmed leukocytoclastic vasculitis (Fig. 1). Cyclosporine A was then replaced with cyclophosphamide (1 g qm) with some subsequent improvement in clinical symptoms. Treatment was suspended after 2 months because of an infection. Two years later, when the patient was 50 years’ old, she received treatment with etanercept (25 mg biw) for 1 month, but with no clinical improvement. Replacement of etanercept with adalimumab yielded no clinical benefit. During the following 3 years, the patient received several additional therapies, including mycophenolate mofetil and hydroxychloroquine (Table 2); however, the leg ulcers persisted and were exacerbated.\n\nTable 1 Behçet diagnosis∗.\n\nTable 2 Therapeutic History.\n\nFigure 1 Leg Ulcer biopsy. Small vessel leukocytoclastic vasculitis (H&E, 20×).\n\nWhen admitted in our hospital at age 53, physical examination revealed wide spread papulopustular lesions, oral and genital ulcers, multiple scars, and a positive pathergy test. Her right lower leg ulcers were located between the knee and ankle, with diffuse swelling (Fig. 2A). Her left lower leg lesion was a painful and destructive ulcer with irregular margin and a ragged overhanging edge (approximately 6 × 5 cm) (Fig. 2B). Laboratory results were negative for rheumatoid factor, antinuclear antibodies, anti-double stranded DNA antibody, p-anti-neutrophil cytoplasmic antibodies, and anti-cardiolipin antibodies. Other laboratory test results were as follows (normal range in parentheses): C-reactive protein of 9.26 mg/L (<5 mg/L), erythrocyte sedimentation rate of 32.0 mm/h (<43 mm/h), IgG of 5.25 g/L (8–15 g/L), IgA of 686.00 mg/L (836–2900 mg/L), IgM of 392.00 mg/L (700–2200 mg/L), and IgG4 of 0.424 g/L (0.035–1.5 g/L). The results of Doppler ultrasound on both legs were normal.\n\nFigure 2 Leg ulcers of patient. (A) Left leg ulcer before treatment with mesenchymal stem cell (MSC) infusion. (B) Right leg ulcer before treatment with MSC infusion. (C) Left leg ulcer after 2 months’ treatment with MSC infusion. (D) Right leg ulcer after 34 months’ treatment with MSC infusion.\n\nBased upon the patient's clinical history (Tables 1 and 2), characterized by persistence and exacerbation of leg ulcers, poor response to conventional treatment, and our ongoing clinical experience with MSC therapy for SSc (in preparation), we decided to treat this patient with MSC infusions therapy. This decision was approved by the West China Hospital Institutional Research Committee in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The patient also provided informed consent to receive the MSC infusion therapy. The patient was intravenously infused with 50 mL, 106 cells/mL, pooled human umbilical cord MSCs (HUC-MSCs) (Kangjing Biotechnology, Chengdu, PR China) 3 times per month, in the first week of the month and at 7 days’ intervals, for 3 months, for 9 total infusions. Prednisone (8 mg/day) and thalidomide (75 mg/day) were administrated to the patient during the same 3-month period. Two months after initiating MSC and low-dosage immunosuppression therapy, the right leg ulcer was markedly improved, and the left ulcer had completely healed (Fig. 2C). Three months after initiating MSC therapy, clinical signs of BD, including papulopustular lesions and oral and genital ulcers, were markedly improved upon clinical examination. MSC infusion therapy was continued with 3 monthly infusions, as above, but only every other month for 14 months, an additional 21 infusions. After 34 months, all symptoms of BD have resolved, the left leg remains ulcer free, and the right lesion has continued to improve (Fig. 2D). The patient has continued a maintenance dosage of 4 mg/day of prednisone. None of the potential side effects commonly associated with MSC transplantation, such as vascular occlusion, fibrosis, or malignancy, were apparent from clinical evaluation during the 17-month period of MSC infusions and 34-month follow-up to present. The patient provided informed consent for her laboratory and clinical results to be included in this manuscript.\n\n3 Discussion\nBD is an autoimmune, chronic inflammatory disease with unknown etiology.[16] BD is characterized clinically as a chronic, relapsing vasculitis with oral and genital ulcers, cutaneous inflammation, uveitis, and gastrointestinal and central nervous system manifestations.[17] In 1990, an ISG attempted to consolidate diagnostic criteria for BD.[1] The ISG criteria for BD, diagnosis required the presence of oral ulceration plus any 2 of the following: genital ulceration, typical defined eye lesions, typical defined skin lesions, or a positive pathergy test. Although the ISG criteria were simpler and had improved discriminatory performance compared to predecessors, the ISG criteria were less than optimal. The more recently adopted ICBD has been documented to have the highest sensitivity for BD diagnosis.[15] For ICBD classification of BD, ocular lesions, oral aphthosis, and genital aphthosis are each assigned 2 points, whereas skin lesions, central nervous system involvement, and vascular manifestations, 1 point each. A positive pathergy test is also assigned 1 point. An ICBD score ≥4 is diagnostic for BD, and when the pathergy test is included, the sensitivity of the ICBD criteria is 95% to 98% with specificity of 92%. Criteria for BD diagnosis in Chinese patients are similar.[18,19] Although BD has moderate association with inheritance of HLA B∗51 (odds ratio 5.8),[15] HLA B∗51 is not included in the ICBD criteria.[15] Worldwide, 41% to 97% of BD patients have skin lesion such as aphthous stomatitis, genital ulcers, erythema nodosum-like lesions, and papulopustular lesions,[20] whereas leg ulcers were rare.[4] Leg ulcers in BD patients were associated with vasculitis or deep vein thrombosis, were recurrent, and refractory to conventional treatment. The BD diagnosis for the patient in the present case was based upon generalized erythema nodosum-like and papulopustular lesions and recurrent oral and genital ulcers, criteria similar to ISG, and including the positive pathergy test, would have had an ICBD score of 7. HLA genotype was not determined.\n\nThe morbidity and mortality of BD are relatively high, and maintaining remission and improving the patients’ quality of life are the main goals of therapy. Appropriate treatment strategy of BD is chosen based on the organs involved and clinical presentations.[2,3] Nonsteroidal anti-inflammatory drugs and colchicine are sufficient for mild manifestations in BD, such as mucocutaneous involvement, but corticosteroids, cyclophosphamide (CTX), azathioprine, and/or cyclosporine A are recommended for the treatment of BD patients with complicating acute, large deep vein thromboses.[2,21] In our case, immunosuppressive drugs including corticosteroids, colchicine, cyclosporine A, CTX, mycophenolate mofetil, and thalidomide were prescribed but did not improve upon the refractory, relapsing, and destructive presentation of the leg ulcers.\n\nImprovement toward understanding of the molecular basis for pathogenic mechanisms in chronic inflammation has contributed to the emergence of immunosuppressive biological therapeutics that target TNF-α. Few studies have indicated that any of the 3 anti-TNF-α agents, infliximab, adalimumab, or etanercept, have therapeutic benefit for chronic mucocutaneous lesions.[5,6] Although adalimumab combined with MTX was reported to successfully treat a patient with vasculitic leg ulcers,[22] neither adalimumab nor etanercept was effective in treating the patient's BD or BD-associated leg ulcers in our case.\n\nBecause of their demonstrative immunomodulatory and anti-inflammatory properties and regenerative potential, MSCs have emerged as a new treatment for refractory and severe autoimmune diseases.[8,9] In a multicenter clinical study, 40 SLE patients with active and refractory disease were treated with umbilical cord-derived MSC transplantation.[10] In that study, 32.5% of the patients achieved a significant clinical response, and 27.5% of patients achieved partial clinical response. In a separate study with 136 active RA patients who were refractory to conventional antirheumatic drugs alone, MSC transplantation combined with antirheumatic drugs induced a significantly clinical improvement.[11] Perturbations of T cell homeostasis that correlate with disease exacerbation have been reported recently in BD patients and include elevated Th1 cytokines[23] and promotion of Th17 responses with suppression of regulatory T cell (Treg) expansion.[24] Within this context, MSC transplantation can lead to reduced Th1-derived interferon-γ production, Treg cell expansion and upregulated Treg capacity[25–27] and reduced Th17 proliferation and cytokine production.[9,28,29] A high level of circulating angiostatin was correlated with disease activity in BD patients.[30] MSC transplantation can return normal homeostatic function to injured tissues including the secretion of factors that suppress inflammation and improve angiogenesis.[31–33] Finally, MSC transplantation induced significant healing of ulcers and necrotic skin lesions in SSc patients that had otherwise not responded to conventional therapy.[12–14] Within the context of several years of failed conventional immunosuppressive therapy and the extensive documentation for the immunosuppressive and anti-inflammatory function of transplanted MSC in the treatment of autoimmune and chronic inflammatory diseases including SSc skin lesions, MSC treatment was provided to our patient with rapid and dramatic therapeutic effect. The left leg ulcers disappeared, and the right ulcer was dramatically improved within 2 months of initiating MSC transplantation and, there have been no detrimental side effects commonly associated with MSC transplantation in follow-up to present.\n\n4 Conclusion\nIn conclusion, MSC therapy for refractory, progressive BD skin lesions has not been reported to date. The present patient had BD with complicating leg ulcers that were refractory to conventional immunosuppressive therapy, including adalimumab and etanercept, for 6 years. Within 2 months of initiating MSC infusions, both BD-associated leg ulcers and other BD-associated lesions showed marked, continuous improvement. The patient's BD remains in remission with no post-infusion complications at 34 months of follow-up. Our experience suggests that MSC infusion might be a potentially successful therapy for intractable, drug-resistant BD patients with concomitant leg ulcer.\n\nAuthor contributions\nConceptualization: Yanhong Li.\n\nData curation: Yanhong Li.\n\nFormal analysis: Yanhong Li, Yubin Luo.\n\nFunding acquisition: Yi Liu.\n\nInvestigation: Yanhong Li, Zhongming Wang, Yubin Luo.\n\nMethodology: Yanhong Li, Zhongming Wang, Yi Zhao, Wangdong Xu.\n\nSoftware: Yi Zhao.\n\nValidation: Yi Zhao.\n\nWriting – original draft: Yanhong Li, Yi Liu.\n\nWriting – review & editing: Yanhong Li, Tony N. Marion, Yi Liu.\n\nAbbreviations: ANCA = anti-neutrophil cytoplasmic antibodies, AZA = azathioprine, BD = Behçet disease, CTX = cyclophosphamide, ISG = International Study Group, MSC = mesenchymal stem cell, MTX= methotrexate, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, SSc = systemic sclerosis, TNF = tumor necrosis factor.\n\nThis work was supported by grants from the Specialized Research Fund for the Doctoral Program of Higher Education of China (20120181110009).\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Criteria for diagnosis of Behcet's disease . International Study Group for Behcet's Disease . Lancet \n1990 ;335 :1078 –80 .1970380 \n[2] Hatemi G Silman A Bang D \nEULAR recommendations for the management of Behcet disease . Ann Rheum Dis \n2008 ;67 :1656 –62 .18245110 \n[3] Hatemi G Silman A Bang D \nManagement of Behcet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behcet disease . Ann Rheum Dis \n2009 ;68 :1528 –34 .18420940 \n[4] Jung JY Kim DY Bang D \nLeg ulcers in Behcet's disease . Br J Dermatol \n2008 ;158 :178 –9 .17941948 \n[5] Song YW Kang EH \nBehcet's disease and genes within the major histocompatibility complex region . Mod Rheumatol \n2012 ;22 :178 –85 .22042097 \n[6] Melikoglu M Fresko I Mat C \nShort-term trial of etanercept in Behcet's disease: a double blind, placebo controlled study . J Rheumatol \n2005 ;32 :98 –105 .15630733 \n[7] Bernardo ME Pagliara D Locatelli F \nMesenchymal stromal cell therapy: a revolution in Regenerative Medicine? \nBone Marrow Transplant \n2012 ;47 :164 –71 .21478914 \n[8] Zappia E Casazza S Pedemonte E \nMesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy . Blood \n2005 ;106 :1755 –61 .15905186 \n[9] Sun L Akiyama K Zhang H \nMesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans . Stem Cells \n2009 ;27 :1421 –32 .19489103 \n[10] Wang D Li J Zhang Y \nUmbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study . Arthritis Res Ther \n2014 ;16 :R79 .24661633 \n[11] Wang L Wang L Cong X \nHuman umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy . Stem Cells Dev \n2013 ;22 :3192 –202 .23941289 \n[12] Yun JH \nAutologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis . Ann Intern Med \n2011 ;155 :65 author reply 65-66 .21727297 \n[13] Christopeit M Schendel M Foll J \nMarked improvement of severe progressive systemic sclerosis after transplantation of mesenchymal stem cells from an allogeneic haploidentical-related donor mediated by ligation of CD137L . Leukemia \n2008 ;22 :1062 –4 .17972956 \n[14] Keyszer G Christopeit M Fick S \nTreatment of severe progressive systemic sclerosis with transplantation of mesenchymal stromal cells from allogeneic related donors: report of five cases . Arthritis Rheum \n2011 ;63 :2540 –2 .21547891 \n[15] International Team for the Revision of the International Criteria for Behcet's D . The International Criteria for Behcet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria . J Eur Acad Dermat Venereol \n2014 ;28 :338 –47 .\n[16] McGonagle D McDermott MF \nA proposed classification of the immunological diseases . PLoS Med \n2006 ;3 :e297 .16942393 \n[17] Sakane T Takeno M Suzuki N \nBehcet's disease . N Engl J Med \n1999 ;341 :1284 –91 .10528040 \n[18] Dong Y Qin XM Zhang NZ \n[Testing different diagnostic criteria of Behcet syndrome in Chinese patients] . Zhonghua Nei Ke Za Zhi \n1990 ;29 :547 –9 . 576 .2086029 \n[19] Wang LY Zhao DB Gu J \nClinical characteristics of Behcet's disease in China . Rheumatol Int \n2010 ;30 :1191 –6 .19777242 \n[20] Lee ES Bang D Lee S \nDermatologic manifestation of Behcet's disease . Yonsei Med J \n1997 ;38 :380 –9 .9509907 \n[21] Desbois AC Wechsler B Resche-Rigon M \nImmunosuppressants reduce venous thrombosis relapse in Behcet's disease . Arthritis Rheum \n2012 ;64 :2753 –60 .22354392 \n[22] Atzeni F Leccese P D’Angelo S \nSuccessful treatment of leg ulcers in Behcet's disease using adalimumab plus methotrexate after the failure of infliximab . Clin Exp Rheumatol \n2010 ;28 (4 suppl 60) :S94 .\n[23] Ben Ahmed M Houman H Miled M \nInvolvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behcet's disease . Arthritis Rheum \n2004 ;50 :2291 –5 .15248229 \n[24] Geri G Terrier B Rosenzwajg M \nCritical role of IL-21 in modulating TH17 and regulatory T cells in Behcet disease . J Allergy Clin Immunol \n2011 ;128 :655 –64 .21724243 \n[25] Aggarwal S Pittenger MF \nHuman mesenchymal stem cells modulate allogeneic immune cell responses . Blood \n2005 ;105 :1815 –22 .15494428 \n[26] Di Ianni M Del Papa B De Ioanni M \nMesenchymal cells recruit and regulate T regulatory cells . Exp Hematol \n2008 ;36 :309 –18 .18279718 \n[27] Selmani Z Naji A Zidi I \nHuman leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells . Stem Cells \n2008 ;26 :212 –22 .17932417 \n[28] Bai L Lennon DP Eaton V \nHuman bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis . Glia \n2009 ;57 :1192 –203 .19191336 \n[29] Gonzalez MA Gonzalez-Rey E Rico L \nTreatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells . Arthritis Rheum \n2009 ;60 :1006 –19 .19333946 \n[30] Keskin D Keskin G Inal A \nSerum angiostatin levels in patients with Behcet's disease: does angiogenesis play a role in the pathogenesis of Behcet's disease? \nActa Clin Belg \n2014 ;69 :246 –50 .25012748 \n[31] Bronckaers A Hilkens P Martens W \nMesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis . Pharmacol Ther \n2014 ;143 :181 –96 .24594234 \n[32] Caplan AI Dennis JE \nMesenchymal stem cells as trophic mediators . J Cell Biochem \n2006 ;98 :1076 –84 .16619257 \n[33] Griffin MD Ritter T Mahon BP \nImmunological aspects of allogeneic mesenchymal stem cell therapies . Hum Gene Ther \n2010 ;21 :1641 –55 .20718666\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "97(16)",
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"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000068879:Adalimumab; D001528:Behcet Syndrome; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D057915:Drug Substitution; D000068800:Etanercept; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007871:Leg Ulcer; D045164:Mesenchymal Stem Cell Transplantation; D008875:Middle Aged; D011241:Prednisone; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "2985248R",
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"pages": "e0515",
"pmc": null,
"pmid": "29668637",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24594234;25012748;15905186;15630733;18420940;21727297;22354392;16942393;17932417;24661633;21724243;16619257;1970380;17941948;23441863;20868581;22042097;19333946;23941289;10528040;21547891;21478914;15248229;18245110;17972956;15494428;19489103;18279718;2086029;20718666;19777242;19191336;9509907",
"title": "Successful mesenchymal stem cell treatment of leg ulcers complicated by Behcet disease: A case report and literature review.",
"title_normalized": "successful mesenchymal stem cell treatment of leg ulcers complicated by behcet disease a case report and literature review"
} | [
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"literaturereference": "LI Y, WANG Z, ZHAO Y, LUO Y, XU W, MARION TN, ET AL. SUCCESSFUL MESENCHYMAL STEM CELL TREATMENT OF LEG ULCERS COMPLICATED BY BEHCET DISEASE: A CASE REPORT AND LITERATURE REVIEW. MEDICINE 2018?97(16):E0515.",
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] |
{
"abstract": "Acute respiratory distress syndrome (ARDS) caused by pneumonia in patients with hematologic malignancies can be life-threatening. Extracorporeal membrane oxygenation (ECMO) is the only temporary treatment for patients with ARDS who are refractory to conventional treatment. However, the immunosuppression and coagulopathies in hematological malignancies such as lymphoma and acute leukemia are relative contraindications for ECMO, due to high risks of infection and bleeding. Here, we report a 22-year-old man with acute myeloid leukemia (AML) who developed pneumonia and ARDS during induction chemotherapy; he was treated with ECMO.",
"affiliations": "Department of Internal Medicine, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Korea.;Division of Pulmonary and Critical Care Medicine, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Korea.;Division of Pulmonary and Critical Care Medicine, Dankook University Hospital, Dankook University College of Medicine, Cheonan, Korea.",
"authors": "Lee|Sang Won|SW|;Kim|Youn Seup|YS|;Hong|Goohyeon|G|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jtd.2017.02.23",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2072-1439",
"issue": "9(2)",
"journal": "Journal of thoracic disease",
"keywords": "Extracorporeal membrane oxygenation (ECMO); acute myeloid leukemia (AML); chemotherapy",
"medline_ta": "J Thorac Dis",
"mesh_terms": null,
"nlm_unique_id": "101533916",
"other_id": null,
"pages": "E133-E137",
"pmc": null,
"pmid": "28275497",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports",
"references": "20581167;10371130;17352671;24475788;6958352;26283185;26390681;23752112;25046529;22369998;26161014;24443905",
"title": "Extracorporeal membrane oxygenation as a rescue therapy for acute respiratory failure during chemotherapy in a patient with acute myeloid leukemia.",
"title_normalized": "extracorporeal membrane oxygenation as a rescue therapy for acute respiratory failure during chemotherapy in a patient with acute myeloid leukemia"
} | [
{
"companynumb": "KR-PFIZER INC-2017142498",
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{
"abstract": "Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1-4. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge1,5 and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases1,2,5. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect human disease pathophysiology at unprecedented resolutions6, particularly in diseases lacking animal models, such as DiHS/DRESS. We performed scRNA-seq on skin and blood from a patient with refractory DiHS/DRESS, identifying the JAK-STAT signaling pathway as a potential target. We further showed that central memory CD4+ T cells were enriched with DNA from human herpesvirus 6b. Intervention via tofacitinib enabled disease control and tapering of other immunosuppressive agents. Tofacitinib, as well as antiviral agents, suppressed culprit-induced T cell proliferation in vitro, further supporting the roles of the JAK-STAT pathway and herpesviruses in mediating the adverse drug reaction. Thus, scRNA-seq analyses guided successful therapeutic intervention in the patient with refractory DiHS/DRESS. scRNA-seq may improve our understanding of complicated human disease pathophysiology and provide an alternative approach in personalized medicine.",
"affiliations": "Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA.;Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA.;Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA.;Cutaneous Microbiome and Inflammation Section, Dermatology Branch, NIAMS, National Institutes of Health (NIH), Bethesda, MD, USA.;Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA.;Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA.;Cancer Research Technology Program, Single-Cell Analysis Facility, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.;Department of Dermatology, MedStar Washington Hospital Center & Georgetown University Hospital, Washington, DC, USA.;Department of Dermatology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;Department of Dermatology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA.;Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA.;Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD, USA.;Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, USA.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.;Cutaneous Microbiome and Inflammation Section, Dermatology Branch, NIAMS, National Institutes of Health (NIH), Bethesda, MD, USA.;Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA.;Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA. keisuke.nagao@nih.gov.",
"authors": "Kim|Doyoung|D|;Kobayashi|Tetsuro|T|;Voisin|Benjamin|B|;Jo|Jay-Hyun|JH|;Sakamoto|Keiko|K|;Jin|Seon-Pil|SP|;Kelly|Michael|M|;Pasieka|Helena B|HB|;Naff|Jessica L|JL|;Meyerle|Jon H|JH|;Ikpeama|Ijeoma D|ID|;Fahle|Gary A|GA|;Davis|Fred P|FP|;Rosenzweig|Sergio D|SD|;Alejo|Julie C|JC|;Pittaluga|Stefania|S|;Kong|Heidi H|HH|http://orcid.org/0000-0003-4424-064X;Freeman|Alexandra F|AF|;Nagao|Keisuke|K|http://orcid.org/0000-0002-7005-3138",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D045567:VDJ Recombinases",
"country": "United States",
"delete": false,
"doi": "10.1038/s41591-019-0733-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-8956",
"issue": "26(2)",
"journal": "Nature medicine",
"keywords": null,
"medline_ta": "Nat Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000998:Antiviral Agents; D001327:Autoimmune Diseases; D015496:CD4-Positive T-Lymphocytes; D049109:Cell Proliferation; D002469:Cell Separation; D063926:Drug Hypersensitivity Syndrome; D005434:Flow Cytometry; D015654:Herpesvirus 6, Human; D006801:Humans; D007166:Immunosuppressive Agents; D007963:Leukocytes, Mononuclear; D008214:Lymphocytes; D008297:Male; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D000081246:RNA-Seq; D015398:Signal Transduction; D059010:Single-Cell Analysis; D050378:T-Lymphocytes, Regulatory; D059467:Transcriptome; D045567:VDJ Recombinases",
"nlm_unique_id": "9502015",
"other_id": null,
"pages": "236-243",
"pmc": null,
"pmid": "31959990",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": null,
"title": "Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report.",
"title_normalized": "targeted therapy guided by single cell transcriptomic analysis in drug induced hypersensitivity syndrome a case report"
} | [
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},
{
"reactionmeddrapt": "Dermatitis exfoliative generalised",
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},
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"reactionmeddrapt": "Renal impairment",
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"literaturereference": "KIM D, KOBAYASHI T, VOISIN B, JO J-H, SAKAMOTO K, JIN S-P, ET AL. TARGETED THERAPY GUIDED BY SINGLE-CELL TRANSCRIPTOMIC ANALYSIS IN DRUG-INDUCED HYPERSENSITIVITY SYNDROME: A CASE REPORT. NATURE-MED 2020?26(2):236-243.",
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},
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{
"abstract": "BACKGROUND\nIt is known that calcium channel blockers are associated with a risk of gingival hyperplasia. These drugs are widely used in the management of gestational hypertensive disorders.\n\n\nMETHODS\nA 27-year-old G1 woman presented with gingival hyperplasia at 27 weeks gestation during a hospitalisation for preeclampsia. She had been on nifedipine for hypertension for the last 9 weeks. Nifedipine was discontinued and replaced by methyldopa and already after 48 hours the gingival hyperplasia improved. She delivered two weeks later and the gingival hyperplasia resolved completely without surgical intervention. The Naranjo's score was used to prove the nifedipine's imputability.\n\n\nCONCLUSIONS\nThis first case report of gingival hyperplasia induced by nifedipine in pregnancy could be used as a reference for clinicians in the management of this adverse effect during the pregnancy.",
"affiliations": "CHU Sainte-Justine, 3175 Chemin de la Cote-Sainte-Catherine, Montreal (Quebec) H3T 1C5. Canada.",
"authors": "Brochet|M S|MS|;Harry|M|M|;Morin|F|F|",
"chemical_list": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D009543:Nifedipine",
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886311666160426141851",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": "12(1)",
"journal": "Current drug safety",
"keywords": "Calcium channel blockers; dental management; gingival hyperplasia; nifedipine; preeclampsia; pregnancy",
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D005260:Female; D005885:Gingival Hyperplasia; D006801:Humans; D009543:Nifedipine; D011247:Pregnancy",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "3-6",
"pmc": null,
"pmid": "27113951",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nifedipine Induced Gingival Hyperplasia in Pregnancy: A Case Report.",
"title_normalized": "nifedipine induced gingival hyperplasia in pregnancy a case report"
} | [
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] |
{
"abstract": "OBJECTIVE\nTakotsubo cardiomyopathy is characterized by the sudden onset of reversible left ventricular dysfunction. Associated refractory cardiogenic shock is a rare occurrence and may require extracorporeal membrane oxygenation (ECMO). We report a case of a patient who, following the inadvertent injection of 1 mg of epinephrine, presented with reverse Takotsubo cardiomyopathy and refractory cardiogenic shock that required the implementation of a percutaneous ECMO.\n\n\nMETHODS\nA 49-yr-old female patient presented with reverse Takotsubo cardiomyopathy in the operating room after an inadvertent injection of epinephrine. The development of refractory cardiogenic shock required emergent use of a mobile percutaneous ECMO system. It was possible to wean this support after four days, and the patient was later discharged without cardiac or neurological sequelae. The investigations performed confirmed the iatrogenic nature of this reverse Takotsubo cardiomyopathy.\n\n\nCONCLUSIONS\nTakotsubo cardiomyopathy following an injection of epinephrine remains a rare but increasingly described occurrence. The severity of the symptoms appears to be patient dependent, but refractory cardiogenic shock may occur and require significant circulatory support. If this situation occurs in a hospital where this necessary equipment is lacking, a mobile ECMO unit appears to be a viable solution to optimize the patient's chances of survival.",
"affiliations": "Unité de réanimation de chirurgie cardiaque, service d'anesthésie réanimation 2, CHU La Timone adultes, Marseille, France, pierre.esnault@gmail.com.",
"authors": "Esnault|Pierre|P|;Née|Laetitia|L|;Signouret|Thomas|T|;Jaussaud|Nicolas|N|;Kerbaul|François|F|",
"chemical_list": "D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1007/s12630-014-0230-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0832-610X",
"issue": "61(12)",
"journal": "Canadian journal of anaesthesia = Journal canadien d'anesthesie",
"keywords": null,
"medline_ta": "Can J Anaesth",
"mesh_terms": "D004837:Epinephrine; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D008875:Middle Aged; D012770:Shock, Cardiogenic; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "8701709",
"other_id": null,
"pages": "1093-7",
"pmc": null,
"pmid": "25187250",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Reverse Takotsubo cardiomyopathy after iatrogenic epinephrine injection requiring percutaneous extracorporeal membrane oxygenation.",
"title_normalized": "reverse takotsubo cardiomyopathy after iatrogenic epinephrine injection requiring percutaneous extracorporeal membrane oxygenation"
} | [
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},
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"reaction": [
{
"reactionmeddrapt": "Hepatocellular injury",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stress cardiomyopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Ventricular fibrillation",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Metabolic acidosis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiogenic shock",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug administration error",
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},
{
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}
],
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"literaturereference": "ESNAULT P, NEE L, SIGNOURET T, JAUSSAUD N, KERBAUL F. REVERSE TAKOTSUBO CARDIOMYOPATHY AFTER IATROGENIC EPINEPHRINE INJECTION REQUIRING PERCUTANEOUS EXTRACORPOREAL MEMBRANE OXYGENATION. CAN-J-ANESTH 2014; 61(12) 1093-1097",
"literaturereference_normalized": "reverse takotsubo cardiomyopathy after iatrogenic epinephrine injection requiring percutaneous extracorporeal membrane oxygenation",
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},
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"receiptdate": "20141230",
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"abstract": "Background: With the availability of direct acting antiviral treatment for hepatitis C (HCV), HIV and HCV co-infected patients show comparable treatment responses to HCV-monoinfected patients. An 8-week course of sofosbuvir/ledipasvir (SOF/LDV) is highly effective for the treatment of HCV genotype 1 infection in treatment-naïve mono-infected patients with HCV viral loads <6 million IU/ml. There is limited data on the efficacy of this 8-week HCV treatment regimen in HIV-infected individuals with similar viral loads. Methods: The study was a retrospective review of HIV-infected adults coinfected with HCV genotype 1 for whom an 8-week course of SOF/LDV was prescribed by providers at two clinics in the Yale-New Haven Health system from November 1, 2014 until April 30, 2016. Treatment efficacy was assessed as the proportion of treatment initiators who achieved a sustained virologic response 12 weeks after completion of therapy (SVR 12). Results: Nineteen patients met study eligibility criteria and included 14 men (74%); and 12 African-Americans (63%). All patients were on antiretroviral therapy with fully suppressed HIV viral loads and were HCV treatment-naïve. All patients had pre-treatment HCV viral loads <6 million IU/mL. Eighteen patients (95%) completed HCV treatment. Overall, SVR 12 was 95%, with 1 treament failure occurring due to suboptimal adherence. Conclusion: Among our HIV-infected patient cohort with HCV genotype 1 infection, 95% of those treated with an 8 week course of SOF/LDV achieved SVR 12. This is comparable to the efficacy of the same treatment regimen in patients without HIV infection. This study lends proof of concept to the use of shorter course SOF/LDV treatment for HIV-HCV genotype 1 coinfected patients with viral loads <6 million IU/ml. Larger studies are indicated to validate our findings.",
"affiliations": "Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06510, USA.;Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06510, USA.;Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06510, USA.;Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06510, USA.;Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06510, USA.",
"authors": "Ogbuagu|Onyema|O|https://orcid.org/0000-0001-7342-2608;Hao|Ritche|R|;Virata|Michael|M|;Villanueva|Merceditas S|MS|https://orcid.org/0000-0003-1022-7746;Malinis|Maricar|M|https://orcid.org/0000-0002-5720-9994",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.12688/f1000research.11397.2",
"fulltext": "\n==== Front\nF1000ResF1000ResF1000ResearchF1000Research2046-1402F1000 Research Limited London, UK 10.12688/f1000research.11397.2Research ArticleArticlesHIV Infection & AIDS: ClinicalEfficacy of an 8-week course of sofosbuvir and ledipasvir for the treatment of HCV infection in selected HIV-infected patients [version 2; referees: 2 approved]\n\nOgbuagu Onyema ConceptualizationData CurationFormal AnalysisInvestigationMethodologyProject AdministrationWriting – Original Draft PreparationWriting – Review & Editinghttps://orcid.org/0000-0001-7342-2608a1Hao Ritche Data CurationMethodologyWriting – Review & Editing1Virata Michael Data CurationInvestigationMethodology1Villanueva Merceditas S. InvestigationWriting – Original Draft PreparationWriting – Review & Editinghttps://orcid.org/0000-0003-1022-77461Malinis Maricar ConceptualizationData CurationFormal AnalysisInvestigationMethodologyProject AdministrationWriting – Original Draft Preparationhttps://orcid.org/0000-0002-5720-99941\n1 Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06510, USAa onyema.ogbuagu@yale.eduOO and MM conceived of the project; OO, RH and MM collected study data; OO, RH, MV, MSV and MM participated in data analysis, drafting and revision of the manuscript.\n\nNo competing interests were disclosed.\n\n21 9 2018 2017 6 62017 9 2018 Copyright: © 2018 Ogbuagu O et al.2018This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground: With the availability of direct acting antiviral treatment for hepatitis C (HCV), HIV and HCV co-infected patients show comparable treatment responses to HCV-monoinfected patients. An 8-week course of sofosbuvir/ledipasvir (SOF/LDV) is highly effective for the treatment of HCV genotype 1 infection in treatment-naïve mono-infected patients with HCV viral loads <6 million IU/ml. There is limited data on the efficacy of this 8-week HCV treatment regimen in HIV-infected individuals with similar viral loads.\n\n\nMethods: The study was a retrospective review of HIV-infected adults coinfected with HCV genotype 1 for whom an 8-week course of SOF/LDV was prescribed by providers at two clinics in the Yale-New Haven Health system from November 1, 2014 until April 30, 2016. Treatment efficacy was assessed as the proportion of treatment initiators who achieved a sustained virologic response 12 weeks after completion of therapy (SVR 12).\n\n\nResults: Nineteen patients met study eligibility criteria and included 14 men (74%); and 12 African-Americans (63%). All patients were on antiretroviral therapy with fully suppressed HIV viral loads and were HCV treatment-naïve. All patients had pre-treatment HCV viral loads <6 million IU/mL. Eighteen patients (95%) completed HCV treatment. Overall, SVR 12 was 95%, with 1 treament failure occurring due to suboptimal adherence.\n\n\nConclusion: Among our HIV-infected patient cohort with HCV genotype 1 infection, 95% of those treated with an 8 week course of SOF/LDV achieved SVR 12. This is comparable to the efficacy of the same treatment regimen in patients without HIV infection. This study lends proof of concept to the use of shorter course SOF/LDV treatment for HIV-HCV genotype 1 coinfected patients with viral loads <6 million IU/ml. Larger studies are indicated to validate our findings.\n\nHepatitis C genotype 1Direct-acting antiviralsHIVshort-course therapyThe author(s) declared that no grants were involved in supporting this work.Revised Amendments from Version 1\nThis version clarifies the criteria for defining cirrhosis in the two patients included in the study; specifically, these two patients had concordant non-invasive testing scores (APRI and FIB-4) that met cut-offs for cirrhosis; however, both were clinically compensated. Additionally, comments were updated to highlight that all patients with HIV/HCV should be treated regardless of stage. The database was also revised to clarify inaccuracies.\n==== Body\nIntroduction\nHIV and hepatitis C virus (HCV) share similar epidemiologic risk factors and routes of transmission, such that among HIV infected individuals, the prevalence of HCV infection is high and estimated at 25% (\nhttps://www.cdc.gov/hepatitis/populations/hiv.htm). Among certain risk groups, such as injection drug users with HIV infection, prevalence rates as high as 90% have been reported (\nhttps://www.cdc.gov/hepatitis/populations/hiv.htm). HIV infection alters the natural history of HCV disease, such that there are higher and faster rates of progression to liver cirrhosis with its resultant complications; this negative interaction may not be impacted by the receipt of effective antiretroviral therapy (ART)\n1,\n2.\n\nSince the sequencing of the HCV genome, there has been an explosion in the number of drugs approved for the treatment of HCV infection. The direct acting antiviral treatment regimens now allow for fully orally administered, well tolerated, and highly effective treatments for HCV infection. However, multiple studies have shown that of the individuals eligible for HCV treatment, few have received treatment\n3,\n4. A primary obstacle to the treatment of HCV infection is the exorbitant cost of the treatment regimens\n5,\n6. Therefore, cost saving measures including shortened duration of therapy are of interest to patients and their providers\n7. Emerging data suggests that 8-week rather than 12-week regimens may be effective for HCV treatment among selected patients\n8,\n9.\n\nThe United States Food and Drug Administration (FDA) approved sofosbuvir/ledipasvir (SOF/LDV) in 2014 for the treatment of chronic HCV genotype 1 infection. The ION-3 study of SOF/LDV that included treatment-naïve non-cirrhotic patients with HCV genotype 1, found that the sustained virologic response 12 weeks after end of therapy (SVR12) was comparable between the 8-week (with and without ribavirin) and 12-week treatment arms in a post hoc analysis for patients who had a pre-treatment HCV viral load (VL) <6 million IU/ml\n10. Based on this data, the American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines recommend that treatment-naïve, genotype 1 patients without cirrhosis, who are non-black, HIV-negative and with a pre-treatment HCV VL <6 million IU/ml (\nhttp://www.hcvguidelines.org/full-report/hcv-testing-and-linkage-care) can be successfully treated with 8 weeks of SOF/LDV. However, the guidelines cite limited data as the reason to not recommend an 8-week SOF/LDV treatment course for HIV-infected patients.\n\nContemporary HCV treatment trials with directly acting antiviral (DAA) agents have shown that HIV infection status no longer independently impacts treatment outcomes\n11,\n12. Therefore, shorter HCV treatment regimens are likely to be as effective in HIV-infected individuals as their non-infected counterparts. Our study describes treatment outcomes of a short (8 week) course of SOF/LDV in HIV/HCV co-infected patients.\n\nMethods\nWe performed a retrospective review of all HIV and HCV co-infected patients, for whom an 8-week SOF/LDV treatment course was initiated from November 1, 2014 until April 30, 2016. The treatment decision for short course therapy was made by individual clinic providers at two clinics based at Yale Health system in New Haven, CT, USA: Nathan Smith Clinic and the Haelen Center.\n\nEligibility criteria for the study included all adult (age >18 years) patients with confirmed HIV infection who had HCV genotype 1 infection. Only individuals for whom treatment with an 8-week course of SOF/LDV was intended, were included in the analysis.\n\nElectronic medical records of eligible patients were reviewed. Data collected included demographics, HIV clinical data (CD4 count, HIV VL, antiretroviral treatment (ART)), and laboratory data, including complete blood counts, electrolytes, and liver function tests and biopsy results. Plasma HCV viral loads and genotypes were determined at our lab using COBAS Ampliprep/COBAS Taqman HCV Test, v2.0 (Roche Diagnostics, Indianapolis, IN, USA). Assessment of liver fibrosis stage at time of treatment initiation was determined by one or more of the following: liver biopsy and non-invasive liver fibrosis scores, such as AST to platelet ratio index (APRI)\n13 and fibrosis-4 (FIB-4) score\n14. Patient-reported adverse events and reasons for non-completion or discontinuation of treatment were based on documentation in electronic medical records. Data were recorded and analyzed using descriptive statistics in Microsoft Excel, v2013. Overall SVR 12 rate was defined as the proportion of individuals for whom an 8-week treatment course was initiated that had undetectable HCV viral loads 12 weeks after completion of therapy.\n\nStudy approval was obtained from the Yale University Human Investigations Committee (number 1506016104).\n\nResults\nA total of 19 patients met the study inclusion criteria. Median age was 53 years (IQR 42-73 years); 14 (74%) were males, and 12 (63%) were African-American. The median body mass index was 28.2 kg/m2. The majority (95%) had glomerular filtration rate >60 ml/min. The major risk factor for HIV was injection drug use (53%). Median CD4 T cell count was 678 cells/µL (IQR 458-1004 cells/µL). All patients were on ART, of which non-nucleoside reverse transcriptase inhibitors (43%) followed by integrase strand transfer inhibitor-based regimens (32%) were most common. Thirteen patients (68%) were on tenofovir/emtricitabine (FTC) and 5 (26%) were taking abacavir/lamivudine (3TC). Patients who were on HIV protease inhibitors were receiving tenofovir/FTC. All patients had fully suppressed HIV VLs (\nTable 1).\n\nTable 1. Baseline demographic and clinical characteristics of 19 HIV and HCV co-infected patients treated with an 8 week course of sofosbuvir and ledipasvir.\nCharacteristic\tValue\t\nAge, median (years; median, IQR)\t53 (49.5-60.0)\t\nGender (male; n, %)\t14 (74)\t\nRace (n, %)\n\n African-American\n\n Caucasian\t\n\n12 (63)\n\n7 (37)\t\nBMI (kg/m\n2; median, IQR)\t28.2 (24.5-29.7)\t\nCreatinine clearance (ml/min; n, %)\n\n <60\n\n >60\t\n\n1 (5)\n\n18 (95)\t\nHIV risk factor (n, %)\n\n IDU\n\n Heterosexual contact\n\n MSM\n\n Blood transfusion\t\n\n10 (53)\n\n6 (31)\n\n2 (11)\n\n1 (5)\t\nCD4 count (cells/µL; median, IQR)\t678 (458-1004)\t\nART regimen (n, %)\n\n NNRTI\n\n PI\n\n INSTI\n\n Other\t\n\n8 (42)\n\n4 (21)\n\n6 (32)\n\n1 (5)\t\nART regimen: NRTI component (n, %)\n\n Tenofovir/FTC\n\n Abacavir/3TC\t\n\n13 (68)\n\n5 (26)\t\nHCV genotype (n, %)\n\n 1a\n\n 1b\n\n 1 unspecified\t\n\n12 (63)\n\n5 (26)\n\n2 (11)\t\nHCV viral load (IU/ml; median, IQR)\t869,000 (275,500-1,925,000)\t\nBaseline LFTs (U/L; median, IQR)\n\n ALT\n\n AST\t\n\n45 (30-70)\n\n39 (30.5-62.5)\t\nAPRI score (n, %)\n\n < 0.7\n\n 0.7- < 1.0\n\n > 1.0\t\n\n10 (53)\n\n4 (21)\n\n5 (26)\t\nFIB 4-score (n, %)\n\n <1.45\n\n 1.45- < 3.25\n\n > 3.25\t\n\n5 (26)\n\n12 (63)\n\n2 (11)\t\nALT, alanine transaminase; APRI, AST to platelet ratio index; ART, antiretroviral; AST, aspartate transaminase; BMI, basal metabolic index; FIB-4, fibrosis 4; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDU, injection drug use; IQR, interquartile range; IU/ml, international units/milliliter; LFT, liver function test; MSM, man who has sex with men; NRTI, nucleoside(tide) reverse transcriptase inhibitor, NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; INSTI, integrase strand transferase inhibitor; U/L, units/litre; FTC, emtricitabine; 3TC, lamivudine.\n\nTwelve (63%) patients had HCV genotype 1a and 5 (26%) had genotype 1b; in 2 patients, genotype 1 subtype was not done. Median AST and ALT values were 39 (IQR 31-63) units/L and 45 (IQR 32-70) units/L, respectively. All patients had baseline HCV VLs of < 6 million IU/mL and were HCV DAA treatment-naïve. Based on concordant non-invasive scoring (APRI and FIB-4 score), we classified two patients as having cirrhosis, (patients 2 and 3 in database), but both were clinically compensated (Child-Pugh Class A). One patient (patient 15) had discordant APRI (above cut-off) and FIB-4 scores (below cut-off), so was not classified as having cirrhosis.\n\nEighteen patients (95%) completed 8 weeks of therapy. One patient was non-adherent due to active substance abuse and only completed the first 4 weeks of treatment. Adverse events while on treatment were reported by 6 patients as follows: diarrhea (n=1), abdominal pain (n=1), nausea (n=1), poor appetite (n=1), diffuse joint pains (n=1), and pruritus without rash (n=1). One patient who experienced fatigue due to influenza temporarily discontinued treatment for 7 days, but resumed treatment afterwards. There were no cases of renal insufficiency, including patients who were on HIV protease inhibitors and tenofovir/FTC. Overall, SOF/LDV was well tolerated with no treatment discontinuations due to adverse effects.\n\nAll eligible patients had at least one HCV VL assay performed either at week 4 or week 8 of treatment and at 12 weeks following completion of therapy. At week 4 of treatment, 11 of 12 patients for whom there was available data, had undetectable HCV VLs; one patient had viremia that was less than the lower limit of detection of the assay (< 15 IU/ ml). At week 8 of treatment, 11 of 12 patients, who had available HCV VLs, had undetectable HCV VLs. The patient who had detectable HCV VL at week 8 had completed only 4 weeks of therapy and was subsequently non-adherent due to active substance use. In total 18 of the 19 patients achieved SVR 12. Therefore, overall SVR 12 rate was 95% (\nTable 2). The two patients who had cirrhosis also achieved SVR 12.\n\nTable 2. Treatment outcomes in 19 HIV and HCV co-infected patients treated with sofosbuvir and ledipasvir.\n\t4 week HCV VL\n\nn=12\n1\n\t8 week HCV VL\n\nn=12\n2\n\tSVR 12\n\nn=19\n3\n\t\nUndetectable\n\nHCV VL (n, %)\t11 (92)\t11 (92)\t18 (95)\t\nHIV, human immunodeficiency virus; HCV, hepatitis C virus; SVR 12, sustained virologic response 12 weeks after completion of therapy; VL, viral load.\n\n\n1Data only available for 12 patients;\n2Data only available for 12 patients (1 patient only completed 4 weeks of treatment);\n3Data obtained from 19 patients 12 weeks after completion of treatment.\n\nSpreadsheet data showing baseline demographic and clinical characteristics, as well as treatment outcomes, of HIV-HCV patients treated with 8-week course of sofosbuvir/ledipasvir Click here for additional data file.\n\nCopyright: © 2018 Ogbuagu O et al.2018Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication). Discussion\nHIV and HCV infections are often referred to as syndemics as they share similar routes of transmission and impact populations that have similar demographic and socio-economic profiles\n15. The presence of HIV infection confers a risk for accelerated progression of liver disease, even when HIV is virally suppressed\n16. For these reasons, it is important to ensure treatment of HCV for all HIV-infected persons, regardless of disease stage. Multiple studies have shown that HIV co-infection is no longer a significant predictor of poor HCV treatment outcomes, such that cure rates among individuals infected with HIV are similar to those who are uninfected\n11,\n17.\n\nThere is interest in shorter HCV treatment durations for a number of reasons: the prohibitive cost of newer DAAs\n18, and issues of adherence and potential development of resistance or toxicity. Kowdley\net al. showed in a post hoc analysis that an 8-week treatment regimen of SOF/LDV resulted in a high SVR 12 rate among non-cirrhotic HCV infected individuals with genotype 1 infection that was non-inferior to an 8-week regimen with ribavirin or a 12-week regimen without ribavirin\n10. Lower relapse rates were observed among patients receiving 8 weeks of SOF/LDV who had baseline HCV RNA levels <6 million IU/ml (2%; 2 of 123). However, this study did not include HIV-infected individuals.\n\nIn a subsequent real-world multi-national retrospective study of 634 patients, an 8-week course of SOF/LDV resulted in an overall SVR 12 of 98.1% in non-cirrhotic treatment-naïve individuals regardless of HCV VLs. This study included 16 HIV-infected individuals, and for those with VL >6 million IU/ml, 100% achieved SVR 12\n9. Unlike the previous study, this study found that pre-treatment HCV VL >6 million IU/ml in a subset of patients with HIV infection did not affect treatment outcomes, including relapse rates.\n\nOur study, showing an SVR 12 of 95%, is similar to the rates observed in a German cohort of 28 HIV-HCV co-infected patients, who showed a 96% response rate to 8 week therapy using SOF/LDV (GECCO-01 study)\n8. All patients in the trial were on antiretroviral therapy with a median CD4 count of 604 cells/mm\n3. However, the cohort consisted of predominantly Caucasian and male patients (89%). Our patient demographic was different with more women (26% versus 11%), and comprised a majority of African-American patients (63%).\n\nIt is important to highlight that not all DAA-based 8 week treatment courses for HIV-infected patients have yielded satisfactory results. The phase 3 ALLY-2 study, explored 8-week and 12-week SOF/daclatasvir treatment courses in HIV-infected individuals with HCV genotypes 1-4\n19. For treatment-naïve patients with HCV genotype 1, SVR 12 was 96% in the 12-week arm and 76% in the 8-week arm. However, it was observed that patients with HCV VL <2 million IU/ml performed better than those with viral loads >2 million IU/ml (SVR 12 of 100% versus 62%) supporting excellent efficacy with lower viral loads\n19.\n\nOur 95% SVR 12 rate in individuals placed on short course treatment may be attributable to certain factors: excellent adherence (supported by well controlled HIV infection) and selection of individuals with low HCV viral loads, factors that are associated with higher likelihood of cure\n17,\n20. It is remarkable that 26% of subjects were women and almost two-thirds were African-American; two groups that are often under-represented in HCV treatment studies, and this thereby increases the generalizability of the study results. The two individuals with cirrhosis also achieved excellent treatment results. In spite of the small number of patients in our study, the concordance of our findings with the European cohort in the GECCO-01 trial, as well as the multi-center study reported by Kowdley\net al, lends support to its validity.\n\nA limitation of our study is that it was retrospective, therefore data captured was dependent on the quality of documentation by patient providers. Our patient demographic may not be representative of patients in settings different from ours. There may be a treatment selection bias, whereby patients who were more likely to adhere to therapy and had characteristics favorable to achieving an optimal response were initiated on therapy by their clinic providers. Due to the low number of patients with cirrhosis in our cohort, it is not advisable to extend the conclusions to this subgroup.\n\nIn summary, our study provides support for the use of an 8-week course of SOF/LDV as an effective treatment option for HIV and genotype 1 HCV co-infected individuals with HCV viral loads <6 million IU/ml.\n\nData availability\nThe data referenced by this article are under copyright with the following copyright statement: Copyright: © 2018 Ogbuagu O et al.\n\nData associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).\n\n\n\nDataset 1: Spreadsheet data showing baseline demographic and clinical characteristics, as well as treatment outcomes, of HIV-HCV patients treated with 8-week course of sofosbuvir/ledipasvir. doi,\n10.5256/f1000research.11397.d218522\n21\n\n\nEthical statement\nThis medical review was approved by Yale University Human Investigations Committee (number 1506016104); individual patient consent was not required in this retrospective chart review.\n\n10.5256/f1000research.17847.r38623Referee response for version 2 Wong David K 12Refereehttps://orcid.org/0000-0002-3310-3538\n1 Immunodeficiency Clinic, University Health Network, Toronto, ON, Canada\n2 University of Toronto, Toronto, Canada\nCompeting interests: No competing interests were disclosed.\n\n24 9 2018 Version 2recommendationapproveRevision is fine.\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.12302.r24844Referee response for version 1 Wong David K 12Refereehttps://orcid.org/0000-0002-3310-3538\n1 Immunodeficiency Clinic, University Health Network, Toronto, ON, Canada\n2 University of Toronto, Toronto, Canada\nCompeting interests: No competing interests were disclosed.\n\n30 8 2018 Version 1recommendationapprove-with-reservationsGeneral:\n\n This is a small retrospective study that adds to the evidence that those with HCV (genotype 1)-HIV co-infection and low viral load can be treated successfully with 8 weeks of Sofosbuvir/Ledipasvir. Adherence matters as the one treatment failure did not complete treatment. The data from this cohort (two patients not described) are not strong enough to recommend this strategy for those with established cirrhosis. On-treatment monitoring of HCV PCR adds little to treatment.\n\n Specific comments:\n\n 1. The introduction is a bit dated. We should no longer need to justify treatment of those with HIV co-infection as a priority population. The simple fact of HCV infection means that these individuals should be offered treatment.\n\n 2. Introduction points out that HIV infection status no longer independently impacts treatment outcomes. The introduction should ALSO point out that those with HCV without HIV, NO cirrhosis and low viral load can be successfully treated with 8 weeks of SOF/LDV.\n\n 3. Two patients were thought to be cirrhotic but clinically compensated - how compensated? They should be described further and they should be pointed out in Table 3 - what were platelet counts, INR, albumin, Bilirubin.\n\n 4. The discussion is repetitive - should not repeat what was said in introduction\n\n 5. Study presents data of on-treatment HCV PCR monitoring. Do the authors think that this is required?\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.\n\nVillanueva Merceditas Yale University, USA\nCompeting interests: No competing interests\n\n14 9 2018 General:\n\nThis is a small retrospective study that adds to the evidence that those with HCV (genotype 1)-HIV co-infection and low viral load can be treated successfully with 8 weeks of Sofosbuvir/Ledipasvir. Adherence matters as the one treatment failure did not complete treatment. The data from this cohort (two patients not described) are not strong enough to recommend this strategy for those with established cirrhosis. On-treatment monitoring of HCV PCR adds little to treatment.\n\n\nResponse- Thanks for the comment. \n\n\n\nRegarding the concern about recommending short course treatment for cirrhotics, we acknowledge in the limitations section that… “\nDue to the low number of patients with cirrhosis in our cohort, it is not advisable to extend the conclusions to this subgroup.”\n\n\n\nAlso, we agree that on-treatment monitoring of HCV viral loads adds little to treatment especially as there are no “stoppage” rules based on pre-set viral load decay parameters monitored over time. We captured HCV viral load assessments as checked by clinic providers which was based on the clinic HCV treatment protocol at the time the study was conducted.\n\n\nSpecific comments:\n\n1. The introduction is a bit dated. We should no longer need to justify treatment of those with HIV co-infection as a priority population. The simple fact of HCV infection means that these individuals should be offered treatment.\n\n\nResponse- we agree that there is no longer a need to justify treatment of HIV infected patients with HCV as they experience similar treatment outcomes. We have eliminated the sentence “owing to this the treatment of HCV infection is prioritized for persons infected with HIV” from the revised manuscript\n\n\n2. Introduction points out that HIV infection status no longer independently impacts treatment outcomes. The introduction should ALSO point out that those with HCV without HIV, NO cirrhosis and low viral load can be successfully treated with 8 weeks of SOF/LDV.\n\n\nResponse: We have modified the 3\nrdsentence of paragraph 3 of the introduction as follows: “\nBased on this data, the American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines recommend that treatment-naïve, genotype 1 patients without cirrhosis, are non-black, HIV-negative and with a pre-treatment HCV VL <6 million IU/ml ( \nhttp://www.hcvguidelines.org/full-report/hcv-testing-and-linkage-care) can be successfully treated with 8 weeks of SOF/LDV.\n\n\n3. Two patients were thought to be cirrhotic but clinically compensated - how compensated? They should be described further and they should be pointed out in Table 3 - what were platelet counts, INR, albumin, Bilirubin.\n\n\nResponse: We noted discrepancies in the dataset attached to our original submission when compared to our original data! (the APRI and Fib-4 scores were erroneously arranged in descending order on the submitted version and not on the same row with appropriate patients). We have corrected this on the re-submission. Both patients had APRI and Fib-4 scores that were above cut-off values that are suggestive of liver cirrhosis. We used the term “compensated” to mean that they had no documented clinical features of decompensation including development of HCC, ascites, porto-systemic encephalopathy or varices. We did calculate Child Pugh scores (inclusive of INR and albumin levels) and both patients were class A. Both of these last points are mentioned in the results section.\n\n\n4. The discussion is repetitive - should not repeat what was said in introduction\n\n\nResponse: Thank you. We have modified the discussion to remove redundant / repetitive statements.\n\n\n5. Study presents data of on-treatment HCV PCR monitoring. Do the authors think that this is required?\n\n\nResponse: as stated in our first response to general comments -\nwe agree that on-treatment monitoring of HCV viral loads adds little to treatment especially as there are no “stoppage” rules based on pre-set viral load decay parameters monitored over time. We captured HCV viral load assessments as checked by clinic providers which was based on the clinic HCV treatment protocol at the time the study was conducted\n\n\n10.5256/f1000research.12302.r22470Referee response for version 1 Ingiliz Patrick 1Referee\n1 Center for Infectiology, Berlin, Germany\nCompeting interests: No competing interests were disclosed.\n\n5 6 2017 Version 1recommendationapproveOgbuago and coworkers provide a small study on 19 HIV-HCV coinfected individuals that were treated with an 8-weeks course of sofosbuvir and ledipasvir. Overall, the SVR rate is 95% with only one individual not responding who was in-adherent. The study, although small, adds knowledge to the existing literature.\n\n Minor comments:\nThe authors should point out more clearly that they are dealing with a difficult-to-treat population here: A high percentage of AAs, high levels of IDU, and high BMI. This values the results even more.\n\nIn the Introduction the authors should point out that DAAs have changed treatment paradigms in HCV, but that 12 weeks treatment duration still proved to be the threshold hard to beat. It only worked so far with this regimen presented here. It will however change with new compounds.\n\nIn the discussion, the description of the ION-3 trial is slightly inaccurate: The non-inferiority of the 8-weeks regimen was an endpoint of the study. The 6 mil viral load threshold was a post-hoc-analysis.\n\n\n\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\nVillanueva Merceditas Yale University, USA\nCompeting interests: None\n\n21 6 2017 In response to Dr Ingiliz's comments:\nIt is correct that our cohort consisting of predominantly AAs, current or ex-IDUs, with high median BMI, and who are HIV co-infected are traditionally hard to treat populations so that it does make the treatment results all the more remarkable and in spite of the small sample size. This is now reflected in the discussion as follows:\n\n\"The high SVR12 rate in our study is even more remarkable given that all patients were HIV infected and a significant proportion were African-American, had a high BMI and were active or current IDUs, all of which are characteristics of traditionally hard to treat populations. \"\n\nWe have modified the sentence in the Introduction referencing 8-week and 12-week treatment regimens to suggest as accurately pointed out that for currently approved DAA regimens, 12-week treatment duration remains the standard for most patients, while 8 week regimens may be used for \"selected cases\". This is now reflected in the introduction as follows:\n\n\"While 12-week DAA-based treatment regimens remain the standard treatment course for most HCV infected patients, emerging data suggests that 8-week rather than 12-week regimens may be effective for treatment among selected patients \"\n\nThe paragraph has been rephrased to accurately reflect the primary results of the open label randomized ION-3 study as well as post hoc analysis as follows:\n\n\"Kowdley \net al, in a phase 3 open label randomized trial, showed that an 8-week treatment regimen of SOF/LDV resulted in a high SVR 12 rate among non-cirrhotic HCV infected individuals with genotype 1 infection that was non-inferior to an 8-week regimen with ribavirin or a 12-week regimen without ribavirin \n10\n . In a post hoc analysis, lower relapse rates were observed among patients receiving 8 weeks of SOF/LDV who had baseline HCV RNA levels <6 million IU/ml (2%; 2 of 123).\" \n==== Refs\n1 \nWeber R Sabin CA Friis-Moller N :\nLiver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. \nArch Intern Med. \n2006 ;166 (15 ):1632 –1641 .\n10.1001/archinte.166.15.1632 \n16908797 \n2 \nKitahata MM Gange SJ Abraham AG :\nEffect of early versus deferred antiretroviral therapy for HIV on survival. \nN Engl J Med. \n2009 ;360 (18 ):1815 –1826 .\n10.1056/NEJMoa0807252 \n\n19339714 \n3 \nButt AA McGinnis K Skanderson M :\nA comparison of treatment eligibility for hepatitis C virus in HCV-monoinfected versus HCV/HIV-coinfected persons in electronically retrieved cohort of HCV-infected veterans. \nAIDS Res Hum Retroviruses. \n2011 ;27 (9 ):973 –979 .\n10.1089/AID.2011.0004 \n\n21338329 \n4 \nCachay ER Hill L Wyles D :\nThe Hepatitis C Cascade of Care among HIV Infected Patients: A Call to Address Ongoing Barriers to Care. \nPLoS One. \n2014 ;9 (7 ):e102883 .\n10.1371/journal.pone.0102883 \n\n25036553 \n5 \nMoon AM Green PK Berry K :\nTransformation of hepatitis C antiviral treatment in a national healthcare system following the introduction of direct antiviral agents. \nAliment Pharmacol Ther. \n2017 ;45 (9 ):1201 –1212 .\n10.1111/apt.14021 \n\n28271521 \n6 \nKonerman MA Lok AS :\nHepatitis C Treatment and Barriers to Eradication. \nClin Transl Gastroenterol. \n2016 ;7 (9 ):e193 .\n10.1038/ctg.2016.50 \n\n27657495 \n7 \nGross C Akoth E Price A :\nHIV/HCV Co-infection: Overcoming Barriers to Treatment. \nJ Assoc Nurses AIDS Care. \n2016 ;27 (4 ):524 –529 .\n10.1016/j.jana.2016.02.009 \n26996983 \n8 \nIngiliz P Christensen S Kimhofer T :\nSofosbuvir and Ledipasvir for 8 Weeks for the Treatment of Chronic Hepatitis C Virus (HCV) Infection in HCV-Monoinfected and HIV-HCV-Coinfected Individuals: Results From the German Hepatitis C Cohort (GECCO-01). \nClin Infect Dis. \n2016 ;63 (10 ):1320 –1324 .\n10.1093/cid/ciw567 \n27535952 \n9 \nKowdley KV Sundaram V Jeon CY :\nEight weeks of Ledipasvir/Sofosbuvir is effective for selected patients with genotype 1 Hepatitis C virus infection. \nHepatology. \n2017 ;65 (4 ):1094 –1103 .\n10.1002/hep.29005 \n28027579 \n10 \nKowdley KV Gordon SC Reddy KR :\nLedipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. \nN Engl J Med. \n2014 ;370 (20 ):1879 –1888 .\n10.1056/NEJMoa1402355 \n24720702 \n11 \nShafran SD :\nHIV Coinfected Have Similar SVR Rates as HCV Monoinfected With DAAs: It's Time to End Segregation and Integrate HIV Patients Into HCV Trials. \nClin Infect Dis. \n2015 ;61 (7 ):1127 –1134 .\n10.1093/cid/civ438 \n26060286 \n12 \nMilazzo L Lai A Calvi E :\nDirect-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV-coinfected patients: real-life safety and efficacy. \nHIV Med. \n2017 ;18 (4 ):284 –291 .\n10.1111/hiv.12429 \n27477612 \n13 \nLin ZH Xin YN Dong QJ :\nPerformance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. \nHepatology. \n2011 ;53 (3 ):726 –736 .\n10.1002/hep.24105 \n21319189 \n14 \nSterling RK Lissen E Clumeck N :\nDevelopment of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. \nHepatology. \n2006 ;43 (6 ):1317 –1325 .\n10.1002/hep.21178 \n16729309 \n15 \nPlatt L Easterbrook P Gower E :\nPrevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis. \nLancet Infect Dis. \n2016 ;16 (7 ):797 –808 .\n10.1016/S1473-3099(15)00485-5 \n26922272 \n16 \nLo Re V 3rdKallan MJ Tate JP :\nHepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus compared with hepatitis C virus-monoinfected patients: a cohort study. \nAnn Intern Med. \n2014 ;160 (6 ):369 –379 .\n10.7326/M13-1829 \n\n24723077 \n17 \nCavalcante LN Lyra AC :\nPredictive factors associated with hepatitis C antiviral therapy response. \nWorld J Hepatol. \n2015 ;7 (12 ):1617 –1631 .\n10.4254/wjh.v7.i12.1617 \n\n26140082 \n18 \nChhatwal J He T Lopez-Olivo MA :\nSystematic Review of Modelling Approaches for the Cost Effectiveness of Hepatitis C Treatment with Direct-Acting Antivirals. \nPharmacoeconomics. \n2016 ;34 (6 ):551 –67 .\n10.1007/s40273-015-0373-9 \n26748919 \n19 \nWyles DL Ruane PJ Sulkowski MS :\nDaclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. \nN Engl J Med. \n2015 ;373 (8 ):714 –725 .\n10.1056/NEJMoa1503153 \n26196502 \n20 \nLouie V Latt NL Gharibian D :\nReal-World Experiences With a Direct-Acting Antiviral Agent for Patients With Hepatitis C Virus Infection. \nPerm J. \n2017 ;21 :16 –096 .\n10.7812/TPP/16-096 \n\n28368787 \n21 \nOgbuagu O Hao R Virata M :\nDataset 1 in: Efficacy of an 8-week course of sofosbuvir and ledipasvir for the treatment of HCV infection in selected HIV-infected patients. \nF1000Research. \n2018 \n10.5256/f1000research.11397.d218522\n\n",
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"title": "Efficacy of an 8-week course of sofosbuvir and ledipasvir for the treatment of HCV infection in selected HIV-infected patients.",
"title_normalized": "efficacy of an 8 week course of sofosbuvir and ledipasvir for the treatment of hcv infection in selected hiv infected patients"
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"abstract": "Secondary prophylaxis with recombinant human granulocyte colony stimulating factor (G-CSF) is recommended where patients have experienced febrile neutropenia in an earlier chemotherapy cycle and for whom the maintenance of chemotherapy dose intensity is important; or where febrile neutropenia has not occurred but prolonged neutropenia is causing excessive dose delay or reduction, where maintenance of dose intensity is important. The objective of this study was to determine the efficacy and feasibility of G-CSF as secondary prophylaxis when used along with full dose moderately myelotoxic chemotherapy following a prior cycle with febrile-neutropenia. Fifty-two patients aged 22-75 years with febrile neutropenia that required intravenous antibiotics following moderately myelotoxic chemotherapy were included. These patients received the next cycle of the same chemotherapy regime without dose modification but with support of filgrastim 24 h after completion of chemotherapy (300 μg/day/subcutaneously (s.c.) for weight < 60 kg, 480 μg/day/s.c. for weight > 60 kg, for at least 10 consecutive days), patients in whom neutropenia was associated with a life-threatening infection and those who developed prolonged myelosuppression were excluded. The use of the hematopoietic growth factor G-CSF was shown to shorten the neutrophil recovery time, resulting in significant reduction of incidence of febrile neutropenia, hospitalization and use of broad spectrum antibiotics. There was no drug related death or adverse events associated with either cycle. In conclusion, recombinant human G-CSF is effective and relatively safe as a secondary prophylaxis with full dose chemotherapy in patients who develop febrile neutropenia following prior cycles of moderately myelotoxic chemotherapy.",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000971:Antineoplastic Combined Chemotherapy Protocols; D005334:Fever; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms; D009503:Neutropenia; D011994:Recombinant Proteins",
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"title": "Efficacy of granulocyte colony stimulating factor as a secondary prophylaxis along with full-dose chemotherapy following a prior cycle of febrile neutropenia.",
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"medicinalproduct": "FILGRASTIM"
}
],
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"reaction": [
{
"reactionmeddrapt": "Hospitalisation",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mucosal inflammation",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Musculoskeletal pain",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dizziness",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fungal infection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PANT, M C. EFFICACY OF GRANULOCYTE COLONY STIMULATING FACTOR AS A SECONDARY PROPHYLAXIS ALONG WITH FULL-DOSE CHEMOTHERAPY FOLLOWING A PRIOR CYCLE OF FEBRILE NEUTROPENIA. BIOSCIENCE TRENDS. 2010?4(5):273-278",
"literaturereference_normalized": "efficacy of granulocyte colony stimulating factor as a secondary prophylaxis along with full dose chemotherapy following a prior cycle of febrile neutropenia",
"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20200316",
"receivedate": "20200316",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
},
{
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
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"drugdosageform": "UNKNOWN FORMULATION",
"drugdosagetext": "300 MICROGRAM/QD FOR WEIGHT {60 KG, 480 PG/DAY, FOR WEIGHT }60 KG, FOR AT LEAST 10 CONSECUTIVE DAYS)",
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"drugindication": "PROPHYLAXIS",
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"medicinalproduct": "FILGRASTIM"
}
],
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bone marrow failure",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PANT, MOHAN C. EFFICACY OF GRANULOCYTE COLONY STIMULATING FACTOR AS A SECONDARY PROPHYLAXIS ALONG WITH FULL-DOSE CHEMOTHERAPY FOLLOWING A PRIOR CYCLE OF FEBRILE NEUTROPENIA. BIOSCIENCE TRENDS. 2010?4(5):273-278",
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"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20200316",
"receivedate": "20200316",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17545710,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "BACKGROUND\nThis phase II study was conducted to evaluate tumor response rate and safety profile of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine given preoperatively to patients with stage II or IIIA breast cancer.\n\n\nMETHODS\nPatients underwent four cycles of dose-dense cyclophosphamide 600 mg/m(2) and epirubicin 90 mg/m(2) every 2 weeks followed by two cycles of docetaxel 36 mg/m(2) on days 1, 8, and 15 plus capecitabine 1250 mg/m(2) on days 5-18 every 4 weeks, with prophylactic pegfilgrastim. The primary objective of the study was to determine the incidence of pathologic complete response defined as the absence of invasive or in situ cancer in the breast and the axillary nodes at definitive surgery.\n\n\nRESULTS\nForty-four patients were enrolled in the study and 41 (93%) were assessable for response to chemotherapy. An objective clinical response was observed in 38 (93%) patients. Seven patients (17.1%) exhibited a pathologic complete response. Breast-conserving surgery was carried out in 36 (88%) patients. Grade 3/4 neutropenia occurred in 4.3% of 252 administered chemotherapy cycles. No febrile neutropenia, cardiac toxicity, thrombocytopenia or other serious adverse event was registered.\n\n\nCONCLUSIONS\nThe sequential combination of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine is an effective and well-tolerated neo-adjuvant chemotherapy for stage II, IIIA breast cancer.",
"affiliations": "Department of Oncology and Neurosciences and Foundation, University G. D'Annunzio, Chieti-Pescara, Italy.",
"authors": "Natoli|C|C|;Cianchetti|E|E|;Tinari|N|N|;Angelucci|D|D|;Grassadonia|A|A|;Zilli|M|M|;Ficorella|C|C|;Ricevuto|E|E|;Grossi|S|S|;De Tursi|M|M|;Carella|C|C|;Rispoli|A I|AI|;Iacobelli|S|S|",
"chemical_list": "D011994:Recombinant Proteins; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D003520:Cyclophosphamide; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdm076",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "18(6)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": null,
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011092:Polyethylene Glycols; D017698:Postmenopause; D017697:Premenopause; D011300:Preoperative Care; D011994:Recombinant Proteins; D043823:Taxoids",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1015-20",
"pmc": null,
"pmid": "17369601",
"pubdate": "2007-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase II study of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine and pegfilgrastim support as preoperative therapy for patients with stage II, IIIA breast cancer.",
"title_normalized": "a phase ii study of dose dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine and pegfilgrastim support as preoperative therapy for patients with stage ii iiia breast cancer"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020024446",
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"occurcountry": "IT",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
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"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "625 MILLIGRAM/SQ. METER, BID, ON DAYS 5-18, EVERY 4 WEEKS",
"drugenddate": null,
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"drugindication": "INVASIVE BREAST CARCINOMA",
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},
{
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"drugdosagetext": "6 MILLIGRAM, AFTER CHEMO",
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},
{
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},
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},
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},
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"medicinalproduct": "CYCLOPHOSPHAMIDE."
},
{
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},
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},
{
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},
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"medicinalproduct": "DIPHENHYDRAMINE."
},
{
"actiondrug": null,
"activesubstance": {
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},
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"drugdosagetext": "50 MILLIGRAM (AT 12 AND 1 HOUR BEFORE DOCETAXEL AND 12 H AFTER DOCETAXEL)",
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"drugstructuredosagenumb": "50",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "AST/ALT ratio abnormal",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product storage error",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mucosal inflammation",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Palmar-plantar erythrodysaesthesia syndrome",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nail disorder",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CIANCHETTI, E.. A PHASE II STUDY OF DOSE-DENSE EPIRUBICIN PLUS CYCLOPHOSPHAMIDE FOLLOWED BY DOCETAXEL PLUS CAPECITABINE AND PEGFILGRASTIM SUPPORT AS PREOPERATIVE THERAPY FOR PATIENTS WITH STAGE II, IIIA BREAST CANCER. ANNALS OF ONCOLOGY. 2007?18 (6):1015-1020",
"literaturereference_normalized": "a phase ii study of dose dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine and pegfilgrastim support as preoperative therapy for patients with stage ii iiia breast cancer",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20200218",
"receivedate": "20200218",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17425267,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "Daratumumab, pomalidomide, and dexamethasone (DPd) is an FDA-approved 3rd or later line of therapy for myeloma. However, as there are limited published data on the efficacy of 2nd-line DPd, we conducted a retrospective analysis (n = 33). Herein, we report our center's data for 2nd-line DPd. Our patient population had a high amount of high risk cytogenetics (45.5%). The overall response rate (ORR) was 84.9% with a 1-year Progression Free Survival (PFS) of 37.7%. In standard risk myeloma (n = 18), the ORR was 88.9% and 1-year PFS was 61.1% (95% CI 42.3-88.3%). In high risk myeloma (45.5%, n = 15), the ORR was 80% with a 1-year PFS of 7.3% (95% CI 1.1-47.9%). This suggests that the efficacy of 2nd-line DPd in myeloma with high risk cytogenetics should be further investigated.",
"affiliations": "Department of Medicine, Saint Louis University, St. Louis, MO, USA.;School of Social Work, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO, USA.;Department of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, USA.;Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.;Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.;Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.;Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.;Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.;Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.",
"authors": "Liu|Lawrence|L|0000-0001-8559-7739;Fiala|Mark|M|;Gao|Feng|F|0000-0002-1425-1623;King|Justin|J|;Goldsmith|Scott|S|;Wildes|Tanya M|TM|;Stockerl-Goldstein|Keith|K|;Vij|Ravi|R|;Schroeder|Mark A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2021.1941940",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "62(12)",
"journal": "Leukemia & lymphoma",
"keywords": "Myeloma; antibody-based immunotherapy; chemotherapeutic approaches; cytogenetics; drug resistance; immunotherapy",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": null,
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "3043-3046",
"pmc": null,
"pmid": "34142630",
"pubdate": "2021-12",
"publication_types": "D016422:Letter",
"references": null,
"title": "A single center retrospective study of daratumumab, pomalidomide, and dexamethasone as 2nd-line therapy in multiple myeloma.",
"title_normalized": "a single center retrospective study of daratumumab pomalidomide and dexamethasone as 2nd line therapy in multiple myeloma"
} | [
{
"companynumb": "US-JNJFOC-20210317815",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "POMALIDOMIDE"
},
"drugadditional": "3",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": null,
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"medicinalproduct": "POMALIDOMIDE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARATUMUMAB"
},
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"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "CONCENTRATE FOR SOLUTION FOR INFUSION",
"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "PLASMA CELL MYELOMA",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"abstract": "A 43-year-old Japanese man presented with a history of bacterial meningitis (BM). He was admitted to our department with a one-day history of headache and was diagnosed with relapse of BM based on the cerebrospinal fluid findings. The conventional imaging studies showed serial findings suggesting left otitis media, a temporal cephalocele, and meningitis. Three-dimensional multi-detector computed tomography (3D-MDCT) showed left petrous bone defects caused by the otitis media, and curative surgical treatment was performed. Skull bone structural abnormalities should be considered a cause of relapsed BM. 3D-MDCT was useful for revealing the causal minimal bone abnormality and performing pre-surgical mapping.",
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"authors": "Akimoto|Takayoshi|T|;Morita|Akihiko|A|;Shiobara|Keiji|K|;Hara|Makoto|M|;Minami|Masayuki|M|;Shijo|Katsunori|K|;Nomura|Yasuyuki|Y|;Shigihara|Shuntaro|S|;Haradome|Hiroki|H|;Abe|Osamu|O|;Kamei|Satoshi|S|",
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"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.7299Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27980270Case ReportSurgically Cured, Relapsed Pneumococcal Meningitis Due to Bone Defects, Non-invasively Identified by Three-dimensional Multi-detector Computed Tomography Akimoto Takayoshi 1Morita Akihiko 1Shiobara Keiji 1Hara Makoto 1Minami Masayuki 1Shijo Katsunori 2Nomura Yasuyuki 3Shigihara Shuntaro 3Haradome Hiroki 4Abe Osamu 4Kamei Satoshi 11 Division of Neurology, Department of Medicine, Nihon University School of Medicine, Japan2 Department of Neurological Surgery, Nihon University School of Medicine, Japan3 Department of Otolaryngology-Head and Neck Surgery, Nihon University School of Medicine, Japan4 Department of Radiology, Nihon University School of Medicine, JapanCorrespondence to Dr. Akihiko Morita, morita.akihiko@nihon-u.ac.jp\n\n15 12 2016 55 24 3665 3669 19 2 2016 26 4 2016 The 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/).A 43-year-old Japanese man presented with a history of bacterial meningitis (BM). He was admitted to our department with a one-day history of headache and was diagnosed with relapse of BM based on the cerebrospinal fluid findings. The conventional imaging studies showed serial findings suggesting left otitis media, a temporal cephalocele, and meningitis. Three-dimensional multi-detector computed tomography (3D-MDCT) showed left petrous bone defects caused by the otitis media, and curative surgical treatment was performed. Skull bone structural abnormalities should be considered a cause of relapsed BM. 3D-MDCT was useful for revealing the causal minimal bone abnormality and performing pre-surgical mapping. \n\npneumococcal meningitisrelapsed bacterial meningitisbone defectthree-dimensional computed tomography (3D-CT)volume rendering CTcephalocele\n==== Body\nIntroduction\nBacterial meningitis (BM) is a neurological emergency. Early and appropriate antibiotic therapy improves the prognosis, but some patients with BM develop recurrence or relapse. The causes of recurrence or relapse are the spread of inflammation from neighboring organs, abscess formation, thrombosis, immunodeficiency, and anatomical abnormalities (1). Computed tomography (CT) and magnetic resonance imaging (MRI) are usually used to investigate the origin of the focus, abscess, and thrombosis. Brain three-dimensional (3D) multi-detector CT (MDCT) imaging is particularly useful for investigating precise bone structural abnormalities in the auditory ossicles or skull base (2). We herein describe a surgically cured case of relapsed pneumococcal BM related to temporal bone defects. In the present case, 3D-MDCT revealed the key features of the causal minimal bone abnormality, which led to successful surgical treatment.\n\nCase Report\nA 43-year-old Japanese man was transported by ambulance to an emergency hospital. At the examination, he was comatose with a temperature of 39.7℃. His left tympanic membrane was red, although tympanic membrane maceration and perforation and cerebrospinal fluid (CSF) rhinorrhea were not observed. The laboratory data showed a high white blood cell count (46,300 cells/μL) and C-reactive protein level (12.04 mg/dL). Lumbar puncture was performed. The results were as follows: CSF white cell count (WCC) 11,643 cells/μL (99% polymorphonuclear cells); total protein 762 mg/dL; glucose 40 mg/dL (serum glucose 237 mg/dL); and Gram-positive cocci on Gram's stain. Ceftriaxone (CTRX) and linezolid (LZD) were administered intravenously. The CSF culture grew penicillin-resistant Streptococcus pneumoniae (minimum inhibitory concentration of benzyl penicillin was 1 μg/mL). On Day 7, the CSF WCC decreased to 49 cells/μL. On Day 14, CTRX and LZD were discontinued, and he was discharged on Day 22 without sequelae.\n\nHowever, 11 days after being discharged from the emergency hospital, he was admitted to our department with a one-day history of headache and vomiting. On admission, he was conscious, with a temperature of 37.9℃, blood pressure of 137/89 mmHg, pulse of 98 beats per minute, and oxygen saturation of 100% on ambient air. The pupils were 4.0 mm in diameter and briskly reactive to light. The neck was not stiff. Neither deafness nor otorrhea was present. The findings from the remainder of the examination were normal. Chest radiographs and an electrocardiogram were negative. The temporal bone CT images showed soft-tissue density that invaded to the left tympanum and right tegmen tympani thinning (Fig. 1A-D). The pneumatization of the left mastoid cells was also decreased on the CT image. A 3D volume rendering CT (3D-CT) image (Ziostation; Ziosoft, Tokyo, Japan) revealed 2 petrous bone defects of 12×9 mm and 9×5 mm in size (Fig. 1E). Plain MRI showed spotty high-intensity areas along the cerebral falx on diffusion-weighted imaging (Fig. 2A). The left mastoid cells and middle ear showed a high-intensity area on T2-weighted imaging and a faint high-intensity area on diffusion-weighted imaging due to the T2 shine-through effect of mastoiditis (Fig. 2B and C). Contrast-enhanced T1-weighted images showed a minimal sac-like left temporal lobe protrusion into the petrous bone defect, suggesting a cephalocele (Fig. 2D-F). The laboratory data showed the following: white blood cell count 13,500/mm3, with 88% neutrophils; C-reactive protein 0.79 mg/dL; creatinine 1.53 mg/dL; HbA1c 6.5%; and D-dimer <1.0 μg/mL. Two sets of blood cultures were sterile. Lumbar puncture was performed, and the results showed: CSF WCC 119 cells/μL (37% polymorphonuclear cells); total protein 78 mg/dL; and glucose 47 mg/dL (serum glucose 110 mg/dL). A CSF pneumococcal antigen test and CSF cultures of bacteria and acid-fast bacteria were negative.\n\nFigure 1. \nA, B, C: The left temporal bone CT images (A axial view; B, C multi-planar reconstruction coronal view) show soft-tissue density at the left epitympanum and a partial defect of the left tegmen part of the petrous bone near the lesion (white arrows). D: A right temporal bone CT image of the multi-planar reconstruction coronal view shows thinning of the right tegmen tympani (white-striped arrow). E: A three-dimensional volume-rendering CT image (looking down on the skull base from above; Ziostation, Ziosoft, Tokyo, Japan) depicts 2 bone defects sized 12×9 mm and 9×5 mm at the tegmen tympani part of the left petrous bone (white arrowheads).\n\n\nFigure 2. \nA: An axial diffusion-weighted image shows several spotty, high-intensity areas along with the cerebral falx, suggesting meningitis-related purulent material (white arrow). B, C: An axial diffusion-weighted image shows a faint high-intensity area, probably due to the T2 shine-through effect of mastoiditis, at the left mastoid cells, but no intense signal (restricted diffusion) suggesting cholesteatoma. An axial T2-weighted image reveals a high-intensity area at the left middle ear corresponding to otitis media (white arrowheads). D, E, F: The axial, coronal, and sagittal contrast-enhanced T1-weighted images show a minimal sac-like left temporal lobe protrusion into the petrous bone defect, suggesting a cephalocele (white-striped arrows).\n\n\nThe patient was diagnosed with relapsed BM with left mastoiditis. He was given intravenous meropenem (2 g every 8 hours), vancomycin (1 g every 12 hours), and dexamethasone (3.3 mg every 8 hours). His fever and headache were improved the next day. The CSF WCC decreased to 15 cells/μL on Day 6. However, on Day 24, he developed a whole-body rash, suggesting a drug eruption. The meropenem and vancomycin were changed to CTRX (2 g every 12 hours), LZD (600 mg every 12 hours), and oral rifampicin (600 mg every 24 hours). The drug-induced lymphocyte stimulation test was positive for both meropenem and vancomycin. On Day 38, his body temperature increased to 38.0℃, and his CSF WCC increased to 21 cells/μL. Furthermore, the pneumococcal antigen was detected in the CSF for the first time. On Day 49, Although the CSF WCC decreased to 11 cells/μL, the low-grade fever continued. Since the defects suggested a connection to the tympanum through the tegmen tympani, cranioplasty was necessary to close the defects, in addition to tympanoplasty. On Day 56, the operation was performed. The corresponding bone defects shown on the 3D-CT images were observed (Fig. 3A). The damaged dura mater protruded into the tympanum through the bone defect, and the temporal lobe could be seen behind the dura mater (Fig. 3B). The incus was seen in the defect, and it was covered by inflammatory tissue (Fig. 3C). The dura mater was repaired, and the bone defects were closed using a bone fragment made of cranial bone and a temporal muscle fascia flap. Tympanoplasty was performed subsequently. The attic cavity was filled with soft tissue for reinforcement, and the ossicles were reconstructed. No cholesteatoma was detected during the operation. After the operation, intravenous levofloxacin (500 mg every 24 hours) was added. On Day 67, the CSF WCC was 11 cells/μL. On Day 81, the CSF WCC normalized (3 cells/μL). The meningitis did not relapse after CTRX, LZD, and levofloxacin were discontinued. The patient was discharged on Day 105 with 40 dB left conductive hearing loss. He continued to be administered oral rifampicin and had no recurrence over 9 months of follow-up at the hospital.\n\nFigure 3. \nA, B, C: The intraoperative findings on cranioplasty (looking down on the skull base from above) show the temporal lobe (white arrow) behind the damaged dura mater (white arrowheads). Two petrous bone defects corresponding to those seen on the 3D-CT image (black arrowhead and black-striped line) are visible. The incus is seen in the defect (black-striped arrow).\n\n\nDiscussion\nRecurrence and relapse are severe problems when treating BM. As in the present case, Streptococcus pneumoniae is the most common pathogen associated with recurrent BM. The risk factors for recurrent BM caused by Streptococcus pneumoniae are head injury, congenital craniopathy, cephalocele, inner ear malformation, asplenia, IgG subclass deficiency, complement system dysfunction, HIV infection, and chronic otitis media/mastoiditis (1). Thus, it is necessary to examine the anatomical, immunological, and otolaryngeal causes.\n\nBefore the era of antibiotics, the intracranial complication of mastoiditis occurred in about 6% of cases, with a mortality rate of 71.5% in 1935 (3). After the introduction of antibiotics, the intracranial complication and mortality rates decreased to 0.36% and 18.4%, respectively, in 1995 (4). The pathophysiological mechanism of otolaryngeal infections involving the central nervous system (CNS) is considered to be the osteitic destruction of the bone and dura mater, hematogenous spread by the network of the dura mater and venous sinuses, direct bacterial spread by bone fracture or otogenic intervention (5), or anatomical malformation, such as Mondini dysplasia (6). CT enables the detection of otolaryngeal infections involving the CNS, such as epidural abscess, subdural empyema, perisinus abscess, subperiosteal abscess, or sigmoid sinus thrombosis. Migirov et al. compared the CT and surgical findings of acute otitis media, and CT revealed these complications with a sensitivity of 97% (7).\n\nHowever, although bone erosion is often detected, reports of bone defects are limited. In 1990, Beaumont reported a case of a 29-year-old woman with recurrent BM related to a petrous bone defect. Her bone defect and cephalocele were at the tegmen part of the petrous bone and were occluded with temporal muscle fascia, as in the present case. Axial and coronal 2-dimensional CT was used to investigate the bone defect (8).\n\nThe introduction in 1998 of MD-CT by major CT vendors has resulted in faster scan speeds, wider-range scanning, and higher z-axis spatial resolution than with traditional CT scanners. In recent years, MD-CT equipped with a larger number of detectors (64 or more) has proven capable of producing isotropic spatial resolution in a shorter scanning time, which can provide a detailed 3D multi-view image of the inner ear or cranial bone. Motojima et al. reported a case of a 6-year-old girl with recurrent BM and bone defects at the petrous apex on 3D-CT imaging (9). In the present case, the bone defect was seen at the tegmen part of the petrous bone on 3D-CT. The 3D-CT findings and intraoperative findings were similar, suggesting that 3D-CT is useful for detecting bone defects at the tegmen part, as at the petrous apex, and for investigating the minute bone structures of the skull base and simulating the intracranial operations.\n\nMoore reported 10 cases of petrous apex cephaloceles (PACs). All of the PACs were observed along the posterolateral portion of Meckel's cave (10). Jeevan reported 32 cases of bone defects in the tegmen part, and 14 of these cases had associated chronic otitis media. A congenital temporal bone defect was reported in 6% (2 of 32 cases) (11). These reports have suggested a relationship between cephaloceles at the petrous part and Meckel's cave and between cephaloceles at the tegmen part and otitis media.\n\nIn the present case, there was bilateral thinning of the petrous bones, a cephalocele at the left side, left otitis media, and mastoiditis. The patient had no history of head trauma or intracranial intervention, nor was there any evidence of bacteremia, thrombosis, cholesteatoma, otorrhea, or inner ear malformation. The pathophysiological mechanism in the present case was thought to be related to the congenitally thin bilateral petrous bone and inflammation of the left middle ear that destroyed the tegmen tympani and neighboring dura mater, inducing a cephalocele and a relapse of BM.\n\nIn conclusion, skull bone structural abnormalities should be considered as potential causes when encountering a patient with a relapse of BM. 3D-CT is useful for detecting key features of the causal minimal bone defects and for pre-surgical mapping for successful treatment.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nJanocha-Litwin J , Simon K \nRecurrent meningitis: a review of current literature . Przeglad epidemiologiczny \n67 : 41 -45 , 2013 .23745374 \n2. \nKatada K \nRecent development of computed tomography in Neuroradiology: Significance of multislice CT . Dansoeizo Kennkyuukai Zasshi (The Journal of the Japanese Association of Tomography) \n28 : 203 -209 , 2001 (in Japanese, Abstract in English).\n3. \nKafka MM \nMortality of mastoiditis and cerebral complications with review of 3225 cases of mastoiditis with complications . Laryngoscope \n45 : 790 -822 , 1935 .\n4. \nKangsanarak J , Navacharoen N , Fooanant S , Ruckphaopunt K \nIntracranial complications of suppurative otitis media: 13 years' experience . Am J Otol \n16 : 104 -109 , 1995 .8579165 \n5. \nBrydoy B , Ellekjaer EF \nOtogenic meningitis: a five-year study . J Laryngol Otol \n86 : 871 -880 , 1972 .5070298 \n6. \nKudoh F , Sasamura Y , Udagawa Y , Iida Y , Sugita Y , Yaku Y \nBilateral Mondini dysplasia associated with recurrent meningitis . Otology Japan \n7 : 207 -212 , 1997 (in Japanese, Abstract in English).\n7. \nMigirov L \nComputed tomographic versus surgical findings in complicated acute otomastoiditis . Ann Otol Rhinol Laryngol \n112 : 675 -677 , 2003 .12940663 \n8. \nBeaumont GD , Sage MR \nEncephalocoele involving the petrous bone . Neuroradiology \n32 : 533 -534 , 1990 .2287391 \n9. \nMotojima T , Fujii K , Ishiwada N , et al \nRecurrent meningitis associated with a petrous apex cephalocele . J Child Neurol \n20 : 168 -170 , 2005 .15794191 \n10. \nMoore KR , Fischbein NJ , Harnsberger HR , et al \nPetrous apex cephaloceles . AJNR Am J Neuroradiol \n22 : 1867 -1871 , 2001 .11733318 \n11. \nJeevan DS , Ormond DR , Kim AH , et al \nCerebrospinal fluid leaks and encephaloceles of temporal bone origin: nuances to diagnosis and management . World Neurosurg \n83 : 560 -566 , 2015 .25514617\n\n",
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{
"abstract": "We report a case of recurrent colon cancer that achieved partial response with chemotherapy of combined 5-fluorouracil (5-FU), irinotecan, Leucovorin(FOLFIRI), and aflibercept. A 65-year-old man was diagnosed with colon cancer with lymph node metastasis. He underwent surgery, but after 1 year, he had a recurrence of peritoneal dissemination, nodal enlargement, and liver metastases. He received chemotherapy(mFOLFOX plus bevacizumab), but suffered progressive disease. Thereafter, FOLFIRI plus aflibercept was administered, and CT revealed a decrease in peritoneal dissemination after 2 cycles of chemotherapy. After 23 cycles, a PET-CT showed no evidence of the disease. We also examined 9 recent cases treated with aflibercept in terms of Grade 3 and 4 adverse effects, leukopenia, neutropenia, thrombocytopenia, hypertension, and sweating. Placentalderived growth factor(PIGF)has been reported to stimulate macrophages and induce production of IL-6, and thus it promotes inflammation and growth of extant cancer. Among the responses to chemotherapy based on the RECIST criteria, a partial response was significantly higher in patients with a low neutrophil-to-lymphocyte ratio(NLR)(p≤0.05)compared to those with high NLR. As regards the relationship between NLR and OS in patients treated with FOLFIRI plus aflibercept, OS was significantly worse in patients with high NLR than those with low NLR(p≤0.05). NLR may be a useful marker in conjunction with aflibercept treatment.",
"affiliations": "Dept. of Gastrointestinal Tract Surgery, Fukushima Medical University.",
"authors": "Gonda|Kenji|K|;Fujita|Shotaro|S|;Shibata|Masahiko|M|;Hatakeyama|Yuichi|Y|;Tachiya|Yosuke|Y|;Rokkaku|Yuichi|Y|;Saze|Zenichiro|Z|;Momma|Tomoyuki|T|;Ohki|Shinji|S|;Saji|Shigehira|S|;Kono|Koji|K|",
"chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D006801:Humans; D008297:Male; D010534:Peritoneal Neoplasms; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012008:Recurrence; D013997:Time Factors",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1539-1542",
"pmc": null,
"pmid": "30382071",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Recurrent Colon Cancer with Peritoneal Dissemination Treated with Aflibercept Showing Partial Response for One Year.",
"title_normalized": "a case of recurrent colon cancer with peritoneal dissemination treated with aflibercept showing partial response for one year"
} | [
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},
{
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{
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{
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{
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{
"reactionmeddrapt": "Hyperhidrosis",
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}
],
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"literaturereference": "GONDA K, FUJITA S, SHIBATA M, HATAKEYAMA Y, TACHIYA Y, ROKKAKU Y, ET AL. A CASE OF RECURRENT COLON CANCER WITH PERITONEAL DISSEMINATION TREATED WITH AFLIBERCEPT SHOWING PARTIAL RESPONSE FOR ONE YEAR. GAN-TO-KAGAKU-RYOHO 2018?45(10):1539-1542.",
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"qualification": "3",
"reportercountry": "JP"
},
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"receiptdate": "20190311",
"receivedate": "20190221",
"receiver": {
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},
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},
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] |
{
"abstract": "BACKGROUND\nVariceal hemorrhage from sinistral portal hypertension has never been reported as a complication of live pancreas donation.\n\n\nMETHODS\nWe present a 68-year-old patient who underwent a simultaneous live-donor laparoscopic segmental pancreatectomy and nephrectomy for the purposes of donating to her daughter. Her postoperative course was significant for an episode of acute pancreatitis with a pseudocyst formation. More than a decade later, she presented with variceal hemorrhage from sinistral portal hypertension, which after a diagnostic work-up, prompted a laparoscopic splenectomy.\n\n\nCONCLUSIONS\nSinistral portal hypertension is a long-term complication of live-donor pancreas donation.",
"affiliations": "Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota. Electronic address: serra061@umn.edu.;St. John's Medical College, Bengaluru, Karnataka, India.;Division of Anatomic Pathology, Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, Minnesota.;Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.",
"authors": "Serrano|O K|OK|;Cunha|R D|RD|;Mettler|T|T|;Sutherland|D E R|DE|;Kandaswamy|R|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2016.09.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "49(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D004932:Esophageal and Gastric Varices; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D006975:Hypertension, Portal; D010179:Pancreas; D016035:Pancreas Transplantation; D010180:Pancreatectomy; D010195:Pancreatitis; D011183:Postoperative Complications; D013156:Splenectomy; D020858:Tissue and Organ Harvesting",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "221-224",
"pmc": null,
"pmid": "28104143",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sinistral Portal Hypertension After Live Segmental Pancreas Donation: A Long-Term Sequelae Presenting With Life-Threatening Upper Gastrointestinal Hemorrhage.",
"title_normalized": "sinistral portal hypertension after live segmental pancreas donation a long term sequelae presenting with life threatening upper gastrointestinal hemorrhage"
} | [
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{
"abstract": "OBJECTIVE\nA case of paralytic ileus in a patient receiving oral diltiazem therapy for atrial fibrillation is reported.\n\n\nCONCLUSIONS\nA 64-year-old man with a history of multiple serious comorbidities, poly-pharmacy, and a recent hospital stay for acute cardiac problems was readmitted to the hospital for gastrointestinal (GI) bleeding. On day 2 of the readmission, he suffered a myocardial infarction complicated by atrial fibrillation with a rapid ventricular response. After initial treatment with oral metoprolol for ventricular rate control was discontinued (due to ineffective rate control and patient complaints of respiratory symptoms), oral diltiazem hydrochloride therapy (30 mg every six hours) was initiated on day 7; the dose was adjusted to a maximum of 120 mg every six hours on day 10. On day 12, the patient complained of nausea, abdominal pain and tenderness, and infrequent bowel movements; imaging studies on day 13 indicated paralytic ileus. Pursuant to a surgical consultation, a nasogastric tube was inserted and nothing was given by mouth except medications. After initial improvement of the GI symptoms, the feeding tube was removed; however, the symptoms worsened over the next two to three days, requiring reinsertion of the tube on day 16. On day 18, after other potential causes of ileus were ruled out, diltiazem therapy was withdrawn. The man experienced rapid symptomatic improvement, with no further GI symptoms, and was discharged four days later.\n\n\nCONCLUSIONS\nA 64-year-old man receiving high-dose diltiazem to treat atrial fibrillation developed paralytic ileus, which quickly resolved after the medication was discontinued.",
"affiliations": "Memphis VA Medical Center, Memphis, TN, USA.",
"authors": "Wright|Sampaguita|S|;Ali|Mahwish|M|;Robinson|Antwon|A|;Ramanathan|Kodangudi|K|;Parker|Robert B|RB|",
"chemical_list": "D002121:Calcium Channel Blockers; D004110:Diltiazem",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp100582",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "68(15)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000284:Administration, Oral; D001281:Atrial Fibrillation; D002121:Calcium Channel Blockers; D004110:Diltiazem; D006801:Humans; D007418:Intestinal Pseudo-Obstruction; D007441:Intubation, Gastrointestinal; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1426-9",
"pmc": null,
"pmid": "21785032",
"pubdate": "2011-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paralytic ileus associated with use of diltiazem.",
"title_normalized": "paralytic ileus associated with use of diltiazem"
} | [
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}
],
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"patientweight": "95",
"reaction": [
{
"reactionmeddrapt": "Melaena",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Upper gastrointestinal haemorrhage",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Epistaxis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Labelled drug-drug interaction medication error",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WRIGHT S, ALI M, ROBINSON A, RAMANATHAN K, PARKER RB. PARALYTIC ILEUS ASSOCIATED WITH USE OF DILTIAZEM. AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY. 2011?68:15:1426-1429",
"literaturereference_normalized": "paralytic ileus associated with use of diltiazem",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200123",
"receivedate": "20200123",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17306333,
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"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"transmissiondate": "20200409"
}
] |
{
"abstract": "Adverse events are anticipated during a clinical development program. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We describe here the process undertaken by Pfizer to investigate a safety signal for pancreatic cancer with tofacitinib. Potential cases of pancreatic cancer across indications from Pfizer's clinical trials and safety databases were identified and underwent in-depth case review and external expert consultation. The magnitude of the signal was quantified. The feasibility of formal signal evaluation via a hypothesis-testing study was explored. As of July 2016, 14 cases of potential pancreatic cancer were identified: eight cases in clinical development trials (psoriasis n = 6; RA n = 1; psoriatic arthritis n = 1), four cases in a postmarketing study in RA patients in Japan, and two spontaneous reports. Incidence rates (95% confidence intervals) per 100 patient-years ranged from 0 (0, 0.02) to 0.14 in RA, 0.05 (0.01, 0.15) to 0.07 (0.02, 0.16) in psoriasis, and 0.25 (0.01, 1.37) in psoriatic arthritis. The majority of patients had established risk factors for pancreatic cancer. The pharmaceutical industry's rapid and transparent response to safety signals is essential for ensuring patient safety and enabling physicians and patients to adequately assess a drug's risk:benefit. Safety signals emerging through pharmacovigilance may be true or false indicators of a causative association with drug exposure. In this example, it was determined that tofacitinib exposure was unlikely to be related to induction and promotion of pancreatic cancer; however, a relationship with pancreatic cancer promotion could not be excluded.",
"affiliations": "Pfizer Inc, New York, NY, USA.;Pfizer Inc, Collegeville, PA, USA.;Pfizer Inc, New York, NY, USA.;Pfizer Inc, Groton, CT, USA.;Pfizer Inc, New York, NY, USA.;Pfizer Inc, New York, NY, USA.",
"authors": "Dasic|Gorana|G|;Jones|Thomas|T|;Frajzyngier|Vera|V|;Rojo|Ricardo|R|;Madsen|Ann|A|;Valdez|Hernan|H|",
"chemical_list": "D000075242:Janus Kinase Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib",
"country": "United States",
"delete": false,
"doi": "10.1002/prp2.371",
"fulltext": "\n==== Front\nPharmacol Res PerspectPharmacol Res Perspect10.1002/(ISSN)2052-1707PRP2Pharmacology Research & Perspectives2052-1707John Wiley and Sons Inc. Hoboken 10.1002/prp2.371PRP2371Original ArticleOriginal ArticlesSafety signal detection and evaluation in clinical development programs: A case study of tofacitinib DASIC et al.Dasic Gorana Gorana.Dasic@pfizer.com \n1\nJones Thomas \n2\nFrajzyngier Vera \n1\nRojo Ricardo \n3\nMadsen Ann \n1\nValdez Hernan \n1\n\n1 \nPfizer Inc\nNew York\nNY\nUSA\n\n2 \nPfizer Inc\nCollegeville\nPA\nUSA\n\n3 \nPfizer Inc\nGroton\nCT\nUSA\n* Correspondence\n\nGorana Dasic, Pfizer Inc, New York, NY, USA.\n\nEmail: Gorana.Dasic@pfizer.com\n15 12 2017 2 2018 6 1 10.1002/prp2.2018.6.issue-1e0037108 9 2017 11 9 2017 © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.This is an open access article under the terms of the 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.Abstract\nAdverse events are anticipated during a clinical development program. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We describe here the process undertaken by Pfizer to investigate a safety signal for pancreatic cancer with tofacitinib. Potential cases of pancreatic cancer across indications from Pfizer's clinical trials and safety databases were identified and underwent in‐depth case review and external expert consultation. The magnitude of the signal was quantified. The feasibility of formal signal evaluation via a hypothesis‐testing study was explored. As of July 2016, 14 cases of potential pancreatic cancer were identified: eight cases in clinical development trials (psoriasis n = 6; RA n = 1; psoriatic arthritis n = 1), four cases in a postmarketing study in RA patients in Japan, and two spontaneous reports. Incidence rates (95% confidence intervals) per 100 patient‐years ranged from 0 (0, 0.02) to 0.14 in RA, 0.05 (0.01, 0.15) to 0.07 (0.02, 0.16) in psoriasis, and 0.25 (0.01, 1.37) in psoriatic arthritis. The majority of patients had established risk factors for pancreatic cancer. The pharmaceutical industry's rapid and transparent response to safety signals is essential for ensuring patient safety and enabling physicians and patients to adequately assess a drug's risk:benefit. Safety signals emerging through pharmacovigilance may be true or false indicators of a causative association with drug exposure. In this example, it was determined that tofacitinib exposure was unlikely to be related to induction and promotion of pancreatic cancer; however, a relationship with pancreatic cancer promotion could not be excluded.\n\nEpidemiologymalignancypharmacovigilancesafetytofacitinibPfizer Inc source-schema-version-number2.0component-idprp2371cover-dateFebruary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:19.02.2018\n\n\nDasic \nG \n, \nJones \nT \n, \nFrajzyngier \nV \n, \nRojo \nR \n, \nMadsen \nA \n, \nValdez \nH \n. Safety signal detection and evaluation in clinical development programs: a case study of tofacitinib . Pharmacol Res Perspect . 2018 ;e00371\nhttps://doi.org/10.1002/prp2.371\n\n\n\n\nFunding information\n\n\nThis work was funded by Pfizer Inc.\n==== Body\nAbbreviations\nASRsage standardized incidence rates\n\nEPAREuropean Public Assessment Report\n\nIRRincidence rate ratio\n\nKPNCKaiser Permanente Northern California\n\nPDACpancreatic ductal adenocarcinoma\n\nSBASummary Basis of Approval\n\nSEERSurveillance, Epidemiology, and End Results database\n\nSIRsstandardized incidence rates\n\nTHINThe Health Improvement Network UK database\n\n1 INTRODUCTION\nAdverse events related and not related to a drug's mechanism of action are anticipated during clinical development programs. An excess of adverse events associated with a product's use compared with the expected rate is referred to as a safety signal.1 Signals can arise at any time during the life‐course of a drug, from the preclinical phase through the postmarketing phase. Signals are generated through the intentional, but hypothesis‐free, comparison of the number of events observed in a population with the number expected. The determination of whether an excess of an adverse event represents a true causal relationship between the drug and the event is a challenge faced by drug developers and clinical researchers, and is particularly difficult with infrequent adverse events.\n\nUpon identifying a safety signal, the signal must be further refined to ascertain whether an association between the event and the drug exists. Specifically, cases must be reviewed for biologic plausibility and potential confounding factors, and the signal must be quantified and contextualized. Finally, causality between product exposure and safety outcomes may be assessed via formal epidemiological hypothesis‐testing studies (signal evaluation).2 Careful and comprehensive signal refinement and evaluation efforts are of paramount importance, and have substantial implications for patient welfare. Here, we describe a case study concerning the drug tofacitinib to illustrate the complexities and challenges of refining and evaluating a signal for an infrequent adverse event.\n\n1.1 Tofacitinib: background to the case study\nTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). A 5 mg twice daily (BID) dose of tofacitinib was first approved for the treatment of RA in the US in November 2012 and is now available in more than 80 countries for the treatment of moderate to severe RA. An 11 mg once daily extended‐release formulation of tofacitinib had first approval in the US in 2016 and now is approved in additional countries at a global level.3 Tofacitinib 5 and 10 mg BID doses are currently in clinical development for other immune‐mediated inflammatory conditions such as psoriatic arthritis and ulcerative colitis. Tofacitinib has also been evaluated for psoriasis, Crohn's disease, ankylosing spondylitis, and as an antirejection agent in renal allograft transplant. The total tofacitinib clinical development program is extensive, having included more than 13 000 patients and provided more than 29 000 patient‐years (PYs) of exposure (up to November 2015; cut‐off date used for the original signal evaluation).4 In addition, postmarketing experience accrued in patients with RA amounted to more than 45 000 PYs of exposure to tofacitinib (to April 2016; cut‐off date used for the original signal evaluation).4 Postmarketing surveillance studies are ongoing in the US and other countries where tofacitinib is approved for the treatment of RA, including a US Consortium of Rheumatology Researchers of North America (CORRONA) registry postapproval safety study (NCT01402661), a postmarketing safety study of tofacitinib vs tumor necrosis factor (TNF) inhibitors in subjects with RA (A3921133; NCT02092467), and a Japanese postmarketing all‐case surveillance study (A3921194; NCT01932372).\n\nPatients with chronic autoimmune and inflammatory diseases are at increased risk of developing certain types of malignancies,5 and immunomodulatory therapies for these conditions have also been associated with a further increased risk.6 Tofacitinib has a novel mechanism of action and, therefore, safety events of special interest that might relate to its effects on the immune system (eg, malignancies and serious infections) have been closely monitored throughout its clinical development.7, 8\n\n\n1.2 Pancreatic cancer\nPancreatic cancer is the 12th most common type of malignancy and the 7th most common cause of cancer‐related deaths worldwide, with incidence varying somewhat by region.9 For instance, the age standardized incidence rates (ASRs; per 100 PYs) for men and women, respectively, are 0.006 and 0.004 in East Asia, 0.009 and 0.005 in Central/Eastern Europe, and 0.009 and 0.006 in North America.9 Risk factors for pancreatic cancer include age, history of chronic pancreatitis, smoking, diabetes mellitus, family history of pancreatic cancer, and metabolic syndrome. Less strongly associated factors include obesity, heavy alcohol intake, non‐O blood group, and Helicobacter pylori infection.10, 11\n\n\nIn this case study, we describe the process undertaken by Pfizer to investigate (ie, identify, refine and evaluate) a signal for pancreatic cancer with tofacitinib therapy, as well as the conclusions and actions from the investigation. By describing this investigation, it is hoped that healthcare professionals can acquire further insight into this aspect of the drug development process and to the importance of timely, complete reports of adverse events.\n\n2 MATERIALS AND METHODS\n2.1 Signal identification\nThe signal for pancreatic cancer with tofacitinib was initially identified in 2014 through routine safety monitoring of the tofacitinib psoriasis clinical development program. After internal review of the cases, the signal was closed because no cases were observed outside of the psoriasis development program, and all patients had one or more risk factors for developing pancreatic cancer. The signal was then reopened in 2015 after an additional case was identified in the tofacitinib psoriasis clinical development program.\n\n2.2 Signal refinement\n2.2.1 Development of case series\nAfter reopening the signal, during the period from October to November 2015, Pfizer's clinical trials and global safety databases were searched across indications using the standard Medical Dictionary for Regulatory Activities (MedDRA) search criteria for malignant tumors to identify reports containing the following MedDRA (Version 18.1) preferred terms (PTs): adenocarcinoma pancreas, ductal adenocarcinoma of the pancreas, acinar cell carcinoma of pancreas, intraductal papillary mucinous carcinoma of pancreas, mucinous cystadenocarcinoma of pancreas, pancreatic carcinoma, pancreatic carcinoma metastatic, pancreatic carcinoma recurrent, pancreatic carcinoma stage 0, pancreatic carcinoma stage I, pancreatic carcinoma stage II, pancreatic carcinoma stage III, pancreatic carcinoma stage IV, pancreatoblastoma, serous cystadenocarcinoma of pancreas, and solid pseudopapillary tumor of the pancreas. By November 17, 2015, these databases comprised >55 000 PYs of tofacitinib exposure for clinical trials, postmarketing studies, and surveillance across all indications. Data collection and analyses for many of these sources were still ongoing at the time of the cut‐off and had not been locked (ie, some values may change for final, locked clinical study databases).\n\nAdverse events reported as potential malignancies in tofacitinib clinical trials are submitted at the time of diagnosis for third party pathologist review and to an external independent Malignancy Adjudication Committee comprised of US board‐certified practicing medical oncologists. These reviewers are independent of the investigative sites and sponsor, and are blinded to sponsor, study, and treatment. Cases identified during the postmarketing period (including the Japanese postmarketing all‐case surveillance study) are not adjudicated.\n\nFor further investigation of the signal, a comprehensive review of cases identified was undertaken (ie, a case series was developed) to also take into consideration the epidemiology and biology of pancreatic cancer, clinical presentation, distribution of cases across indications, and risk factors. In addition, data from the nonclinical development tofacitinib program on the mechanism of action of tofacitinib and findings related to the pancreas were also reviewed. This further investigation included consultation with an independent panel of experts. Five medical oncologists (three with expertise in pancreatic cancer) reviewed detailed case profiles, including results from the malignancy adjudication process, where available. The cases were classified according to whether they were most likely to be pancreatic ductal adenocarcinoma (PDAC), other types of pancreatic cancer, or nonpancreatic cancer, and the potential role of tofacitinib in the etiology, progression, and mechanistic relationship with tofacitinib was assessed.\n\n2.2.2 Signal contextualization\nHaving characterized the case series, their occurrence was quantified and considered in the context of the overall exposed population and other populations, ie, contextualized. Five experts in epidemiology/pharmacoepidemiology reviewed high‐level details of the cases, the estimated incidence rates (IRs)/standardized incidence rates (SIRs), and the epidemiology analysis plan for investigation of the signal.\n\nGiven the differences in patient populations (different indications studied) and methods of ascertainment in clinical trials and postmarketing surveillance, IRs of pancreatic cancer per 100 PYs were calculated by indication. To contextualize observed IRs of pancreatic cancer, a search was conducted for pancreatic cancer rates among psoriasis patients, RA patients, and in the general population from the published literature, publically available FDA Summary Basis of Approval (SBA), and/or European Public Assessment Report (EPAR) documents, as well as data available in the CORRONA registry.\n\nObserved vs expected analyses were conducted, using different data cut points and methods, as available in the course of the signal refinement process. Initial analyses comprised SIRs, comparing the ratio of observed cases in psoriasis patients vs expected cases in four reference populations: the general population in the Japan National Cancer Program (http://www.ncc.go.jp/en/); the US general population in the Surveillance, Epidemiology, and End Results (SEER) database (http://seer.cancer.gov/); moderate to severe patients in the Kaiser Permanente Northern California (KPNC) database; and patients with psoriasis of various levels of severity in The Health Improvement Network (THIN) UK database. All SIRs were adjusted for age and gender, and those using the THIN database as a reference population were also adjusted for smoking and diabetes. These analyses, using data accrued through June 2015, were included in communications to regulatory agencies in December 2015.\n\nAdditional analyses were then conducted using an updated data cut (December 2015) from the tofacitinib clinical development program, and adjusted for additional/refined potential confounding variables in the KPNC (smoking, diabetes, and age as a time‐dependent variable) and THIN populations (age as a time‐dependent variable). In addition to SIRs, incidence rate ratios (IRRs) were calculated via Poisson regression. It was not possible to adjust for other pancreatic cancer risk factors such as chronic pancreatitis, alcohol use, Helicobacter pylori infection, obesity, etc., due to the inability to measure these factors either in the study and/or reference populations.\n\nDefinitions of pancreatic cancer differed across comparator data sources. Pancreatic cancers in the SEER and Japanese registries and the KPNC comparison cohort were defined as any invasive or in situ pathology type within specific sites of the pancreas (ICD‐10 code C25); KPNC cases were adjudicated. Within THIN, the definition included only invasive neoplasms within similar sites, as well as ectopic pancreatic tissue; these cases were not adjudicated.\n\nSIRs were not calculated for the tofacitinib RA program as there were no cases in the Phase 1, 2, or 3 studies, or long‐term extension studies, and the remaining cases occurred in an ongoing trial, a Japanese postmarketing study, and from spontaneous reports where overall demographic data were not available.\n\n2.3 Signal evaluation\nPfizer commissioned a feasibility assessment for the evaluation of the signal in the postmarketing clinical practice setting.\n\n3 RESULTS\n3.1 Signal identification\nThe initial signal identification is described in the methods section.\n\n3.2 Signal refinement\n3.2.1 Case series summary\nAs of July 2016, 14 cases of potential pancreatic cancer had been identified: eight cases in clinical development trials (psoriasis n = 6; RA n = 1; psoriatic arthritis n = 1), four cases in a postmarketing study in RA patients in Japan, and two spontaneous reports (Table 1). Eleven cases (8 from clinical trials and 3 of the cases from the Japanese postmarketing study) underwent review by an independent panel of experts, and all 14 cases underwent internal review (Figure 1). The additional three cases were reported to Pfizer after the independent panel of experts performed their review.\n\nTable 1 Summary of case series\n\nGender/age (years)\tExposure time to clinical presentation (days)\tRelevant risk factors\tTofacitinib dosea\n\t\nPsoriasis program\t\nMale/66g\n\t107\t\nEx‐smoker\n\nDiabetes\n\nHigh BMI\n\nFamily history of malignancy\n\t10 mg BID\t\nMale/68h\n\t136b\n\t\nEx‐smoker\n\nChronic pancreatitis\n\nFamily history of pancreatic cancer and other malignancies\n\t10 mg BID\t\nFemale/52c\n,\nh\n\t339\t\nSmoker\n\nChronic pancreatitis\n\nHigh BMI\n\t10 mg BID\t\nMale/65c\n,\nh\n\t946\t\nEx‐smoker\n\nDiabetes\n\nFamily history of pancreatic cancer\n\t10 mg BID\t\nMale/53c\n,\nh\n\t921\tSmoker\t10 mg BID\t\nMale/54d\n,\nh\n\tUnknown\t\nDiabetes\n\nOverweight\n\t5 mg BID\t\nPsoriatic arthritis\t\nMale/54e\n,\ni\n\t84\t\nSmoker\n\nOverweight\n\t5 mg BID\t\nRheumatoid arthritis\t\nFemale/66j\n\t395\t\nEx‐smoker\n\nOverweight\n\t5 mg BID\t\nFemale/75k\n\t132b\n\tNone reported\t5 mg BID\t\nFemale/73k,l\n\t56b\n\tNone reported\t5 mg BID\t\nFemale/72f\n,\nk,l\n\t5 months\tSmoker\t5 mg BID\t\nFemale/80f\n,\nk\n\t578\tNone reported\t5 mg QD\t\nFemale/85f\n,\nl\n\t~3‐4 monthsb\n\t\nEx‐smoker\n\nObesity\n\t5 mg BID\t\nFemale/78f\n,\nl\n\t~5‐6 monthsb\n\tNone reported\t5 mg BID\t\n\nBID twice daily, BMI body mass index, QD once daily.\n\na Dose at time of event.\n\nb Time to diagnosis; time to clinical presentation unknown.\n\nc Case included as part of sensitivity analyses in the contextualization of events in the psoriasis program.\n\nd Ampulla of Vater carcinoma.\n\ne Case excluded from PDAC classification by expert panel review due to absence of abnormalities on CT scan of pancreas; note that the patient had been exposed to adalimumab in the index study and was exposed to tofacitinib for 84 days prior to diagnosis.\n\nf Case not reviewed by expert panel.\n\ng A3921111, NCT01186744\n\nh A3921061, NCT01163253\n\ni A3921092, NCT01976364\n\nj A3921133, NCT02092467\n\nk A3921194, NCT01932372\n\nl Spontaneously reported postmarketing case.\n\nJohn Wiley & Sons, LtdFigure 1 Disposition of the 14 cases identified for analysis. (A) All cases identified in the clinical trial program. (B) One case identified in the clinical trial program; 4 cases identified in a postmarketing study in Japan and; 2 cases identified in spontaneous postmarketing reports. (C) Cases excluded from PDAC classification by an independent panel of experts following detailed case review. (D) Cases excluded based on input from independent experts. PDAC pancreatic ductal adenocarcinoma, RA rheumatoid arthritis, SIR standardized incidence ratio\n\nThe panel of medical oncologists recommended excluding 2 of the first 10 reported cases from PDAC classification. Specifically, the carcinoma of the ampulla of Vater in a psoriasis patient was excluded on the basis of differences in biology from PDAC.12, 13 The case reported in the psoriatic arthritis program was excluded as PDAC classification by the oncologists due to absence of abnormalities on a computed tomography scan of the pancreas. However, the case in the psoriatic arthritis program was subsequently adjudicated by the Malignancy Adjudication Committee as being pancreatic cancer. This individual was exposed to adalimumab for 1 year in the index study and was also exposed to tofacitinib for 84 days prior to diagnosis. Among the eight cases for which there was agreement among the panel of oncologists that the cancer was consistent with PDAC, one or more established risk factors for pancreatic cancer were identified in 6 of the cases, and the remaining 2 cases were reported in patients aged >70 years.\n\nThe panel also considered the cases in terms of a temporal relationship between tofacitinib and PDAC diagnosis. Research suggests that the span of time from tumorigenesis induction to tumor appearance may be an average of 12 years, with metastasis occurring on average of 5 years later.14 The tofacitinib‐exposure time until clinical presentation (sponsor's assessment of onset of symptoms compatible with pancreatic cancer) was <1 year for 4 out of the 8 cases (range 56‐339 days), and in 1 case, clinical presentation very likely predated treatment with tofacitinib. Among the 3 other cases, the longest tofacitinib‐exposure time until clinical presentation was 946 days. Thus, induction was deemed implausible for all cases.\n\nThe panel then considered the cases with respect to promoting tumor progression. Any potential effect on tumor promotion was thought to be very unlikely for the four cases with clinical presentation beginning <6 months after the start of tofacitinib treatment. Such cases were removed from the sensitivity analyses for the contextualization of events in the psoriasis program as described below. Although thought by the experts to be unlikely, a role in promotion could not be excluded in the remaining four cases (three of which occurred in the psoriasis program) in which tofacitinib‐exposure time until clinical presentation ranged from 339 to 946 days.\n\n3.2.2 Contextualization of the signal\nPatient exposure by indication and the IRs of pancreatic cancer per 100 PYs are shown in Table 2. For comparison, there were no pancreatic cancer cases among malignancies reported in EPARs/SBAs for apremilast 15, 16 and secukinumab,17, 18 and one case of pancreatic cancer was reported in the etanercept EPAR.19 However, patient follow‐up was considerably shorter in those clinical development programs than in the tofacitinib program. In the tofacitinib program, 68% of participants were followed up for >1 year, compared with 35% to 48% with etanercept, secukinumab, and apremilast; furthermore, 45% of tofacitinib patients were followed up for >2 years, compared with 13% and 3% for adalimumab and apremilast, respectively. In a long‐term safety analysis of ustekinumab, in which average patient follow‐up was longer, Papp et al. 20 reported two cases of pancreatic cancer occurring in up to 5 years of follow‐up (8998 PYs), corresponding to an IR of 0.02 per 100 PYs. Rates of pancreatic cancer were also obtained from published 21 and internally commissioned observational studies among psoriasis patients; estimates were consistent with those above (IR 0.015‐0.02 per 100 PYs; Pfizer, data on file). Among RA populations, rates ranged from 0.01 to 0.04 per 100 PYs across US (Pfizer, data on file) and EU 22 disease registries, respectively.\n\nTable 2 Patient exposure and incidence rates by tofacitinib indication (confirmed cases)\n\nTofacitinib indication\tData cut\tEvents (n)\tNo. of patients/PYs of exposure\tIRs per 100 PYs (95% CI)\t\nRA\tPooled data for Phase 1, 2, and 3, and LTE\t0\t6194/19 406\t0 (0‐0.02)\t\nPooled data for Phase 1, 2, and 3, and LTE (Sept 30, 2015)\t1\t7857/21 391\t0.0047 (<0.01‐0.03)\t\nJapan PMS (Nov 05, 2015)\t3\t2823/2200a\n\t0.14a\n\t\nPMS (Nov 05, 2015)\t0\t~34 911 PYs\t—\t\nTotal RA\t4\t>55 000 PYs\t—b\n\t\nPsoriasis\tPooled data for Phase 2 and 3, and LTE (Jun 30, 2015)\t5\t3627/7282\t0.07 (0.02‐0.16)\t\n\tPooled data for Phase 2 and 3, and LTE censoring for 2 cases occurring after <6 months of exposure (Jun 30, 2015)c\n\t3\t2969/5663\t0.05 (0.01‐0.15)\t\nPsoriatic arthritis\tPooled data for Phase 3 and LTE (Nov 02, 2015)\t1d\n\t783/406\t0.25 (0.01‐1.37)\t\nCI, confidence interval; IR, incidence rate; LTE, long‐term extension study; PMS, postmarketing surveillance; PYs, patient‐years; RA, rheumatoid arthritis.\n\na Numbers are estimates based on drug shipping volumes and may not be accurate.\n\nb Total exposure accrued in clinical trials, postmarketing studies, and experience. IR not determined due to heterogeneity of data sources.\n\nc Excluding the first 6 months, based on expert input that cases occurring within 6 or 12 months of exposure should be excluded from IR estimates; the sponsor took a conservative approach and selected 6 months.\n\nd The patient was exposed to adalimumab in the index study and was exposed to tofacitinib for 84 days prior to diagnosis.\n\nJohn Wiley & Sons, LtdStandardized incidence ratios and IRRs were produced for the PDAC cases within the psoriasis program using THIN and KPNC (all psoriasis and moderate to severe psoriasis) comparison cohorts as reference populations using a December 2015 data cut, as shown in Table 3. These analyses adjust for time‐varying age, gender, diabetes, and smoking status. The SIRs based on an earlier data cut (described in Table 2), and which adjusted for more limited covariates and also used Japan and US SEER general population reference populations (not shown), were consistent with results of the updated analyses. Age‐ and gender‐adjusted SIRs based on the 5 cases of pancreatic cancer, regardless of plausibility, reported in the psoriasis program were five to ~ninefold higher than expected. A sensitivity analysis was conducted censoring the exposure within the first 6 months of tofacitinib (including 2 possible pancreatic cancer cases, as their relationship to tofacitinib was considered by independent experts to be implausible). Age‐ and gender‐adjusted SIRs based on these three cases ranged from 3.01 to 5.62. The IRRs were consistent with SIRs, with the exception of analyses conducted within the moderate to severe psoriasis subcohort in KPNC, likely due to few cases and many zero cells in this smaller comparison population.\n\nTable 3 Standardized incidence ratio and incidence rate ratio (95% CI) estimates based on pancreatic cancer cases observed in the tofacitinib psoriasis program compared with reference populations\n\n\tTHIN Psoriasis patientsa\n\tKPNC Moderate to severe psoriasis patientsb\n\tKPNC All psoriasis patientsb\n\t\nSIRs\t\n5 cases\t8.44 (2.74, 19.69)\t9.11 (2.96, 21.26)\t4.92 (1.60, 11.47)\t\n3 casesc\n\t5.18 (1.07, 15.15)\t5.62 (1.16, 16.43)\t3.01 (0.62, 8.80)\t\nIRRsd\n\t\n5 cases\t8.53 (2.63, 21.47)\t5.96 (1.32, 24.80)\t4.91 (1.45, 13.03)\t\n3 casesc\n\t5.21 (1.03, 16.30)\t3.82 (0.56, 19.51)\t2.97 (0.56, 9.80)\t\nCI, confidence interval; IRR, incidence rate ratio; KPNC, Kaiser Permanente Northern California database; SIR, standardized incidence ratio; THIN the Health Improvement Network UK database.\n\na Age‐, time‐, gender‐, smoking‐, and diabetes‐adjusted.\n\nb Age‐ gender‐, smoking‐, and diabetes‐adjusted.\n\nc 6‐month exposure censored. As a sensitivity analysis, SIRs were calculated for only three patients in the psoriasis program based on the feedback from the expert consultants that pancreatic cancer in patients with <6 months of exposure is highly unlikely to be related to tofacitinib. As the reference group is defined based on disease status, as opposed to the start of a particular exposure, and therefore there is no equivalent time frame to remove, the exposure time in the reference groups remained the same.\n\nd Takes into account variability of external comparator population.\n\nJohn Wiley & Sons, Ltd3.2.3 Interpretation of results\nThe overall conclusion of the independent medical oncologists’ and epidemiologists’ review of the data was that, despite the elevated SIR within the psoriasis development program, they considered it unlikely that tofacitinib had a role in the etiology of pancreatic cancer based on the evidence associating both pancreatic cancer with immunosuppression and small molecule drugs as promoters of tumor growth/progression, and also the known latency of PDAC in relation to tofacitinib‐exposure times. Given the above, the majority of experts deemed the signal most likely due to chance or selection bias.\n\n3.3 Signal evaluation\nGiven that tofacitinib is currently approved for RA, and the majority of its use is in the US, the study population required to evaluate the signal in the postmarketing clinical practice setting would comprise RA patients in the US. There were an estimated 18 000 current users of tofacitinib in the US (as of September, 2015). To rule out a relative risk of 3 with 80% power for a one‐sided test at alpha of 0.05, 21 000 PYs of tofacitinib exposure would be required, achievable with 5250 tofacitinib users, followed up for an average of 4 years, and four times the number of PYs in the comparator population. For such a study to be feasible, several large automated data resources with linkage to the US national death index (eg, Truven, Optum, etc.) would need to be combined. It was deemed that a study designed to rule out a relative risk in the order of 2 would not be feasible with observational data available in the US in the next few years, given estimates of tofacitinib use and the required follow‐up time (54 000 PYs).\n\n4 DISCUSSION\nAs part of the ongoing clinical development of tofacitinib, we identified a signal of pancreatic cancer. The initial preponderance of cases was limited to the psoriasis trial population compared with other indications; however, it should be noted that this finding had no bearing on the decision to discontinue the clinical development program in patients with psoriasis. Among the four cases identified among RA patients, three cases were reported in the Japanese RA postmarketing surveillance study. It is important to recognize that the latter observations are also spontaneous reports from the tofacitinib arm of an observational study.\n\nThe body of evidence presented can also be considered using the Bradford Hill framework of causality, which consists of criteria for strength, consistency, specificity, temporality, dose‐response, plausibility, coherence, experimental evidence, and analogy.23 The only causal consideration within the Bradford Hill framework that was clearly met was ‘strength of association’, demonstrated in elevated incidence rates and SIRs/IRRs. The lack of a signal in other indications in the tofacitinib clinical program (ie, lack of ‘consistency’) mitigates the strength of association and makes it less likely that the signal is a true positive. Further, in terms of temporality, pancreatic cancer has a long latency period (21 years on average from the initiating event to patient death),24 rendering induction of pancreatic cancer by tofacitinib implausible, though a role in cancer promotion cannot be excluded.\n\nReview of the 8 confirmed cases revealed established risk factors for pancreatic cancer for the majority of the patients, and for all of the cases from the psoriasis program. Risk factors for pancreatic cancer, such as smoking and diabetes, were prevalent among patients in the psoriasis clinical development program as expected for this patient population.25 Nonetheless, the observed number of cases was higher than expected even after adjustment for these risk factors. While this imbalance might be accounted for by additional unidentified risk factors, extraordinary conditions would need to be met for this to be the case. For instance, chronic pancreatitis is the strongest risk factor for pancreatic cancer.11 In order for chronic pancreatitis to explain the magnitude of effect detected, the tofacitinib trial population would need to have a 100‐fold greater risk of chronic pancreatitis than the reference population and the relative risk between chronic pancreatitis and pancreatic cancer would need to be in the order of 42, lending credibility to chance or selection bias as alternative explanations.\n\nWith regard to selection bias, analogies may be drawn with illnesses such as pancreatitis and recent‐onset diabetes, which have been noted to occur in the year or two prior to pancreatic cancer diagnosis.26 A Swedish study 27 found a particularly high incidence of pancreatic cancer in the year following an index hospitalization for psoriasis, suggesting that a psoriatic flare may also be a marker of undiagnosed pancreatic cancer. Thus, selection bias could occur if patients enrolling in tofacitinib clinical trials were more likely to be those recently experiencing health problems, such as pancreatitis and diabetes, or were experiencing psoriatic flare, due to extant pancreatic neoplasms.\n\nIn summary, based on the lack of a signal in RA and other indications, the latency of pancreatic cancer, and lack of a plausible biologic mechanism, an independent external panel of experts deemed it unlikely that there is a causal association between tofacitinib use and pancreatic cancer. Pfizer agreed with this conclusion. However, in December 2015, Pfizer reported the signal to several regulatory agencies, including the FDA, PMDA, and EMA, as well as to country ethics committees and investigators, if required by regulatory agencies. There had been no accumulation of evidence since this regulatory communication, which if observed, would indicate a causal association between tofacitinib and pancreatic cancer, and the company determined the signal investigation closed. Nonetheless, Pfizer took the decision to include reference to pancreatic cancer in the tofacitinib product label and will continue pharmacovigilance through systematic monitoring of the clinical database and postmarketing surveillance via routine adverse event reporting systems and prospective studies in disease registries. Indeed, it is possible that the publication of this article may lead to an increase in spontaneously reported events, resulting from reporting/notoriety bias, thereby complicating continuous signal evaluation efforts. Clinicians must remain vigilant regarding this potential drug–event association, while taking care in their reports to provide as much contextual information as possible to facilitate signal investigation. If the pancreatic cancer signal investigation is reopened, Pfizer will reconsider evaluating the signal via a formal hypothesis‐testing study, provided that there is sufficient tofacitinib exposure, or a determination that the study that can rule out a relative risk of 3 with 80% power meets signal evaluation needs.\n\nIn conclusion, the pharmaceutical industry's commitment to rapid and open response to safety signals is essential for ensuring patient safety and enabling physicians and patients to consider the risk:benefit of a drug for their individual circumstances. Safety signals emerging through pharmacovigilance may be true or false indicators of a causative association with drug exposure. The tofacitinib example reported here illustrates the challenges of evaluating malignancy signals and emphasizes the need for comprehensive and complete case reporting by physicians. Based on currently available evidence, we believe that tofacitinib exposure is unlikely to be related to the induction or promotion of pancreatic cancer; however, a relationship to promotion cannot be excluded. Pfizer will continue to monitor pancreatic cancer incidence both via routine pharmacovigilance as well as long‐term prospective active surveillance efforts.\n\nAUTHOR CONTRIBUTIONS\nAll authors provided substantial contribution to the collection, evaluation, and interpretation of data described in this article. All authors provided intellectual input into every stage of the manuscript's development and approved the final manuscript.\n\nDISCLOSURE\nAll authors are employees and shareholders of Pfizer Inc. Pfizer Inc was responsible for all aspects of the data collection, analysis, and interpretation and the reporting of safety findings and recommendations to regulatory authorities. The opinions expressed in this article reflect those of the authors, not necessarily Pfizer Inc.\n\nACKNOWLEDGEMENTS\nThe authors wish to thank Mary Boy of Pfizer Inc, for critical evaluation of this manuscript. Medical writing support was provided, under the guidance for the authors, by Kirsteen Munn, Karleen Nicholson, and Jason Gardner for Complete Medical Communications, Macclesfield, UK, and was funded by Pfizer Inc, New York, NY, USA, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).\n==== Refs\nREFERENCES\n1 \nUS Food and Drug Administration \n. Guidance for Industry. Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessments . 2005 \nhttp://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf. Accessed March 6, 2017\n2 \n\nRobb \nMA \n, \nRacoosin \nJA \n, \nSherman \nRE \n, et al. The US Food and Drug Administration's Sentinel Initiative: expanding the horizons of medical product safety . 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-1707",
"issue": "6(1)",
"journal": "Pharmacology research & perspectives",
"keywords": "Epidemiology; malignancy; pharmacovigilance; safety; tofacitinib",
"medline_ta": "Pharmacol Res Perspect",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid; D002986:Clinical Trials as Topic; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D015994:Incidence; D000075242:Janus Kinase Inhibitors; D007564:Japan; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D060735:Pharmacovigilance; D010880:Piperidines; D011358:Product Surveillance, Postmarketing; D011743:Pyrimidines; D011758:Pyrroles",
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"pmid": "29417755",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25207767;24857067;14283879;24684204;19352386;16705109;22262587;22493341;25503345;20981102;25502106;25220842;23301632;29417755;24692527;20861148;19440219;26049860;23416985",
"title": "Safety signal detection and evaluation in clinical development programs: A case study of tofacitinib.",
"title_normalized": "safety signal detection and evaluation in clinical development programs a case study of tofacitinib"
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],
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{
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}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20140725"
}
},
"primarysource": {
"literaturereference": "DASIC, G.. SAFETY SIGNAL DETECTION AND EVALUATION IN CLINICAL DEVELOPMENT PROGRAMS: A CASE STUDY OF TOFACITINIB. PHARMACOLOGY RESEARCH AND PERSPECTIVES. 2018?6 (1):10.1002/PRP2.371",
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},
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},
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},
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"seriousnessdeath": 1,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180508"
},
{
"companynumb": "CO-PFIZER INC-2016125405",
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"occurcountry": "CO",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
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"drugdosagetext": "15 MG, WEEKLY",
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"medicinalproduct": "METHOTREXATE."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TOFACITINIB CITRATE"
},
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"drugindication": "RHEUMATOID ARTHRITIS",
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"medicinalproduct": "XELJANZ"
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"medicinalproduct": "LOSARTAN."
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{
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"activesubstancename": "FOLIC ACID"
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"medicinalproduct": "FOLIC ACID."
}
],
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"reactionoutcome": "6"
}
],
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},
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"literaturereference": "DASIC, G.. SAFETY SIGNAL DETECTION AND EVALUATION IN CLINICAL DEVELOPMENT PROGRAMS: A CASE STUDY OF TOFACITINIB. PHARMACOLOGY RESEARCH AND PERSPECTIVES. 2018?6(1):10.1002/PRP2.371",
"literaturereference_normalized": "safety signal detection and evaluation in clinical development programs a case study of tofacitinib",
"qualification": "1",
"reportercountry": "US"
},
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"receiptdate": "20180226",
"receivedate": "20160229",
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},
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"safetyreportid": 12126593,
"safetyreportversion": 5,
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},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180508"
}
] |
{
"abstract": "A 41-year-old woman had undergone a left mastectomy breast cancer three years prior to presentation. No for at six months she had recurrence, this time in the right breast and skin. Despite first-and second-line chemotherapy, the mass showed progression of the disease. Thereafter, a weekly treatment of vinorelbine and trastuzumab was started, but one month later, she developed a slight fever and dry cough. A chest CT scan revealed an infiltration shadow showing non-specific interstitial pattern in the right lung. A bronchoscopic examination showed lymphocyte dominance in bronchial lavage fluid, and lymphocyte infiltration into the interstium with fibrosis in the tissue specimens was found by transbronchial lung biopsy. After discontinuing the above vinorelbine therapy, the patient's condition improved. We therefore diagnosed this as a case of vinorelbine-and trastuzumab-induced interstitial pneumonia.",
"affiliations": "Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.",
"authors": "Yanagitani|Noriko|N|;Shimizu|Yasuo|Y|;Kaira|Kyoichi|K|;Tatsuno|Sayaka|S|;Sunaga|Noriaki|N|;Ishizuka|Tamotsu|T|;Mori|Masatomo|M|",
"chemical_list": "D000970:Antineoplastic Agents; D014747:Vinblastine; D000077235:Vinorelbine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "35(9)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001706:Biopsy; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D011014:Pneumonia; D014057:Tomography, X-Ray Computed; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1619-21",
"pmc": null,
"pmid": "18799925",
"pubdate": "2008-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary toxicity associated with vinorelbine-based chemotherapy in breast cancer.",
"title_normalized": "pulmonary toxicity associated with vinorelbine based chemotherapy in breast cancer"
} | [
{
"companynumb": "JP-PFIZER INC-2019266355",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugdosagetext": "UNK, CYCLIC",
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"drugindication": "BREAST CANCER",
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"medicinalproduct": "TRASTUZUMAB."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINORELBINE TARTRATE"
},
"drugadditional": "1",
"drugadministrationroute": null,
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"drugdosagetext": "UNK, WEEKLY (INFUSION)",
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"drugindication": "BREAST CANCER",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
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"drugstartdateformat": "102",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "VINORELBINE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
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"drugindication": "BREAST CANCER",
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"medicinalproduct": "DOCETAXEL."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
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"drugcharacterization": "2",
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"drugindication": "BREAST CANCER",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CAPECITABINE."
}
],
"patientagegroup": null,
"patientonsetage": "41",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Interstitial lung disease",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pulmonary toxicity",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2005"
}
},
"primarysource": {
"literaturereference": "YANAGITANI, N.. PULMONARY TOXICITY ASSOCIATED WITH VINORELBINE-BASED CHEMOTHERAPY IN BREAST CANCER. JPN J CANCER CHEMOTHER. 2008?35(9):1619-1621",
"literaturereference_normalized": "pulmonary toxicity associated with vinorelbine based chemotherapy in breast cancer",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190904",
"receivedate": "20190626",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16478953,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
}
] |
{
"abstract": "Combined MEK-BRAF inhibition is a well-established treatment strategy in BRAF-mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF-MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high-risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. KEY POINTS: BRAF mutations constitute an attractive druggable target in multiple myeloma. This is the first genomic dissection of the central nervous system involvement in a multiple myeloma patient harboring a druggable BRAFV600E mutation. Deep genomic characterization of the extramedullary lesion prompted a personalized therapeutic approach. Acquisition of CIC mutation confers a mechanism of BRAF-MEK inhibitor drug resistance in multiple myeloma. The in silico interrogation of the CoMMpass clinical study revealed 10 patients with somatic mutations of CIC and its downregulation at gene expression level in multiple myeloma. CIC gene silencing decreases the sensitivity of multiple myeloma cells to BRAF-MEK inhibition in vitro. The correlation between CIC downregulation and ETV4/5 nuclear factor expression in multiple myeloma BRAF-mutant cells is shown for the first time. CIC mutation, its downregulation, and the related downstream effect on MMP24 support disseminative potential providing new clues in the extramedullary biology definition.",
"affiliations": "Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.;Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.",
"authors": "Da Vià|Matteo Claudio|MC|0000-0002-5396-6584;Solimando|Antonio Giovanni|AG|0000-0002-2293-9698;Garitano-Trojaola|Andoni|A|0000-0003-4710-6753;Barrio|Santiago|S|;Munawar|Umair|U|;Strifler|Susanne|S|;Haertle|Larissa|L|;Rhodes|Nadine|N|;Teufel|Eva|E|;Vogt|Cornelia|C|;Lapa|Constantin|C|0000-0001-7536-2207;Beilhack|Andreas|A|0000-0002-3165-2648;Rasche|Leo|L|0000-0002-9536-9649;Einsele|Hermann|H|0000-0002-7680-0819;Kortüm|K Martin|KM|0000-0002-7011-0286",
"chemical_list": "D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2019-0356",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "25(2)",
"journal": "The oncologist",
"keywords": "BRAF mutation; Capicua transcriptional repressor; Drug resistance; Extramedullary disease; Multiple myeloma",
"medline_ta": "Oncologist",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002490:Central Nervous System; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases; D009101:Multiple Myeloma; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "112-118",
"pmc": null,
"pmid": "32043788",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "29064484;21900099;28592387;29954938;26282654;22798288;24670642;26228812;25774333;22663011;26918361;27074969;27458004;25743686;29797255;28295365;22535658;26884375;23696246;23248257;20962272;27979926;23480694;27869830;21087211;30094711;26955792;25975811;29568363;28288114;27775549;28504689;19633044;28178529;25473003;24265153;28824728;20179705;24434212;28814763;24429703;22286070;23612012;30026573",
"title": "CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF-MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement.",
"title_normalized": "cic mutation as a molecular mechanism of acquired resistance to combined braf mek inhibition in extramedullary multiple myeloma with central nervous system involvement"
} | [
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"medicinalproduct": "THIOTEPA."
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{
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"activesubstancename": "BORTEZOMIB"
},
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"medicinalproduct": "VELCADE"
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{
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},
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"medicinalproduct": "PREDNISONE."
}
],
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"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Bacterial sepsis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "STRIFLER S, SOLIMANDO A, GARITANO?TROJAOLA A, BARRIO S, MUNAWAR U, ET AL.. CIC MUTATION AS A MOLECULAR MECHANISM OF ACQUIRED RESISTANCE TO COMBINED BRAF?MEK INHIBITION IN EXTRAMEDULLARY MULTIPLE MYELOMA WITH CENTRAL NERVOUS SYSTEM INVOLVEMENT. ONCOLOGIST. 2020?25(2):112?8",
"literaturereference_normalized": "cic mutation as a molecular mechanism of acquired resistance to combined braf mek inhibition in extramedullary multiple myeloma with central nervous system involvement",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20210617",
"receivedate": "20200810",
"receiver": {
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},
"reporttype": "1",
"safetyreportid": 18130956,
"safetyreportversion": 3,
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"sendertype": "2"
},
"serious": 1,
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"transmissiondate": "20210717"
}
] |
{
"abstract": "A 73-year-old man with chronic obstructive pulmonary disease presented to the emergency department with a two-day history of coffee ground emesis and melena. The patient had been treated with the PD-1 inhibitor nivolumab because of a lung adenocarcinoma stage IV. On examination, he was tachycardic (130 beats per minute) and hypotensive (95/55 mm Hg). Laboratory studies revealed anemia (6.9 g/dL), leukocytosis, and hyper-lactatemia (lactate 6.3 mmol/l). Upper gastrointestinal endoscopy showed diffuse circumferential blackish, necrotic-appearing mucosa of the first third of the esophagus. These findings were consistent with the diagnosis of acute esophageal necrosis (AEN). Biopsy of the esophageal mucosa showed fragments of necrotic tissue with predominant lymphocyte infiltration. The patient was treated with a nothing per mouth diet, total parenteral nutrition, double-dose proton pump inhibitors and broad-spectrum antibiotics (piperacillin/tazobactam). Despite these measures, the patient underwent a progressive clinical deterioration and he died of multiple organ failure 12 days after admission.",
"affiliations": "Medical Oncology, Hospital Universitario de Salamanca, España.;Medical Oncology, Hospital Universitario de Salamanca.;Medical Oncology, Hospital Universitario de Salamanca.;Medical Oncology, Hospital Universitario de Salamanca.;Medical Oncology, Hospital Universitario de Salamanca.",
"authors": "Figuero Pérez|Luis|L|0000-0002-0906-5076;Olivares-Hernández|Alejandro|A|;Amores-Martín|Arantzazu|A|;Cruz-Hernández|Juan Jesús|JJ|;Fonseca-Sánchez|Emilio|E|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.17235/reed.2021.8418/2021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-0108",
"issue": null,
"journal": "Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva",
"keywords": null,
"medline_ta": "Rev Esp Enferm Dig",
"mesh_terms": null,
"nlm_unique_id": "9007566",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34781684",
"pubdate": "2021-11-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute esophageal necrosis induced by immune checkpoint inhibitors.",
"title_normalized": "acute esophageal necrosis induced by immune checkpoint inhibitors"
} | [
{
"companynumb": "ES-BRISTOL-MYERS SQUIBB COMPANY-BMS-2022-005120",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
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},
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"drugindication": "Lung adenocarcinoma stage IV",
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"medicinalproduct": "NIVOLUMAB"
}
],
"patientagegroup": null,
"patientonsetage": "73",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Necrotising oesophagitis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Figuero Perez L, Olivares-Hernandez A, Amores-Martin A, Cruz-Hernandez JJ, Fonseca-Sanchez E. Acute esophageal necrosis induced by immune checkpoint inhibitors. The Spanish Journal of Gastroenterology. 2021",
"literaturereference_normalized": "acute esophageal necrosis induced by immune checkpoint inhibitors",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20220117",
"receivedate": "20220117",
"receiver": {
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},
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"sender": {
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},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220424"
}
] |
{
"abstract": "We describe two hemodialysis patients with high-risk myelodysplastic syndrome (MDS) treated with azacitidine. A 65-year-old woman (case 1) received azacitidine at 75 mg/m(2) for 7 days, and a 52-year-old man (case 2) with liver cirrhosis received a 70% dose of azacitidine. Both cases developed grade 4 cytopenia, but they achieved transfusion independence after 3 and 2 courses, and the durations of remission were 10 and 11 months, respectively. Case 1 had the complication of febrile neutropenia (FN) twice during the 1(st) and 2(nd) courses, but continued to receive azacitidine treatment thereafter. Case 2 developed infectious peritonitis during the sixth course, and azacitidine treatment was thus discontinued. After a 4-month treatment interruption, he became transfusion-dependent, and re-induction of azacitidine was successful. Of note, the course of case 1 was complicated by erythema nodosum on admission, which then disappeared after one course of azacitidine treatment. The mean durations of hospitalization were 17.5 and 23 days per course of azacitidine treatment, respectively. Though there are few reports of azacitidine treatment for hemodialysis patients with high-risk MDS, we advocate administering azacitidine to such patients, while paying close attention to the dose intensity of azacitidine and taking prompt action to manage infectious complications.",
"affiliations": "Department of General Medicine, Japan Community Health Care Organization (JCHO) Kyushu Hospital.",
"authors": "Yoshihiro|Tomoyasu|T|;Muta|Tsuyoshi|T|;Aoki|Kenichi|K|;Shimamoto|Syo|S|;Tamura|Yasuhisa|Y|;Ogawa|Ryosuke|R|",
"chemical_list": "D001374:Azacitidine",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.57.1004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "57(8)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": null,
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D001374:Azacitidine; D001803:Blood Transfusion; D064147:Febrile Neutropenia; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D006435:Renal Dialysis; D012307:Risk Factors",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "1004-10",
"pmc": null,
"pmid": "27599416",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Efficacy and adverse events of azacitidine in the treatment of hemodialysis patients with high-risk myelodysplastic syndrome.",
"title_normalized": "efficacy and adverse events of azacitidine in the treatment of hemodialysis patients with high risk myelodysplastic syndrome"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-2016093440",
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"occurcountry": "JP",
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},
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"drugdosageform": "UNKNOWN",
"drugdosagetext": "60 MILLIGRAM",
"drugenddate": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "LACTULOSE."
},
{
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"activesubstance": {
"activesubstancename": "ISOLEUCINE\\LEUCINE\\VALINE"
},
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},
{
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},
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},
{
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},
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},
{
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},
{
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},
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "10 MILLIGRAM",
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"medicinalproduct": "SODIUM RABEPRAZOLE"
}
],
"patientagegroup": null,
"patientonsetage": "52",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Asterixis",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cytopenia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Peritonitis",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20150721"
}
},
"primarysource": {
"literaturereference": "YOSHIHIRO T. EFFICACY AND ADVERSE EVENTS OF AZACITIDINE IN THE TREATMENT OF HEMODIALYSIS PATIENTS WITH HIGH-RISK MYELODYSPLASTIC SYNDROME.. RINSHO KETSUEKI - JAPANESE JOURNAL OF CLINICAL HEMATOLOGY. 2016 AUG;57(8):1004-1010.",
"literaturereference_normalized": "efficacy and adverse events of azacitidine in the treatment of hemodialysis patients with high risk myelodysplastic syndrome",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20170501",
"receivedate": "20160921",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12768714,
"safetyreportversion": 3,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
},
{
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"patient": {
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{
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"activesubstance": {
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},
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"drugauthorizationnumb": "050794",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "INJECTION",
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "MYELODYSPLASTIC SYNDROME",
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"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "VIDAZA"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "050794",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": null,
"drugenddate": null,
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"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugstartdateformat": null,
"drugstructuredosagenumb": "75",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VIDAZA"
}
],
"patientagegroup": null,
"patientonsetage": "65",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cytopenia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Erythema nodosum",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YOSHIHIRO T, AOKI K, SHIMAMOTO S, TAMURA Y, OGAWA R, MUTA T. EFFICACY AND ADVERSE EVENTS OF AZACITIDINE IN THE TREATMENT OF HEMODIALYSIS PATIENTS WITH HIGH-RISK MYELODYSPLASTIC SYNDROME.. RINSHO KETSUEKI - JAPANESE JOURNAL OF CLINICAL HEMATOLOGY. 2016 AUG;57(8):1004-10.",
"literaturereference_normalized": "efficacy and adverse events of azacitidine in the treatment of hemodialysis patients with high risk myelodysplastic syndrome",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20161104",
"receivedate": "20160921",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12769397,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170207"
}
] |
{
"abstract": "In the last ten years, the prescriptions of the gabapentinoids gabapentin and pregabalin increased largely also in Germany. Since several national and international pharmacovigilance-databases have warned for abuse liabilities and overdose fatalities in association with both gabapentinoids, which moreover, became to be sold on internet and black-markets, their addictive power has been subject to an ongoing clinical debate. As pre- and post-approval clinical trials did not reveal significant signs of dependence on gabapentin or pregabalin, we systematically searched in PubMed and Scopus for clinical studies and case reports being associated with abuse of and dependence on these drugs. We found 14 clinical-epidemiologic studies and 38 case reports/series. These were evaluated for i) fulfilled dependence criteria according to ICD-10, ii) non-medical self-administration and their duration, iii) relapses, iv) social sequels, and v) cases seeking treatment for misusing gabapentin or pregabalin. Mostly, the cases of abuse of and dependence on gabapentinoids appeared to be associated with other substance dependencies, primarily opiate dependence and polyvalent drug use. Drug users preferred pregabalin citing a faster and stronger euphoria (\"liking\") than achievable with oral gabapentin. Both gabapentinoids were anxiolytic in therapeutic doses, stimulating in lower and sedating along with increasing doses. Fatalities have been described mainly in the population of opiate dependents and polyvalent drug users, predominantly together with excessive pregabalin overdosing. It is debated whether the gabapentinoids were indeed the main cause of death in these cases or whether gabapentin and pregabalin had been only bystanders. Tolerance and withdrawal symptoms (physical dependence) of gabapentinoids appeared to be common in medical and non-medical use of gabapentinoids. There were only 4 persons who had fulfilled behavioral dependence criteria of gabapentinoids (all had used pregabalin) and had no association with other substance use disorders (apart from nicotine). Regarding the transitions from prescription to non-medical self-administration, the frequency and duration of self-administrations as well as the number of reported relapses, pregabalin appeared also to be more addictive than gabapentin. However, all these events were reported rather infrequently compared with traditional substances of abuse. We did not find a case with social sequalea due to the use of gabapentinoids or a person who sought treatment for his gabapentin or pregabalin use. Therefore, the gabapentinoids were assumed to possess a lower \"wanting\" in consideration of Berridge's and Robinsons's incentive-sensitization theory of addiction. Also, anti-adverse selection of gabapentinoids is discussed to be present in the population of opioid and multi-drug users. Based upon all these results and assumptions, we have estimated the relative risk of dependence on gabapentinoids by using an algorithm which was previously developed by Griffith and Johnson for evaluation of the abuse liabilities of sedatives. Overall, the risk of harm and dependence on gabapentinoids appeared to be lower than that of other sedatives (and stimulants). In addition, pregabalin appeared to be somewhat riskier than gabapentin. We think that in patients with current or past substance use disorders, the treatment with gabapentinoids should be avoided or if indispensable, these drugs should be administered exclusively over a limited time span with caution by using a therapeutic and prescription monitoring.",
"affiliations": "Klinik für Psychiatrie, Psychotherapie und Psychosomatik im Evangelischen Krankenhaus Castrop-Rauxel, Castrop-Rauxel, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen, Deutschland.;LVR-Klinikum Essen, Klinik für Psychiatrie und Psychotherapie, Medizinische Fakultät der Universität Duisburg-Essen, Essen, Deutschland.",
"authors": "Bonnet|Udo|U|;Scherbaum|Norbert|N|",
"chemical_list": "D000700:Analgesics; D000069583:Pregabalin; D000077206:Gabapentin",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0043-122392",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0720-4299",
"issue": "86(2)",
"journal": "Fortschritte der Neurologie-Psychiatrie",
"keywords": null,
"medline_ta": "Fortschr Neurol Psychiatr",
"mesh_terms": "D000700:Analgesics; D016739:Behavior, Addictive; D000077206:Gabapentin; D005858:Germany; D006801:Humans; D000069583:Pregabalin; D012306:Risk; D019966:Substance-Related Disorders",
"nlm_unique_id": "8103137",
"other_id": null,
"pages": "82-105",
"pmc": null,
"pmid": "29179227",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review",
"references": null,
"title": "On the risk of dependence on gabapentinoids.",
"title_normalized": "on the risk of dependence on gabapentinoids"
} | [
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{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anxiety",
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},
{
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},
{
"reactionmeddrapt": "Product use in unapproved indication",
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},
{
"reactionmeddrapt": "Palpitations",
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{
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},
{
"reactionmeddrapt": "Feelings of worthlessness",
"reactionmeddraversionpt": "21.1",
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},
{
"reactionmeddrapt": "Restlessness",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Energy increased",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Suicide attempt",
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},
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"reactionmeddrapt": "Suicidal ideation",
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},
{
"reactionmeddrapt": "Dysphoria",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
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"summary": null
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"literaturereference": "BONNET, U.. ON THE RISK OF DEPENDENCE ON GABAPENTINOIDS. FORTSCHRITTE DER NEUROLOGIE-PSYCHIATRIE. 2018?86(2):82-105",
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{
"abstract": "Myroides spp. are common environmental organisms and they can be isolated predominantly in water, soil, food and in sewage treatment plants. In the last two decades, an increasing number of infections such as urinary tract infections and skin and soft tissue infections, caused by these microorganisms has been reported. Selection of appropriate antibiotic therapy to treat the infections caused by Myroides spp. is difficult due to the production of a biofilm and the organism's intrinsic resistance to many antibiotic classes.\n\n\n\nWe report the case of a 69-year-old immunocompromised patient who presented with repeated episodes of macroscopic haematuria, from Northern Italy.A midstream urine sample cultured a Gram negative rod in significant amounts (> 105 colony-forming units (cfu)/mL), which was identified as Myroides odoratimimus. The patient was successfully treated with trimethoprim/sulfamethoxazole after antibiotic susceptibility testing confirmed its activity.\n\n\n\nThis case underlines the emergence of multidrug resistant Myroides spp. which are ubiquitous in the environment and it demands that clinicians should be more mindful about the role played by atypical pathogens, which may harbour or express multidrug resistant characteristics, in immunocompromised patients or where there is a failure of empiric antimicrobial therapy.",
"affiliations": "1Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili, P. le Spedali Civili 1, 25123 Brescia, Italy.;1Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili, P. le Spedali Civili 1, 25123 Brescia, Italy.;2Department of Nephrology, University of Brescia, Hospital of Montichiari, Brescia, Italy.;2Department of Nephrology, University of Brescia, Hospital of Montichiari, Brescia, Italy.;1Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili, P. le Spedali Civili 1, 25123 Brescia, Italy.;1Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili, P. le Spedali Civili 1, 25123 Brescia, Italy.;1Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili, P. le Spedali Civili 1, 25123 Brescia, Italy.",
"authors": "Lorenzin|Giovanni|G|;Piccinelli|Giorgio|G|;Carlassara|Lucrezia|L|;Scolari|Francesco|F|;Caccuri|Francesca|F|;Caruso|Arnaldo|A|;De Francesco|Maria Antonia|MA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014295:Trimethoprim; D013420:Sulfamethoxazole",
"country": "England",
"delete": false,
"doi": "10.1186/s13756-018-0391-4",
"fulltext": "\n==== Front\nAntimicrob Resist Infect ControlAntimicrob Resist Infect ControlAntimicrobial Resistance and Infection Control2047-2994BioMed Central London 39110.1186/s13756-018-0391-4Case ReportMyroides odoratimimus urinary tract infection in an immunocompromised patient: an emerging multidrug-resistant micro-organism Lorenzin Giovanni giovanni.lorenzin@hotmail.it 13Piccinelli Giorgio giorgio.piccinelli@gmail.com 1Carlassara Lucrezia lucrezia.carlassara@gmail.com 2Scolari Francesco francesco.scolari@unibs.it 2Caccuri Francesca francesca.caccuri@unibs.it 1Caruso Arnaldo arnaldo.caruso@unibs.it 1De Francesco Maria Antonia (+39) 030 3995860maria.defrancesco@unibs.it 11 0000000417571846grid.7637.5Institute of Microbiology, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili, P. le Spedali Civili 1, 25123 Brescia, Italy 2 0000000417571846grid.7637.5Department of Nephrology, University of Brescia, Hospital of Montichiari, Brescia, Italy 3 0000 0004 1757 2822grid.4708.bInstitute of Microbiology and Virology, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy 6 8 2018 6 8 2018 2018 7 969 6 2018 31 7 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\nMyroides spp. are common environmental organisms and they can be isolated predominantly in water, soil, food and in sewage treatment plants. In the last two decades, an increasing number of infections such as urinary tract infections and skin and soft tissue infections, caused by these microorganisms has been reported. Selection of appropriate antibiotic therapy to treat the infections caused by Myroides spp. is difficult due to the production of a biofilm and the organism’s intrinsic resistance to many antibiotic classes.\n\nCase presentation\nWe report the case of a 69-year-old immunocompromised patient who presented with repeated episodes of macroscopic haematuria, from Northern Italy.\n\nA midstream urine sample cultured a Gram negative rod in significant amounts (> 105 colony-forming units (cfu)/mL), which was identified as Myroides odoratimimus. The patient was successfully treated with trimethoprim/sulfamethoxazole after antibiotic susceptibility testing confirmed its activity.\n\nConclusion\nThis case underlines the emergence of multidrug resistant Myroides spp. which are ubiquitous in the environment and it demands that clinicians should be more mindful about the role played by atypical pathogens, which may harbour or express multidrug resistant characteristics, in immunocompromised patients or where there is a failure of empiric antimicrobial therapy.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThe Myroides spp., which were previously classified as Flavobacterium spp., are Gram negative, non-fermentative and non-motile bacteria. They do not traditionally belong to the normal human flora. Myroides genus includes two species: Myroides odoratus and Myroides odoratimimus [1]. They are considered low-grade opportunistic pathogens and are rarely isolated from clinical samples but, occasionally, they are life-threatening [2]. Due to the presence of flexirubin, they are yellow pigmented on culture and they are obligated aerobic rod bacteria with a characteristic fruity odour (strawberry-like) [2, 3].\n\nDespite the low pathogenicity potential, managing Myroides odoratimimus is difficult because most strains are multi-drug resistant [4, 5]. In addition, Myroides has different virulence factors [5], has the capacity of co-aggregation and self-aggregation to form biofilm [6]. and possess a polysaccharide capsule, which makes the bacterial surface extremely hydrophobic.\n\nCase report\nWe present the case of a 69-year-old man with type II diabetes mellitus with ocular end-organ dysfunction, on oral hypoglycaemic agents, and with hypertension. He was also affected by an end stage renal failure requiring haemodialysis three times a week. Furthermore, he had other co-morbidities: ischaemic cardiomyopathy treated with oral anticoagulant therapy, mild chronic myelomonocytic leukemia (CMML), dyslipidemia and obesity.\n\nIn June 2016, a permanent urinary Foley’s catheter was positioned due to urinary retention.\n\nIn August 2017, the patient was seen to the emergency room (ER) of the Montichiari Hospital, Brescia, Italy. On admission, the patient was afebrile and upon physical examination, his vital signs (arterial pressure, heart rate and respiratory rate) were within normal limits. The patient gave a 3-day history of ongoing macroscopic haematuria and reported no lower urinary tract symptoms or other symptoms suggesting an inflammatory response or bleeding tendency. The patient had no history of abdominal or pelvic surgery. The international normalized ratio (INR) was 2.5 and hematologic parameters were within the normal range except red blood cell count, which was decreased (3 × 10 6 /μL), related to kidney failure. Glycated haemoglobin (HbA1c) was 52 mmol/mol. Finally, he was discharged with a hemorrhagic cystitis diagnosis and he was empirically treated with ciprofloxacin at a renally-adjusted dose (250 mg 2/die for 1 week) with the complete resolution of the macroscopic heamaturia.\n\nIn September 2017, the patient was seen again to the ER for another episode of macro-hematuria. On admission, he had a temperature of 36.5 °C, the blood pressure and the heart rate were within the normal limits, and there weren’t relevant findings on physical examination; blood cultures were performed but they were negative. Glycated haemoglobin (HbA1c) was 39 mmol/mol.\n\nThe patient had already started at home ciprofloxacin (250 mg 2/die) independently, so the clinician suggested that he continued this therapy for 1 week.\n\nIn the same month, the patient underwent a full urological investigation of haematuria, to exclude cancer or other abnormalities, a transrectal ultrasound, which identified a benign prostate adenoma, a cystoscopy which was negative for neoplasia, and a urinary cytology screening, which was negative for malignant cells. Despite the antibiotic therapy, the patient had symptoms related to urinary tract infection: bladder tenderness, hematuria and pelvic discomfort.\n\nTherefore, a urine sample for culture was obtained by removing the indwelling catheter and obtaining a midstream specimen analysed by the laboratory of Microbiology and Virology of the Spedali Civili Hospital, Brescia, Italy; then, a new Foley’s catheter has been replaced. Urinalysis showed the presence of nitrites, leukocyte esterase and 6–7 leukocytes per high power field by microscopy.\n\nPatient was discharged with clear instructions given to him for a proper care of the urinary catheter and for a correct hand hygiene to prevent infections, and the prescription of an empirical antibiotic therapy. It comprised levofloxacin at 250 mg for 10 days, switched then to amikacin 500 mg intravenously for the following three dialysis sessions (for a total of one week) for cover against multi-drug resistant Pseudomonas aeruginosa, as guided by local epidemiology.\n\nThe urine culture grew a > 105 colony-forming units (cfu)/ml of a gram-negative rod. The bacterium was isolated from Columbia CNA agar (BioMérieux, Florence, Italy) after 24 h of incubation in aerobic conditions. The colonies appeared round, mucoid, yellow pigmented and with a fruity smell. The initial identification as Myroides spp. was performed using a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) according to the manufacturer’s instructions. The definitive identification was obtained with 16SrRNA gene sequencing. The obtained sequence was compared with the sequences in the GenBank database (http://ncbi.nlm.gov/blast) and it exhibited a 100% identity homology with Myroides odoratimimus strain BK21.\n\nThe antimicrobial susceptibility testing (AST) was first performed by using the standard disc diffusion on Mueller-Hinton agar. Then, the minimum inhibitory concentrations (MICs) were determined by automated microdilution broth test (BD-Phoenix NMIC-502, Becton Dickinson, Milan, Italy). The minimum inhibitory concentrations (MICs) were confirmed by Etest (BioMérieux). Since the breakpoints for Myroides spp. were unavailable, the interpretation of the results was performed according to the EUCAST guidelines for non-species related PK-PD breakpoints. The isolated strain was resistant to all beta-lactams, with and without inhibitors (Piperacillin/Tazobactam, MIC = 64; Ticarcillin/Clavulanate, MIC = 128; Ceftazidime/Avibactam, MIC = 32; Imipenem, MIC = 8; Meropenem, MIC = 4) and it was also resistant to fluoroquinolones, aminoglycosides, fosfomycin, nitrofurantoin and polymyxin. This conferred to the isolated strain a multi-drug resistance pattern. This strain was susceptible only to trimethoprim /sulfamethoxazole with a MIC of 1/19. A test was performed to assess beta-lactamase and carbapenemase production (ROSCO diagnostics, Biolife, Milan, Italy) according to the manufacturer’s instructions. The results showed the absence of synergy between the meropenem disk and the dipicolinic acid, the phenylboronic acid, the EDTA and the cloxacillin.\n\nIn October 2017, due to the inadequacy of empiric therapy, the patient suffered from another hemorrhagic cystitis episode. Another urine culture confirmed the presence of a multi-drug resistant Myroides odoratimimus strain. According to the antibiotic susceptibility results, the patient was treated with trimethoprim/sulfamethoxazole at a renally-adjusted dose (160/800 mg daily for 2 weeks) which led to the resolution of macroscopic haematuria. In addition, in the same month, in order to reduce the possibility of recurrent UTIs, the urinary catheter was definitively removed.\n\nThen, we tested its ability to grow in the form of biofilm. A Crystal Violet assay (CV) was performed to evaluate the production of biofilm at different concentrations of glucose and it was measured by spectrophotometry (NanoDrop™ Spectrophotometer, Thermo Fisher). The results indicated that this strain could be classified as a “strong biofilm-producer” [7], which is able to produce a high amount of biofilm when it is compared to the reference strains (Pseudomonas aeruginosa PAO1, strain ATCC 15692). The increase of glucose concentration facilitates the production of biofilm by Myroides odoratimimus, contributing to an increase in vivo of its virulence. Therefore, a strong biofilm-producing bacteria, like Myroides odoratimimus, is well protected against antibiotics. A phylogenetic analysis was performed using the Quick Bioinformatics Phylogeny of Prokaryotes web-server and the data were then re-analysed using the Molecular Evolutionary Genetics Analysis software (MEGA 7.0.26) [8]. Geographical phylogeny was then extrapolated from the Gene-Bank database with a self-written programme. The results showed that our strain clustered with a strain isolated in Jena, Germany (Fig. 1a). The geographic analysis showed that this pathogen is poorly represented in Western Europe (Fig. 1b).Fig. 1 Geographical analysis (a) and phylogenetic analysis (b) based on Myroides odoratimumus 16SrRNA gene sequences. The strain from the immunocompromised patient in Italy is indicated with the red point. Reference strains from GenBank with their accession number are shown. The tree was constructed by the neighbor-joining method based on Kimura’s two-parameter model distance matrices with the MEGA program (version 7.0.26). Branch values are shown in the figure\n\n\n\nDiscussion\nNowadays, the range of community and hospital acquired infections caused by atypical pathogens is continuously being updated. This increase in the number of newly described microorganisms is due to the use of both molecular identification, such as 16S rRNA sequencing and to the introduction in clinical microbiology laboratories of matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry.\n\nThe emergence of these microorganisms is associated with and impacted on by infection control and antimicrobial stewardship.\n\nThe antimicrobial resistance (AMR) has reached alarming levels in different parts of the world. As a result, many available treatment options are becoming ineffective. The major concern in AMR is the dissemination of bacteria with resistance to several antibiotics, also known as “superbugs”.\n\nThe inappropriate, and often uncontrolled, use of antibiotics has led to a global AMR epidemic, as it is defined today.\n\nCurrent antibiotic use in great amounts in humans and animals and subsequent release of antibiotic residues in the environment give rise to a selection pressure that leads to the increase in antibiotic resistant bacteria. In fact, once ingested, most antibiotics are eliminated not metabolized. They can move through sewage systems or directly into water and soil, and mix with environmental bacteria adding pressure for selection of antibiotic resistant organisms. Human exposure to environmental bacteria can occur through drinking water, eating food or by direct contact with the environment.\n\nMyroides spp. can be classified as a multi-drug resistant environmental organism and can harbour different resistance mechanisms simultaneously, as demonstrated in this paper and in other studies [9]. Intrinsic resistance to β-lactamases is due to the presence of two metallo-β-lactamases, MUS-1 and TUS-1, which share a 73% of amino acid identity [4]. Furthermore, a resistance island was found on the chromosome of the bacterium [10]. This region has different types of resistance genes, including tetX (conferring tetracycline resistance), cat (chloramphenicol resistance) and bla-OXA-347 and bla-OXA-209 (conferring β-lactam resistance).\n\nMoreover, it has been recently found that Myroides odoratimimus not only have common virulence factors, like bauE gene to acquire iron competing with the host and adherence factors (DnaK, Hsp60), but also can survive intracellularly (katA, clpP, EF-Tu, and sodB), even in human stomach (ureA, ureB, ureG), can disseminate easily and is able to destroy human tissues [5].\n\nIn addition, our strain is a strong biofilm producer. Biofilms are the sessile bacterial communities which adhere to both biotic and abiotic surfaces, such as medical devices. The bacteria are entrapped within a self-produced extracellular polymeric matrix [11]. Biofilm formation is an important virulence factor for many pathogens; in fact, it has become obvious that sessile bacterial cells in the biofilms express properties which are different from the properties of planktonic cells, for example, the ability to escape host defense, but also the higher resistance to antibacterial agents [12, 13]. The production of a strong biofilm is a serious problem because it increases pathogenicity in device-related infections and it is often associated with therapeutic failure, as well as persistence of infections [14]. The development of biofilm by Myroides spp can be of significant health hazard often leading to recurrent infections, as demonstrated in this paper and in other studies [6].\n\nOur isolate was resistant to all the tested antibiotics except trimethoprim/sulfamethoxazole. The empirical therapy with fluoroquinolones and aminoglycoside was unsuccessful. The resistance observed might be due to an uncontrolled and excessive use of these drugs, in particular fluoroquinolones, which are used, when empirical clinical measures are required after taking urine samples for analysis and culture, as the first-choice drugs in treatment of patients with complicated UTI, according to the European guidelines [15].\n\nIn our patient, different risk factors played an important role in causing a multi-drug resistant Myroides urinary infection, such as the presence of prolonged urinary catheterisation and an immunocompromised condition. Repeated hospital admissions of the patient might represent an independent risk factor for colonization and infection with multi-resistant microorganisms such as Myroides spp. Outbreaks of UTIs due to Myroides odoratimimus and hospital acquired are already reported [16–18].\n\nIn this case, the source of the infection has not been determined, but our hypothesis is that the patient may have acquired the infection from an environmental source, maybe related to poor hand hygiene during the catheter care.\n\nIn literature there are several cases which associate Myroides spp. with different types of infections such as soft tissue infections [6, 19], UTI [16–18], sepsis [2, 20], bacteremia [21, 22], cellulitis [23, 24], pericardial effusion [25], pediatric severe burn injury [26], fulminant erysipelas [27] and urosepsis [28]. Many of these case reports were from India, Turkey, Syria Tunisia, Belgium, Italy and Greece. The phylogenetic analysis showed a small cluster of our strain with a European isolate.\n\nConclusions\nClinicians should be aware of atypical pathogens, in particular, in immunocompromised population, and urine culture should be considered at an earlier stage in these kind of patients due to the presence of less virulent organisms that may be harbouring important resistance mechanisms.\n\nA well-designed antimicrobial stewardship associated with an efficient infection control are essential to limit the spread of these new emerging pathogens.\n\nAbbreviations\nCA-UTICatheter associated urinary tract infection\n\nCNAColumbia nalidixic acid\n\nMICMinimal inhibitory concentration\n\nPK-PDPharmacokinetic-pharmacodynamic\n\nThe Authors thank Dr. Buratti for reviewing the paper for English language.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article (and its supplementary information files).\n\nAuthor’s contributions\nG.L performed the antibiotic susceptibility assays and the biofilm production assay; G.P. performed the sequence analysis; L.C. and F.S. collected and interpreted all the clinical data; F.C. and A.C. contributed to data analysis; M.A. D. F. analysed data and wrote the paper. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot necessary for case reports.\n\nConsent for publication\nWritten informed consent was provided by the patient for the publication of this case report.\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. Vancanneyt M Segers P Torck U Hoste B Bernardet JF Vandamme P Kersters K Reclassification of Flavobacterium odoratum (Stutzer 1929) strains to a new genus, Myroides, as Myroides odoratus comb. Nov. and Myroides odoratimimus sp. nov Int J Syst Bacteriol 1996 46 926 932 10.1099/00207713-46-4-926 \n2. Benedetti P Rassu M Pavan G Sefton A Pellizzer G Septic shock, pneumonia, and soft tissue infection due to Myroides odoratimimus: report of a case and review of Myroides infections Infection 2011 39 161 165 10.1007/s15010-010-0077-1 21246247 \n3. Holmes B Snell JJ Lapage SP Revised description, from clinical isolates, of Flavobacterium, odoratum Stutzer and Kwaschnina 1929, and designation of the neotype strain Int J Syst Bacteriol 1977 27 330 336 10.1099/00207713-27-4-330 \n4. Mammeri H Bellais S Nordmann P Chromosome-encoded beta-lactamases TUS-1 and MUS-1 from Myroides odoratus and Myroides odoratimimus (formerly Flavobacterium odoratum), new members of the lineage of molecular subclass B1 metalloenzymes Antimicrob Agents Chemother 2002 46 11 3561 3567 10.1128/AAC.46.11.3561-3567.2002 12384365 \n5. Hu S, Cao L, Wu Y, Zhou Y, Jiang T, Wang L, Wang Q, Ming D, Chen S, Wang M. Comparative genomic analysis of Myroides odoratimimus isolates. Microbiologyopen. 2018; 10.1002/mbo3.634.\n6. Pompilio A Galardi G Gherardi G Verginelli F Geminiani C Pilloni AP Catalanotti P Di Bonaventura G Infection of recurrent calcaneal ulcer caused by a biofilm-producer Myroides odoratimimus strain Folia Microbiol 2018 63 203 207 10.1007/s12223-017-0552-5 28956275 \n7. Stepanović S Vuković D Hola V Di Bonaventura DS Cirković I Ruzicka F Quantification of biofilm in microtiter plates: overview of testing conditions and practical recommendations for assessment of biofilm production by staphylococci APMIS 2007 115 891 899 10.1111/j.1600-0463.2007.apm_630.x 17696944 \n8. Tamura K Peterson D Peterson N Stecher G Nei M Kuma S MEGA 5: molecular evolutionary genetic analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods Mol Biol Evol 2011 28 2371 2379 10.1093/molbev/msr121 21385829 \n9. Gunzer F Rudolph WW Bunk B Schober I Peters S Muller T Oberheitmann B Schröttner T Whole-genome sequencing of a large collection of Myroides odoratimimus and Myroides odoratus isolated and antimicrobial susceptibility studies Emerg Microbes Infect 2018 7 61 10.1038/s41426-018-0061-x 29618738 \n10. De Song M Chen Q Chen X Analysis of resistance genes in pan-resistant Myroides odoratimimus clinical strain PR 63039 using whole genome sequencing Microb Path 2017 112 164 170 10.1016/j.micpath.2017.09.012 \n11. Niveditha S Pramodhini S Umadevi S Kumar S Stephen S The isolation and biofilm formation of uropathogens in the patients with catheter associated urinary tract infections (CAUTI) J Clin Diagn Res 2012 6 1478 1482 23285434 \n12. O'Toole G Kaplan HB Kolter R Biofilm formation as microbial development Annu Rev Microbiol 2000 54 49 79 10.1146/annurev.micro.54.1.49 11018124 \n13. Singh S Singh SK Chowdhury I Singh R Understanding the mechanism of bacterial biofilms resistance to antimicrobial agents Open Microbiol J 2017 11 53 62 10.2174/1874285801711010053 28553416 \n14. Donlan RM Biofilm formation: a clinically relevant microbiological process Clin Infect Dis 2001 33 1387 1392 10.1086/322972 11565080 \n15. Bartoletti R Cai T Wagenlehner FM Naber K Bjerklund-Johansen TE Treatment of urinary tract infections and antibiotic stewardship Eur Urol Suppl 2016 15 81 87 10.1016/j.eursup.2016.04.003 \n16. Ktari S Mnif B Koubaa M Mahioubi F Ben Jemmaa M Mhiri MN Hammami A Nosocomial outbreak of Myroides odoratimimus urinary tract infection in a Tunisian hospital J Hosp Infect 2012 80 77 51 10.1016/j.jhin.2011.09.010 22099498 \n17. Yağci A Cerikçioğlu N Kaufmann ME Malnick H Söyletir G Babacan F Pitt TL Molecular typing of Myroides odoratimimus (Flavobacterium odoratum) urinary tract infections in a Turkish hospital Eur J Clin Microbiol Infect Dis 2000 19 731 732 10.1007/s100960070001 11057514 \n18. Licker M Sorescu T Rus M Cirlea N Horhat F Jurescu C Botoca M Cumpanas A Timar R Muntean D Extensively drug-resistant Myroides odoratimimus-a case series of urinary tract infections in immunocompromised patients Infect Drug Resist 2018 11 743 749 10.2147/IDR.S161069 29849466 \n19. Maraki S Sarchianaki E Barabagadakis S Myroides odoratimimus soft tissue infection in an immunocompetent child following a pig bite: case report and literature review Braz J Infect Dis 2012 16 390 392 10.1016/j.bjid.2012.06.004 22846131 \n20. Jover-Sáenz A Pérez-Villar F Barcenilla-Gaite F Severe sepsis caused by infected prosthesis joint due to Myroides odoratimimus Medicina Clinica (English edition) 2016 147 276 277 10.1016/j.medcle.2016.10.010 \n21. Endicott-Yazdani TR Dhiman N Benavides R Spak CV Myroides odoratimimus bacteremia in a diabetic patient Proc (Bayl Univ Med Cent) 2015 28 342 343 10.1080/08998280.2015.11929268 26130883 \n22. Belloir L Billy PA Hentgen C Fille A Barrans A Myroides odoratimimus bacteremia Med Mal Infect 2016 46 396 397 10.1016/j.medmal.2016.05.003 27292170 \n23. Bachmeyer C Entressengle H Khosrotehrani K Goldman G Delisle F Arlet G Grateaum G Cellulitis due to Myroides odoratimimus in a patient with alcoholic cirrhosis Clin Experim Dermatol 2007 33 97 98 \n24. Motwani B Krezolek D Symeonides S Khayr W Myroides odoratum cellulitis and bacteremia: a case report Infect Dis Clin Pract 2004 12 343 344 10.1097/01.idc.0000144904.51074.79 \n25. Prateek S Gupta P Mittal G Singh AK Fatal case of pericardial effusion due to Myroides odoratus: a rare case report J Clin Diagn Res 2015 9 DD01 DD02 26672889 \n26. Soydan S Ignak S Demirei OU Karadag G Ocak Z Myroides species in a Paediatric burn patient J Clin Diagn Res 2017 11 DD03 DD04 28764162 \n27. Willems P Muller J Verhaegen J Saegeman V Desmet S How to treat a fulminant erysipelas and sepsis caused by Myroides odoratimimus : case report and literature review Acta Clin Belg 2017 72 331 335 10.1080/17843286.2016.1245173 27765000 \n28. Ranjan M Karade S Rahi P Singh SP Sen S Urosepsis due to Multi Drug Resistant Myroides odoratimimus : A Case Report Int J Curr Microbiol App Sci 2017 6 1930 1935 10.20546/ijcmas.2017.608.228\n\n",
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"abstract": "METHODS\nWe report the case of a 13-year-old boy with Duchenne muscular dystrophy (DMD) who sustained bilateral femoral neck fractures associated with glucocorticoid-induced osteoporosis. Denosumab therapy for 18 months markedly improved the lumbar bone mineral density and the bone turnover markers. No fractures or complications were recorded during the treatment period.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first description of denosumab treatment for glucocorticoid-induced osteoporosis in a patient with DMD. The drug merits additional testing as an effective therapy for osteoporosis in patients with DMD.",
"affiliations": "Departments of Orthopaedic Surgery (D.K., Y.N., T.S., and H.K.) and Medical Genetics (T.K.) and Third Department of Medicine (A.N.), Shinshu University School of Medicine, Matsumoto, Japan.;Departments of Orthopaedic Surgery (D.K., Y.N., T.S., and H.K.) and Medical Genetics (T.K.) and Third Department of Medicine (A.N.), Shinshu University School of Medicine, Matsumoto, Japan.;Departments of Orthopaedic Surgery (N.S.) and Child Neurology (S.H.), Nagano Prefectural Children's Hospital, Azumino, Japan.;Departments of Orthopaedic Surgery (D.K., Y.N., T.S., and H.K.) and Medical Genetics (T.K.) and Third Department of Medicine (A.N.), Shinshu University School of Medicine, Matsumoto, Japan.;Departments of Orthopaedic Surgery (D.K., Y.N., T.S., and H.K.) and Medical Genetics (T.K.) and Third Department of Medicine (A.N.), Shinshu University School of Medicine, Matsumoto, Japan.;Departments of Orthopaedic Surgery (N.S.) and Child Neurology (S.H.), Nagano Prefectural Children's Hospital, Azumino, Japan.;Departments of Orthopaedic Surgery (D.K., Y.N., T.S., and H.K.) and Medical Genetics (T.K.) and Third Department of Medicine (A.N.), Shinshu University School of Medicine, Matsumoto, Japan.;Center of Osteoporosis and Spinal Disorders, Kamimura Orthopaedic Clinic, Matsumoto, Japan.;Departments of Orthopaedic Surgery (D.K., Y.N., T.S., and H.K.) and Medical Genetics (T.K.) and Third Department of Medicine (A.N.), Shinshu University School of Medicine, Matsumoto, Japan.",
"authors": "Kumaki|Daiki|D|;Nakamura|Yukio|Y|0000-0002-3911-7180;Sakai|Noriko|N|;Kosho|Tomoki|T|;Nakamura|Akinori|A|;Hirabayashi|Shinichi|S|;Suzuki|Takako|T|;Kamimura|Mikio|M|;Kato|Hiroyuki|H|",
"chemical_list": "D050071:Bone Density Conservation Agents; D005938:Glucocorticoids; D010281:Parathyroid Hormone; D000069448:Denosumab; D000469:Alkaline Phosphatase",
"country": "United States",
"delete": false,
"doi": "10.2106/JBJS.CC.17.00190",
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"issue": "8(2)",
"journal": "JBJS case connector",
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"abstract": "Second primary malignancy (SPM) is a severe issue for cancer survivors, particularly for osteosarcoma (OS) survivors. To date, the associations between subsequent SPM and OS have been well reported. Hematogenic and solid malignancies tend to occur following OS treatment. Reportedly, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is mainly used in OS patients for initial cancer staging, to evaluate the response of neoadjuvant chemotherapy, and when recurrence or metastasis is clinically suspected. The present case report describes a 70-year-old man diagnosed with three primary malignancies: jaw OS, myelodysplastic syndrome and colorectal adenocarcinoma. To the best of our knowledge, this combination of malignancies has not been reported previously. Until now, there is no specific protocol of postoperative FDG-PET for OS patients. Few studies have described OS follow-up methods; therefore, there is no consensus on proper follow-up methods. In the present case report, the colorectal early-stage SPM was observed, without any symptoms, by FDG-PET/computed tomography. To avoid overlooking solid SPMs, it is suggested that FDG-PET should be performed in the long-term follow-up of OS patients.",
"affiliations": "Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Oral and Maxillofacial Surgery, University Hospital of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Pathology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Endoscopy, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Oral and Maxillofacial Surgery, University Hospital of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Pathology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.;Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan.",
"authors": "Maruyama|Nobuyuki|N|;Nishihara|Kazuhide|K|;Nakasone|Toshiyuki|T|;Saio|Masanao|M|;Maruyama|Tessho|T|;Tedokon|Iori|I|;Ohira|Tetsuya|T|;Nimura|Fumikazu|F|;Matayoshi|Akira|A|;Karube|Ken-Nosuke|KN|;Yoshimi|Naoki|N|;Arasaki|Akira|A|",
"chemical_list": null,
"country": "Greece",
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"doi": "10.3892/ol.2018.8594",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2018.8594OL-0-0-8594ArticlesTriple primary malignancies of surface osteosarcoma of jaw, myelodysplastic syndrome and colorectal cancer as a second primary cancer detected by PET2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography: A case report Maruyama Nobuyuki 12Nishihara Kazuhide 12Nakasone Toshiyuki 2Saio Masanao 345Maruyama Tessho 12Tedokon Iori 6Ohira Tetsuya 7Nimura Fumikazu 1Matayoshi Akira 2Karube Ken-Nosuke 8Yoshimi Naoki 34Arasaki Akira 121 Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan2 Department of Oral and Maxillofacial Surgery, University Hospital of the Ryukyus, Nishihara, Okinawa 903-0215, Japan3 Department of Pathology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan4 Department of Pathology, University Hospital of the Ryukyus, Nishihara, Okinawa 903-0215, Japan5 Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma 371-8514, Japan6 Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan7 Department of Endoscopy, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan8 Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, JapanCorrespondence to: Dr Tessho Maruyama, Department of Oral and Maxillofacial Functional Rehabilitation, Graduate School of Medicine, University of The Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan, E-mail: h075324@eve.u-ryukyu.ac.jp6 2018 27 4 2018 27 4 2018 15 6 9901 9907 08 11 2017 12 4 2018 Copyright: © Maruyama 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.Second primary malignancy (SPM) is a severe issue for cancer survivors, particularly for osteosarcoma (OS) survivors. To date, the associations between subsequent SPM and OS have been well reported. Hematogenic and solid malignancies tend to occur following OS treatment. Reportedly, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is mainly used in OS patients for initial cancer staging, to evaluate the response of neoadjuvant chemotherapy, and when recurrence or metastasis is clinically suspected. The present case report describes a 70-year-old man diagnosed with three primary malignancies: jaw OS, myelodysplastic syndrome and colorectal adenocarcinoma. To the best of our knowledge, this combination of malignancies has not been reported previously. Until now, there is no specific protocol of postoperative FDG-PET for OS patients. Few studies have described OS follow-up methods; therefore, there is no consensus on proper follow-up methods. In the present case report, the colorectal early-stage SPM was observed, without any symptoms, by FDG-PET/computed tomography. To avoid overlooking solid SPMs, it is suggested that FDG-PET should be performed in the long-term follow-up of OS patients.\n\nosteosarcomasecond primaryhead and neckoralmyelodysplastic syndromecolorectal cancerFDG-PETmultiple primary neoplasms\n==== Body\nIntroduction\nOsteosarcoma (OS) is a terrible malignancy characterized by osteoblastic differentiation (1). The tumor affects a wide range of age groups (2). Recent improvements in the survival of patients with malignant cancers (including OS) may contribute to an increase in the incidence of second primary malignancies (SPMs) (3). SPM is a serious problem for the survivors of OS during the follow-up period after treatment (4). The relationship between subsequent SPM and OS has been well reported (4–7), and both hematogenic and solid malignancies tend to occur after OS treatment (7). In OS patients, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is primarily used for initial cancer staging (8,9), to evaluate the response of neoadjuvant chemotherapy (10–12), and when recurrence or metastasis is clinically suspected (9,13,14).\n\nTo date, no accurate protocol of postoperative FDG-PET for OS patients has been reported, and there is uncertainty regarding the most appropriate methods for follow-up (15–17). In addition, no accurate protocol for detecting SPMs after OS treatment exists. SPM can occur anywhere in the body. Early-stage malignancy sometimes manifests no clinical symptoms; in contrast, advanced-stage malignancy generally indicates a poorer prognosis. Therefore, malignancies, including SPM, should be detected as early as the clinicians can. We report a case of a patient with triple primary malignancies (PMs): OS of the jaw, myelodysplastic syndrome (MDS), and adenocarcinoma of the colorectum. After follow-up FDG-PET/computed tomography (CT) was performed, rectal cancer was detected unexpectedly as no clinical symptoms had been observed.\n\nCase report\nA 70-year-old man was referred to the Department of Oral and Maxillofacial Surgery, University Hospital of the Ryukyus (Nishihara, Japan) in December 2015, for further evaluation of an oral mass. The patient had a 10-month history of swelling with gradual pain in the gums of his lower jaw. He had no previous malignancies and had never been exposed to ionizing radiation or been administered chemotherapy. He also had no history of family cancer syndrome; however, his mother had a history of kidney cancer. He was a smoker and drinker at the first visit. Written informed consent was obtained from the patient.\n\nIncisional biopsy was performed in his previous clinic, and the lesion had previously been pathologically diagnosed as a spindle cell sarcoma highly suggestive of OS. For details, the histological findings of the initially diagnosed specimens revealed an irregular arrangement of spindle- or oval-shaped tumor cells, accompanying eosinophilic matrix suggesting osteoid formation. Most of the lesions showed mild atypia with rich osteoid formation (Fig. 1A). Conversely, tumor cells showing high-grade atypia with low osteoid formation existed in part (Fig. 1B). According to immunohistochemical examination, Ki-67 labeling index was 30–40% (Fig. 1C). Tumor cells were positively stained for CD56 and were partially positive for smooth muscle actin. The cells were negatively stained for CD34, S100, or bc1-2.\n\nPhysical examination showed an elastic-hard, 3.5×2.0-cm mass of the right mandibular premolar gum (Fig. 2A). No lymphadenopathy was found in the neck region. Panorama X-ray and subsequent contrast-enhanced CT scans from the head to chest and contrast-enhanced magnetic resonance imaging (MRI) of the head and neck were performed. A 3.5×3.0×2.5-cm mass without bone resorption or infiltration was observed. CT scan showed new bone formation on the mandible surface (Fig. 2B and C). Contrast-enhanced fat-suppression T1-weighted MRI showed a high-signal mass around the mandible bone; however, no invasion to the bone was found (Fig. 2D). The signal of the bone marrow was considered as a slight bone marrow edema. No other lesion was detected in the neck, bones, or lungs by the above tests. Next, FDG-PET/CT and bone scintigraphy were evaluated to identify the OS staging and any other potential lesions in the whole body. FDG-PET showed increased FDG uptake in the surface of right mandible [maximum standardized uptake value (SUVmax)=8.82] (Fig. 3A). In contrast, no other FDG uptake was seen in the whole body. Bone scintigraphy showed abnormal bone intake on the mandibular surface, but no other sign was found. Based on the above findings, we diagnosed the disease as jaw surface OS without metastasis at the initial presentation. The patient was administered a four-drug preoperative regimen; that is, two cycles of cisplatin and doxorubicin, four cycles of high-dose methotrexate, and additional oral TS-1 for 7 days preoperatively. No preoperative radiotherapy was performed. Second, FDG-PET/CT was performed to evaluate the effect of chemotherapy, and the mass of the lower jaw shrank clinically and radiologically. The FDG uptake in the right mandible was decreased (SUVmax=5.66) (Fig. 3B). No other indications of lesions were detected in the whole body. Thrombocytopenia, resulting from administration of chemotherapy, was controlled by pegfilgrastim. Subsequently, the patient underwent segmental resection of the right mandible (that is, wide local resection) with reconstruction of a vascularized fibular graft and ipsilateral supraomohyoid neck dissection (April 2016). Histopathological examination revealed ‘OS, post-therapeutic state’, and the surgical margins were negative. Surgical materials obtained by segmental resection of the right mandible showed a lot of newly formed woven bone attached to the existing mandibular bone, and most of the osteocytes and tumor cells were dead due to chemotherapy. Namely, tumor showed characteristics of bone formation on the surface of mandibular bone (Fig. 4). No tumor cell was found in the bone marrow. According to these findings, the initially obtained biopsy, clinical and radiological findings, it was suggested that a part of tumor cells showed high-grade atypia, although most of the tumor mass showed abundant bone formation, which arose from the bone surface. Therefore, we considered two possible diagnoses: high-grade OS of the mandible or parosteal OS with partial dedifferentiation to high-grade OS (18). However, because of the death of tumor cells due to chemotherapy, we could not determine which diagnosis was correct. There was no indication of metastasis to the lymph nodes. Postoperative chemo/radiotherapy for OS was not performed. Following the surgery, the patient has not shown recurrence or metastasis of OS till the time of this writing.\n\nOn the other hand, MDS was found because of a hematoma of the jaw after the surgery, and thrombocytopenia after the surgery was found during the blood testing performed for postoperative follow-up. In spite of platelet transfusion, the thrombocytopenia continued. Therefore, an additional blood test, a bone marrow examination, and a chromosome analysis were performed one month after the surgery (May 2016). Wilms' tumor gene was positive (74 copies/µg RNA) from the blood test. Histopathological examination of the bone marrow revealed that the marrow was hypercellular, and micromegakaryocytes were abnormally highly expressed in cluster of differentiation 41 staining. The fat-to-cell ratio in the marrow was approximately 2:1, and no OS cells were found. The chromosome analysis revealed a Y-chromosome deficiency. On the basis of the examination results, low-risk MDS (refractory cytopenia of unilineage dysplasia) was diagnosed. The patient was given only a packed red blood cells and platelets transfusion, and no other treatment has been required till the time of this writing.\n\nEight months after the surgery for OS, the patient complained that his lower jaw felt different. Local recurrence was suspected and contrast-enhanced CT was performed; however, no lesion was found in the head and neck-to-chest region (range of the CT scan). Follow-up third FDG-PET/CT was performed 11 months postoperatively, and abnormal uptake was detected in the rectum (SUVmax=14.58) (Fig. 5); on the other hand, no other lesion identified by uptake was found in the whole body, including the jaw, neck, bone, or lung. A colorectal tumor was suspected, and subsequent excision by endoscopic mucosal resection was performed (April 2017). Histopathological examination showed an adenocarcinoma and showed that the surgical margin was negative with no vascular invasion. On the other hand, due to the submucosal tumor invasion depth (3,000 µm), the additional radical surgery has been considered. Based on the above, MDS and colorectal cancer were diagnosed after treatment of the jaw cancer. Five months after the resection of the rectal cancer (one year and five months after the jaw OS surgery), the patient was free of any malignant lesion. However, we plan to follow his progress carefully.\n\nDiscussion\nThis case highlights two important points: i) this combination of three PMs (jaw OS, MDS, and colorectal adenocarcinoma) has not been previously reported; and ii) to avoid overlooking solid SPMs, we suggest that FDG-PET should be performed in the long-term follow-up of OS patients.\n\nFirstly, to our knowledge, there also have been no reports of cases involving both hematologic and solid malignancies after OS. We defined our case as involving three PMs by the Warren and Gates criteria reported in 1932 (19); that is, each malignancy was distinct and we excluded disease due to metastasis of one of the other malignancies. Using the criteria of Lee et al (7), we also discriminated between hematologic (leukemia, myeloproliferative disease, myelodysplastic disease, such as MDS, or lymphoma) and solid malignancies (all other malignancies). Thus, our patient had three PMs, including OS and subsequent SPMs involving hematologic and solid tumors. When we then searched PubMed and Google Scholar for English literature between 1932 and 2017, we found no cases describing the same combination of three malignancies, indicating the uniqueness of this case.\n\nPatients with OS tend to develop both hematologic and solid SPMs after treatment (7). Compared with cancer-free individuals in the Childhood Cancer Survivor Study, survivors of OS tended to develop SPMs at a greater incidence (the standardized incidence ratio was 4.79) (20). Moreover, in a single-institution study, 26 of 1205 patients with OS of their extremities developed SPMs after treatment, which was significantly more frequent compared with the control group (1160 with benign tumors) (21). Cancer survivors are generally at risk of SPMs (22), with chemotherapy, radiotherapy, and a family history of cancer recognized to contribute to SPMs after OS (21,23–25). Our patient had received preoperative chemotherapy and his mother had a history of kidney cancer, but he had no history of family cancer syndrome (25). In addition, smoking and alcohol consumption are known independent risk factors of two of the malignancies in our patient (26–29). Further, old age is a risk factor for cancers such as colorectal cancer (30).\n\nOther reports of triple to quintuple PMs involving OS as index malignancy (21,24,31–33) (Table I) have been associated with intervals of 1–26 years between the diagnoses of OS and the SPMs (31–33), indicating that the occurrence of SPM, particularly solid malignancies, does not decrease over time, after OS treatment. Studies have generally reported that the average interval between OS and subsequent SPMs was 6.0–7.6 years (5,7,21,24). Further, in large series, it has been shown that most SPMs occur >10 years after OS diagnosis, whereas most local or distant recurrences occur ≤5 years, with as few as 5% of patients with OS developing their first local recurrence or distant metastasis greater than or equal to 5 years after initial treatment (20,34). In a smaller study of OS survivors, the cumulative incidences of SPMs at 10, 20, and 30 years were 2.1, 4.0, and 7.4%, respectively, with solid malignancy developing at all times (7). Therefore, a long follow-up period is needed after primary treatment for OS to detect both SPMs as well as recurrence, metastasis, or multiple OS (9,24,35,36). SPMs after OS can be fatal (6,7), and together with metastasis, chemotherapy response, tumor characteristics, patient characteristics, surgical margins, and toxicity, SPMs are an important prognostic factor (37). Indeed, the prognosis is poor once SPMs occur (20). In these patients, given that advanced malignancy generally indicates a poorer prognosis, we recommend monitoring to detect SPMs early.\n\nThe surface OS of jaw is rare (38). Pathologically, we considered two possible histological diagnoses: high-grade surface OS and parosteal OS with partial dedifferentiation to high grade OS. Although the current case could not be clearly diagnosed due to tumor mass degeneration of surgical materials post chemotherapy. According to the findings of osteoid formation with tumor cell atypia showed in Fig. 1A-C, it was possible that the tumor was high-grade surface OS. However, the incidence of the high-grade surface OS at age 70 years was very unusual. Therefore, we should consider the possibility of parosteal OS with partial dedifferentiation to high-grade OS. Namely, all of the surface OSs of jaw tend to develop approximately 20–30 years old (39). Among those, parosteal OS occurs at a relatively higher rate in elderly patients, similar to our patient (38). In contrast, high-grade surface OS of jaw is very rare (38). Therefore, the current case may be parosteal OS with dedifferentiation of high-grade surface OS (40). In OS of the jaw (particularly the surface-type), metastasis is rare but can occur (41,42). The most common site is the lung (41,42). FDG-PET is a useful tool for detecting metastasis of OS (43). Conversely, SPM was detected by testing our patient.\n\nAnother issue is that FDG-PET should be performed during the long-term follow-up of OS to avoid overlooking solid SPMs. To date, the importance of detecting SPMs during follow-up after OS treatment has not been emphasized. In our case, MDS and colorectal cancer were metachronous according to Moertel's definition (i.e., recognized ≥6 months after diagnosis) (44). MDS was easily diagnosed because of the hematoma observed after surgery and during the postoperative routine blood test (1 month after resection), which prompted early diagnostic bone marrow aspiration. By contrast, no clinical symptoms of colorectal cancer were present, and the tumor was found incidentally by FDG-PET/CT. Recent improvements in patient survival (including from OS) may lead to increased rates of SPMs (3). Further, old age is a risk factor of SPMs such as colorectal cancer (30). Therefore, PET/CT studies are recommended to screen for SPMs (22).\n\nPET/CT is useful for detecting SPMs in survivors of OS. However, they are not routinely included in OS follow-up protocols because few studies have used them for that purpose (14,45). Indeed, FDG-PET tends to have been reserved for initial cancer staging and for evaluating the response of neoadjuvant chemotherapy (8–12), even though PET is especially useful after treatment for OS because it is not adversely affected by metal plates or implants (14). These scans can also detect three important disease patterns for which whole body examination is needed (5,7,21,24,35,46): i) recurrence or metastasis (9,13,14); ii) multiple synchronous or metachronous OS (35,46); and iii) synchronous or metachronous SPMs (5,7,21,24). CT and MRI are inadequate because their coverage range is incomplete. Although OS is associated with a high incidence of lung metastases, indicating that chest CT is probably the best screening tool in most cases (14,47), this can fail to identify SPMs at other sites. In the present case, we could not detect the rectal lesion by contrast-enhanced CT that was performed because local recurrence was suspected 8 months after OS treatment.\n\nIn daily practice, clinicians check local, regional, and distant sites where OS recurrences typically occur. Further, regarding SPMs for patients with head and neck cancers, they tend to recur locally in the head and neck, esophagus, or lung (48). SPMs at other sites (e.g., the colorectum) are relatively rare (49). In the current case, the early-stage colorectal SPM was found incidentally by FDG-PET/CT 11 months after treatment. OS is commonly associated with pain or swelling as an early symptom (1,50), and recurrence may be suspected based on clinical symptoms (14). However, some SPMs are not associated with clinical symptoms, and it is known that early-stage colorectal cancer can be clinically silent (51). In practice, clinicians should consider the benefits and risks of performing FDG-PET/CT for patients after OS treatment. Although we have emphasized the benefits, the following are equally important considerations when choosing FDG-PET/CT: i) the test is generally expensive for patients (47); ii) physiological accumulation makes the detection of malignant lesions difficult, especially in the kidney or bladder (the major excretion route of FDG; Fig. 3); and iii) background activity may obscure the presence of lesions (52).\n\nTo date, no protocol exists which guides the use of FDG-PET after treatment for OS. Some studies have reported that follow-up PET/CT was useful even when there was no clinical evidence of recurrence or metastasis (14,53–56). However, no literature has emphasized the importance of detecting SPMs during follow-up for OS. We recommend that PET/CT should be performed during the follow-up of OS, specifically to detect SPMs.\n\nIn conclusion, the specific combination of triple PMs in this case (i.e., jaw OS, MDS, and colorectal adenocarcinoma) has not been reported previously. Based on our research, we recommend that FDG-PET be performed during the long-term follow-up of OS to avoid overlooking solid SPMs. However, our conclusions are based on a single case report, which limits their generalizability. Further cases are needed to help develop a protocol that describes the optimal role of FDG-PET or FDG-PET/CT scans in the identification of hidden synchronous or metachronous SPMs during the follow-up of patients with OS.\n\nAcknowledgements\nThe authors would like to thank Dr. Hirofumi Matsumoto (Department of Pathology, University Hospital of the Ryukyus, Nishihara, Japan), for the pathological advice. The authors would also like to thank Ms. Chinatsu Toguchi and Ms. Ai Tokeshi (Department of Pathology, University Hospital of the Ryukyus) for their technical support.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors' contributions\nNM and TM acquired the data, performed the literature review and edited the manuscript. AA substantially contributed to the concept and design of the study. KN, TN, IT, TO, FN and AM acquired the data and contributed clinical advice. MS, IT, TO and AA revised the manuscript. MS, KK and NY evaluated the specimens. MS gave histopathological advice. TM had a major role in writing the manuscript.\n\nEthics approval and consent to participate\nThe present case report was submitted for ethical review to the Ethics Committee of The University of the Ryukyus (Nishihara, Japan), which waived the requirement for review per institutional protocol as the case report does not contain content that requires ethical approval. The Ethics Committee approved the submission and publication of the manuscript. Written informed consent was obtained from the patient.\n\nConsent for publication\nWritten informed consent was obtained from the patient for the publication of this case report and the accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAbbreviations\nSPMsecond primary malignancy\n\nOSosteosarcoma\n\nFDG-PET2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography\n\nPMprimary malignancy\n\nMDSmyelodysplastic syndrome\n\nCTcomputed tomography\n\nMRImagnetic resonance imaging\n\nSUVmaxmaximum standardized uptake value\n\nFigure 1. Histopathological examination revealed irregular arrangement of spindle- or oval-shaped tumor cells. In addition, osteoid lesions with an eosinophilic matrix in those cells were revealed. (A) The majority of the lesions were mild atypia with rich osteoid lesion (original magnification, ×200); (B) Conversely, partially high-grade atypia with few osteoid lesions was observed (original magnification, ×200). (C) Immunohistochemical examination for Ki-67 determined that the labeling index was 30–40% (original magnification, ×40).\n\nFigure 2. (A) Physical examination revealed an elastic, hard mass of the right mandibular premolar gum. A 3.5×3.0×2.5-cm mass, without bone resorption or infiltration, was observed. (B and C) CT scan showed novel bone formation on the mandible surface. (D) Contrast-enhanced fat-suppression T1-weighted magnetic resonance imaging revealed the high-signal mass around the mandible bone; however, no invasion to the bone was identified. The signal of the bone marrow was considered as a slight bone marrow edema.\n\nFigure 3. FDG-PET/CT and bone scintigraphy were performed to identify the osteosarcoma staging and any other lesions in the whole body. (A) FDG-PET showing increased FDG uptake in the right mandible (SUVmax=8.82; indicated by an arrow). (B) FDG-PET/CT for evaluating the effect of chemotherapy was performed and the mass of the lower jaw shrank radiologically. The FDG uptake in the right mandible was decreased (SUVmax=5.66; indicated by an arrow). FDG-PET, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography; CT, computed tomography; SUVmax, maximum standardized uptake value.\n\nFigure 4. Histopathological examination revealed ‘OS, post-therapeutic state’, and the surgical margins were negative. A mass with irregular bone formation was observed. Degenerative tissues caused by the chemotherapy were identified in the mass; by contrast, no viable tumor cells were observed. The novel rich bone formation remained in the resected tumor, and the tumor was in contact with the mandibular bone (original magnification, ×200). OS, osteosarcoma.\n\nFigure 5. A total of 11 months following the treatment of jaw osteosarcoma, follow-up FDG-PET/computed tomography was performed, and an abnormal uptake was detected in the rectum (SUVmax=14.58; indicated by an arrow). In front of the uptake, physiological accumulation of the bladder was observed (indicated by an arrowhead) as the bladder is the major excretion route for FDG. FDG-PET, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography; SUVmax, maximum standardized uptake value.\n\nTable I. Triple to quintuple primary malignancies involving OS as index malignancy.\n\n\t\tType of cancer (age at onset)\t\n\t\t\t\nAuthor, year\tSex\tFirst\tSecond\tThird\tFourth\tFifth\t(Refs.)\t\nKubota et al, 1997\tMale\tNon-Hodgkin's lymphoma (4Y and 9M)\tOS of right femur (7Y and 2M)\tMDS (16Y and 4M)\t–\t–\t(31)\t\nBacci et al, 2006\tNA\tOS\tNA\tNA\t–\t–\t(21)\t\nKimura et al, 2001\tFemale\tOS of left femur (9Y)\tPaget Ca. of left breast (19Y)\tPaget Ca. of right breast (24Y)\tOS of right femur (25Y)\tLung adeno Ca. (26Y)\t(32)\t\nYonemoto et al, 2004\tNA\tOS (29Y)\tNA\tUterine leiomyosarcoma (35Y)\t–\t–\t(24)\t\nKousaka et al, 2014\tFemale\tOS of left lower leg (15Y)\tTongue squamous cell Ca. (23Y)\tPapillary thyroid Ca. (40Y)\tDuct Ca. of right breast (41Y)\t–\t(33)\t\nPresent study\tMale\tOS of jaw (70Y)\tMDS\tRectal adeno Ca.\t–\t–\t–\t\nOS, osteosarcoma; NA, not applicable; Y, years; M, months; Ca., carcinoma; MDS, myelodysplastic syndrome.\n==== Refs\nReferences\n1 Zhao L Zhang J Tan H Wang W Liu Y Song R Wang L Gene function analysis in osteosarcoma based on microarray gene expression profiling Int J Clin Exp Med 8 10401 10410 2015 26379830 \n2 Isakoff MS Bielack SS Meltzer P Gorlick RL Osteosarcoma: Current treatment and a collaborative pathway to success J Clin Oncol 33 3029 3035 2015 10.1200/JCO.2014.59.4895 26304877 \n3 Kim JS Chung CY Park HC Myung DS Cho SB Lee WS Min JJ Joo YE Synchronous quadruple primary tumors of thyroid, breast, pancreas and stomach: A case report Anticancer Res 33 2135 2138 2013 23645766 \n4 Aung L Gorlick RG Shi W Thaler H Shorter NA Healey JH Huvos AG Meyers PA Second malignant neoplasms in long-term survivors of osteosarcoma: Memorial sloan-kettering cancer center experience Cancer 95 1728 1734 2002 10.1002/cncr.10861 12365021 \n5 Pratt CB Meyer WH Luo X Cain AM Kaste SC Pappo AS Rao BN Fleming ID Jenkins JJ III Second malignant neoplasms occuring in survivors of osteosarcoma Cancer 80 960 965 1997 10.1002/(SICI)1097-0142(19970901)80:5<960::AID-CNCR19>3.0.CO;2-U 9307198 \n6 Kim SH Shin KH Seok SO Cho YJ Noh JK Suh JS Yang WI Secondary malignant neoplasms after osteosarcoma: Early onset and cumulative alkylating agent dose dependency Ann Surg Oncol 22 859 865 2015 10.1245/s10434-014-4070-2 25192682 \n7 Lee JS DuBois SG Boscardin WJ Wustrack RL Goldsby RE Secondary malignant neoplasms among children, adolescents and young adults with osteosarcoma Cancer 120 3987 3993 2014 10.1002/cncr.28936 25116228 \n8 Quartuccio N Treglia G Salsano M Mattoli MV Muoio B Piccardo A Lopci E Cistaro A The role of Fluorine-18-Fluorodeoxyglucose positron emission tomography in staging and restaging of patients with osteosarcoma Radiol Oncol 47 97 102 2013 10.2478/raon-2013-0017 23801904 \n9 Costelloe CM Chuang HH Daw NC PET/CT of Osteosarcoma and ewing sarcoma Semin Roentgenol 52 255 268 2017 10.1053/j.ro.2017.04.007 28965545 \n10 Harrison DJ Parisi MT Shulkin BL The Role of 18F-FDG-PET/CT in pediatric sarcoma Semin Nucl Med 47 229 241 2017 10.1053/j.semnuclmed.2016.12.004 28417853 \n11 Byun BH Kong CB Lim I Choi CW Song WS Cho WH Jeon DG Koh JS Lee SY Lim SM Combination of 18F-FDG PET/CT and diffusion-weighted MR imaging as a predictor of histologic response to neoadjuvant chemotherapy: Preliminary results in osteosarcoma J Nucl Med 54 1053 1059 2013 10.2967/jnumed.112.115964 23670899 \n12 Byun BH Kong CB Lim I Kim BI Choi CW Song WS Cho WH Jeon DG Koh JS Lim SM Early response monitoring to neoadjuvant chemotherapy in osteosarcoma using sequential 18F-FDG PET/CT and MRI Eur J Nucl Med Mol Imaging 41 1553 1562 2014 10.1007/s00259-014-2746-2 24652233 \n13 Hurley C McCarville MB Shulkin BL Mao S Wu J Navid F Daw NC Pappo AS Bishop MW Comparison of (18) F-FDG-PET-CT and bone scintigraphy for evaluation of osseous metastases in newly diagnosed and recurrent osteosarcoma Pediatr Blood Cancer 63 1381 1386 2016 10.1002/pbc.26014 27082077 \n14 Angelini A Ceci F Castellucci P Graziani T Polverari G Trovarelli G Palmerini E Ferrari S Fanti S Ruggieri P The role of 18F-FDG PET/CT in the detection of osteosarcoma recurrence Eur J Nucl Med Mol Imaging 44 1712 1720 2017 10.1007/s00259-017-3698-0 28405727 \n15 Rothermundt C Seddon BM Dileo P Strauss SJ Coleman J Briggs TW Haile SR Whelan JS Follow-up practices for high-grade extremity Osteosarcoma BMC Cancer 16 301 2016 10.1186/s12885-016-2333-y 27154292 \n16 Paioli A Rocca M Cevolani L Rimondi E Vanel D Palmerini E Cesari M Longhi A Eraldo AM Marchesi E Osteosarcoma follow-up: chest X-ray or computed tomography? Clin Sarcoma Res 7 3 2017 10.1186/s13569-017-0067-5 28228934 \n17 Quartuccio N Fox J Kuk D Wexler LH Baldari S Cistaro A Schöder H Pediatric bone sarcoma: Diagnostic performance of 18F-FDG PET/CT versus conventional imaging for initial staging and follow-up AJR Am J Roentgenol 204 153 160 2015 10.2214/AJR.14.12932 25539251 \n18 Lazar A Mertens F Parosteal osteosarcoma WHO classification of tumors of soft tissue and bone Fletcher CDM Bridge JA Hogendoorn PCW Mertens F IARC Press Lyon 292 293 2013 \n19 Warren S Gates O Multiple primary malignant tumors: a survey of the literature and a statistical study Am J Cancer 16 1358 1414 1932 \n20 Nagarajan R Kamruzzaman A Ness KK Marchese VG Sklar C Mertens A Yasui Y Robison LL Marina N Twenty years of follow-up of survivors of childhood osteosarcoma: A report from the Childhood Cancer Survivor Study Cancer 117 625 634 2011 10.1002/cncr.25446 20922787 \n21 Bacci G Ferrari C Longhi A Ferrari S Forni C Bacchini P Palmerini E Briccoli A Pignotti E Balladelli A Second malignant neoplasm in patients with osteosarcoma of the extremities treated with adjuvant and neoadjuvant chemotherapy J Pediatr Hematol Oncol 28 774 780 2006 10.1097/01.mph.0000243664.02174.73 17164644 \n22 Almangush A Coletta RD Bello IO Bitu C Keski-Säntti H Mäkinen LK Kauppila JH Pukkila M Hagström J Laranne J A simple novel prognostic model for early stage oral tongue cancer Int J Oral Maxillofac Surg 44 143 150 2015 10.1016/j.ijom.2014.10.004 25457829 \n23 Bacci G Ferrari S Bertoni F Ruggieri P Picci P Longhi A Casadei R Fabbri N Forni C Versari M Campanacci M Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: An updated report J Clin Oncol 18 4016 4027 2000 10.1200/JCO.2000.18.24.4016 11118462 \n24 Yonemoto T Tatezaki S Ishii T Hagiwara Y Inoue M Multiple primary cancers in patients with osteosarcoma: Influence of anticancer drugs and genetic factors Am J Clin Oncol 27 220 224 2004 10.1097/01.COC.0000054534.43117.76 15170137 \n25 Hauben EI Arends J Vandenbroucke JP van Asperen CJ Van Marck E Hogendoorn PC Multiple primary malignancies in osteosarcoma patients. Incidence and predictive value of osteosarcoma subtype for cancer syndromes related with osteosarcoma Eur J Hum Genet 11 611 618 2003 10.1038/sj.ejhg.5201012 12891382 \n26 Liu P Holman CD Jin J Zhang M Alcohol consumption and risk of myelodysplastic syndromes: A case-control study Cancer Causes Control 27 209 216 2016 10.1007/s10552-015-0698-x 26590915 \n27 Tong H Hu C Yin X Yu M Yang J Jin J A meta-analysis of the relationship between cigarette smoking and incidence of myelodysplastic syndromes PLoS One 8 e67537 2013 10.1371/journal.pone.0067537 23805315 \n28 Johnson CM Wei C Ensor JE Smolenski DJ Amos CI Levin B Berry DA Meta-analyses of colorectal cancer risk factors Cancer Causes Control 24 1207 1222 2013 10.1007/s10552-013-0201-5 23563998 \n29 Parajuli R Bjerkaas E Tverdal A Le Marchand L Weiderpass E Gram IT Cigarette smoking and colorectal cancer mortality among 602,242 Norwegian males and females Clin Epidemiol 7 137 145 2014 \n30 Siegel RL Miller KD Fedewa SA Ahnen DJ Meester RGS Barzi A Jemal A Colorectal cancer statistics, 2017 CA Cancer J Clin 67 177 193 2017 10.3322/caac.21387 28248415 \n31 Kubota M Sawada M Watanabe K Koishi S Kataoka A Usami I Lin YW Okuda A Akiyama Y Furusho K Myelodysplastic syndrome presenting as third malignancy after non-Hodgkin's lymphoma and osteosarcoma Ann Hematol 74 95 97 1997 10.1007/s002770050264 9063380 \n32 Kimura K Shinmura K Hasegawa T Beppu Y Yokoyama R Yokota J Germline p53 mutation in a patient with multiple primary cancers Jpn J Clin Oncol 31 349 351 2001 10.1093/jjco/hye070 11518751 \n33 Kousaka J Fujii K Yorozuya K Mouri Y Yoshida M Nakano S Fukutomi T Takahashi E Yokoi T A case of quadruple primary malignancies including breast, tongue and thyroid cancers and osteosarcoma in a young female without karyotype abnormality Breast Cancer 21 500 503 2014 10.1007/s12282-011-0271-8 21562838 \n34 Hauben EI Bielack S Grimer R Jundt G Reichardt P Sydes M Taminiau AH Hogendoorn PC Clinico-histologic parameters of osteosarcoma patients with late relapse Eur J Cancer 42 460 466 2006 10.1016/j.ejca.2005.09.032 16426841 \n35 Jaffe N Pearson P Yasko AW Lin P Herzog C Raymond K Single and multiple metachronous osteosarcoma tumors after therapy Cancer 98 2457 2466 2003 10.1002/cncr.11800 14635081 \n36 Currall VA Dixon JH Synchronous multifocal osteosarcoma: Case report and Literature review Sarcoma 2006 53901 2006 10.1155/SRCM/2006/53901 17251658 \n37 Anderson ME Update on survival in osteosarcoma Orthop Clin North Am 47 283 292 2016 10.1016/j.ocl.2015.08.022 26614941 \n38 van den Berg H Schreuder WH de Lange J Osteosarcoma: A comparison of jaw versus nonjaw localizations and review of the literature Sarcoma 2013 316123 2013 10.1155/2013/316123 23956680 \n39 Kumar VS Barwar N Khan SA Surface osteosarcomas: Diagnosis, treatment and outcome Indian J Orthop 48 255 261 2014 10.4103/0019-5413.132503 24932030 \n40 Bertoni F Bacchini P Staals EL Davidovitz P Dedifferentiated parosteal osteosarcoma: The experience of the Rizzoli Institute Cancer 103 2373 2382 2005 10.1002/cncr.21039 15852358 \n41 Bertoni F Dallera P Bacchini P Marchetti C Campobassi A The Istituto Rizzoli-Beretta experience with osteosarcoma of the jaw Cancer 68 1555 1563 1991 10.1002/1097-0142(19911001)68:7<1555::AID-CNCR2820680717>3.0.CO;2-0 1893357 \n42 Sawair FA Cheng J Hao N Maruyama S Hoshina H Takagi R Koyama J Hayashi T Saku T Periosteal osteosarcoma of the jaw bones: a clinicopathologic review Oral Med Pathol 12 3 10 2007 10.3353/omp.12.3 \n43 Brenner W Bohuslavizki KH Eary JF PET imaging of osteosarcoma J Nucl Med 44 930 942 2003 12791822 \n44 Moertel CG Dockerty MB Baggenstoss AH Multiple primary malignant neoplasms. I. Introduction and presentation of data Cancer 14 221 230 1961 10.1002/1097-0142(196103/04)14:2<221::AID-CNCR2820140202>3.0.CO;2-6 13771652 \n45 Kim MS Sim YS Lee SY Jeon DG Occult thyroid carcinoma detected by FDG-PET scan in elderly osteosarcoma patients: Report of two cases Ann Nucl Med 21 529 532 2007 10.1007/s12149-007-0058-3 18030586 \n46 Gavane S Price AP Magnan H Mahajan S Pandit-Taskar N Multifocal osteosarcoma: Unusual presentation and imaging findings Clin Nucl Med 42 e202 e206 2017 10.1097/RLU.0000000000001560 28166155 \n47 Kneisl JS Patt JC Johnson JC Zuger JH Is PET useful in detecting occult nonpulmonary metastases in pediatric bone sarcomas? Clin Orthop Relat Res 450 101 104 2006 10.1097/01.blo.0000229329.06406.00 16906103 \n48 Jain KS Sikora AG Baxi SS Morris LG Synchronous cancers in patients with head and neck cancer: Risks in the era of human papillomavirus-associated oropharyngeal cancer Cancer 119 1832 1837 2013 10.1002/cncr.27988 23423883 \n49 Coyte A Morrison DS McLoone P Second primary cancer risk-the impact of applying different definitions of multiple primaries: Results from a retrospective population-based cancer registry study BMC Cancer 14 272 2014 10.1186/1471-2407-14-272 24742063 \n50 Yildiz FR Avci A Dereci O Erol B Celasun B Gunhan O Gnathic osteosarcomas, experience of four institutions from Turkey Int J Clin Exp Pathol 7 2800 2808 2014 25031699 \n51 Kahi CJ Imperiale TF Juliar BE Rex DK Effect of screening colonoscopy on colorectal cancer incidence and mortality Clin Gastroenterol Hepatol 7 770 775 2009 10.1016/j.cgh.2008.12.030 19268269 \n52 Wang HY Ding HJ Chen JH Chao CH Lu YY Lin WY Kao CH Meta-analysis of the diagnostic performance of [18F]FDG-PET and PET/CT in renal cell carcinoma Cancer Imaging 12 464 474 2012 10.1102/1470-7330.2012.0042 23108238 \n53 Chang KJ Kong CB Cho WH Jeon DG Lee SY Lim I Lim SM Usefulness of increased 18F-FDG uptake for detecting local recurrence in patients with extremity osteosarcoma treated with surgical resection and endoprosthetic replacement Skeletal Radiol 44 529 537 2015 10.1007/s00256-014-2063-7 25431093 \n54 Franzius C Daldrup-Link HE Wagner-Bohn A Sciuk J Heindel WL Jürgens H Schober O FDG-PET for detection of recurrences from malignant primary bone tumors: Comparison with conventional imaging Ann Oncol 13 157 160 2002 10.1093/annonc/mdf012 11863097 \n55 Piperkova E Mikhaeil M Mousavi A Libes R Viejo-Rullan F Lin H Rosen G Abdel-Dayem H Impact of PET and CT in PET/CT studies for staging and evaluating treatment response in bone and soft tissue sarcomas Clin Nucl Med 34 146 150 2009 10.1097/RLU.0b013e3181966f9d 19352275 \n56 Fuglø HM Jørgensen SM Loft A Hovgaard D Petersen MM The diagnostic and prognostic value of 18F-FDG PET/CT in the initial assessment of high-grade bone and soft tissue sarcoma. A retrospective study of 89 patients Eur J Nucl Med Mol Imaging 39 1416 1424 2012 10.1007/s00259-012-2159-z 22699526\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-1074",
"issue": "15(6)",
"journal": "Oncology letters",
"keywords": "FDG-PET; colorectal cancer; head and neck; multiple primary neoplasms; myelodysplastic syndrome; oral; osteosarcoma; second primary",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "9901-9907",
"pmc": null,
"pmid": "29928362",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "28965545;28417853;23108238;28248415;27154292;23563998;16426841;13771652;19268269;26304877;11863097;14635081;26590915;9063380;25116228;23956680;24742063;15170137;12791822;17164644;18030586;16906103;23805315;12365021;28166155;12891382;15852358;17251658;28405727;25539251;9307198;27082077;23670899;25457829;19352275;23645766;26614941;20922787;23423883;24741327;21562838;11118462;23801904;26379830;22699526;25031699;24652233;28228934;11518751;25192682;1893357;25431093;24932030",
"title": "Triple primary malignancies of surface osteosarcoma of jaw, myelodysplastic syndrome and colorectal cancer as a second primary cancer detected by PET2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography: A case report.",
"title_normalized": "triple primary malignancies of surface osteosarcoma of jaw myelodysplastic syndrome and colorectal cancer as a second primary cancer detected by pet2 18f fluoro 2 deoxy d glucose positron emission tomography a case report"
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"literaturereference": "MARUYAMA, N.. TRIPLE PRIMARY MALIGNANCIES OF SURFACE OSTEOSARCOMA OF JAW, MYELODYSPLASTIC SYNDROME AND COLORECTAL CANCER AS A SECOND PRIMARY CANCER DETECTED BY PET2-[18F]-FLUORO-2-DEOXY-D-GLUCOSE POSITRON EMISSION TOMOGRAPHY: A CASE REPORT. ONCOLOGY LETTERS. 2018?15(6):9901-9907",
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{
"abstract": "OBJECTIVE\nThe aim of this study was to assess the safety profile of ferumoxytol as an intravenous magnetic resonance imaging contrast agent in children.\n\n\nMETHODS\nWe prospectively evaluated the safety of ferumoxytol administrations as an \"off-label\" contrast agent for magnetic resonance imaging in nonrandomized phase 4 clinical trials at 2 centers. From September 2009 to February 2015, 49 pediatric patients (21 female and 28 male, 5-18 years) and 19 young adults (8 female and 11 male, 18-25 years) were reported under an investigator-initiated investigational new drug investigation with institutional review board approval, in health insurance portability and accountability act compliance, and after written informed consent of the child's legal representative or the competent adult patient was obtained. Patients received either a single dose (5 mg Fe/kg) or up to 4 doses of ferumoxytol (0.7-4 mg Fe/kg) intravenously, which were approximately equivalent to one third of the dose for anemia treatment. We monitored vital signs and adverse events directly for up to 1 hour after injection. In addition, we examined weekly vitals, hematologic, renal, and liver serum panels for 1 month after injection in over 20 pediatric patients. At fixed time points before and after ferumoxytol injection, data were evaluated for significant differences by a repeated measures linear mixed model.\n\n\nRESULTS\nFour mild adverse events, thought to be related to ferumoxytol, were observed within 1 hour of 85 ferumoxytol injections: 2 episodes of mild hypotension and 1 case of nausea in 65 injections in pediatric patients without related clinical symptoms. One young adult patient developed warmness and erythema at the injection site. All adverse events were self-resolving. No spontaneous serious adverse events were reported. At a dose of 5 mg Fe/kg or lower, intravenous ferumoxytol injection had no clinical relevance or statistically significant effect (P > 0.05) on vital signs, hematological parameters, kidney function, or liver enzymes within 1 month of the injection.\n\n\nCONCLUSIONS\nFerumoxytol was overall well tolerated among 49 pediatric and 19 young adult patients experiencing various tumors or kidney transplants without major adverse events or signs of hematologic and kidney impairment or liver toxicity. Larger studies are needed to determine the incidence of anaphylactic reactions.",
"affiliations": "Department of Radiology, Molecular Imaging Program at Stanford (MIPS) and Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.;Department of Radiology, Molecular Imaging Program at Stanford (MIPS) and Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.;Department of Radiation Oncology, Stanford University, Stanford, CA, USA.;Department of Pediatrics, Section of Pediatric Hematology and Oncology, Stanford University, Stanford, CA, USA.;Department of Pediatrics, Section of Pediatric Hematology and Oncology, Stanford University, Stanford, CA, USA.;University of South Carolina School of Medicine, Columbia, SC, USA.;Departments of Neurology and Neurosurgery, Oregon Health & Science University, Portland, OR, USA, Portland Veterans Affairs Medical Center, Portland, OR, USA.;Departments of Neurology and Neurosurgery, Oregon Health & Science University, Portland, OR, USA, Portland Veterans Affairs Medical Center, Portland, OR, USA.;Department of Radiology, Molecular Imaging Program at Stanford (MIPS) and Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.",
"authors": "Muehe|Anne M|AM|;Feng|Dan|D|;von Eyben|Rie|R|;Luna-Fineman|Sandra|S|;Link|Michael P|MP|;Muthig|Travis|T|;Huddleston|Amy E|AE|;Neuwelt|Edward A|EA|;Daldrup-Link|Heike E|HE|",
"chemical_list": "D003287:Contrast Media; D052203:Ferrosoferric Oxide",
"country": "United States",
"delete": false,
"doi": "10.1097/RLI.0000000000000230",
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"abstract": "Rituximab (RTX) is a monoclonal chimeric antibody directed against the CD20 antigen of B lymphocytes. Late onset neutropenia (LON) is a recognised complication of rituximab usually occurring 4 weeks after the last dose and is reported in both haematological and rheumatological conditions. However, it has never been described in a patient with myositis and systemic sclerosis overlap disease. We describe a case of LON in a 54-year-old man who was diagnosed with myositis and then systemic sclerosis overlap disease. It resolved within 7 days, and the patient did not suffer neutropenic sepsis or any other complications. We propose similar mechanisms for LON as described in other conditions and routine blood monitoring in such patients.",
"affiliations": "Rheumatology Department, Salford Royal Foundation Trust, Manchester, United Kingdom.;Neurology Department, Salford Royal Foundation Trust, Manchester, United Kingdom.;Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pennsylvania, USA.;Rheumatology Department, Salford Royal Foundation Trust, Manchester, United Kingdom.;Rheumatology Department, Salford Royal Foundation Trust, Manchester, United Kingdom.",
"authors": "Akram|Qasim|Q|;Roberts|Mark|M|;Oddis|Chester|C|;Herrick|Arianne|A|;Chinoy|Hector|H|",
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"fulltext": "\n==== Front\nReumatologiaReumatologiaRUReumatologia0034-62332084-9834Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 2717310.5114/reum.2016.58760Case ReportRituximab-induced neutropenia in a patient with inflammatory myopathy and systemic sclerosis overlap disease Akram Qasim 1Roberts Mark 2Oddis Chester 3Herrick Arianne 1Chinoy Hector 11 Rheumatology Department, Salford Royal Foundation Trust, Manchester, United Kingdom2 Neurology Department, Salford Royal Foundation Trust, Manchester, United Kingdom3 Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pennsylvania, USAAddress for correspondence: Qasim Akram, Rheumatology Department, Salford Royal Foundation Trust, M6 8HD Manchester, United Kingdom. e-mail: qasim.akram.qa@gmail.com24 3 2016 2016 54 1 35 37 10 12 2015 31 1 2016 Copyright © Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie 20162016This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Rituximab (RTX) is a monoclonal chimeric antibody directed against the CD20 antigen of B lymphocytes. Late onset neutropenia (LON) is a recognised complication of rituximab usually occurring 4 weeks after the last dose and is reported in both haematological and rheumatological conditions. However, it has never been described in a patient with myositis and systemic sclerosis overlap disease. We describe a case of LON in a 54-year-old man who was diagnosed with myositis and then systemic sclerosis overlap disease. It resolved within 7 days, and the patient did not suffer neutropenic sepsis or any other complications. We propose similar mechanisms for LON as described in other conditions and routine blood monitoring in such patients.\n\nrituximabmyositissystemic sclerosisneutropenia\n==== Body\nIntroduction\nRituximab, a monoclonal chimeric antibody directed against the CD20 antigen of B lymphocytes, is used in the treatment of haematological malignancies, rheumatoid arthritis and ANCA-associated vasculitis. There is evidence for use of rituximab in systemic lupus erythematosus (SLE) and idiopathic inflammatory myopathy (IIM).\n\nA recognised complication of rituximab in lymphoma is late onset neutropenia (LON), which may be defined as grade 3 (neutrophil count 0.5–1.0 × 106) or grade 4 (< 0.5 × 106) in the absence of other causes, occurring at least 4 weeks after rituximab [1]. Data regarding LON in rheumatic autoimmune conditions are sparse [1]. To date, there have been no reports of rituximab-induced neutropenia in idiopathic inflammatory myopathy (IIM) [2]. We describe a case of rituximab-induced neutropenia in a patient with refractory IIM/systemic sclerosis overlap.\n\nCase report\nA 54-year-old man presented with a 10-month history of chest pain and painful hands, shoulders and thighs. He described difficulty rising from a chair and lifting his arms above his head. Cardio-respiratory and abdominal systems were unremarkable, with no sclerodermatous features initially evident. There was quadriceps wasting with associated proximal weakness on Kendall scale manual muscle testing [3]: hip flexion 7/10, knee extension 8/10, and shoulder abduction 9/10 bilaterally (MMT24 248/260). Serum creatine kinase (CK) was 10.813 µ/l (< 190 µ/l), cardiac troponin T (cTnT) 169 ng/l (<14 ng/l), ANA 1/1000 speckled pattern. Myositis specific/associated antibody testing using serum immunoprecipitation was negative, although anti-Ro52 was weakly positive on immunoblot. Anti-topoisomerase, anti-RNA polymerase III and anti-HMG CoA reductase antibody tests were also negative. The initial ECG and echocardiogram were unremarkable. Electromyography showed lower limb myopathic unit potentials. MR thigh imaging showed muscle oedema on short tau inversion recovery sequences with no T1 fatty muscle replacement. A trapezius muscle biopsy showed necrotic/regenerative activity, occasional non-necrotic fibres with invasion by inflammatory cells, and widespread strong HLA-1 upregulation. An initial diagnosis of IIM with additional features of necrotizing myopathy was made.\n\nHe was commenced on 60 mg prednisolone and after one month due to clinical non-response received six cycles of cyclophosphamide as per CYCLOPS [4]. He improved clinically but the CK remained raised (4,500 µ/l). Cyclophosphamide was discontinued as the patient felt markedly unwell after treatment. Steroids were further weaned as IIM symptoms had improved. Methotrexate was not tolerated; mycophenolate mofetil was then introduced but stopped one year later after symptoms of abdominal pain and diarrhoea thought to be due to pseudo-intestinal obstruction. He then received three cycles of IV immunoglobulin, which dramatically improved his symptoms.\n\nFour months later the patient was admitted due to dizziness and loss of consciousness, with shortness of breath, poor exercise tolerance, orthopnoea and paroxysmal nocturnal dyspnoea. ECG showed runs of non-sustained ventricular tachycardia, an echocardiogram showed left ventricular systolic dysfunction with severe impairment, and cardiac MR showed dilated biventricular size and poor global systolic function. The patient also reported widespread skin tightness with worsening Raynaud's phenomenon but no digital ulcers. A modified Rodnan score of 24 confirmed the diagnosis of IIM/systemic sclerosis overlap with inflammatory cardiac disease activity and damage. An emergency cardiac defibrillator was implanted.\n\nFor treatment escalation, he received 2 × 1 g IV rituximab infusions as per the standard rheumatoid arthritis protocol [5]. Four months later, there was a significant improvement; MMT24 252/260, CK 282 µ/l, cTnT 79 ng/l. A second cycle of 1 g rituximab was commenced six months after the first cycle.\n\nA full blood count one month after the 2nd cycle revealed leucopenia (2.5 × 109) and profound neutropenia (0 × 109), confirmed on repeat testing, with normal haemoglobin and platelets. The patient remained well with no infectious symptoms and was on no medications that could cause leucopenia. Haematology consultation advised repeating the full blood count one week later and admission to hospital should he develop pyrexia or systemic features. A full blood count one week later showed resolution of both the neutropenia and leucopenia (Fig. 1), and during this period he remained well.\n\nFig. 1 Diagram showing trend of neutrophils following rituximab (RTX) administration.\n\nDiscussion\nRituximab-induced neutropenia in autoimmune disease has been reported at a similar frequency seen in haematological malignancies, between 3% and 27%, after approximately 5 months of rituximab administration [1, 6, 7]. In the landmark Rituximab in Myositis Trial, no cases of neutropenia were recorded [2]. Oddis et al. [2] reported seven episodes of leucopenia in 200 cases, ranging from 2.7 to 3.9 × 109 (personal correspondence).\n\nThe underlying mechanism of rituximab-induced LON remains poorly understood. Theories have included the development of novel anti-neutrophil antibodies and proliferation of rituximab-induced T cell large granulocyte lymphocytes leading to apoptosis of mature neutrophils [7]. Perturbation of stromal derived factor 1 level during B cell recovery may prevent neutrophil egress from bone marrow [6, 7]. However, Tesfa et al. [7] have presented flow cytometry data indicating that LON may occur at any stage of B cell recovery. Patients with LON also seem to have a longer and excessive duration of B cell depletion, generally resolving without requirement for colony stimulating factor. The clinical picture observed in our case is similar to that seen in haematological malignancies and other autoimmune diseases, where studies quote resolution of the neutropenia after a mean of 6.5 days [6].\n\n ***\n\nThis is the first case of neutropenia related to rituximab in a patient with IIM spectrum disorder.\n\n\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 Breuer G Ehrenfeld M Rosner I Late onset neutropenia following rituximab for rheumatic conditions Clin Rheumatol 2014 33 1337 1340 24599679 \n2 Oddis CV Reed AM Aggarwal R RIM Study Group Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis A Randomized, Placebo-Phase Trial Arthritis Rheum 2013 65 314 324 23124935 \n3 Rider LG Giannini EH Harris-Love M International Myositis Assessment and Clinical Studies Group Defining Clinical Improvement in Adult and Juvenile Myositis J Rheumatol 2003 30 603 617 12610824 \n4 De Groot K Muhler M Reinhold-Keller E Randomised controlled trial of daily oral versus pulsed cyclophosphamide for induction of remission in ANCA associated systemic vasculitis (abstract) Kidney Blood Pressure Res 2005 28 195 \n5 Emery P Rigby WF Combe B Efficacy and safety of rituximab (RTX) as first-line biologic therapy in patients with active rheumatoid arthritis (RA): results of a phase III randomized controlled study (SERENE) Arthritis Rheum 2008 58 S302 \n6 Besada E Koldingsnes W Nossent J Characteristics of late onset neutropenia in rheumatology patients: a case review analysis from a single centre QJ Med 2012 105 545 560 \n7 Tesfa D Ajeganova S Hagglund H Late onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections Arthritis Rheum 2011 63 2209 2214 21560117\n\n",
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{
"abstract": "β-blocker and calcium channel blocker toxicity generally present with bradycardia and hypotension. A 69-year-old woman presented after a suicide attempt with a β-blocker and calcium channel blocker overdose. Her blood pressure was 69/35 mm Hg and her HR was in the 40s. She was treated with calcium chloride, glucagon, a dextrose-insulin infusion and three vasopressors, but remained hypotensive. She suffered two cardiac arrests and required a transvenous pacemaker. When all interventions failed, she was started on a methylene blue infusion for refractory vasodilatory shock which resulted in a dramatic improvement in her blood pressure. The patient was successfully weaned off all vasopressors and from mechanical ventilation without any end-organ damage.",
"affiliations": "Department of Medicine Division of Pulmonary & Critical Care Medicine, Maimonides Medical Center, Brooklyn, New York, USA.",
"authors": "Aggarwal|Nidhi|N|;Kupfer|Yizhak|Y|;Seneviratne|Chanaka|C|;Tessler|Sidney|S|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D008751:Methylene Blue",
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"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000368:Aged; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D008751:Methylene Blue; D012769:Shock",
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"references": "21547182;10838557;14646355;20716671;1328604;22719809;8750129;7679577;21463621",
"title": "Methylene blue reverses recalcitrant shock in β-blocker and calcium channel blocker overdose.",
"title_normalized": "methylene blue reverses recalcitrant shock in blocker and calcium channel blocker overdose"
} | [
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{
"abstract": "Atherosclerosis is considered an irreversible process, with crucial contribution of inflammation and immune cells. Impact of cancer immunotherapy on a partly immune-driven disease, such as atherosclerosis, is poorly understood, but preclinical models suggest its worsening on programmed death/ligand-1 (PD-1/PD-L1) inhibitors. In a previously reported cohort of 11 patients with non-small cell lung cancer (NSCLC) treated with nivolumab and pre-existing complicated atheromatous plaques, 3 patients had a dramatic radiologic reduction of aortic plaques while on nivolumab; of these 3, 2 died receiving no further treatment. The remaining patient was an 83-year-old woman with history of arterial hypertension and hypothyroidism who was diagnosed with locally advanced squamous NSCLC. At relapse, complicated aortic atheromatous plaques were demonstrated on scans. The patient was then treated with nivolumab obtaining stable disease at radiological assessment, which also demonstrated almost complete vanishing of aortic plaques. After relapse and interval treatment with chemotherapy, she experienced new development of aortic atheromatous plaques. At further relapse she received atezolizumab, which yielded disease response and new reduction in aortic plaques, until nearly complete resolution. The observation of a repeated improvement of atheromatous plaques on treatment with PD-1/PD-L1 inhibitors favors the protective role of T cells on atheromatous plaques that is impaired by PD-L1 expression by plaque-associated macrophages. Validation by independent and prospective observation is needed.",
"affiliations": "Medical Oncology, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy.;Medical Oncology Unit, Policlinico S.Orsola-Malpighi, Via P. Albertoni, 15, Bologna, 40138, Italy.;Radiology Unit, Policlinico S.Orsola-Malpighi, Bologna, Italy.;Radiology Unit, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy.;Medical Oncology Unit, Policlinico S.Orsola-Malpighi, Bologna, Italy.;Medical Oncology Unit, Policlinico S.Orsola-Malpighi, Bologna, Italy.;Vascular Surgery, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy.;Internal Medicine, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy.;Pathological Anatomy Unit, Maggiore Hospital, Bologna, Italy.;Medical Oncology, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy.",
"authors": "Lamberti|Giuseppe|G|https://orcid.org/0000-0003-3069-7630;Gelsomino|Francesco|F|https://orcid.org/0000-0002-9204-1728;Brocchi|Stefano|S|;Poerio|Antonio|A|;Melotti|Barbara|B|;Sperandi|Francesca|F|;Gargiulo|Mauro|M|;Borghi|Claudio|C|;Fiorentino|Michelangelo|M|;Ardizzoni|Andrea|A|",
"chemical_list": null,
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"doi": "10.1177/1758835920913801",
"fulltext": "\n==== Front\nTher Adv Med Oncol\nTher Adv Med Oncol\nTAM\nsptam\nTherapeutic Advances in Medical Oncology\n1758-8340 1758-8359 SAGE Publications Sage UK: London, England \n\n10.1177/1758835920913801\n10.1177_1758835920913801\nCase Report\nNew disappearance of complicated atheromatous plaques on rechallenge with PD-1/PD-L1 axis blockade in non-small cell lung cancer patient: follow up of an unexpected event\nhttps://orcid.org/0000-0003-3069-7630Lamberti Giuseppe Medical Oncology, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy\n https://orcid.org/0000-0002-9204-1728Gelsomino Francesco Medical Oncology Unit, Policlinico S.Orsola-Malpighi, Via P. Albertoni, 15, Bologna, 40138, Italy\n Brocchi Stefano Radiology Unit, Policlinico S.Orsola-Malpighi, Bologna, Italy\n Poerio Antonio Radiology Unit, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy\n Melotti Barbara Medical Oncology Unit, Policlinico S.Orsola-Malpighi, Bologna, Italy\n Sperandi Francesca Medical Oncology Unit, Policlinico S.Orsola-Malpighi, Bologna, Italy\n Gargiulo Mauro Vascular Surgery, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy\n Borghi Claudio Internal Medicine, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy\n Fiorentino Michelangelo Pathological Anatomy Unit, Maggiore Hospital, Bologna, Italy\n Ardizzoni Andrea Medical Oncology, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy\nMedical Oncology Unit, Policlinico S.Orsola-Malpighi, Bologna, Italy\n francesco_gelsomino@aosp.bo.it\n24 7 2020 \n2020 \n12 175883592091380121 8 2019 5 2 2020 © The Author(s), 20202020SAGE Publications Ltd 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 (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Atherosclerosis is considered an irreversible process, with crucial contribution of inflammation and immune cells. Impact of cancer immunotherapy on a partly immune-driven disease, such as atherosclerosis, is poorly understood, but preclinical models suggest its worsening on programmed death/ligand-1 (PD-1/PD-L1) inhibitors. In a previously reported cohort of 11 patients with non-small cell lung cancer (NSCLC) treated with nivolumab and pre-existing complicated atheromatous plaques, 3 patients had a dramatic radiologic reduction of aortic plaques while on nivolumab; of these 3, 2 died receiving no further treatment. The remaining patient was an 83-year-old woman with history of arterial hypertension and hypothyroidism who was diagnosed with locally advanced squamous NSCLC. At relapse, complicated aortic atheromatous plaques were demonstrated on scans. The patient was then treated with nivolumab obtaining stable disease at radiological assessment, which also demonstrated almost complete vanishing of aortic plaques. After relapse and interval treatment with chemotherapy, she experienced new development of aortic atheromatous plaques. At further relapse she received atezolizumab, which yielded disease response and new reduction in aortic plaques, until nearly complete resolution. The observation of a repeated improvement of atheromatous plaques on treatment with PD-1/PD-L1 inhibitors favors the protective role of T cells on atheromatous plaques that is impaired by PD-L1 expression by plaque-associated macrophages. Validation by independent and prospective observation is needed.\n\natherosclerosisimmunotherapyNSCLCPD-1PD-L1cover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nNon-small cell lung cancer (NSCLC) has the highest mortality rate among solid tumors, irrespective of gender.1 Immunotherapy with immune checkpoint inhibitors (ICIs) is meant to restore immune response against tumor cells. This approach improved survival and revolutionized treatment algorithm in different settings and in many cancer types, including NSCLC.2,3 Inhibition of binding of programmed cell death 1 (PD-1) to its ligand (PD-L1) is the most exploited immune-enhancing mechanism in NSCLC. Alongside improved outcome, ICIs introduced a new set of side effects because of their ability to hyperactivate the immune system, whose severity spans from mild to fatal.4,5\n\nAtherosclerosis is a chronic multi-step inflammatory process characterized by deposition of lipids underneath the endothelium of medium-sized and large arteries. This process is led by high lipid plasma levels and activation of T cells and macrophages. The latter, in particular, phagocyte oxidized low-density lipoproteins (oxLDL), turning them into the classic ‘foam cells’.6 Atherosclerosis is largely considered a progressive phenomenon that eventually becomes irreversible; thus, available treatments to date, for example, acetylsalicylic acid and statins, are meant to prevent its progression, rather than revert it.\n\nHowever, the contribution of inflammation in atherosclerosis is clinically relevant, considering the results obtained through targeting of the pro-inflammatory cytokine IL-1β with the monoclonal antibody canakinumab in the CANTOS trial in patients with previous myocardial infarction and high C-reactive protein levels.7\n\nWe previously reported a retrospective analysis on 38 NSCLC patients who received nivolumab, a fully human IgG4 anti-PD-1 monoclonal antibody, within the Italian Expanded Access Program (EAP) at our institution.8 We then identified 11 patients who presented atherosclerotic disease, characterized by the presence of pre-existing complicated aortic plaques, according to the assessment by two independent radiologists. All patients had a history of smoking, and had received a prior platinum-based chemotherapy. Of the 11 patients, 10 had at least one cardiovascular risk factor, for which only 1 patient was taking statins. Among these patients, three (27%) had a significant improvement in atherosclerotic plaques while on nivolumab. No correlation between plaque reduction and other variable was observed, also because of the small sample size, but all three patients had immune-related adverse events while on nivolumab. Two of these patients died without receiving further treatment. Here, we report follow up of the remaining patient. Written consent was obtained from the patient, while local Institutional Review Board approval was waived as the patient in the report is not identifiable.\n\nCase report\nThe patient was an 83-year-old woman, who is a former heavy smoker. Her past medical history was notable for a long history of arterial hypertension, on pharmacological treatment with calcium channel blockers and angiotensin-converting enzyme inhibitors, and for autoimmune thyroiditis that had occurred 10 years ago and eventually resulted in hypothyroidism on hormone replacement therapy. The patient was diagnosed in July 2014 with stage IIIB squamous NSCLC and received sequential chemotherapy (carboplatin and paclitaxel) and radiation therapy, achieving nearly complete response. At 5 months after the end of treatment, an 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scan showed disease relapse in a single supraclavicular lymph node that was treated with definitive radiation therapy (45 grays in 18 fractions). However, at the subsequent response evaluation after 3 months, the patient developed a more extensive relapse (lung and mediastinal lymph nodes). She was then enrolled in the nivolumab Italian EAP, which was available at the time. The patient stayed on nivolumab for 2 years, achieving stable disease as best objective response. The treatment was well-tolerated saving grade 2 hypothyroidism flare, which required increase of the hormone replacement therapy dose. Before treatment with nivolumab, a CT scan demonstrated a complicated atheromatous plaque in the abdominal aorta wall (Figure 1a), that almost completely resolved while on nivolumab (Figure 1b), as previously reported.8 However, disease eventually progressed (lung and thoracic lymph nodes) so that carboplatin and paclitaxel chemotherapy was delivered, given the long time that had elapsed since the previous chemotherapy treatment. After five chemotherapy courses and initial partial response, the disease progressed again and the patient was enrolled in a phase IV clinical trial of atezolizumab, a humanized Fc-optimized anti-PD-L1 monoclonal antibody (TAIL study, NCT03285763). A core biopsy performed on one of the progressing supraclavicular lymph nodes demonstrated nodal metastasis consistent with squamous NSCLC and PD-L1 immunohistochemistry staining (SP263 clone, Ventana) in 30% of tumor cells. At the time atezolizumab was started, a computed tomography (CT) scan demonstrated the appearance of a new complicated atheromatous plaque in the thoracic aorta (Figure 2a). Interestingly, after 4 months of atezolizumab, the thoracic aorta plaque considerably improved again until nearly complete resolution (Figure 2b). In addition, partial response of disease was observed (Figure 3) so the patient is still on treatment. Atezolizumab was again well-tolerated but a grade 2 hypothyroidism flare [thyroid-stimulating hormone (TSH) level increased from 1.03 to 5.51 µU/ml and positive anti-thyroglobulin antibodies titer] required increase of patient’s hormone replacement therapy, as during the previous nivolumab course.\n\nFigure 1. Abdominal aorta atheromatous plaque (arrowhead) at (a) nivolumab start and (b) resolution after treatment.\n\nFigure 2. Thoracic aorta atheromatous plaque (arrowhead) at (a) atezolizumab start and (b) resolution after 4 months of treatment.\n\nFigure 3. Pathologic soft tissue at right hilum (arrowhead) at (a) atezolizumab start and (b) its reduction after 4 months of treatment consisting with disease response.\n\nDiscussion\nThe immune system plays a pivotal role in atherosclerosis.6 The interplay among immune cells and the complex cytokine network that regulates their differentiation and behavior have different and opposite effects on atheromatous plaque formation and progression. Moreover, the effect of some cells, for example, dendritic cells, can vary depending on plaque microenvironment and in early versus advanced plaque. Costimulatory and coinhibitory molecules are integrated in this network and modulate activity of the different cell populations.\n\nThe regression of complicated atheromatous plaques on anti-PD-1 and anti-PD-L1 treatment is opposed to what would be expected based on available preclinical data.\n\nIn fact, data from mouse models have shown that the interaction between PD-1 and PD-L1 promotes T cell tolerance towards vascular wall antigens,9 and disruption of the PD-1/PD-L1 signal accelerates atheromatous plaque formation.10 These data outline PD-1/PD-L1 as a protective pathway on atheromatous plaques, and suggest that anti-PD-1/PD-L1 ICIs could worsen atherosclerosis. Moreover, PD-1 expressed on human CD-8+ T cells acts synergistically with other immune-checkpoints molecules, such as Tim-3, in reducing pro-atherogenic cytokines (e.g. IFN-γ and TNF-α) while increasing anti-atherogenic ones (e.g. IL-10).11 These data seem consistent with the case of a patient with metastatic giant cell bone tumor receiving pembrolizumab, a humanized IgG4 anti-PD-1 monoclonal antibody, who suffered from two episodes of non-ST elevated myocardial infarction 2 months apart.12 The latter authors raised the possibility of a role of pembrolizumab treatment in accelerating coronary plaque growth or rupture due to the short time that had elapsed between the two events. However, this patient also had multiple cardiovascular risk factors (hypertension, diabetes and smoking habit) and experienced the second coronary event while off the dual antiplatelet therapy that had been started right after previous stent positioning. Dual antiplatelet therapy was held to perform a liver biopsy, scheduled due to elevation in liver function tests, which eventually demonstrated drug-induced liver injury and primary biliary cholangitis.\n\nMacrophages associated with atheromatous plaques in human arteries release pro-inflammatory cytokines, namely IL-1β and IL-6, that enhance innate immunity, and express high levels of PD-L1, that inhibit T cell response.13 Hypothesizing an immune-suppressive microenvironment, T cells from blood of patients with coronary artery disease (CAD) were exposed to nonself antigens, such as varicella-zoster virus (VZV) antigens, and found to response poorly, but responsiveness was enhanced in the presence of anti-PD-L1 antibodies. VZV infection reactivation and CAD had also been correlated since CAD patients show increased risk for VZV infection reactivation,14 and patients who develop VZV infection reactivation are at higher risk of cardiovascular events for 2 years.15\n\nMacrophages in human arteries hamper the protective role of T-cells on the atheromatous plaques through expression of PD-L1.13 As we reported previously,8 in noncancer patients with atheromatous plaques, strong PD-L1 expression was observed only on dendritic cells of complicated plaques. All these data taken together seem to suggest that the atheromatous plaque formation process in mice is different from that in humans, where T cells fulfill tissue-protective functions, which are controlled by PD-1-derived signals.16 This leads to the hypothesis that some aspects of atheromatous plaque formation in humans might not be reproducible in mouse models.\n\nThe resolution of complicated atheromatous plaques on treatment with both nivolumab and atezolizumab in this patient might suggest that the PD-1/PD-L1 interaction might hamper the T cell potentially protective action on atheromatous plaques. Several confounding factors may have affected this observation. For example, the tumor-related factors or the response to treatment (prolonged radiological stable disease on nivolumab and partial response on atezolizumab) might have played a role in plaque changes. It should also be considered that the observed phenomenon could have been an isolated idiosyncratic event in this patient. In addition, the possible contribution of immune-mediated adverse event occurrence should also be considered, since it can reflect an abnormal immune-system activation. If improvement of complicated plaques while on anti-PD-1/PD-L1 ICIs can be confirmed by independent researchers from other groups (e.g. by radiological imaging revision of clinical trial patients), it might be questioned whether the mouse models in use are adequate to represent the relationship between the immune system and atheromatous plaque, at least in theory, and if ICIs might be investigated as atherosclerosis treatments.\n\nConclusion\nIn conclusion, we observed repeated atheromatous plaque vanishing in a NSCLC patient during treatment with both nivolumab and atezolizumab. In our Center, two other patients have previously shown reduction of atheromatous plaque while on nivolumab. The interactions among cancer, atherosclerosis, and immune system are far from being comprehensively understood.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n\nORCID iDs: Giuseppe Lamberti \nhttps://orcid.org/0000-0003-3069-7630\n\nFrancesco Gelsomino \nhttps://orcid.org/0000-0002-9204-1728\n==== Refs\nReferences\n1 \nSiegel RL Miller KD Jemal A \nCancer statistics, 2019\n. CA Cancer J Clin \n2019 ; 69 : 7 –34\n.30620402 \n2 \nPlanchard D Popat S Kerr K , et al\nMetastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up\n. Ann Oncol \n2018 ; 29 : iv192–iv237.\n3 \nNCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) . Non-small cell lung cancer - Version 5\n, https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. (2019 , accessed 21 December 2019 ).\n4 \nAbdel-Wahab N Alshawa A Suarez-Almazor ME \nAdverse events in cancer immunotherapy\n. Adv Exp Med Biol \n2017 ; 995 : 155 –174\n.28321817 \n5 \nWang DY Salem JE Cohen JV , et al\nFatal toxic effects associated with immune checkpoint inhibitors\n. JAMA Oncol \n2018 ; 4 : 1721 –1728\n.30242316 \n6 \nLegein B Temmerman L Biessen EAL , et al\nInflammation and immune system interactions in atherosclerosis\n. Cell Mol Life Sci \n2013 ; 70 : 3847 –3869\n.23430000 \n7 \nRidker PM Everett BM Thuren T , et al\nAntiinflammatory therapy with canakinumab for atherosclerotic disease\n. N Engl J Med \n2017 ; 377 : 1119 –1131\n.28845751 \n8 \nGelsomino F Fiorentino M Zompatori M , et al\nProgrammed death-1 inhibition and atherosclerosis: can nivolumab vanish complicated atheromatous plaques?\n\nAnn Oncol \n2018 ; 29 : 284 –286\n.29106493 \n9 \nGotsman I Grabie N Dacosta R , et al\nProatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice\n. J Clin Invest \n2007 ; 117 : 2974 –2982\n.17853943 \n10 \nBu D Tarrio M Maganto-Garcia E , et al\nImpairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation\n. Arterioscler Thromb Vasc Biol \n2011 ; 31 : 1100 –1107\n.21393583 \n11 \nQiu MK Wang SC Dai YX , et al\nPD-1 and tim-3 pathways regulate CD8+ T cells function in atherosclerosis\n. PLoS One \n2015 ; 10 : e0128523 .26035207 \n12 \nKwan JM Cheng R Feldman LE \nHepatotoxicity and recurrent NSTEMI while on pembrolizumab for metastatic giant cell bone tumor\n. Am J Med Sci \n2019 ; 357 : 343 –347\n.30638772 \n13 \nWatanabe R Shirai T Namkoong H , et al\nPyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity\n. J Clin Invest \n2017 ; 127 : 2725 –2738\n.28604383 \n14 \nKe CC Lai HC Lin CH , et al\nIncreased risk of herpes zoster in diabetic patients comorbid with coronary artery disease and microvascular disorders: a population-based study in Taiwan\n. PLoS One \n2016 ; 11 : e0146750 .26751202 \n15 \nWu P Lin CL Sung FC , et al\nIncreased risk of cardiovascular events in patients with herpes zoster: a population-based study\n. J Med Virol \n2014 ; 86 : 772 –777\n.24482346 \n16 \nWeyand CM Berry GJ Goronzy JJ \nThe immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease\n. J Leukoc Biol \n2018 ; 103 : 565 –575\n.28848042\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1758-8340",
"issue": "12()",
"journal": "Therapeutic advances in medical oncology",
"keywords": "NSCLC; PD-1; PD-L1; atherosclerosis; immunotherapy",
"medline_ta": "Ther Adv Med Oncol",
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"pmid": "32782484",
"pubdate": "2020",
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"title": "New disappearance of complicated atheromatous plaques on rechallenge with PD-1/PD-L1 axis blockade in non-small cell lung cancer patient: follow up of an unexpected event.",
"title_normalized": "new disappearance of complicated atheromatous plaques on rechallenge with pd 1 pd l1 axis blockade in non small cell lung cancer patient follow up of an unexpected event"
} | [
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"abstract": "A 48-year-old male was referred to our hospital for evaluation of motor speech disorders and difficulty in the movement of both the hands. The clinical diagnosis was Trousseau's syndrome due to advanced gallbladder cancer (cT3aN1M0). The patient received anticoagulation therapy and systemic chemotherapy (gemcitabine and cisplatin). Motor speech disorders and difficulty in movement of both hands were recovered. After 2 courses of chemotherapy, the primary tumor developed a massive hepatic invasion and the peripheral blood eosinophils increased gradually. The patient was admitted to our hospital for abdominal distension, fever, right upper quadrant pain, systemic edema, loss of appetite, and general malaise. The peripheral blood eosinophil count was markedly elevated to 45,900/μl (90.3%). The serum level of GM-CSF was high and there was no evidence of leukemia, allergic status and other diseases. The patient was diagnosed as paraneoplastic eosinophilia with advanced gallbladder cancer, which was suspected to produce GM-CSF. The patient received palliative support and died of disseminated intravascular coagulation 15 days after admission. We herein reported a fatal case of gallbladder cancer suspected of producing GM-CSF.",
"affiliations": "Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461 Japan.;Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461 Japan.;Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461 Japan.;Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461 Japan.;Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461 Japan.",
"authors": "Tsunematsu|Masashi|M|0000-0001-6953-1801;Haruki|Koichiro|K|;Uwagawa|Tadashi|T|;Shiba|Hiroaki|H|;Yanaga|Katsuhiko|K|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-019-00395-1",
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"issn_linking": "2192-3183",
"issue": "9(2)",
"journal": "International cancer conference journal",
"keywords": "Eosinophilia; GM-CSF; Gallbladder cancer",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "55-58",
"pmc": null,
"pmid": "32257754",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": "10608500;9103460;26265628;15726608;17868854;28112388;24633025;25952647;17178706;11918455;2642572;9603798",
"title": "Gallbladder cancer accompanied by uncontrollable eosinophilia: report of a case.",
"title_normalized": "gallbladder cancer accompanied by uncontrollable eosinophilia report of a case"
} | [
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"drugstructuredosageunit": "009",
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"medicinalproduct": "CISPLATIN."
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"activesubstancename": "CISPLATIN"
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"drugdosagetext": "REGIMEN WAS REPEATED AT A 21-DAY, ON DAYS 1 AND 8",
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"drugindication": "GALLBLADDER CANCER STAGE III",
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"medicinalproduct": "CISPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": "48",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Disseminated intravascular coagulation",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Eosinophilia",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Granulocyte-colony stimulating factor level increased",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TSUNEMATSU M, HARUKI K, UWAGAWA T, SHIBA H, YANAGA K. GALLBLADDER CANCER ACCOMPANIED BY UNCONTROLLABLE EOSINOPHILIA: REPORT OF A CASE. INTERNATIONAL CANCER CONFERENCE JOURNAL. 2020? 9(2):55-58.",
"literaturereference_normalized": "gallbladder cancer accompanied by uncontrollable eosinophilia report of a case",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200429",
"receivedate": "20200429",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17723131,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20200714"
},
{
"companynumb": "JP-PFIZER INC-2020149175",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "25 MG/M2, EVERY 3 WEEKS (ON DAYS 1 AND 8, REPEATED AT A 21-DAY INTERVAL)",
"drugenddate": null,
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"drugindication": "GALLBLADDER CANCER METASTATIC",
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"medicinalproduct": "CISPLATIN."
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},
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"drugdosagetext": "UNK, CYCLIC (GEMCITABINE AND S-1 COMBINATION CHEMOTHERAPY)",
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"drugindication": "GALLBLADDER CANCER METASTATIC",
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"medicinalproduct": "TS-1"
},
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"drugindication": "GALLBLADDER CANCER METASTATIC",
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"medicinalproduct": "GEMCITABINE HYDROCHLORIDE."
},
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},
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"medicinalproduct": "GEMCITABINE HYDROCHLORIDE."
}
],
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"patientonsetage": "48",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Granulocyte-colony stimulating factor level increased",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Eosinophilia",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TSUNEMATSU, M.. GALLBLADDER CANCER ACCOMPANIED BY UNCONTROLLABLE EOSINOPHILIA: REPORT OF A CASE. INTERNATIONAL CANCER CONFERENCE JOURNAL. 2020?9 (2):55-58",
"literaturereference_normalized": "gallbladder cancer accompanied by uncontrollable eosinophilia report of a case",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200423",
"receivedate": "20200413",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17662533,
"safetyreportversion": 2,
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"sendertype": "2"
},
"serious": 1,
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}
] |
{
"abstract": "BACKGROUND\nLacosamide (LCM) is a new antiseizure medication, and intravenous (IV) loading of LCM is recently used against status epilepticus. IV loading of LCM is usually well-tolerated; however, there are concerns about LCM-induced serious adverse cardiac events. This study was aimed at investigating whether rapid IV loading of LCM is associated with adverse cardiac or hemodynamic events in cases of epilepsy emergencies in real-world settings.\n\n\nMETHODS\nWe reviewed medical records of consecutive adult epilepsy patients who received a single loading dose (400 mg) of IV LCM between January 2019 and December 2020 and included patients who exhibited status epilepticus or acute repetitive seizures. Electrocardiography findings, blood pressure, and heart rate before and after the IV infusion of LCM were collected.\n\n\nRESULTS\nOf the 85 patients included, 32.9 % (28/85 patients) had experienced at least one cardiac adverse event. The most common adverse events were new-onset first-degree atrioventricular block (19 patients) and hypotension (seven patients). Atrial fibrillation and bradycardia developed in two patients and atrial flutter in one. There were significant increases in the mean PR interval (from 169.3 msec to 184.5 msec, P < 0.01) and decreases in the mean heart rate (from 91.7 to 86.9, P = 0.01) after IV loading of LCM. Older age was significantly associated with a higher magnitude of the PR interval difference between before and after IV loading of LCM.\n\n\nCONCLUSIONS\nIn cases of epilepsy emergencies, adverse cardiac events commonly developed after IV loading of LCM, although most adverse events were mild in severity or not clinically significant. Elderly patients or patients with underlying cardiac diseases were prone to exhibiting a more prolonged PR interval after IV loading of LCM. Thus, the loading dose of IV LCM should be infused under careful ECG monitoring in these patients.",
"affiliations": "Department of Neurology, National Medical Center, Seoul, Republic of Korea.;Department of Neurology, Konkuk University School of Medicine, Seoul, Republic of Korea.;Department of Neurology, Inha University Hospital, Incheon, Republic of Korea.;Department of Neurology, Konkuk University School of Medicine, Seoul, Republic of Korea. Electronic address: drdongwkim@kuh.ac.kr.",
"authors": "Kim|Hyun Kyung|HK|;Lee|Hyemi|H|;Bae|Eun-Kee|EK|;Kim|Dong Wook|DW|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.eplepsyres.2021.106710",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "176()",
"journal": "Epilepsy research",
"keywords": "Lacosamide; PR interval; Sodium channel blocker; Status epilepticus",
"medline_ta": "Epilepsy Res",
"mesh_terms": null,
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "106710",
"pmc": null,
"pmid": "34265537",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cardiac effects of rapid intravenous loading of lacosamide in patients with epilepsy.",
"title_normalized": "cardiac effects of rapid intravenous loading of lacosamide in patients with epilepsy"
} | [
{
"companynumb": "KR-UCBSA-2021035956",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
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"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": "400 MILLIGRAM IV LOADING DOSE",
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"drugindication": "STATUS EPILEPTICUS",
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"medicinalproduct": "LACOSAMIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LACOSAMIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "SEIZURE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "LACOSAMIDE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Atrioventricular block first degree",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Electrocardiogram PR prolongation",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Atrial fibrillation",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bradycardia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Atrial flutter",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KIM HK, LEE H, BAE E?K, KIM DW. CARDIAC EFFECTS OF RAPID INTRAVENOUS LOADING OF LACOSAMIDE IN PATIENTS WITH EPILEPSY. EPILEPSY RESEARCH. 2021?176",
"literaturereference_normalized": "cardiac effects of rapid intravenous loading of lacosamide in patients with epilepsy",
"qualification": "1",
"reportercountry": "KR"
},
"primarysourcecountry": "KR",
"receiptdate": "20210730",
"receivedate": "20210730",
"receiver": {
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},
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"safetyreportid": 19642734,
"safetyreportversion": 1,
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},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "Heart transplantation is performed in patients with end-stage heart failure. The number of suitable donors for patients on the urgent heart transplantation waiting list is still low, and effort has been made to increase the number of suitable donors, including extended-criteria donors. We present a case report of heart retransplantation because of graft failure from an hepatitis B core antibody (anti-HBcore-positive, HBcAb [+]) and HBs antigen-negative (HBsAg [-]) donor to a seronegative recipient. We show that the procedure, with the use of antiviral prophylaxis, is a safe option for the recipient. Based on anatomopathologic and histopathologic examination of the explanted graft, we also suggest that acute cellular rejection in the transplanted heart may exist despite negative findings in right-sided endomyocardial biopsy.",
"affiliations": "Department of Cardiac, Vascular, and Endovascular Surgery and Transplantology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Zabrze, Poland. Electronic address: agnieszka.kuczaj@gmail.com.;Students' Scientific Association, Department of Cardiac, Vascular, and Endovascular Surgery and Transplantology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland.;Collegium Medicum, Jagiellonian University, Krakow, Poland.;Cardiac Surgery Ward, Silesian Center for Heart Diseases in Zabrze, Zabrze, Poland.",
"authors": "Kuczaj|Agnieszka|A|;Warwas|Szymon|S|;Przybyłowski|Piotr|P|;Zembala|Michał|M|",
"chemical_list": "D000998:Antiviral Agents; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D007166:Immunosuppressive Agents; D019259:Lamivudine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.11.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "53(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000998:Antiviral Agents; D006084:Graft Rejection; D006333:Heart Failure; D016027:Heart Transplantation; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006801:Humans; D007166:Immunosuppressive Agents; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D012086:Reoperation; D012307:Risk Factors; D014019:Tissue Donors",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1369-1370",
"pmc": null,
"pmid": "33551187",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Heart Retransplantation From an Hepatitis B Core Antibody (Anti-HBcore)-Positive Donor: A Case Report.",
"title_normalized": "heart retransplantation from an hepatitis b core antibody anti hbcore positive donor a case report"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-307881",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
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},
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{
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"drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION",
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"medicinalproduct": "GANCICLOVIR."
},
{
"actiondrug": "5",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"drugadministrationroute": "065",
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"drugindication": "IMMUNOSUPPRESSION",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "1 GRAM, DAILY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TRANSPLANT REJECTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstructuredosageunit": "002",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPREDNISOLONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "089247",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugindication": "TRANSPLANT REJECTION",
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"medicinalproduct": "PREDNISONE."
}
],
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"patientonsetage": "45",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pneumonia bacterial",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Burkholderia cepacia complex infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Blood alkaline phosphatase increased",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Transplant rejection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Gamma-glutamyltransferase increased",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KUCZAJ A, WARWAS S, PRZYBYLOWSKI P, ZEMBALA M. HEART RETRANSPLANTATION FROM AN HEPATITIS B CORE ANTIBODY (ANTI?HBCORE)?POSITIVE DONOR: A CASE REPORT. TRANSPLANT PROC. 2021?53:1369?1370",
"literaturereference_normalized": "heart retransplantation from an hepatitis b core antibody anti hbcore positive donor a case report",
"qualification": "3",
"reportercountry": "PL"
},
"primarysourcecountry": "PL",
"receiptdate": "20210816",
"receivedate": "20210816",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19705555,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "A 60-year-old man had a past history of urothelial carcinoma of the left renal pelvis treated with laparoscopic left total nephroureterectomy in October 2004. He underwent transurethral resection of the bladder tumor (TUR-Bt) twice for recurrence of urothelial carcinoma in the bladder in April 2014 and February 2015, and subsequently received intravesical Bacillus Calmette-Guerin (BCG) instillation at weekly intervalsfor prevention of recurrence. In November 2016, a year and a half after BCG induction, he received BCG therapy after urethral bougie to dilate the urethral stricture. After BCG therapy, he exhibited a continuously high fever. Immediate antituberculosis drug therapy in consideration of BCG sepsis failed to improve the symptoms, and all cultures from urine and blood were negative for mycobacterium tuberculosis. Serum liver enzyme was markedly elevated and chest CT showed diffuse interstitial shadows in both lower lungs. Thus, we considered that these symptoms were caused by a hypersensitivity reaction to BCG and started pulse steroid therapy. After pulse steroid therapy, body temperature, and hepatic function became normal and interstitial pneumonia subsided.",
"affiliations": "The Department of Urology, Hitachi General Hospital.;The Department of Urology, Hitachi General Hospital.;The Department of Urology, Hitachi General Hospital.;The Department of Urology, Hitachi General Hospital.;The Department of Urology, Hitachi General Hospital.;The Department of Urology, Faculty of Medicine, University of Tsukuba.",
"authors": "Nitta|Satoshi|S|;Sakka|Shotaro|S|;Endo|Tsuyoshi|T|;Komine|Manabu|M|;Tsutsumi|Masakazu|M|;Nishiyama|Hiroyuki|H|",
"chemical_list": "D001500:BCG Vaccine",
"country": "Japan",
"delete": false,
"doi": "10.14989/ActaUrolJap_63_10_427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-1994",
"issue": "63(10)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": "BCG; Hypersensitivity reaction",
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000283:Administration, Intravesical; D001500:BCG Vaccine; D005334:Fever; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "427-430",
"pmc": null,
"pmid": "29103257",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Fever, Hepatic Dysfunction and Interstitial Pneumonia Caused by Intravesical Bacillus Calmette-Guerin (BCG) Instillation after Urethral Bougie : A Case Report.",
"title_normalized": "fever hepatic dysfunction and interstitial pneumonia caused by intravesical bacillus calmette guerin bcg instillation after urethral bougie a case report"
} | [
{
"companynumb": "JP-SA-2018SA027061",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
"drugadditional": null,
"drugadministrationroute": "043",
"drugauthorizationnumb": "103943",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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"drugdosageform": null,
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"drugenddate": "201611",
"drugenddateformat": "610",
"drugindication": "BLADDER CANCER",
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"drugstartdate": "201611",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "BCG FOR IMMUNOTHERAPY"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
"drugadditional": null,
"drugadministrationroute": "043",
"drugauthorizationnumb": "103943",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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"drugindication": "BLADDER CANCER",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "BCG FOR IMMUNOTHERAPY"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
"drugadditional": null,
"drugadministrationroute": "043",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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"drugindication": "BLADDER CANCER",
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"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IMMUNOBLADDER"
}
],
"patientagegroup": "5",
"patientonsetage": "60",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hypersensitivity",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Interstitial lung disease",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatic function abnormal",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SAKKA S, ENDO T, KOMINE M, TSUTSUMI M, NISHIYAMA H. FEVER, HEPATIC DYSFUNCTION AND INTERSTITIAL PNEUMONIA CAUSED BY INTRAVESICAL BACILLUS CALMETTE-GUERIN (BCG) INSTILLATION AFTER URETHRAL BOUGIE: A CASE REPORT. HINYOKIKA KIYO. ACTA UROLOGICA JAPONICA, 2017? 63 (10): 427-430. DOI: 10.14989/ACTAUROLJAP_63_10_427.",
"literaturereference_normalized": "fever hepatic dysfunction and interstitial pneumonia caused by intravesical bacillus calmette guerin bcg instillation after urethral bougie a case report",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20180220",
"receivedate": "20180205",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14484965,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180509"
}
] |
{
"abstract": "OBJECTIVE\nTo describe a patient who developed hepatic failure, Stevens-Johnson syndrome (SJS), and died after receiving amoxicillin/clavulanate therapy.\n\n\nMETHODS\nA 37-year-old white man without significant past medical history received a 10-day course of amoxicillin/clavulanate for treatment of pneumonia. Thirty-two days after starting amoxicillin/clavulanate, he developed jaundice, rash, pruritus, and increasing fatigue. On further evaluation, with the exclusion of toxicity from other drugs or diseases, the time course to development of cholestatic jaundice correlated with the use of amoxicillin/clavulanate. The patient consequently died with progressive hepatic failure, renal failure, and SJS.\n\n\nCONCLUSIONS\nHepatic injury has been reported with amoxicillin/clavulanate. Signs and symptoms of jaundice and pruritus may appear up to to six weeks after stopping therapy. Most cases of liver injury have been benign and reversible on discontinuation of the amoxicillin/clavulanate. Reported hepatic reactions have been mainly cholestatic, with some mixed cholestatic/hepatocellular liver function test abnormalities.\n\n\nCONCLUSIONS\nClinicians should be aware of amoxicillin/clavulanate as a drug capable of causing hepatitis with eventual systemic dysfunction. While recovery is usually complete following withdrawal of the drug, in patients with rash associated with hepatic dysfunction, renal insufficiency, or other unusual symptoms, earlier consideration of initiating systemic steroids or liver transplantation referral, in hopes of avoiding progressive systemic response, might be worthwhile.",
"affiliations": "Division of Gastroenterology, Allegheny University Hospitals/Allegheny General, Pittsburgh, PA 15212, USA.",
"authors": "Limauro|D L|DL|;Chan-Tompkins|N H|NH|;Carter|R W|RW|;Brodmerkel|G J|GJ|;Agrawal|R M|RM|",
"chemical_list": "D019980:Amoxicillin-Potassium Clavulanate Combination",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.18104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "33(5)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D019980:Amoxicillin-Potassium Clavulanate Combination; D001774:Blood Chemical Analysis; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D006801:Humans; D017093:Liver Failure; D008297:Male; D011014:Pneumonia; D051437:Renal Insufficiency; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "560-4",
"pmc": null,
"pmid": "10369618",
"pubdate": "1999-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Amoxicillin/clavulanate-associated hepatic failure with progression to Stevens-Johnson syndrome.",
"title_normalized": "amoxicillin clavulanate associated hepatic failure with progression to stevens johnson syndrome"
} | [
{
"companynumb": "US-RANBAXY-2015US-93800",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "65109",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PNEUMONIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "AMOXICILLIN/CLAVULANATE"
}
],
"patientagegroup": null,
"patientonsetage": "37",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Renal failure",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Stevens-Johnson syndrome",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hepatic failure",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Jaundice cholestatic",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LIMAURO DL, CHAN-TOMPKINS NH, CARTER RW, BRODMERKEL GJ JR, AGRAWAL RM.. AMOXICILLIN/CLAVULANATE-ASSOCIATED HEPATIC FAILURE WITH PROGRESSION TO STEVENS-JOHNSON SYNDROME. ANN PHARMACOTHER. 1999;MAY;33(5):560-4",
"literaturereference_normalized": "amoxicillin clavulanate associated hepatic failure with progression to stevens johnson syndrome",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170925",
"receivedate": "20150305",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10891023,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171127"
}
] |
{
"abstract": "BACKGROUND\nPatients, providers, communities and health systems have struggled to achieve balance between access to opioid treatment for chronic pain and its potential harmful consequences: especially misuse, addiction and overdose. We developed an interdisciplinary clinic embedded within primary care (the Opioid Reassessment Clinic-ORC) with the goal of improving the quality of care of patients with co-occurring chronic pain and issues related to opioid safety, efficacy and/or misuse.\n\n\nMETHODS\nWe present three cases referred to the ORC that highlight complex clinical scenarios related to assessment and treatment of patients with chronic pain and issues related to opioid safety, efficacy and misuse.\n\n\nRESULTS\nIn the context of the three cases, with respect to assessment, we discuss: making the diagnosis of opioid use disorder; allowing the patient space to endorse lack of efficacy; identification of co-occurring hazardous alcohol use; and recognizing barriers to multimodal pain care. With respect to treatment, we discuss: making a change in treatment with which the patient may not agree; effectiveness of buprenorphine/naloxone for the treatment of chronic pain; responding to low efficacy; and making continued opioid therapy contingent on engagement with substance abuse treatment.\n\n\nCONCLUSIONS\nThe core components of our approach-biopsychosocial assessment and multimodal treatment planning with an emphasis on promoting functional goals and safety using clear communication and a patient-centered stance-should guide providers in the management of similar clinical scenarios. More evidence is needed to definitively guide specific interventions and points of clinical equipoise.",
"affiliations": "VA Connecticut Healthcare System, 950 Campbell Avenue, Mail Stop 151B, West Haven, CT, 06516, USA. william.becker@yale.edu.;University of Alabama at Birmingham, BBRB 220a, 1720 2nd Avenue South, Birmingham, AL, 35233, USA. jessicasarahmerlin@gmail.com.;VA Connecticut Healthcare System, 950 Campbell Avenue, Mail Stop 151B, West Haven, CT, 06516, USA. ajay.manhapra@yale.edu.;VA Connecticut Healthcare System, 950 Campbell Avenue, Mail Stop 151B, West Haven, CT, 06516, USA. ellen.edens@yale.edu.",
"authors": "Becker|William C|WC|;Merlin|Jessica S|JS|;Manhapra|Ajay|A|;Edens|Ellen L|EL|",
"chemical_list": "D000701:Analgesics, Opioid; D000069479:Buprenorphine, Naloxone Drug Combination",
"country": "England",
"delete": false,
"doi": "10.1186/s13722-016-0050-0",
"fulltext": "\n==== Front\nAddict Sci Clin PractAddict Sci Clin PractAddiction Science & Clinical Practice1940-06321940-0640BioMed Central London 5010.1186/s13722-016-0050-0Case StudyManagement of patients with issues related to opioid safety, efficacy and/or misuse: a case series from an integrated, interdisciplinary clinic Becker William C. +1 203-932-5711william.becker@yale.edu Merlin Jessica S. jessicasarahmerlin@gmail.com Manhapra Ajay ajay.manhapra@yale.edu Edens Ellen L. ellen.edens@yale.edu VA Connecticut Healthcare System, 950 Campbell Avenue, Mail Stop 151B, West Haven, CT 06516 USA Yale University School of Medicine, 367 Cedar Street, New Haven, CT 06510 USA University of Alabama at Birmingham, BBRB 220a, 1720 2nd Avenue South, Birmingham, AL 35233 USA 28 1 2016 28 1 2016 2016 11 330 7 2015 15 1 2016 © Becker et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPatients, providers, communities and health systems have struggled to achieve balance between access to opioid treatment for chronic pain and its potential harmful consequences: especially misuse, addiction and overdose. We developed an interdisciplinary clinic embedded within primary care (the Opioid Reassessment Clinic—ORC) with the goal of improving the quality of care of patients with co-occurring chronic pain and issues related to opioid safety, efficacy and/or misuse.\n\nCase descriptions\nWe present three cases referred to the ORC that highlight complex clinical scenarios related to assessment and treatment of patients with chronic pain and issues related to opioid safety, efficacy and misuse.\n\nDiscussion and evaluation\nIn the context of the three cases, with respect to assessment, we discuss: making the diagnosis of opioid use disorder; allowing the patient space to endorse lack of efficacy; identification of co-occurring hazardous alcohol use; and recognizing barriers to multimodal pain care. With respect to treatment, we discuss: making a change in treatment with which the patient may not agree; effectiveness of buprenorphine/naloxone for the treatment of chronic pain; responding to low efficacy; and making continued opioid therapy contingent on engagement with substance abuse treatment.\n\nConclusions\nThe core components of our approach—biopsychosocial assessment and multimodal treatment planning with an emphasis on promoting functional goals and safety using clear communication and a patient-centered stance—should guide providers in the management of similar clinical scenarios. More evidence is needed to definitively guide specific interventions and points of clinical equipoise.\n\nKeywords\nChronic painOpioid use disorderPrescription drug misuseOpioid safetyInterdisciplinary careIntegrated carehttp://dx.doi.org/10.13039/100000738U.S. Department of Veterans Affairs (US)CDA 08-276Becker William C. http://dx.doi.org/10.13039/100000025National Institute of Mental Health (US)K23MH104073-01A1Merlin Jessica S. issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nWhile rates of opioid prescribing for pain may have reached a plateau in the US, adverse outcomes related to opioid therapy, most notably unintentional overdose deaths, remain a serious public health problem [1]. Patients, providers, communities and health systems have struggled to achieve balance between access to opioid treatment for chronic pain and potential harmful consequences of long term opioid therapy, especially misuse, addiction and overdose. Regulatory agencies and expert groups have published prescriber guidelines aimed at improving uptake of evidence-based practices including: (1) use of opioid treatment agreements; (2) regular monitoring for efficacy, safety and misuse using tools such urine drug testing and querying prescription monitoring databases; and (3) provision of or referral to addiction treatment if recurrent misuse or opioid use disorder is identified [2, 3]. These are becoming the standard of care for individuals on long-term opioid therapy.\n\nIn practice, primary care providers (PCPs), responsible for most of chronic pain management and opioid prescribing in the US, struggle to follow these guidelines, citing lack of clinic time for opioid management, inadequate training, and low confidence [4]. Use of opioid risk mitigation strategies has been low in primary care [5], even among patients at high risk for misuse [6]. It is therefore understandable that the most complex cases—those in which individuals on long-term opioids, often at high doses, have persistently poor function, exhibit concerning behaviors such as running out of opioids early, or develop a substance use disorder to an opioid or other drug—are extremely challenging to manage in primary care. Notably, even among experts in the field, there is no consensus regarding how to best address these clinical situations.\n\nIn an effort to support primary care in the management of patients with complex chronic pain on long-term opioid therapy, a multi-disciplinary team designed the Opioid Reassessment Clinic (ORC) at VA Connecticut Healthcare System [7]. (Co-author JSM directs a chronic pain clinic for individuals with HIV, with a similar scope of practice as the ORC [8]).\n\nEmbedded within primary care and staffed by an addiction psychiatrist, an internist with addiction and pain training, a behavioral health advanced practice nurse (APRN) and a clinical health psychologist, the ORC has served as a learning opportunity for management of complex chronic pain and opioids over the past 3 years. The purpose of this study is to present actual ORC cases (with some details changed to preserve anonymity) as a platform to describe our approach to assessment and treatment, with the goal of highlighting evidence-based practices as well as some approaches we employ based on pragmatic considerations where evidence is lacking. While not intended to be a comprehensive clinical discussion of each case, our aim is to provide practicing clinicians guidance on generalizable issues related to pain, opioid safety and addiction within each case. We intend the discussion in each case to be relevant to generalists and specialists alike.\n\nORC flow (see Fig. 1)\nThe team’s internist reviews all referrals and appropriate patients are scheduled for an initial intake. The team’s APRN performs a chart review prior to the initial evaluation covering information such as: summary of the consultation question, history of the pain complaint(s), engagement in multimodal pain treatment, current opioid dose and prescriber, evidence of aberrant medication-taking behavior, mental health diagnosis and degree of engagement in treatment, past medical history, and overall utilization of health services.Fig. 1 Opioid reassessment clinic flow\n\n\n\nThe patient is scheduled for a 1.5–2-h initial evaluation—the first part with the psychiatrist and subsequently, the internist. The psychiatric evaluation includes an assessment of pain generators, current level of functioning and pain interference, current treatment approaches, functional goals as identified by the patient, and the use and effectiveness of opioids for the pain condition. A discussion of any noted aberrancies occurs and education about current best-practice pain treatment is initiated. Additionally, a targeted mental health and substance use history is gathered along with any other pertinent medical history. Following this evaluation, the team meets to discuss the case and an initial plan is developed. The team internist then meets with the patient to discuss general impressions, perform a physical examination, elicit responses to any remaining questions, and collaborate with the patient in determining a plan.\n\nAn important point to emphasize in our general approach is the recognition that the intersection of chronic pain and opioid issues may be fraught with frustration, mistrust and dissatisfaction for both patients and providers. In view of this, we place special emphasis on transparency and clear communication both with the patient and teams of providers involved in the patient’s care. When communicating a potential treatment plan with the patient, we summarize our approach as the “7E’s”: empathize; elicit functional goals; educate; endorse an alternative plan consistent with patient’s functional goals; enlist patient’s buy-in; enact a follow-up plan; and equanimity. Anecdotally, we find this approach to increase the likelihood of preserving a therapeutic alliance and the patient’s engagement in the treatment process. In case 1, we include how this approach was employed, including specific useful phrases.Table 1 Core opioid reassessment clinic (ORC) treatment strategies in three cases\n\nCase\tPlan regarding opioid therapy\tPlan regarding multi-modal pain treatment\tPlan regarding management of co-occurring conditions\t\n64-year-old with severe COPD, PTSD and degenerative joint disease of the lumbar spine, chronic pain and long-term, high-dose opioid therapy. Diagnosed with mild opioid use disorder (OUD) in ORC\tPrior to OUD diagnosis: offered lower dose full-agonist opioid versus switch to buprenorphine/naloxone (BUP/NX)\nAfter OUD diagnosis: offered switch to BUP/NX maintenance or taper off\nWhen BUP/NX was deemed unsafe, it was discontinued and non-opioid pain treatment was continued\t\nHealth psychology met with patient at each ORC visit to establish functional goals and monitor progress\n\nPulmonary rehabilitation engaged patient in upper body and breathing exercises\t\nTreatment of significant PTSD symptoms. When a co-occurring condition is significantly contributing to pain, we make engagement in treatment of the condition part of the opioid treatment agreement\t\n65-year-old with history of low back pain, cervical and lumbar surgeries, spinal cord stimulator placement and high-dose opioid therapy. No opioid misuse present. Assessed as having low efficacy, high-dose opioid therapy\tInitially offered options: (1) taper down/off current opioid; (2) rotate to another full agonist, at a lower equivalent dose; (3) switch to BUP/NX for off-label treatment of pain. (Patient chose option 3)\nWhen BUP/NX was maximized without benefit, patient was offered a choice to taper off or switch to low dose full agonist opioid. He chose the latter option and is continued at a moderate opioid dose\t\nHealth psychology met with patient at each ORC visit for engagement in cognitive-behavioral therapy for pain\n\nNon-opioid medications were prescribed for neuropathic component of pain\tPatient had no significant pain-impacting co-occurring conditions\t\n56-year-old with alcohol use disorder and bilateral hip pain due to severe osteoarthritis treated with morphine. Exhibited opioid misuse and experienced a return to alcohol use\tInitially, expectations regarding safe opioid use were made explicit; morphine was continued and closely monitored\nFollowing return to alcohol use, morphine was tapered off. Tramadol was continued as long as safe use is demonstrated\t\nOrthopedics was engaged to develop a plan for hip replacement\n\nHealth Psychology met with patient at each ORC visit for engagement in cognitive-behavioral therapy for pain\n\nNon-opioid medications were prescribed to treat inflammation\t\nAddiction treatment was a requirement for ongoing opioid therapy. Breathalyzers were obtained at each visit along with urine drug testing. We collaborated closely with addiction treaters to ensure their ability to reinforce the pain care plan\t\n\n\nGeneral ORC approach\nExamples of typical reasons for referral to the ORC include: concerning medication-taking behaviors (e.g. request for an early refill or a urine drug screen with an unexpected result); sole reliance on opioids with limited or no engagement in other pain treatment modalities; unhealthy alcohol use; co-prescribed high-dose opioids and sedatives (most commonly benzodiazepines); significant co-occurring mental health symptoms; and an opioid use disorder on medication assisted therapy (i.e. methadone or buprenorphine/naloxone) with persistent, impairing pain. While these issues are complex, the principles we employ are the same standards for any patient with chronic pain, as described by the Institute of Medicine: biopsychosocial assessment and multi-modal pain treatment matched to the needs identified in the assessment [9]. As such, we structure each treatment plan around three core questions: What is the plan regarding opioid therapy?; What is the plan regarding multi-modal pain treatment?; and What is the plan regarding management of co-occurring conditions that will impact the likelihood of success of the pain care plan? This framework, including opioid management options described below, and how it was applied in the three cases is presented in Table 1.\n\nEmphasis on opioid safety\nRegarding opioid therapy, typically three potential scenarios emerge from the initial assessment:Misuse or safety without clear opioid use disorder: If misuse or safety are a concern, yet opioid use disorder is not clear, a trial of structured opioid therapy with or without an opioid dose reduction may be initiated. Structured opioid therapy consists of frequent monitoring of prescribed opioids as well as close follow-up of multimodal pain treatment engagement, achievement of functional goals, mood and patterns of medication use [10]. If after 3–9 months, patients are able to demonstrate safe medication use, improved function, and engagement in multimodal treatment, they are discharged back to primary care for continued implementation of the pain care plan. On the other hand, if addiction to opioids or other substances is identified during this period of structured monitoring, patients are transitioned to addiction treatment, including potentially initiation of buprenorphine/naloxone (BUP/NX) within ORC (both MDs are certified prescribers). If other safety issues emerge that do not require ongoing maintenance therapy, an opioid taper is initiated.\n\nClear lack of efficacy: If lack of efficacy is apparent–high levels of pain and limited or worsening function despite moderate or high dose opioids (≥50 mg morphine equivalent daily dose), without evidence of opioid misuse or addiction–opioid reduction is initiated, with the potential for complete discontinuation.\n\nClear opioid use disorder: If opioid use disorder is clear at the initial evaluation, a trial of medication assisted therapy (MAT) is provided either within our clinic (i.e. initiation of BUP/NX) or in a specialty SA treatment program.\n\n\n\nCase 1 presentation\nThis is a 64-year-old patient with severe chronic obstructive pulmonary disease, post-traumatic stress disorder (PTSD) and degenerative joint disease of the lumbar spine, accompanied by many years of chronic pain and long-term high dose opioid therapy. Three months before ORC referral, the patient was admitted with recurrent hypercapneic respiratory failure, confusion, and a fall with head trauma. The inpatient team counseled the patient that high-dose opioid therapy (in the patient’s case 240 mg morphine equivalent daily dose [MEDD], well above the most common definition of high-dose therapy: ≥100 mg) likely contributed to these events and that dose lowering or discontinuation would be necessary. The patient’s opioid dose was lowered on discharge; the patient’s significant dissatisfaction with this decision prompted the PCP to refer the patient to the ORC. Over several visits to ORC spanning several months, we carefully observed the patient’s behavior relative to opioids. The patient repeatedly focused the conversation on opioids to the exclusion of other treatment modalities, and was largely unwilling to engage in discussions about the harms of opioids to his health. Providers’ attempts at patient-centered discussions to this end were met with escalating anger and agitation by the patient. Additionally, despite setting clear expectations and boundaries regarding how to take his medications, he ran out early twice during this time. As a result, we made the diagnosis of mild opioid use disorder, elicited goals of care—to be more engaged with family and make more outings with them, and further assessed the patient as having marked deconditioning, poorly-controlled PTSD and non-engagement in evidence-based mental health and multi-modal pain treatments. We tapered the patient off of full agonist opioids, transitioning to BUP/NX at 4/1 mg TID and delivered mental health, addiction, and multi-modal pain treatments within our clinic. Thrice daily dosing of BUP/NX is a common practice when the drug is used for pain as it is believed to have a 6–8 h analgesic half-life [11].\n\nCase 1 discussion\nAssessment: making the diagnosis of opioid use disorder\nAs described by many experts in the field [12–14], assessing the diagnostic criteria for opioid use disorder in a patient prescribed opioids for chronic pain can be challenging for a number of reasons. As per the DSM-5, tolerance (which this patient exhibited) and withdrawal symptoms cannot count towards the diagnosis in long-term opioid therapy for pain since some degree of tolerance is expected and withdrawal symptoms would likely occur if opioids were abruptly discontinued. Also, patients may characterize aberrant medication-taking behaviors (e.g. taking more opioid than prescribed) as pain-relief-seeking whereas providers may view these as evidence of loss of control [15]. To disentangle this, we rely heavily on the use of clear communication with the patient on what constitutes safe use, using a written treatment agreement to document the discussion. We clearly state: “If you are unable to follow these rules, you will have demonstrated that opioid treatment is not safe for you and we will stop it.” We view a patient’s inability to extinguish unsafe medication-taking behavior after he or she is aware that continued behavior will result in discontinuation of opioid therapy as, in and of itself, loss of control. Furthermore, recurrent behaviors inconsistent with the treatment agreement typically map onto DSM-5 criteria for opioid use disorder. For example, in this case, we made the diagnosis of mild opioid use disorder based on our assessment of the presence of three diagnostic criteria: craving, or a strong desire or urge to use opioids; recurrent opioid use in situations in which it was physically hazardous; and continued opioid use despite knowledge of having a persistent physical and psychological problems that were likely to have been caused or exacerbated by use.\n\nTreatment: making a change in treatment plan with which the patient may not agree\nIn this case, the presence of opioid use disorder and life-threatening complications exacerbated by opioid therapy were two criteria for which ongoing opioid therapy were contraindicated. Prescribing full opioid agonists like oxycodone to someone with an opioid use disorder is explicitly discouraged by existing guidelines [16]. Despite this, providers in both the inpatient and outpatient settings continued full agonist opioid therapy for the treatment of pain; in our experience, this is not an uncommon occurrence. This paradox highlights the clinical challenges and uncertainties these situations present. We hypothesize that there are several reasons why physicians continue to prescribe full opioid agonists in individuals with opioid use disorders. First, as above, opioid use disorder can be challenging to diagnose especially in individuals on long-term opioid therapy for chronic pain. Second, clinical inertia—not making an indicated change in opioid regimen—may be partly driven by wanting to avoid conflict with the patient [17], who might have strong beliefs related to effectiveness and necessity of opioid therapy [18], and partly in general empathy towards the suffering of the patient [19].\n\nUsing the 7Es, we negotiated a switch to BUP/NX over several months. We expressed empathy by stating clearly, “We know your pain is real and can understand the thought of being in more pain is frightening and stressful.” We elicited functional goals by asking, “What would you like to be able to do that pain is keeping you from doing these days?” In this case, the patient noted that he was not interacting with family as he wished. He was provided education about the risks of high dose opioids emphasizing those risks most relevant to him (i.e. respiratory failure) and given a description of what safe opioid use would look like (not taking more than prescribed, only one pharmacy and provider, etc.) We endorsed an alternative plan of continuing the lowered opioid dosing with engagement of multimodal treatment. We pointed out that his functional goal (family engagement) wasn’t being met with the high doses of opioids. Though sometimes counterintuitive to patients, we repeatedly reinforced the concept that his function might actually improve on lower doses once he was less sedated and having fewer medical emergencies. Also, over time, his pain might improve as well with lower opioid doses and engagement in multimodal pain care. Enlisting patient buy-in was difficult with this patient given his singular focus on obtaining higher doses of opioids. Nonetheless, we worked to increase the patient’s buy-in by providing him with options for treatment when available and sharing decisions when possible. While the “macro” treatment decision in this case (namely, discontinuing full agonist opioids) was not a shared decision, we find that when there are “micro” decisions where flexibility is possible (for example, frequency of BUP/NX dosing), letting the patient’s preferences guide such decisions is an important way to build trust and buy-in. Additionally, motivational interviewing, with its emphases on eliciting a person’s innate motivation and linking stated priorities to positive behavior change, can be useful in securing patient buy-in. A follow up plan was enacted after discussion and agreement with the entire ORC team. In all of our interactions, we strive for equanimity. In this case, the patient was often upset with the team, believing he had been lied to about the possibility of going back on full agonist opioids, sometimes even screaming at providers. Having a team to process interactions and, when needed, to step in or provide follow up coverage has been helpful in maintaining calm and staying patient-centered in the face of patient emotions.\n\nTreatment: effectiveness of BUP/NX for the treatment of chronic pain with co-occurring OUD\nWhile a full review is beyond the scope of this study, there are a number of observational studies [20] and case series [21–23] suggesting that BUP/NX can be an effective treatment for chronic pain. As with many pain treatments, predicting who will respond to BUP/NX has proved more challenging [24]. An important generalizable point is that had the patient not tolerated BUP/NX, either because of poor efficacy or side effects, a return to full agonist opioids for the treatment of chronic pain would not have been offered because of the diagnoses of opioid use disorder and life-threatening opioid-related complications, unless the patient’s goals of care were to change to comfort measures.\n\nTreatment: non-opioid options\nA wide array of generally safer non-opioid pharmacologic and non-pharmacologic options exist for managing this patient’s chronic pain, some of which have superior efficacy data to support them. Along these lines, our message to all patients in the ORC is as follows: the data are clear that a multi-modal pain management approach works best in the long-run for helping our patients achieve their functional goals; let us work with you to identify which combination will work best for you.\n\nCase 1 epilogue: After transitioning to BUP/NX, the patient had three more hospital admissions for COPD exacerbation with marked hypercapnia and somnolence. Dose reduction was employed; however, even with BUP/NX at 2 mg daily, markedly depressed sensorium was intermittently present. While non-adherence with home BiPAP and worsening COPD were perhaps most responsible for this symptom, we felt that BUP/NX was at best not helping the situation, and at worst, could be contributing. Additionally, the patient did not report improved pain with BUP/NX. Thus, it was discontinued altogether. The patient remains on non-pharmacologic and non-opioid pain treatments.\n\nCase 2 presentation\nThis is a 65-year-old patient with widespread degenerative joint disease and longstanding low back pain that has continued despite multiple cervical and lumbar surgeries and spinal cord stimulator placement. The PCP referred the patient to the ORC for consideration of an opioid rotation with dose reduction given tolerance to high doses of opioids (in this case, >200 mg MEDD). The patient was functionally quite active, pursuing an exercise-based hobby that required regular travel, and had no history of unsafe opioid use or misuse. However, the patient reported that the opioid regimen did not improve pain to a significant degree; he continued it because he had been on it for so long and worried what would happen if he were to stop. Therefore, in our clinical assessment, the patient did not have opioid use disorder, but would likely benefit—in terms of long-term safety—from decreasing the opioid dose. In the ORC, following a full assessment, the patient was provided a choice between (a) slow taper off opioids; (b) rotation to a different full agonist opioid but at a markedly lower dose; or (c) rotation to a trial of BUP/NX for treatment of chronic pain. After a thorough discussion, the patient favored the latter option given significant ambivalence about being on full agonist opioids long-term.\n\nCase 2 discussion\nAssessment: allowing the patient space to endorse lack of efficacy\nIn our experience, some providers doubt that patients would endorse low or absent efficacy of long-term opioids, since doing so would threaten ongoing receipt of opioids. However, in observational studies, a substantial minority of patients self-discontinue opioids due to lack of efficacy [25]. As illustrated by this case and prior literature [26], patients understandably fear the potential for withdrawal symptoms that often occurs when opioids are discontinued abruptly. We have observed that if concerns about ongoing, high-dose opioid therapy are clearly explained, and patients are reassured that a taper would occur in a cautious, step-wise fashion with close oversight, patients seem open to disclosing lack of efficacy. Importantly, this patient discussed this with the PCP first, demonstrating that a specialist’s involvement was not needed upfront.\n\nTreatment: responding to low efficacy\nIn our view, continuing ineffective opioid treatment is suboptimal, as it exposes the patient to cumulative opioid toxicity (e.g. osteoporosis, hypogonadism, and fall risk) with no corresponding benefit. In contrast to case 1, there was no evidence-guided indication for BUP/NX compared to rotation to a lower dose of a full agonist or taper off entirely, so the patient was given the choice. Also in contrast to case 1, had the trial of BUP/NX not succeeded, a return to full agonist opioids would have been considered, but, again, at a markedly lower dose. Of note, the use of BUP/NX in this setting is “off-label” insofar as it does not have FDA approval for treatment of chronic pain; however the DEA has endorsed such off-label use [27].\n\nCase 2 epilogue: The patient made the transition to BUP/NX easily, taking his initial dose at home. After the first 2 weeks, his dose was increased from 12 mg daily (divided 4 mg TID) to 18 mg because of inadequately controlled pain. His dose was ultimately increased to 24 mg daily, yet he still experienced significant pain that was interfering with his function. The ORC team considered this a failed trial of BUP/NX and offered him the option to taper off BUP/NX with no opioid after versus rotation to lower dose oxycodone. The patient chose the latter option and is now on 10 mg oxycodone QID (60 mg MEDD), noting markedly improved pain control.\n\nCase 3 presentation\nThis is a 56-year-old patient with bilateral hip pain due to severe osteoarthritis that significantly interfered with functioning for which the patient was prescribed morphine for several years. Nine months prior to ORC referral, the patient successfully completed a residential treatment program for his long-standing alcohol use disorder while continuing on long-term opioid therapy. Presently, the PCP referred the patient to the ORC after two episodes of running out of opioid prescriptions early (without early refill) and a brief return to alcohol use. In the ORC, we facilitated engagement in outpatient alcohol treatment by making continued opioid therapy contingent upon adherence with follow-up and required frequent ORC visits including breathalyzer tests and urine drug screens. Following another return to drinking, the patient was admitted to an intensive outpatient alcohol use disorder treatment program and was simultaneously tapered off morphine, transitioning to tramadol with adjuvant non-opioid medications including an NSAID, gabapentin, and topical lidocaine. While tramadol, a weak mu-receptor agonist with more prominent serotonin and norepinephrine reuptake inhibition, was still a risky medication in this patient in recovery, it is classified by the DEA as less risky (schedule V compared to oxycodone and morphine’s schedule II designation); plus the patient’s tramadol dose was markedly lower in terms of mg MEDD.\n\nAdditionally, orthopedics was consulted and agreed to schedule hip replacement surgery contingent upon several months of documented alcohol abstinence. This motivated the patient to adhere to appointments and monitoring as required by both ORC and addiction treatment providers. While the patient continued to request a switch to a “stronger” opioid, the ORC repeatedly reiterated that this was not an option given the recent history of misuse, the lack of evidence of improved functioning on such medications, and benefit of being on the lowest possible opioid dose prior to surgery. After 6 months of abstinence from alcohol, safe use of tramadol, and engagement in multimodal therapy including ongoing SA treatment, the patient was discharged from ORC to follow-up with PCP while awaiting scheduled surgery.\n\nCase 3 discussion\nAssessment: identification of co-occurring hazardous alcohol use\nIn this case, there was a documented history of alcohol use disorder, alerting us from the outset to the need for ongoing and frequent monitoring of alcohol use. In this patient, alcohol abstinence was the goal so we employed breathalyzer testing at each office visit and added on ethyl glucuronide (EtG) testing to each urine drug screen. As a highly sensitive assay [28], we find EtGs especially helpful in documenting abstinence but less helpful when some alcohol use is acceptable (e.g. in patients on low-dose opioid therapy without history of alcohol use disorder) and an easy test to incorporate into practice because the urine sample for the drug screen can be used. Relatedly, we believe alcohol abstinence should be a treatment goal for any patient on moderate- to high-dose of opioid therapy (≥50 mg MEDD) since NIAAA guidelines recommend abstinence in patients taking medications that enhance central sedation (http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking).\n\nAssessment: recognizing barriers to multimodal pain care\nNot infrequently, patients are ambivalent about the benefits of multimodal care. In these instances, we employ education and motivational interviewing—components of the 7Es approach–in an attempt to help the patient recognize the discrepancy between their stated functional goals and their plans to reach those goals. On the other hand, there are instances where misunderstanding of addiction by healthcare providers can prove its own barrier [29]. It is very reasonable for medical and surgical specialists to expect that addiction be treated prior to any invasive procedure. However, lack of collaboration between specialists and PCPs often means delays for patients in getting appropriate and timely interventions.\n\nTreatment: making continued opioid therapy contingent on engagement with addiction treatment\nAs stated above, opioid therapy should never be the sole treatment modality in chronic pain. We consider optimization of medical and psychiatric co-morbidities a necessary component of the multi-modal pain treatment approach. For example, attempts at optimization of diabetes control must accompany pain pharmacotherapy for the treatment of painful peripheral diabetic neuropathy. Analogously, we required engagement in addiction treatment as a pre-condition for ongoing opioid therapy in this patient, not only to mitigate risk, but to maximize potential benefit of the pain care plan. This requirement is communicated upfront with the patient as part of the treatment agreement.\n\nCase 3 epilogue: The patient underwent total hip replacement and received 2 weeks of full agonist opioid treatment (MSIR 15 mg Q6 PRN) following the surgery. After the 2-week post-operative period, the patient was transitioned back to tramadol. He remains abstinent from alcohol and participates fully in his hip rehabilitation program.\n\nConclusions\nThese three cases from the ORC were meant to represent common challenges at the intersection between chronic pain and opioid safety, efficacy and misuse. We summarized our approach related to several challenging issues regarding assessment and treatment. It is important to note that in this field where evidenced-based guidance is fairly sparse, the details of the treatment plans may vary from setting to setting. However, the core components–biopsychosocial assessment and multimodal treatment planning with an emphasis on promoting functional goals and safety using clear communication and a patient-centered stance—should hold constant.\n\nAdditionally, we recognize that the majority of pain care in the US is provided by front-line PCPs, providers who may not feel that the management strategies presented here fall within their scope of practice. Even among pain specialists, comfort with identifying and addressing opioid use disorders may vary. Chronic pain and addiction specialists like we have on the ORC team are helpful in such situations, but are not widely available. Until a systematic change occurs to increase the availability of such specialists, this disparity between need and availability will be present.\n\nAs the number of anecdotal recommendations above implied, there are several areas in this field where clinical research is needed: for example, comparative effectiveness of various opioid tapering and rotation strategies; randomized studies of BUP/NX for the treatment of chronic pain; and motivational interviewing techniques for these common scenarios. Of note, work is underway by an expert consensus group (including authors JSM and WCB) to help define best practices in providers’ management of unsafe medication-taking behaviors [30]. And, finally, as called for by the Institute of Medicine [9], improved pain-related instruction in undergraduate and graduate medical education programs is also a high priority in the path towards improved quality of care.\n\nAuthors’ contributions\nELE, AM, and WCB designed the study. ELE and WCB drafted the case presentations and discussions after a group discussion with all authors. JSM and AM provided substantial editorial input on the entire manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nThis work was supported by the VA’s Office of Research and Development, Health Services Research [CDA2 (08-276), Becker, PI] and the Substance Use Disorder QUERI (12-197, Becker PI) as well as the National Institutes of Health [K23MH104073-01A1, Merlin, PI]. Study sponsors had no role in study design; in the collection, analysis and interpretation of data; in the writing of the manuscript nor in the decision to submit the manuscript for publication.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Centers for Disease Control and Prevention Policy impact: prescription painkiller overdoses 2011 Atlanta Centers for Disease Control and Prevention \n2. 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Savage SR Definitions related to the medical use of opioids: evolution towards universal agreement [see comment] J Pain Symptom Manag 2003 26 1 655 667 10.1016/S0885-3924(03)00219-7 \n13. Compton WM Volkow ND Abuse of prescription drugs and the risk of addiction Drug Alcohol Depend 2006 83 Suppl 1 S4 S7 10.1016/j.drugalcdep.2005.10.020 16563663 \n14. Alford DP Compton P Samet JH Acute pain management for patients receiving maintenance methadone or buprenorphine therapy Ann Intern Med 2006 144 2 127 134 10.7326/0003-4819-144-2-200601170-00010 16418412 \n15. Upshur CC Bacigalupe G Luckmann R “They don’t want anything to do with you”: patient views of primary care management of chronic pain Pain Med 2010 11 12 1791 1798 10.1111/j.1526-4637.2010.00960.x 21029353 \n16. Federation of State Medical Boards Model policy on the use of opioid analgesics in the treatment of chronic Pain 2013 Euless Federation of State Medical Boards \n17. Nicolaidis C Police officer, deal-maker, or health care provider? Moving to a patient-centered framework for chronic opioid management Pain Med 2011 12 6 890 897 10.1111/j.1526-4637.2011.01117.x 21539703 \n18. Schieffer BM Pain medication beliefs and medication misuse in chronic pain J Pain 2005 6 9 620 629 10.1016/j.jpain.2005.04.004 16139781 \n19. Lembke A Why doctors prescribe opioids to known opioid abusers N Engl J Med 2012 367 17 1580 1581 10.1056/NEJMp1208498 23094719 \n20. Becker WC Buprenorphine/naloxone dose and pain intensity among individuals initiating treatment for opioid use disorder J Subst Abuse Treat 2015 48 1 128 131 10.1016/j.jsat.2014.09.007 25312475 \n21. Malinoff HL Barkin RL Wilson G Sublingual buprenorphine is effective in the treatment of chronic pain syndrome Am J Ther 2005 12 5 379 384 10.1097/01.mjt.0000160935.62883.ff 16148422 \n22. Daitch J Conversion of chronic pain patients from full-opioid agonists to sublingual buprenorphine Pain Phys 2012 15 3 suppl 59 66 \n23. Roux P Buprenorphine/naloxone as a promising therapeutic option for opioid abusing patients with chronic pain: reduction of pain, opioid withdrawal symptoms, and abuse liability of oral oxycodone Pain 2013 154 8 1442 1448 10.1016/j.pain.2013.05.004 23707283 \n24. Rosenblum A Sublingual buprenorphine/naloxone for chronic pain in at-risk patients: development and pilot test of a clinical protocol J Opioid Manag 2012 8 6 369 10.5055/jom.2012.0137 23264315 \n25. Noble M, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;1(1).\n26. Weiss RD Reasons for opioid use among patients with dependence on prescription opioids: the role of chronic pain J Subst Abuse Treat 2014 47 2 140 145 10.1016/j.jsat.2014.03.004 24814051 \n27. Heit HA Covington E Good PM Dear DEA Pain Med 2004 5 3 303 308 10.1111/j.1526-4637.2004.04044.x 15367311 \n28. Wurst FM Ethyl glucuronide discloses recent covert alcohol use not detected by standard testing in forensic psychiatric inpatients Alcohol Clin Exp Res 2003 27 3 471 476 10.1097/01.ALC.0000057942.57330.E2 12658113 \n29. Smith R Medicine and the marginalised: they deserve the best, not the poorest, care Br Med J (BMJ) 1999 319 7225 1589 10.1136/bmj.319.7225.1589 10600948 \n30. Merlin JS Common and challenging behaviors among patients taking long-term opioid therapy: Preliminary results of a Delphi study 2015 Washington, DC Oral presentation, The Association of Medical Education and Research in Substance Abuse\n\n",
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"mesh_terms": "D000437:Alcoholism; D000701:Analgesics, Opioid; D000069479:Buprenorphine, Naloxone Drug Combination; D059350:Chronic Pain; D006801:Humans; D009293:Opioid-Related Disorders; D059408:Pain Management; D011320:Primary Health Care; D058996:Quality Improvement",
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"abstract": "Gadolinium-based contrast agents (GBCAs) are frequently used in patients undergoing magnetic resonance imaging. In GBCAs gadolinium (Gd) is present in a bound chelated form. Gadolinium is a rare-earth element, which is normally not present in human body. Though the blood elimination half-life of contrast agents is about 90 minutes, recent studies demonstrated that some tissues retain gadolinium, which might further pose a health threat due to toxic effects of free gadolinium. It is known that the bone tissue can serve as a gadolinium depot, but so far only bulk measurements were performed. Here we present a summary of experiments in which for the first time we mapped gadolinium in bone biopsy from a male patient with idiopathic osteoporosis (without indication of renal impairment), who received MRI 8 months prior to biopsy. In our studies performed by means of synchrotron radiation induced micro- and submicro-X-ray fluorescence spectroscopy (SR-XRF), gadolinium was detected in human cortical bone tissue. The distribution of gadolinium displays a specific accumulation pattern. Correlation of elemental maps obtained at ANKA synchrotron with qBEI images (quantitative backscattered electron imaging) allowed assignment of Gd structures to the histological bone structures. Follow-up beamtimes at ESRF and Diamond Light Source using submicro-SR-XRF allowed resolving thin Gd structures in cortical bone, as well as correlating them with calcium and zinc.",
"affiliations": "TU Wien, Atominstitut, Stadionallee 2, Vienna, 1020, Austria. anna.turyanskaya@tuwien.ac.at.;TU Wien, Atominstitut, Stadionallee 2, Vienna, 1020, Austria.;TU Wien, Atominstitut, Stadionallee 2, Vienna, 1020, Austria.;Karlsruher Institute for Technology (KIT), ANKA Synchrotron Radiation Source, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Karlsruhe, 76344, Germany.;European Synchrotron Radiation Facility, Avenue des Martyrs 71, Grenoble, 38043, France.;Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, Oxfordshire, OX11 0DE, UK.;Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, Oxfordshire, OX11 0DE, UK.;Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich-Collin-Strasse 30, Vienna, 1140, Austria.;Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich-Collin-Strasse 30, Vienna, 1140, Austria.;Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich-Collin-Strasse 30, Vienna, 1140, Austria.;TU Wien, Atominstitut, Stadionallee 2, Vienna, 1020, Austria.;TU Wien, Atominstitut, Stadionallee 2, Vienna, 1020, Austria.",
"authors": "Turyanskaya|Anna|A|;Rauwolf|Mirjam|M|;Pichler|Vanessa|V|;Simon|Rolf|R|;Burghammer|Manfred|M|;Fox|Oliver J L|OJL|;Sawhney|Kawal|K|;Hofstaetter|Jochen G|JG|;Roschger|Andreas|A|;Roschger|Paul|P|;Wobrauschek|Peter|P|;Streli|Christina|C|",
"chemical_list": "D003287:Contrast Media; D005682:Gadolinium",
"country": "England",
"delete": false,
"doi": "10.1038/s41598-020-63325-9",
"fulltext": "\n==== Front\nSci Rep\nSci Rep\nScientific Reports\n2045-2322 Nature Publishing Group UK London \n\n63325\n10.1038/s41598-020-63325-9\nArticle\nDetection and imaging of gadolinium accumulation in human bone tissue by micro- and submicro-XRF\nTuryanskaya Anna anna.turyanskaya@tuwien.ac.at 1 Rauwolf Mirjam 1 Pichler Vanessa 1 Simon Rolf 2 Burghammer Manfred 3 Fox Oliver J. L. 4 Sawhney Kawal 4 Hofstaetter Jochen G. 56 Roschger Andreas 57 Roschger Paul 5 Wobrauschek Peter 1 Streli Christina 1 1 0000 0001 2348 4034grid.5329.dTU Wien, Atominstitut, Stadionallee 2, Vienna, 1020 Austria \n2 0000 0001 0075 5874grid.7892.4Karlsruher Institute for Technology (KIT), ANKA Synchrotron Radiation Source, Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen, Karlsruhe, 76344 Germany \n3 0000 0004 0641 6373grid.5398.7European Synchrotron Radiation Facility, Avenue des Martyrs 71, Grenoble, 38043 France \n4 0000 0004 1764 0696grid.18785.33Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE UK \n5 0000 0000 8987 0344grid.413662.4Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich-Collin-Strasse 30, Vienna, 1140 Austria \n6 0000 0004 1769 0968grid.416939.0Orthopaedic Hospital Vienna-Speising, Speisinger Strasse 109, Vienna, 1130 Austria \n7 0000000110156330grid.7039.dParis-Lodron-University of Salzburg, Department of Chemistry and Physics of Materials, Jakob-Haringer-Strasse 2a, Salzburg, 5020 Austria \n14 4 2020 \n14 4 2020 \n2020 \n10 63019 10 2019 21 3 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.Gadolinium-based contrast agents (GBCAs) are frequently used in patients undergoing magnetic resonance imaging. In GBCAs gadolinium (Gd) is present in a bound chelated form. Gadolinium is a rare-earth element, which is normally not present in human body. Though the blood elimination half-life of contrast agents is about 90 minutes, recent studies demonstrated that some tissues retain gadolinium, which might further pose a health threat due to toxic effects of free gadolinium. It is known that the bone tissue can serve as a gadolinium depot, but so far only bulk measurements were performed. Here we present a summary of experiments in which for the first time we mapped gadolinium in bone biopsy from a male patient with idiopathic osteoporosis (without indication of renal impairment), who received MRI 8 months prior to biopsy. In our studies performed by means of synchrotron radiation induced micro- and submicro-X-ray fluorescence spectroscopy (SR-XRF), gadolinium was detected in human cortical bone tissue. The distribution of gadolinium displays a specific accumulation pattern. Correlation of elemental maps obtained at ANKA synchrotron with qBEI images (quantitative backscattered electron imaging) allowed assignment of Gd structures to the histological bone structures. Follow-up beamtimes at ESRF and Diamond Light Source using submicro-SR-XRF allowed resolving thin Gd structures in cortical bone, as well as correlating them with calcium and zinc.\n\nSubject terms\nImagingBoneImaging techniquesissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nThe method of contrast-enhanced MRI (CE-MRI) dates to 1988, when the first gadolinium (Gd)-based contrast agent (GBCA), gadopentetate dimeglumine (Magnevist, Bayer), was approved for clinical use. CE-MRI is a useful imaging tool nowadays, with approximately 30 million procedures done each year worldwide, and more than 300 million procedures already performed to date1. Estimates show that the GBCAs are administered in 25–35% of all MRI examinations1,2.\n\nAccording to the data available, most of the administered dose of GBCAs (regardless of an agent used), should be cleared in less than 2 and >95% by 24 hours3. Recent findings, however, demonstrate that the GBCAs are not fully excreted and the accumulation of Gd in, e.g. neuronal tissues and organs such as brain takes place4.\n\nThe GBCAs are considered to be rather safe, yet there is a number of papers reporting nephrotoxic, hematotoxic, hepatotoxic and neurotoxic effects observed in animals and humans5. One of the most serious adverse reactions associated with the use of GBCAs is nephrogenic systemic fibrosis (NSF), which had been observed in patients with renal insufficiency6. NSF is a rare, but serious disease characterized by widespread tissue hardening (primarily skin is affected) with fibrotic nodules and plaques. First described in 1997, it was finally linked to the use of GBCAs in patients with kidney dysfunction in 20066,7. The pathophysiological mechanism involved remains unclear, though the dissociation of Gd from GBCA is usually indicated as the causative factor3,8. Due to renal insufficiency, the elimination of GBCA will be reduced, more of the dissociated Gd will be available, leading to tissue accumulation and further manifestation of Gd toxicity. The linear GBCAs due to their lower thermodynamic and kinetic stability (compared to macrocyclic GBCAs) are now considered as high-risk agents in patients with severe renal disease9.\n\nThe analysis by secondary ion mass spectrometry (SIMS) and inductively coupled plasma mass spectrometry (ICP-MS) techniques of skin biopsies from patients suffering from NSF after GBCA intake revealed Gd accumulations, which were inhomogeneous and co-localized with calcium10 and phosphorus11. In 2010 application of synchrotron radiation induced X-ray fluorescence spectroscopy (SR-XRF) for investigation of skin samples of NSF patients independently by High et al. and George et al. also confirmed depositions of Gd coinciding with other elements12,13. Multiorgan Gd depositions in NSF patient, involving skin, liver, lungs, intestinal wall (ileum), kidney, lymph node, skeletal muscle, dura mater and cerebellum, were reported by Sanyal et al. by performing scanning electron microscopy (SEM) with energy-dispersive X-ray spectroscopy (EDS) analysis14.\n\nThere is a growing body of research devoted to the investigation of possible GBCAs adverse effects in patients with normal renal function and, specifically, the retention of Gd. It would not be an overstatement to say, that a main focus lies on the retention of Gd by brain tissues. A recent study by Flood et al. connects increased signal intensity in children with repeated exposure to linear GBCAs15. Again, the use of less stable linear GBCAs is more likely to result in the deposition, however studies demonstrate, that the macrocyclic agents might be retained as well4,16. In view of this, the European Medicines Agency (EMA) issued recommendations for the restriction of linear GBCAs in body scans9.\n\nRecently, accumulation of Gd in bone tissue received deserved attention, especially given the fact that bone tissue retains Gd from GBCAs to a greater degree (23 times higher levels) compared to brain16. Darrah et al. used ICP-MS to measure Gd content (bulk) in bone tissue in osteoporotic and osteoarthritic (previously exposed to Gd) and osteoarthritic (non-exposed, used as controls) patients, and concluded that Gd can be retained for longer than 8 years after the exposure17. Series of in vivo experiments by M. Lord et al. contributed substantially to the current knowledge about Gd retention. The group developed an in vivo XRF device and obtained quantitative data on Gd content in the bone tissue of exposed patients in comparison with control subjects18,19.\n\nHowever, very little is known about the distribution of Gd in bone on the microscopic level. Our group has already employed the method of synchrotron radiation induced micro-X-ray fluorescence (SR-micro-XRF) for the characterization of distribution of trace elements, such as lead (Pb), zinc (Zn) and strontium (Sr) in healthy and diseased bone and cartilage samples20–22. Within this project we applied SR-micro- and submicro-XRF for the detection and mapping of Gd distribution within bone tissue. To the best of our knowledge these measurements are the first attempt to image Gd accumulations in the bone.\n\nMaterials and methods\nPatient and bone samples preparation\nPatient - male individual, 54 y, diagnosed with male idiopathic osteoporosis, multiple vertebral fractures and low bone mineral density, without indication of renal impairment. A transiliac crest biopsy was harvested from the patient for diagnostic reasons. All study-related procedures were approved and supervised by the local ethical committee of the St. Vincent Hospital Vienna, Austria, an academic teaching hospital of the Medical University of Vienna following the Declaration of Helsinki (DoH). The patient provided written consent for anonymized outcomes to be further used in scientific examinations.\n\nIt is known that the patient received MRI eight months prior to biopsy. Unfortunately, up to date we were not able to confirm whether and which contrast agent was used. No other sources of Gd intake are known.\n\nThe biopsy was dehydrated and fixed in ethanol and embedded in polymethylmethacrylate (PMMA). In order to avoid contaminations, only fresh and clean solutions of pro analysis quality were used during sample preparation. Typical contamination originating from the polishing procedure and consisting of Cr-Mn-Fe-Ni was identified in only one sample area and routinely excluded in the data analysis (sample demonstrated in supplementary material). The thick PMMA block was trimmed using a low-speed diamond saw (Buehler Isomet, Lake Pluff, USA), and further sandpapered with decreasing grit size and finally polished by silk cloths loaded with diamond grains (3 μm and 1 μm) using a precision polishing device (PM5; Logitech Ltd., Glasgow, UK). This ensured the block having a smooth and flat surface, which is necessary for both quantitative backscattered electron imaging (qBEI) and SR-micro-XRF measurements (ANKA).\n\nA 3 µm-thin cut was prepared out of the PMMA block for the measurements on two high-resolution SR-submicro-XRF beamlines (ESRF and Diamond Light Source synchrotrons), using a microtome (LEICA SM2500; Leica Microsystems GmbH, Wetzlar, Germany). The cutting was performed as close as possible to the original surface – we estimate the offset to less than 15 µm. The resultant cut was sandwiched between two 8 µm Kapton foils and fastened to a plexiglass frame.\n\nQuantitative backscattered electron imaging (qBEI)\nqBEI was used to determine the degree of tissue mineralization. Making use of the dependency of the backscatter electron coefficient on the local electron density (average atomic number) of the target material, this method allows to derive the degree of mineralization of bone and further to evaluate the calcium concentration (weight percent, wt% Ca). Hence, bright areas in the grey scale qBEI images refer to higher, and the dark ones to lower mineralized matrix (higher vs. lower Ca content). This method requires flat polished surface in order to derive quantitative information, therefore is only possible for bone samples as PMMA embedded blocks. The measurements were preformed using a digital scanning electron microscope equipped with a four quadrant semiconductor backscattered electron detector (DSM 962; Zeiss, Oberkochen, Germany), operated at 20 keV beam energy. Areas were scanned with ×200 nominal magnification (pixel resolution 1 μm). The information depth of qBEI depends on the mineralization and is in the range of 1–1.5 μm. The details on the technique can be found in ref. 23\n\nSR-XRF measurements and data processing\nANKA\nThe measurements on the PMMA block sample were performed at the confocal FLUO beamline at ANKA (KIT, Karlsruhe, Germany). For the first beamtime (two areas on the surface of the block, Fig. 1) beam size was defined at Ti-Ka (4.51 keV) as 27 μm × 18 μm × 24.5 µm (hor. × vert. × dep.), with the excitation energy of 9.2 keV (the energy optimized for the detection of manganese due to the original purpose of the experiment). The step size was 25 µm × 15 µm. For the second beamtime (another two areas, supplementary material Fig. S1) the beam size was defined at Ti-Ka as 28 μm × 19.5 μm × 35 µm (hor. × vert. × dep.), the step size was 25 µm × 17 µm, same excitation energy 9.2 keV. In both measurement sessions the setup included W-Si multilayer monochromator, 2 polycapillary half-lenses, 20 µm Al detector-filter, Vortex 50 mm2 silicon-drift detector, and XIA Mercury digital pulse processor. The angle between source and detector was 90°. The acquisition time was 15–17 seconds per spot (pixel) depending on the area.\n\nESRF\nMeasurements on the thin section with submicrometer resolution were performed at the ID13 microfocus beamline at ESRF (Grenoble, France); beam size 50 nm, defined using Siemens star standard. The excitation energy was set to 12.7 keV (corresponds to highest flux available at the beamline). The beamline was equipped with multilayer Laue lens optics, Vortex-EM silicon drift detector (Hitachi, USA), positioned on the rear side, “behind” the sample (i.e. the angle between source and detector is more than 90°). The step size was 500 nm with 20 s acquisition time per spot.\n\nDiamond Light Source\nMeasurements on the same slice as analysed at the ESRF were also conducted at submicro-X-ray fluorescence setup on the B16 beamline at Diamond Light Source (Didcot, UK). The excitation energy was set to 12.7 keV to match that used at ESRF. The beam size (FWHM at 12.7 keV) was determined as about 500 nm × 610 nm (V × H) – taking into account the overlap in 45° geometry – using a 50 µm-diameter Au wire knife edge. The setup included a RuB4C multilayer monochromator, 150 µm pinhole and a single-element 90 Ex Vortex detector (50 mm2), positioned at 90° to the beam. The step size was 500 nm with an acquisition time 15 s per spot. Additional information on the setup we used for the experiment can be found in ref. 24\n\nData processing\nFor the ANKA dataset, the spectra were processed using AXIL software25. Spectra recorded at ESRF and Diamond Light Source were processed with PyMCA26. The quality of fitting was further validated and text images for each element of interest were obtained using in-house software LP-map27. Finally, ImageJ28 was used to process the text images and to produce the elemental maps and overlays. Elemental maps are presented in counts per second (cps).\n\nResults\nThe SR-micro-XRF measurements in the cortical region of the human iliac crest biopsy revealed highly localized accumulations of Gd. This observation was done at the ANKA synchrotron during the beamtime dedicated to the detection of manganese. The two scans recorded during this first beamtime are presented in Fig. 1. During the follow-up beamtime we scanned two additional areas, but as the setup was adjusted differently, it was less sensitive to Gd. For illustrative purposes those two additional areas are demonstrated in supplementary material (Fig. S1).\n\nFigure 1 shows Gd and Ca elemental maps as well as a composite image, where qBEI is superimposed on the Ca map (marked as qBEI/Ca). On the Gd map all the pixels above a certain threshold (in the range of 1–3 counts per second (cps), selected individually for each map) are selected and marked via mask (green lines). The exact same mask is applied to the Ca map and, finally, the Ca map with the mask is superimposed on the qBEI, creating the qBEI/Ca composite image. The resolution of qBEI images is higher than that of the elemental maps and facilitates assignment of the Gd structures. Indeed, it can be seen, that Gd accumulation happens within the specific restricted compartments: (i) in cement lines separating two bone packets (signified with black arrows on Fig. 1), and (ii) at the interface between mineralized matrix and vascular canals, corresponding to the walls of Haversian and Volkmann’s canals (marked with red asterisks).Figure 1 Elemental maps of Gd and Ca (in cps) obtained at ANKA, composite qBEI/Ca overlay and corresponding qBEIs of two areas. The area size for maps of 21 × 41 pixels corresponds to 500 × 600 µm2; for qBEIs 450 × 570 µm2. The black arrows (composite image and qBEI) point at cement lines; red asterisk – canals.\n\n\n\nThe alleged cement line Gd structures are mainly 1-pixel thick (elemental maps), however the correct estimation of their thickness is not possible based on these maps only. As can be seen from the qBEI image, cement lines have a thickness <5 µm. Hence, the confocal system at ANKA with the resolution of ~20 µm can be used for locating the Gd accumulation, but gives an overestimation of the sizes of those structures, while underestimating the relative elemental content.\n\nTherefore, as a next step, we aimed to resolve the thin structures within the mineralized bone tissue in higher resolution. These scans were performed at ESRF and Diamond Light Source synchrotrons at beamlines featuring submicrometer beam sizes. The non-confocal setups on both synchrotrons call for thin samples, therefore a slice of 3 µm thickness was prepared out of the original PMMA block as close as possible to the qBEI-measured surface (see Materials and Methods). As the excitation energy was higher compared to the ANKA synchrotron, we detected a broader range of elements including zinc (Zn), which is also known to accumulate in cement lines22. Therefore, correlating Gd and Zn distributions provided additional information.\n\nFigure 2 shows the elemental maps of Ca, Gd and Zn obtained at ESRF. The Ca map confirms that the entire field of view was positioned within the mineralized matrix. It can be seen, that Gd is only found in a restricted region, roughly the horizontal width of this structure can be estimated as 10–15 µm. Gd shows a unique distribution, and remarkably, it is exclusively detected in the area, where also Zn is present in high content. As reliable qBEI imaging cannot be performed on thin sections, here the composite image is prepared by overlaying Ca (red) and Gd (green) elemental maps. Due to the high intensity of the beam at ESRF, the area mapped there was subject to radiation damage and can be recognised by darker colour compared to the surrounding tissue – the respective area is marked on the light microscopy.Figure 2 Elemental maps (in cps), composite image obtained at ESRF and light microscopy. Area size is 61 × 41 pixels corresponding to 30 × 20 µm2.\n\n\n\nThe very same sample which we have measured at ESRF, although a different area of it, was later investigated during the beamtime at Diamond Light Source. Figure 3 shows the elemental maps of Ca, Gd and Zn obtained at the Diamond Light Source and the composite image of Ca (red) and Gd (green) overlay. The horizontal width of this Gd structure is around 10 µm. In this experiment Gd found to be located within the calcified area as well – and again Zn and Gd locally correlate, supporting the previous observations based on the ESRF measurements.Figure 3 Elemental maps (in cps) and composite image obtained at Diamond Light Source. Area size is 33 × 36 pixels corresponding to 16 × 17.5 µm2.\n\n\n\nIt should be noted that we also detected cobalt (Co) in both regions measured at ESRF and Diamond Light Source – exhibiting a similar local distribution as Ca, though its origin remains unknown.\n\nThe exemplary spectra from ANKA and ESRF synchrotrons, Co maps (ESRF and Diamond Light Source), as well as additional composite images of Zn and Gd overlays (ESRF and Diamond Light Source) are included in the supplementary material (Figs. S2, S3, and S4 respectively).\n\nDiscussion and Conclusion\nSources of exposure\nIn the present paper we demonstrated the distribution of Gd within cortical bone tissue, and its correlation with the other detected elements. It is known from the patient’s history, that MRI was carried out 8 months prior to the biopsy, but it remains unknown whether a contrast agent was used. Hence, we cannot assert that the Gd signal originates from retention from this single exposure event. It is fair to note, that other than CE-MRI sources of exposure to Gd are possible29,30.\n\nRare-earth elements (REE) mining and processing can be mentioned in this respect, although the reports on the occupational exposure associated with negative health outcomes other than pneumoconiosis are sporadic. Li et al. found higher urinary levels of La, Nd, Ce and Gd in exposed workers dealing with Ce and La oxides ultrafine particles and nanoparticles compared to non-exposed31, however the next paper from the group (presumably on the same subjects), on creatinine adjusted urinary levels of REEs, did not show significant difference in gadolinium levels32. We were unable to find reports on deposition of gadolinium in occupationally exposed subjects.\n\nIn the recent years the anthropogenic Gd pollution, especially in aquatic systems, became a topic of extensive research33–35. However, we doubt that the low concentrations of Gd in tap water could lead to the found accumulation in bone tissue; and given the likely subject’s occupational history, the likelihood of presumable occupational exposure to elevated concentrations of gadolinium is remote.\n\nOur hypothesis is that the observations made in this study could be generally characteristic for the Gd uptake by bone, regardless of the source. Imaging experiments on larger number of biopsies from patients with known history of Gd exposure are required to systematically determine Gd accumulation/retention with respect to the source and are planned to be done after this pioneer study.\n\nAnalysis ex vivo, localization within bone\nTo date the Gd retention in bone was investigated in bulk, and in many cases ICP-based techniques were employed for the analysis16,17,36,37. Research undertaken by inductively coupled plasma atomic emission spectroscopy (ICP-AES) and ICP-MS compared linear GBCA (Omniscan) to macrocyclic (ProHanse) and revealed higher levels of retention in bone in case of linear contrast agent36,37. One investigation employing SEM-EDS for the analysis reported that no Gd was detected in the bone. That might be due to the detection limits of the chosen method or due to the preceding sample preparation, as the sample had been decalcified14. While the detection limits of EDS are typically around 0.5 wt%, SR-XRF spectrometry (as employed in the present study) features a much higher sensitivity down to sub-ppm24, thus making this method more suitable for the local analysis of trace elements like Gd. Indeed, the anticipated Gd concentrations in bone after exposure to GBCA are within few ppm, which is supported by the bulk measurements (up to 1.77 µg Gd/g bone37) and in vivo experiments (mean 1.19 µg Gd/g bone19).\n\nSince the concentration of gadolinium in the detected structures is of considerable interest, we attempted the quantification of local Gd content - and obtained the maximum values in the range of 70–270 µg/g (locally detected maximum concentration, indicative, not to be confused with bulk values mentioned above!) – the detailed procedure is described in supplementary material. This correlates well with the results obtained in a comparable elemental imaging experiment using skin biopsy, where the hot spot concentrations in Gd maps exceed 100 μg/g38.\n\nBy correlating elemental maps obtained at ANKA synchrotron and qBEI images, we were able to assign the histological structures, which seem to be prone to Gd accumulation, namely (i) cement lines and (ii) vascular pore walls (interface to Haversian/Volkmann’s canals). Conceivably, deposition within the walls of canals is due to the direct vicinity to the blood vessels which feature the main delivery pathway of Gd after exposure. The cement lines are marking the osteon boundaries, they are mineral-rich and collagen deficient (compared to the mineralized matrix of the osteon), and also contain non-collagenous proteins, such as osteopontin, glycosaminoglycans, osteocalcin, and bone sialoprotein39. The cement lines are laid down at the reversal phase of osteon formation (i.e. before the formation of the new sequential lamellae)40. Supposing that the transient Gd exposure occurred at this phase of osteon formation, it is plausible, that Gd may be included in the composition of the cement line and adjacent lamellas.\n\nCorrelation with other elements, possible mechanisms of retention\nThe correlation of Gd with other elements can shed light on the chemical environment of Gd within the accumulations and on the mechanism of retention. Data available on Gd depositions in skin suggest a colocalization with such elements as Ca, P and Zn. Abraham et al. observed Gd in association with Ca by SIMS10. Birka et al. used LA-ICP-MS and concluded, that matching Gd and P distributions suggest the presence of insoluble deposits of GdPO4 in the tissue section; and the Gd and Ca correlation could suggest that Gd causes calcium-containing depositions, which trigger calcification11. George et al. investigated Gd accumulation in skin affected by NSF using SR-XRF, and found clear correlation between Gd, Ca and P distributions, and the use of extended absorption fine structure spectroscopy (EXAFS) further allowed to assume Gd presence in form of GdPO4-like structures13. An inhomogeneous Zn distribution was also found throughout the Gd and Ca deposits, though it was concluded that Zn does not show a simple correlation with those elements in skin. At the same time, High et al. also with the use of SR-XRF observed colocalization of Gd, Ca and Zn in skin tissue and hypothesized that Ca and Zn facilitate displacement of Gd from the chelating agent12. Interesting results were obtained by Clases et al., who investigated not only skin, but also brain depositions, using LA-ICP-MS. In skin elemental distribution of Gd, P, Ca and Zn correlated in location and shape, pointing to the abundance of insoluble phosphate species, while in brain correlations and co-localisation of Gd with P, Ca, Zn, as well as Fe was observed38.\n\nHowever, despite of all the ongoing research, the mechanism of the Gd incorporation in bone remains undetermined, and the form, in which it is deposited, is not known. The investigation of spatial distribution of Gd within bone can be instrumental in understanding that, and such studies are called for41. Although skin deposition mechanism might differ from the accumulation in bone, we also found Gd in calcified regions. Darrah et al. suggested, that ionic Gd3+ released from Gd-chelates is subsequently incorporated into the carbonated calcium hydroxyapatite mineral phase of bone17. Such a process, so-called “transmetallation”, in which the molecule of GBCA supposedly undergoes in in vivo environment, refers to the competition between endogenous cations (Fe3+, Zn2+, Mg2+, Ca2+, etc.) and Gd3+, as well as between endogenous anions (carbonate, hydroxide, phosphate, etc.) and the ligand. The Ca-transmetallation is supported by Gd similarity to Ca, the ionic radii of the ions are 107.8 pm for Gd and 114 pm for calcium. In this context, we would like to mention our previous study on Sr incorporation into bone, as Sr is also chemically similar to Ca. In patients who received Sr ranelate for treatment of osteoporosis, Sr was predominantly found in the newly formed bone matrix (formed in the period of increased Sr serum levels) and it was incorporated into the hydroxyapatite crystals changing/increasing the crystal lattice constant42,43. Therefore, we could hypothesise, that Gd retention is of the same nature, which can be further assessed by speciation analysis.\n\nThe other possible transmetallation competitor is Zn, which was already suggested by some of the ex vivo measurements of skin depositions discussed above. In 2010, S. Greenberg published a case report on a patient with chronic Zn poisoning, pointing at possible Gd retention due to Gd-Zn transmetallation44. With our measurements performed at Diamond Light Source and ESRF synchrotrons with submicrometer beams we focused on the Gd structures within mineralized bone. These imaging experiments revealed a local overlapping of Gd and Zn. Although their distribution patterns are not the same, Gd appears to be present only in the areas of high Zn content. The previous investigations by our group demonstrated high content of Zn, Pb and Sr in the cement lines22. Present findings showing interdependencies between Gd and Zn, might support the Gd-Zn transmetallation as mechanism of Gd retention.\n\nSignificance and possible toxicity\nGadolinium belongs to the group of rare-earth elements, it is normally not found in living organisms, and it is highly toxic in its free ionic Gd3+ form3. Bone tissue is metabolically active, and continually undergoes remodelling. Therefore, slow endogenous Gd release into the bloodstream is likely to occur, and the risk is even higher in subjects with increased bone resorption (pregnancy, lactation, during menopause; in osteoporotic patients)17,45. Increase in safety concerns regarding the use of GBCAs triggered animal research, investigating Gd retention by various tissues, under single or repeated administration of GBCAs in healthy animals, as well as in induced disease models. Jost et al. compared linear and macrocyclic GBCAs with regard to brain deposition in rats after 2 weeks of repeated administration using LA-ICP-MS46. Previously unknown site of Gd accumulation was identified by Delfino et al., who observed Gd deposition in the periodontal tissues in murine model with induced renal disease, using SR-XRF and LA-ICP-MS47. Interesting results showing differential accumulation of Gd by different bone tissues – cortical, trabecular bone and bone marrow in juvenile and adult rats by ICP-MS were published by Fretellier et al.48. An interesting line of research – usage of GBCAs in pregnancy and potential effect of Gd on foetus, were investigated by Prola-Netto et al. in rhesus macaques, and although only extremely low levels of Gd were found in juvenile tissues after in utero exposure, femur was identified as a site of consistent Gd retention in all the animals49. Until now, however, the studies allowing elucidation of mechanisms of Gd incorporation into bone, as well as its further fate, were not undertaken, therefore, animal models and studies involving human biopsies are called for50.\n\nThe knowledge about deposition of Gd from GBCAs in bone is of importance, especially in the view of recently gained evidence of its accumulation behaviour in brain tissue, and possible risks associated with toxicity of free Gd. To the best of our knowledge these measurements are the first attempt of imaging Gd accumulations in the bone tissue, which is of exceptional value for understanding the mechanisms of Gd retention and, further, for predictions regarding the safety of GBCAs.\n\nOutlook\nSummarizing the key questions for the further research we suggest to focus on: (i) systematic analysis of biopsies from patients with known history of GBCA intake in comparison with controls without clinical Gd exposure, (ii) animal studies comparing Gd supplemented and control animals to distinguish accumulation patterns for continuous, as well as short time exposure events, (iii) quantification of Gd within bone which can be achieved using matrix-matched standards (the other elemental imaging methods, such as LA-ICP-MS and SIMS could be applied as well); (iv) the speciation of the deposited Gd has to be performed, e.g. by XANES and EXAFS to gain knowledge about the specific chemical form, which is essential in predicting the possible health hazard (toxicity).\n\nSupporting information\n\nSupporting information.\n\n\nSupporting information2.\n\n\nSupporting information3.\n\n\nSupporting information4.\n\n\nSupporting information5.\n\n\nSupporting information6.\n\n\nSupporting information7.\n\n\n\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nis available for this paper at 10.1038/s41598-020-63325-9.\n\nAcknowledgements\nWe acknowledge the Synchrotron Light Source ANKA for provision of instruments at the FLUO beamline. Part of the submicro-XRF imaging experiments were performed on beamline ID13 at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. We thank Tilman A. Grünewald for introduction to PyMCA. We acknowledge Diamond Light Source for time on Beamline B16 under Proposal MT16260-1. We thank Igor Dolbnya for invaluable help in getting the beam at Diamond Light Source even more brilliant and Ian Pape for supporting the measurements at the Diamond Light Source. The research leading to this result has been supported by the project CALIPSOplus under the Grant Agreement 730872 from the EU Framework Programme for Research and Innovation HORIZON2020. The research leading to these results has received funding from Austrian Science Fund (FWF, project number: P27715), the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n.312284.\n\nAuthor contributions\nA.T., M.R., C.S., P.W. designed experiments. A.R., P.R. prepared samples, performed qBEI. R.S., M.B., O.F., K.S. provided support on the synchrotron beamlines. A.T., M.R., V.P., C.S. performed synchrotron measurements. A.T. analysed data. A.T., M.R., C.S., A.R., P.R.; J.H. interpreted the data. C.S., P.W., A.R., P.R.; J.H. provided scientific support. A.T. drafted the manuscript. All authors reviewed the manuscript.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Lohrke J 25 Years of Contrast-Enhanced MRI: Developments, Current Challenges and Future Perspectives Adv. Ther. 2016 33 1 28 10.1007/s12325-015-0275-4 26809251 \n2. Fraum TJ Ludwig DR Bashir MR Fowler KJ Gadolinium-based contrast agents: A comprehensive risk assessment J. Magn. Reson. Imaging 2017 46 338 353 10.1002/jmri.25625 28083913 \n3. Ramalho J Gadolinium-based contrast agent accumulation and toxicity: An update Am. J. Neuroradiol. 2016 37 1192 1198 10.3174/ajnr.A4615 26659341 \n4. 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Biol. 2019 51 212 218 10.1016/j.jtemb.2018.10.021 30466933 \n39. Milovanovic P Bone tissue aging affects mineralization of cement lines Bone 2018 110 187 193 10.1016/j.bone.2018.02.004 29427789 \n40. Skedros JG Clark GC Sorenson SM Taylor KW Qiu S Analysis of the Effect of Osteon Diameter on the Potential Relationship of Osteocyte Lacuna Density and Osteon Wall Thickness Anat. Rec. Adv. Integr. Anat. Evol. Biol. 2011 294 1472 1485 10.1002/ar.21452 \n41. Gräfe, J. L. & McNeill, F. E. Measurement of gadolinium retention: current status and review from an applied radiation physics perspective. Physiol. Meas. 39, 06TR01, (2018).\n42. Roschger P Bone material quality in transiliac bone biopsies of postmenopausal osteoporotic women after 3 years of strontium ranelate treatment J. Bone Miner. Res. 2010 25 891 900 10.1359/jbmr.090702 20437609 \n43. Li C Strontium is incorporated into mineral crystals only in newly formed bone during strontium ranelate treatment J. Bone Miner. Res. 2010 25 968 975 19874195 \n44. Greenberg SA Zinc Transmetallation and Gadolinium Retention after MR Imaging: Case Report Radiology 2010 257 670 673 10.1148/radiol.10100560 20829541 \n45. Swaminathan, S. Gadolinium Toxicity: Iron and Ferroportin as Central Targets. Magn. Reson. Imaging 8–11 10.1016/j.mri.2016.08.016 (2016).\n46. Gregor Jost et al. Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model. Radiology10.1148/radiol.2018180135 (2018).\n47. Delfino R Gadolinium tissue deposition in the periodontal ligament of mice with reduced renal function exposed to Gd-based contrast agents Toxicol. Lett. 2019 301 157 167 10.1016/j.toxlet.2018.11.014 30476537 \n48. Fretellier N Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues? Invest. Radiol. 2019 54 61 71 10.1097/RLI.0000000000000517 30394964 \n49. Prola-Netto J Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure Radiology 2017 286 122 128 10.1148/radiol.2017162534 28873045 \n50. Kanal E Tweedle MF Residual or Retained Gadolinium: Practical Implications for Radiologists and Our Patients Radiology 2015 275 630 634 10.1148/radiol.2015150805 25942418\n\n",
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"issn_linking": "2045-2322",
"issue": "10(1)",
"journal": "Scientific reports",
"keywords": null,
"medline_ta": "Sci Rep",
"mesh_terms": "D001706:Biopsy; D003287:Contrast Media; D000071538:Cortical Bone; D005682:Gadolinium; D006207:Half-Life; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis; D013052:Spectrometry, X-Ray Emission; D017356:Synchrotrons; D013997:Time Factors; D014018:Tissue Distribution",
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"pmid": "32286449",
"pubdate": "2020-04-14",
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"title": "Detection and imaging of gadolinium accumulation in human bone tissue by micro- and submicro-XRF.",
"title_normalized": "detection and imaging of gadolinium accumulation in human bone tissue by micro and submicro xrf"
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"abstract": "Although Clostridium difficile infection (CDI) often results in severe manifestations due to toxin-producing clostridium, the correlation between CDI and having a fever in gynecological malignancies is not completely understood.\n\n\n\nThe incidence, and clinical features, and clinical management of CDI in patients with gynecological malignancies who have fevers were investigated, and the clinical managements of this complication are discussed.\n\n\n\nWe retrospectively reviewed 485 patients newly diagnosed with invasive gynecological cancers who underwent anticancer treatment between July 2012 and December 2016. The diagnosis of CDI was performed using enzyme immunoassays for C difficile glutamate dehydrogenase and toxin A/B enzyme immunoassay. The cumulative risk of CDI was 9.5% (six of 63) in overall fever patients and 6.3% (six of 95) in patients with fever episodes. Two CDI patients (33.3%) did not show diarrheal symptoms, with the fever of unknown origin criteria prompting their CDI testing and diagnosis. CDI patients were treated using vancomycin or metronidazole without suffering from fatal clinical course. Overall, eight patients with gynecological malignancies were diagnosed with CDI, including two patients with fever lower than 38.5°C. The cumulative risk of CDI was 0.48% (eight of 1652) for all admitted patients and 1.6% (eight of 485) in those with gynecological malignancies. Of all the patients with confirmed CDI, only one had a history of administration of antibiotics prior to onset of CDI symptoms.\n\n\n\nCDI does not always present with typical manifestations in malignancy patients. Investigation of CDI, regardless of gastrointestinal symptoms or history of antibiotic use, is warranted in cases of fever of unknown origin in gynecological malignancy.",
"affiliations": "Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.;Department of Gynecology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.;Department of Gynecology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan.;Department of Obstetrics and Gynecology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.",
"authors": "Yanazume|Shintaro|S|0000-0003-2297-6648;Tokudome|Akio|A|0000-0001-8454-3317;Fukuda|Mika|M|0000-0002-7487-9711;Togami|Shinichi|S|0000-0003-1920-9405;Kamio|Masaki|M|0000-0002-8620-333X;Ota|Shunichiro|S|0000-0001-7395-1673;Kobayashi|Hiroaki|H|0000-0003-2491-2189",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/cnr2.1200",
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"issn_linking": "2573-8348",
"issue": "2(5)",
"journal": "Cancer reports (Hoboken, N.J.)",
"keywords": "Clostridium difficile infection; chemoradiotherapy; chemotherapy; diarrhea; fever; gynecology",
"medline_ta": "Cancer Rep (Hoboken)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016360:Clostridioides difficile; D003015:Clostridium Infections; D005260:Female; D005334:Fever; D005833:Genital Neoplasms, Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101747728",
"other_id": null,
"pages": "e1200",
"pmc": null,
"pmid": "32721136",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "7916358;12032893;8641617;9305296;14599633;9784328;22814157;2761938;16080485;11095331;1497405;15597970;9522288;32721136;625309;15937201;21728113;2643913;27804875;28672282;3585958;3516192;11252111;77366;16574203",
"title": "Clostridium difficile infection in fever patients with gynecological malignancies.",
"title_normalized": "clostridium difficile infection in fever patients with gynecological malignancies"
} | [
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{
"abstract": "We describe the case of a 68-year-old man who has a complex medical background that included renal transplantation, rheumatoid arthritis and atrial fibrillation. Because of this, he was taking a number of immunosuppressant medications including leflunomide, prednisone and tacrolimus. He had experienced chronic diarrhoea over 18 months which had acutely worsened over the 6 weeks prior to hospital presentation. Recent colonoscopies had been performed to investigate this diarrhoea with biopsies revealing acute and chronic inflammatory changes in the terminal ileum and colon. No infectious cause could be found, with all bacterial and viral stool cultures returning negative. An enterocutaneous fistula had also spontaneously developed through his renal transplant scar in the days preceding hospital admission which complicated the clinical picture. Following dose reduction of leflunomide, there was a significant improvement in the frequency and severity of the patient's diarrhoea. He continues to be managed non-operatively for his fistula as he is at high risk of peri-operative morbidity and mortality.",
"affiliations": "Department of Surgery, Wollongong Hospital, South Cost Mail Centre, Locked Bag 8808, Wollongong, NSW, 2521, Australia.;Department of Surgery, Wollongong Hospital, South Cost Mail Centre, Locked Bag 8808, Wollongong, NSW, 2521, Australia. amf.kwok@gmail.com.",
"authors": "Kwok|Allan Mun Fai|AMF|http://orcid.org/0000-0002-8742-6236;Morosin|Tia|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D000077339:Leflunomide",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-019-00954-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "12(4)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Colitis; Enterocutaneous fistula; Immunosuppression; Leflunomide; Transplant",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D003092:Colitis; D003967:Diarrhea; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007412:Intestinal Fistula; D016030:Kidney Transplantation; D000077339:Leflunomide; D008279:Magnetic Resonance Imaging; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "310-315",
"pmc": null,
"pmid": "30820830",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1354228;15565393;16978214;26494588;27888222",
"title": "Leflunomide-induced colitis in association with enterocutaneous fistula in an immunosuppressed patient with renal transplant and rheumatoid arthritis.",
"title_normalized": "leflunomide induced colitis in association with enterocutaneous fistula in an immunosuppressed patient with renal transplant and rheumatoid arthritis"
} | [
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{
"abstract": "Introduction. Treating patients with acute ischemic stroke, proximal arterial vessel occlusion, and absolute contraindication for administering intravenous recombinant tissue plasminogen activator (rtPA) poses a therapeutic challenge. Intra-arterial thrombectomy constitutes an alternative treatment option. Materials and Methods. We report a case of a 57-year-old patient with concomitant gastric adenocarcinoma, who received three intra-arterial thrombectomies in 72 hours due to repeated occlusion of the left medial cerebral artery (MCA). Findings. Intra-arterial recanalization of the left medial cerebral artery was performed three times with initially good success. However, two days later, the right medial cerebral artery became occluded. Owing to the overall poor prognosis at that time and knowing the wishes of the patient, we decided not to perform another intra-arterial recanalization procedure. Conclusion. To our knowledge, this is the first case illustrating the use of repeated intra-arterial recanalization in early reocclusion of intracranial vessels.",
"affiliations": "Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.",
"authors": "Laible|Mona|M|;Möhlenbruch|Markus|M|;Hacke|Werner|W|;Bendszus|Martin|M|;Ringleb|Peter Arthur|PA|;Rizos|Timolaos|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/872817",
"fulltext": "\n==== Front\nCase Rep Vasc MedCase Rep Vasc MedCRIVAMCase Reports in Vascular Medicine2090-69862090-6994Hindawi Publishing Corporation 10.1155/2015/872817Case ReportRepeated Intra-Arterial Thrombectomy within 72 Hours in a Patient with a Clear Contraindication for Intravenous Thrombolysis Laible Mona \n1\n\n*\nMöhlenbruch Markus \n2\nHacke Werner \n1\nBendszus Martin \n2\nRingleb Peter Arthur \n1\nRizos Timolaos \n1\n1Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany2Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany*Mona Laible: mona.laible@med.uni-heidelberg.deAcademic Editor: Halvor Naess\n\n2015 27 1 2015 2015 8728174 10 2014 9 12 2014 10 12 2014 Copyright © 2015 Mona Laible et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction. Treating patients with acute ischemic stroke, proximal arterial vessel occlusion, and absolute contraindication for administering intravenous recombinant tissue plasminogen activator (rtPA) poses a therapeutic challenge. Intra-arterial thrombectomy constitutes an alternative treatment option. Materials and Methods. We report a case of a 57-year-old patient with concomitant gastric adenocarcinoma, who received three intra-arterial thrombectomies in 72 hours due to repeated occlusion of the left medial cerebral artery (MCA). Findings. Intra-arterial recanalization of the left medial cerebral artery was performed three times with initially good success. However, two days later, the right medial cerebral artery became occluded. Owing to the overall poor prognosis at that time and knowing the wishes of the patient, we decided not to perform another intra-arterial recanalization procedure. Conclusion. To our knowledge, this is the first case illustrating the use of repeated intra-arterial recanalization in early reocclusion of intracranial vessels.\n==== Body\n1. Introduction\nEvidence-based therapeutic options for patients with acute cerebral ischemia and an absolute contraindication for intravenous thrombolysis are highly limited. Although intra-arterial thrombectomy (IT) represents an alternative approach to revascularizing particular proximal intracerebral artery occlusions, no data exist concerning repeatedly performed IT in patients with early reocclusion after initial IT, to our knowledge. Here, we report the case of a patient who received three intra-arterial thrombectomies in 72 hours due to repeated occlusion of the left medial cerebral artery (MCA).\n\n2. Case Report\nA 57-year-old, nonsmoking man with newly diagnosed gastric adenocarcinoma (cT3 cN+cM1) was transferred to our department because of the sudden onset of right hemiparesis and global aphasia. Except for the gastric carcinoma, the patient was previously healthy with no medical history of cerebrovascular risk factors. Initial cerebral computed tomography (cCT) was normal. CT angiography (CTA) revealed an occlusion of the left MCA (M1 segment) without relevant arteriosclerosis of the carotid arteries. Due to active systemic bleeding with severe melena as a result of his tumor, intravenous thrombolysis was contraindicated. Therefore, we decided to conduct mechanical thrombectomy, which was successful after five thrombectomy maneuvers and intra-arterial administration of 10 mg recombinant tissue plasminogen activator (rtPA; Figure 1, TICI III; symptom-to-recanalization time: 90 min). Clinical symptoms improved remarkably (National Institutes of Health Stroke Scale, NIHSS 21 to 3) until the next day. Then, aphasia and hemiparesis worsened and CTA revealed recurrent occlusion of the left MCA (M2 segment). Again, intra-arterial thrombectomy was conducted. One thrombectomy maneuver resulted in recanalization and considerable clinical improvement (TICI III, symptom-to-recanalization time 110 min; NIHSS 11 to 3). Two days later, hemiparesis developed again on the right side and global aphasia also recurred; NIHSS worsened from 2 to 10 points. At this time, magnetic resonance imaging (MRI) again detected occlusion of the middle branch of the left MCA in the M2 segment and revealed a relevant diffusion/perfusion mismatch. Once again, thrombectomy was conducted, but the clinical result was less satisfactory (TICI IIb, symptom-to-recanalization time 240 min, NIHSS 10 to 9). Less than 5 hours after the last thrombectomy, the patient suffered a general epileptic seizure. Clinical stroke severity was unchanged (NIHSS 10). Another MRI displayed a larger diffusion weighted imaging (DWI) lesion in the left MCA territory without vessel occlusion or mismatch on diffusion/perfusion weighted imaging (PWI).\n\nAnother two days later, the clinical state of our patient deteriorated further (NIHSS 16). Radiographic findings (CCT and CTA) at this time revealed an occlusion of the right MCA (M1 segment). Due to the overall poor prognosis at that time and knowing the wishes of the patient, we decided not to perform another IT. The patient died five days later.\n\n3. Discussion\nTo our knowledge, this is the first report of repeated intra-arterial thrombectomy in acute ischemic stroke. While no corresponding vessel stenosis was present in the MCA or carotid artery and all other diagnostic tests, including continuous electrocardiogram (ECG) monitoring, were normal, we assume that a prothrombotic state caused by the malignancy was the reason for the repeated arterial occlusions, as strokes are very common in the presence of a malignancy [1, 2]. Particularly acute stroke patients with adenocarcinomas face a substantial short-term risk of recurrent ischemic stroke [3] and an autopsy study of patients with different malignancies reported cardiovascular disease with thromboembolism in up to 15% of patients [4].\n\nNo intraprocedural complication developed in our patient, but he finally died due to repeated severe cerebral thromboemboli. In our patient, antiplatelet therapy was initiated for secondary stroke prevention. However, the optimal secondary stroke prevention in this particular group of patients remains unknown. Randomized trials comparing anticoagulation to antiplatelet therapy in patients with cancer and first-ever acute ischemic stroke may contribute to this important clinical question (e.g., clinicaltrials.gov NCT01763606).\n\nWhereas the efficacy of intravenous rtPA has been proven in multiple randomized controlled trials [5], no evidence-based treatment alternatives exist for patients with a clear contraindication for rtPA. The three larger multicenter studies of intra-arterial thrombectomy in patients with an occlusion of the first segment of the MCA, the ICA, or basilar artery did not show that IT was superior to intravenous thrombolysis [6–8]. Our case demonstrates impressively that even repeated intracranial intra-arterial thrombectomy is technically feasible and safe and can induce a remarkable clinical improvement. However, the value of IT in patients with a contraindication to intravenous thrombolysis was not the subject of the aforementioned studies.\n\n4. Conclusion\nRepeated intra-arterial thrombectomy within a short time is technically feasible and was safe in our patient. Further research, particularly in the relevant subgroup of patients in whom alternative treatment would consist of purely conservative, observant, and standard stroke treatment, is urgently needed.\n\nConflict of Interests\nWerner Hacke received consulting honoraria, travel grants, and speakers' honoraria from Bayer, Boehringer-Ingelheim, Phototera, and Johnson & Johnson and payments for development of educational presentations from Bayer and Boehringer-Ingelheim. Martin Bendszus received honoraria for consultancy from Guerbet, Codman, and DSMB for vascular dynamics and for talks from Novartis, Roche, Guerbet, and Codman. He received research funding from DFG, Hopp Foundation, Arthrose Foundation, Novartis, Guerbet, and Bayer. Peter Arthur Ringleb received speaker honoraria and travel compensation from Boehringer-Ingelheim, GlaxoSmithKline, Ferrer, and Bayer. Timolaos Rizos received consulting honoraria and speakers' honoraria from BMS Pfizer and Boehringer-Ingelheim. Markus Möhlenbruch and Mona Laible have no interests to disclose.\n\nFigure 1 Findings before (a) and after (b) the first thrombectomy with 5 thrombectomy maneuvers of the left medial cerebral artery in the M1 segment.\n==== Refs\n1 Rogers L. R. Cerebrovascular complications in cancer patients Neurologic Clinics 2003 21 1 167 192 12690649 \n2 Cestari D. M. Weine D. M. Panageas K. S. Segal A. Z. DeAngelis L. M. Stroke in patients with cancer: incidence and etiology Neurology 2004 62 11 2025 2030 10.1212/01.wnl.0000129912.56486.2b 2-s2.0-2942627941 15184609 \n3 Navi B. B. Singer S. Merkler A. E. Recurrent thromboembolic events after ischemic stroke in patients with cancer Neurology 2014 83 1 26 33 10.1212/WNL.0000000000000539 24850486 \n4 Graus F. Rogers L. R. Posner J. B. Cerebrovascular complications in patients with cancer Medicine 1985 64 1 16 35 3965856 \n5 Hacke W. Kaste M. Bluhmki E. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke The New England Journal of Medicine 2008 359 13 1317 1329 10.1056/nejmoa0804656 2-s2.0-52649165720 18815396 \n6 Ciccone A. Valvassori L. Nichelatti M. Endovascular treatment for acute ischemic stroke The New England Journal of Medicine 2013 368 10 904 913 10.1056/nejmoa1213701 2-s2.0-84874711452 23387822 \n7 Broderick J. P. Palesch Y. Y. Demchuk A. M. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke The New England Journal of Medicine 2013 368 10 893 903 10.1056/nejmoa1214300 2-s2.0-84874734317 23390923 \n8 Kidwell C. S. Jahan R. Gornbein J. A trial of imaging selection and endovascular treatment for ischemic stroke The New England Journal of Medicine 2013 368 10 914 923 10.1056/nejmoa1212793 2-s2.0-84874751053 23394476\n\n",
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"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "23394476;12690649;23390923;18815396;15184609;24850486;23387822;3965856",
"title": "Repeated Intra-Arterial Thrombectomy within 72 Hours in a Patient with a Clear Contraindication for Intravenous Thrombolysis.",
"title_normalized": "repeated intra arterial thrombectomy within 72 hours in a patient with a clear contraindication for intravenous thrombolysis"
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"abstract": "BACKGROUND\nOutcomes for patients with metastatic Ewing sarcoma (ES) remain poor. We investigated whether the intensification of ifosfamide improved survival for patients with metastatic ES.\n\n\nMETHODS\nWe conducted a retrospective chart review of 30 patients with metastatic ES treated with the MSKCC \"EFT regimen.\" The regimen included an intensification of ifosfamide dosing from 1,800 mg/m(2) /day × 5 days per cycle to 2,800 mg/m(2) /day × 5 days per cycle.\n\n\nRESULTS\nTwenty six of the 30 patients completed planned chemotherapy. Two patients experienced disease progression during therapy. There were no toxic deaths. One patient developed secondary leukemia. The 4-year event free survival (EFS) was 27% and the overall survival (OS) was 39%.\n\n\nCONCLUSIONS\nIntensification of ifosfamide was tolerated and did not increase toxicity in patients with metastatic ES. The intensification did not improve outcomes for these patients with metastatic disease.",
"affiliations": "Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York.",
"authors": "Magnan|Heather|H|;Goodbody|Christine M|CM|;Riedel|Elyn|E|;Pratilas|Christine A|CA|;Wexler|Leonard H|LH|;Chou|Alexander J|AJ|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25373",
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"issn_linking": "1545-5009",
"issue": "62(4)",
"journal": "Pediatric blood & cancer",
"keywords": "Ewing sarcoma; chemotherapy; outcomes",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D001859:Bone Neoplasms; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007069:Ifosfamide; D008297:Male; D009362:Neoplasm Metastasis; D012512:Sarcoma, Ewing; D015996:Survival Rate; D013997:Time Factors",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "594-7",
"pmc": null,
"pmid": "25630954",
"pubdate": "2015-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "10963639;12594313;12972518;2201433;7595741;9275000;9602261;16760184;17569105;17584910;18525458;23091096",
"title": "Ifosfamide dose-intensification for patients with metastatic Ewing sarcoma.",
"title_normalized": "ifosfamide dose intensification for patients with metastatic ewing sarcoma"
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{
"abstract": "Lapatinib is an inhibitor of the tyrosine kinases of human epidermal growth factor receptor type 2 (HER2) and epidermal growth factor receptor type 1, with clinical activity in HER2-positive metastatic breast cancer. We present here a 60 year-old patient with metastatic breast cancer who presented with jaundice and increased serum aminotransferase levels and who had been treated with lapatinib for the previous 14 days. Laboratory tests excluded other causes of acute liver injury. Liver biopsy revealed lesions compatible with drug-induced hepatotoxicity. Bilirubin and liver enzymes returned to normal within three months of lapatinib discontinuation. Lapatinib should be included among the causes of drug-induced hepatitis.",
"affiliations": "Department of Medical Oncology, University Hospital of Patras, 26500 Rio, Patras, Greece. panio@upatras.gr",
"authors": "Peroukides|Stavros|S|;Makatsoris|Thomas|T|;Koutras|Angelos|A|;Tsamandas|Athanasios|A|;Onyenadum|Adimchi|A|;Labropoulou-Karatza|Chryssoula|C|;Kalofonos|Haralabos|H|",
"chemical_list": "D000970:Antineoplastic Agents; D011799:Quinazolines; D000077341:Lapatinib",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v17.i18.2349",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "17(18)",
"journal": "World journal of gastroenterology",
"keywords": "Breast cancer; Hepatitis; Hepatotoxicity; Human epidermal growth factor receptor type 2; Lapatinib",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007565:Jaundice; D000077341:Lapatinib; D008875:Middle Aged; D011799:Quinazolines",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "2349-52",
"pmc": null,
"pmid": "21633602",
"pubdate": "2011-05-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18309947;15955900;20110044;15761078;17192538;20564754;19088019;18458039;18421051;19179558;3798106",
"title": "Lapatinib-induced hepatitis: a case report.",
"title_normalized": "lapatinib induced hepatitis a case report"
} | [
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"literaturereference": "PEROUKIDES S, MAKATSORIS T, KOUTRAS A, TSAMANDAS A, ONYENADUM A, LABROPOULOU?KARATZA C ET AL.. LAPATINIB?INDUCED HEPATITIS: A CASE REPORT. WORLD JOURNAL OF GASTROENTEROLOGY. 2011?17(18):2349?52",
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{
"abstract": "We report a patient with a high-titer factor VIII inhibitor refractory to immunosuppression. He initially presented with myocardial infarction requiring percutaneous coronary intervention (PCI) with bare metal stent placement. Despite Feiba prophylaxis, inadequate hemostasis prompted premature discontinuation of dual antiplatelet therapy (DAPT). Fifteen weeks later, the patient presented with a left anterior descending artery in-stent restenosis. This case report examines the Key Clinical Question of how to manage in-stent restenosis in a patient with acquired hemophilia A (AHA). After multidisciplinary discussions including hematology, cardiology, cardiac surgery, laboratory medicine, and pharmacy, emicizumab was initiated to facilitate PCI. Four weeks after emicizumab initiation, the patient underwent successful PCI with drug-eluting stent placement. Five months after discharge, he remains without signs or symptoms of cardiac disease or bleeding on DAPT and emicizumab. This case provides evidence of the potential of emicizumab for bleeding prophylaxis in AHA.",
"affiliations": "The Johns Hopkins Hospital Department of Pharmacy Baltimore Maryland.;The Johns Hopkins Hospital Department of Pharmacy Baltimore Maryland.;Division of Hematology Department of Medicine Johns Hopkins University School of Medicine Baltimore Maryland.;Division of Hematology Department of Medicine Johns Hopkins University School of Medicine Baltimore Maryland.;Division of Medical Oncology and Hematology Kaiser Permanente Baltimore Maryland.;Division of Hematology Department of Medicine Johns Hopkins University School of Medicine Baltimore Maryland.",
"authors": "Dane|Kathryn E|KE|;Lindsley|John P|JP|;Streiff|Michael B|MB|;Moliterno|Alison R|AR|;Khalid|Mian K|MK|;Shanbhag|Satish|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/rth2.12201",
"fulltext": "\n==== Front\nRes Pract Thromb HaemostRes Pract Thromb Haemost10.1002/(ISSN)2475-0379RTH2Research and Practice in Thrombosis and Haemostasis2475-0379John Wiley and Sons Inc. Hoboken 10.1002/rth2.12201RTH212201Case ReportCase ReportsSuccessful use of emicizumab in a patient with refractory acquired hemophilia A and acute coronary syndrome requiring percutaneous coronary intervention DANE et al.Dane Kathryn E. PharmD\n1\nLindsley John P. PharmD\n1\nStreiff Michael B. MD\n2\nMoliterno Alison R. MD\n2\nKhalid Mian K. MD\n3\nShanbhag Satish MBBS, MPHsshanbh2@jhmi.edu \n2\n\n1 \nThe Johns Hopkins Hospital Department of Pharmacy\nBaltimore\nMaryland\n\n2 \nDivision of Hematology\nDepartment of Medicine\nJohns Hopkins University School of Medicine\nBaltimore\nMaryland\n\n3 \nDivision of Medical Oncology and Hematology\nKaiser Permanente\nBaltimore\nMaryland\n* Correspondence\n\nSatish Shanbhag, Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. \n\nEmail: sshanbh2@jhmi.edu\n09 4 2019 7 2019 3 3 10.1002/rth2.2019.3.issue-3420 423 13 1 2019 04 3 2019 © 2019 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\nEssentials\n\nAcquired hemophilia A is a rare bleeding disorder often accompanied by other comorbidities.\n\nWe describe emicizumab use in acquired hemophilia A complicated by acute coronary syndrome.\n\nEmicizumab proved safe and effective in a patient with acquired hemophilia A.\n\nEmicizumab facilitated successful administration of dual antiplatelet therapy.\n\n\n\n\n\n\n\nAbstract\nWe report a patient with a high‐titer factor VIII inhibitor refractory to immunosuppression. He initially presented with myocardial infarction requiring percutaneous coronary intervention (PCI) with bare metal stent placement. Despite Feiba prophylaxis, inadequate hemostasis prompted premature discontinuation of dual antiplatelet therapy (DAPT). Fifteen weeks later, the patient presented with a left anterior descending artery in‐stent restenosis. This case report examines the Key Clinical Question of how to manage in‐stent restenosis in a patient with acquired hemophilia A (AHA). After multidisciplinary discussions including hematology, cardiology, cardiac surgery, laboratory medicine, and pharmacy, emicizumab was initiated to facilitate PCI. Four weeks after emicizumab initiation, the patient underwent successful PCI with drug‐eluting stent placement. Five months after discharge, he remains without signs or symptoms of cardiac disease or bleeding on DAPT and emicizumab. This case provides evidence of the potential of emicizumab for bleeding prophylaxis in AHA.\n\nacute coronary syndromeblood coagulation factor inhibitorscoronary artery diseasehemophilia Aplatelet aggregation inhibitorsRaymond Stralka Fund for Research source-schema-version-number2.0component-idrth212201cover-dateJuly 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.5 mode:remove_FC converted:05.07.2019\n\n\nDane \nKE \n, \nLindsley \nJP \n, \nStreiff \nMB \n, \nMoliterno \nAR \n, \nKhalid \nMK \n, \nShanbhag \nS \n. Successful use of emicizumab in a patient with refractory acquired hemophilia A and acute coronary syndrome requiring percutaneous coronary intervention . Res Pract Thromb Haemost . 2019 ;3 :420 –423 . 10.1002/rth2.12201 \n\n\n\n\nFunding information\n\n\nThis work was funded by the Raymond Stralka Fund for Research.\n==== Body\n1 BACKGROUND\nAcquired hemophilia A (AHA) results from the development of autoantibodies against factor VIII (FVIII). Although rare, AHA is the most common acquired coagulation factor inhibitor. AHA primarily arises in patients 65 years of age or older, and can be seen in association with autoimmune disease or malignancies.1, 2, 3, 4 The United Kingdom Hemophilia Centre Doctor's Organization prospective surveillance study estimated the incidence of AHA to be 1.48 cases per million per year.2 Compared to patients with congenital hemophilia A, achievement of hemostasis in AHA is difficult because of the reduced efficacy of standard FVIII replacement products and need for bypassing agent administration in many patients. The management of AHA‐related bleeding is particularly challenging in patients with coronary artery disease (CAD) because of the increased risk of thromboembolism associated with the administration of bypassing agents.5, 6 This case report examines the Key Clinical Question of how to manage in‐stent restenosis in a patient with refractory AHA.\n\n2 CASE\nOur patient is a 72‐year‐old male with a history of bullous pemphigoid–associated AHA with a high‐titer FVIII inhibitor who developed symptomatic CAD. He developed AHA in August 2012. His FVIII inhibitor was refractory to multiple immunosuppression therapies, including corticosteroids, rituximab, cyclophosphamide, cyclosporine, azathioprine, bortezomib, mycophenolate, cladribine, and tacrolimus (Figure 1). For 2 years before presentation, he was managed solely with FVIII inhibitor bypassing activity (Feiba, Shire US, Inc.) prophylaxis dosed at 50 units/kg 3 times weekly. In the year before presentation, he required treatment with Feiba only occasionally. His only risk factor for CAD was his age. Although long‐term exposure to Feiba may have also contributed, no data exist describing the risk of CAD development in patients with AHA receiving long‐term prophylactic Feiba. In March 2018 he developed chest pain and was diagnosed at an outside hospital with non–ST‐segment elevation myocardial infarction. Feiba was held, and loading doses of aspirin (325 mg) and clopidogrel (600 mg) were administered, resulting in large bilateral forearm hematomas. At the time of transfer to The Johns Hopkins Hospital, his FVIII inhibitor titer was 409 Bethesda Units (BU)/mL, and his most recent FVIII activity was undetectable. He underwent percutaneous coronary intervention (PCI) via radial approach upon arrival to repair critical mid–left anterior descending (LAD) artery stenosis. A bare metal stent (BMS) was placed to minimize dual antiplatelet therapy duration. Feiba 75 units/kg was administered 30 minutes before PCI and 12 hours after the preprocedure dose. Due to soft tissue bleeding in the setting of dual antiplatelet therapy (DAPT) administration, aspirin 81 mg and clopidogrel 75 mg were administered daily for 2 weeks with concomitant Feiba 50 units/kg every 12 hours, initiated 24 hours after the preprocedural dose. This regimen was tolerated without recurrent chest pain or bleeding, and the patient was discharged on his preadmission Feiba prophylaxis regimen with aspirin 81 mg daily. Additional inhibitor eradication therapy was not attempted due to prior nonresponse to multiple immunosuppressive regimens.\n\nFigure 1 Immunosuppression course. R, rituximab; IVIG, intravenous immune globulin; AZA, azathioprine; M, mycophenolate; CS, corticosteroids; C, cyclophosphamide; tacro, tacrolimus; BU, Bethesda unit; cyclophosphamide: patient received oral low‐dose 8/7/2013‐11/27/2013 and 5/28/2015‐6/17/2015; intravenous high‐dose administration occurred 12/3/2013‐1/14/2014 \n\nThe patient returned to our institution 15 weeks after discharge with severe angina. Feiba 75 units/kg was administered 30 minutes before diagnostic left heart catheterization via radial approach, which revealed 99% in‐stent restenosis of the distal portion of the mid‐LAD BMS. Because of previous Feiba failure in the setting of DAPT and concern regarding the use of other prothrombotic agents, we explored alternative approaches to promote adequate hemostasis during coronary artery bypass graft (CABG) surgery or drug‐eluting stent (DES) placement.\n\nMultidisciplinary discussions were held involving hematology, cardiology, cardiac surgery, pharmacy, and laboratory medicine to evaluate potential treatment options. Although recombinant FVIIa (NovoSeven; Novo Nordisk Inc., Plainsboro, NJ) has demonstrated efficacy in patients refractory to Feiba, there were significant concerns about the thrombogenicity of this agent and the possibility of stent occlusion given the tenuous status of his BMS.7 In this setting, emicizumab (Hemlibra; Genetech USA, Inc., San Francisco, CA) was considered a safer option to facilitate either PCI with DES placement or CABG surgery. However, timely emicizumab initiation was not possible because of delays in insurance approval for off‐label administration. Therefore, recombinant porcine FVIII (Obizur; Shire US, Inc.) was initiated. One hour after administration of 300 units/kg, peak FVIII activity was 0.25 IU/dL, which declined to 0.21 IU/dL 3.5 hours after administration. In light of these results, porcine FVIII therapy did not appear to be a viable management option for achieving periprocedural hemostasis. This patient's suboptimal response was likely secondary to a high antiporcine FVIII inhibitor (titer of 18 BU/mL measured before porcine FVIII initiation).\n\nWith porcine FVIII no longer an option, we were able to obtain insurance approval for emicizumab administration. Because emicizumab administration results in a false reduction of the activated clotting time, intraoperative titration of unfractionated heparin during CABG surgery was no longer considered feasible.8 Although intraoperative heparin monitoring could occur utilizing anti‐Xa levels, this was not a viable strategy because of the prolonged turnaround time for this assay at our institution. Therefore, DES placement with 6‐12 months of DAPT was pursued instead of CABG surgery. Emicizumab was initiated at 3 mg/kg (255 mg) once weekly 3 days after discontinuation of Feiba prophylaxis. Twenty‐two days after emicizumab initiation, the patient was loaded with aspirin 325 mg and clopidogrel 600 mg, followed by administration of aspirin 81 mg and clopidogrel 75 mg daily. In the absence of clinically significant bleeding with DAPT exposure, the patient was taken for PCI with successful placement of 2 mid‐LAD DESs 27 days after emicizumab initiation. To avoid the challenges of monitoring intraprocedural unfractionated heparin anticoagulation in the presence of emicizumab, a bivalirudin 0.75 mg/kg bolus was administered intraprocedurally, followed by an infusion of 1.75 mg/kg/h for the duration of the procedure without activated clotting time monitoring.8 The patient tolerated the procedure and continued DAPT without breakthrough bleeding or the need for bypassing agent administration. The patient was transitioned to emicizumab 1.5 mg/kg (120 mg) once weekly 28 days after emicizumab initiation. Two days after PCI, he was discharged on emicizumab 120 mg once weekly and aspirin 81 mg daily to be administered indefinitely, with clopidogrel 75 mg daily for 6‐12 months after DES placement. Five months after discharge, the patient remains free from bleeding and recurrent cardiac complications.\n\n3 DISCUSSION\nAHA is a rare coagulopathy that preferentially affects older individuals who are also at greater risk for cardiovascular disease. Immunosuppression is first‐line therapy for AHA, and although the majority of patients with AHA achieve a complete remission with immunosuppressive therapy (71% in the United Kingdom Hemophilia Centre Doctor's Organization registry), a significant proportion relapse or are refractory despite multiple attempts at inhibitor eradication.2 Therefore, it is likely that hematologists will care for patients with refractory FVIII inhibitors and age‐related cardiovascular events.\n\nSeveral methods should be employed in this population to reduce procedural‐related bleeding. The use of radial access over femoral access has proven to decrease procedural bleeding by 30% in the general population and has increasingly become the access of choice for PCI.9, 10, 11, 12, 13 The use of a BMS over DES is also recommended to limit the duration of DAPT.12, 13 However, BMSs are associated with significantly higher rates of in‐stent restenosis compared to DES—a complication that led to our patient's second presentation and need for further intervention to restore patency to the mid‐LAD stent.14 Additionally, when P2Y12 inhibitor therapy is indicated, relative platelet inhibition potency among available agents should be considered to minimize bleeding.12, 15, 16 For our patient, radial access was used, and clopidogrel was chosen over more potent P2Y12 inhibitors associated with higher bleeding risk. However, a DES was placed due to the location of the coronary lesion and the prior failure of a BMS.\n\nAlthough bypassing therapies are effective for management of most acute bleeding events,17 Feiba prophylaxis was unable to provide adequate hemostasis during DAPT in our patient. Our case report demonstrates that emicizumab may represent an attractive option for patients with AHA and may facilitate safe DAPT administration. However, further investigation is warranted to confirm the safety and efficacy of emicizumab in AHA.\n\nTwo open‐label, randomized trials have demonstrated that emicizumab is an effective therapy for bleeding prevention in patients with hemophilia with and without inhibitors.18, 19 However, concomitant administration of Feiba in doses of 100 units/kg/day or higher for 24 hours or more was associated with a significant increase in the risk of thrombotic complications. Therefore, recombinant FVIIa should be used preferentially for the treatment of bleeding events in patients receiving emicizumab. Early experience with emicizumab in 22 patients with congenital hemophilia with inhibitors who underwent 29 invasive procedures was reported by Kruse‐Jarres et al20 at the American Society of Hemophilia meeting in December 2017. Twenty procedures were performed without administration of bypassing agents, and adequate hemostasis was achieved in 70%. Of the 6 procedures complicated by postoperative bleeding, only 2 (a dental extraction and an arthroscopic knee surgery) required administration of bypassing agents. Similarly, our patient underwent PCI with DES placement without preprocedural bypassing agents and experienced no hemostatic difficulties despite periprocedural bivalirudin and DAPT administration.\n\nAlthough emicizumab administration was not associated with adverse effects in our patient, the thrombotic risk of emicizumab in AHA remains unknown. One published report to date described the development of thromboembolism in an 80‐year‐old patient with AHA and several medical comorbidities receiving emicizumab postoperatively following abdominal surgery21. This patient experienced a minor thromboembolic stroke on day 16 of emicizumab treatment, at which time she was receiving concomitant recombinant FVIIa. This event occurred in the setting of FVIII activity of 10%. It is unclear whether this event was precipitated by emicizumab administration or if this patient was predisposed to thromboembolism due to comorbidities, postsurgical risk, and concomitant recombinant FVIIa administration. In our patient, the risk of emicizumab‐induced thromboembolism may have been mitigated by concomitant DAPT administration. Additionally, our patient's FVIII inhibitor was deemed permanent after failure of multiple attempts at eradication. In patients with AHA successfully undergoing inhibitor eradication, thromboembolic risk may increase as FVIII inhibitor titers decline and FVIII levels normalize.\n\nIn conclusion, we present a patient with AHA refractory to multiple immunosuppressive regimens presenting with ACS requiring PCI who was successfully managed with emicizumab. We believe this case supports further investigation of emicizumab in patients with AHA.\n\nRELATIONSHIP DISCLOSURE\nKED, JPL, ARM and MKK have no conflicts of interest to disclose. SS has received institutional grant support from Daiichi‐Sankyo outside the purview of this work. MBS reports grants from Boehringer‐Ingelheim, Roche, personal fees from Daiichi‐Sankyo, Bayer, grants and personal fees from Janssen, Portola, personal fees from Pfizer and CSL Behring, all outside the submitted work. MBS also provides expert testimony for various legal cases involving venous thromboembolism management.\n\nAUTHOR CONTRIBUTION\nKD, JL, MS, and SS drafted and critically revised the manuscript. AM and MK critically revised the manuscript.\n==== Refs\nREFERENCES\n1 \n\nKnoebl \nP \n, \nMarco \nP \n, \nBaudo \nF \n, \nCollins \nP \n, \nHuth‐Kuhne \nA \n, \nNemes \nL \n, et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2) . J Thromb Haemost . 2012 ;10 :622 –31 .22321904 \n2 \n\nCollins \nPW \n, \nHirsch \nS \n, \nBaglin \nTP \n, \nDolan \nG \n, \nHanley \nJ \n, \nMakris \nM \n, et al. Acquired hemophilia A in the United Kingdom: a 2‐year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation . Blood . 2007 ;109 :1870 –7 .17047148 \n3 \n\nCollins \nP \n, \nMacartney \nN \n, \nDavies \nR \n, \nLees \nS \n, \nGiddings \nJ \n, \nMajer \nR \n. 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2475-0379",
"issue": "3(3)",
"journal": "Research and practice in thrombosis and haemostasis",
"keywords": "acute coronary syndrome; blood coagulation factor inhibitors; coronary artery disease; hemophilia A; platelet aggregation inhibitors",
"medline_ta": "Res Pract Thromb Haemost",
"mesh_terms": null,
"nlm_unique_id": "101703775",
"other_id": null,
"pages": "420-423",
"pmc": null,
"pmid": "31294330",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "14675412;15456478;17047148;17982182;19717846;19837978;21323799;22321904;22618709;22776238;24270744;25791214;27106121;28691557;28763308;30157389",
"title": "Successful use of emicizumab in a patient with refractory acquired hemophilia A and acute coronary syndrome requiring percutaneous coronary intervention.",
"title_normalized": "successful use of emicizumab in a patient with refractory acquired hemophilia a and acute coronary syndrome requiring percutaneous coronary intervention"
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{
"abstract": "Ewing sarcoma (EWS) is a primary bone tumor that most often occurs in the long bones of young patients. EWS is typically an aggressive tumor that is highly sensitive to radiation therapy; recurrences often occur, usually within a year of treatment. We present a case of EWS that first presented in a patient at the age of 40 with extraosseous disease. The patient was treated initially with radiation and surgery. Over the following 36-year period, the tumor recurred once and metastasized twice. The morphologic, immunohistochemical, and cytogenetic features of this tumor were typical of EWS, and the tumor was highly responsive to radiation therapy. The unusually prolonged course in this patient demonstrates significant heterogeneity in the biological behavior of EWS, and the importance of randomized trials in cancer therapy.",
"affiliations": "*Department of Medicine †Department of Pathology and Laboratory Medicine, Veterans Administration Medical Center ‡Department of Orthopaedic Surgery, University of Minnesota Medical School, Minneapolis, MN.",
"authors": "Gordon|Max J|MJ|;Manivel|J Carlos|JC|;Cheng|Edward Y|EY|;Skubitz|Keith M|KM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "36(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001859:Bone Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012512:Sarcoma, Ewing; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e463-4",
"pmc": null,
"pmid": "24577550",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual case of Ewing sarcoma: a middle-aged woman with multiple recurrences over 36 years.",
"title_normalized": "an unusual case of ewing sarcoma a middle aged woman with multiple recurrences over 36 years"
} | [
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"abstract": "A 24-year-old female patient diagnosed with cyanotic CHD had undergone a correction procedure at the age of eight. She had a normal motor and mental development until the age of 23. Later she had functional and cognitive decline following heart failure. Brain MRI showed enlargement of the cerebral arterial and venous system. The changes of central nervous system vasculature occurring in operated cyanotic CHD are not well known. Thanks to advances in this field, more cyanotic CHD patients reach adulthood nowadays and clinicians need to be familiar with the neurological conditions and potential neuroradiological changes.",
"affiliations": "Cerebrovascular Diseases Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Cerebrovascular Diseases Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.;Cerebrovascular Diseases Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.",
"authors": "Emekli|Ahmed S|AS|https://orcid.org/0000-0002-5673-3014;Ekizoglu|Esme|E|;Yesilot|Nilufer|N|",
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"issue": "30(5)",
"journal": "Cardiology in the young",
"keywords": "Stroke; cerebrovascular disease; cyanotic CHD; heart failure; hypoxia",
"medline_ta": "Cardiol Young",
"mesh_terms": "D001921:Brain; D002561:Cerebrovascular Disorders; D003490:Cyanosis; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D002534:Hypoxia, Brain; D008279:Magnetic Resonance Imaging; D055815:Young Adult",
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"pmid": "32249724",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Diffuse enlargement of cerebral vasculature in an adult patient operated for cyanotic congenital heart disease.",
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"abstract": "BACKGROUND Herpes zoster is caused by the reactivation of the varicella zoster virus (VZV) and usually presents with vesicular skin lesions with a dermatomal distribution. Disseminated herpes zoster (DHZ) infection is characterized by non-dermatomal skin eruptions, often with involvement of other organs, and occurs in immunocompromised patients. CASE REPORT A 69-year-old man who was treated with prednisolone for amiodarone-associated interstitial lung disease, presented with seizures and altered consciousness. He had an erythematous rash with raised vesicles involving the skin of the genital region, left thigh, and abdomen. Following a diagnosis of DHZ with herpes zoster meningoencephalitis, he was treated with intravenous acyclovir. However, his level of consciousness did not improve, and he died of respiratory failure due to aspiration pneumonia. CONCLUSIONS A diagnosis of DHZ should be considered in immunosuppressed patients treated with steroids who present with seizures. A detailed search for skin eruptions should be conducted to enable early diagnosis and treatment.",
"affiliations": "Department of Respiratory Medicine, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan.;Department of Respiratory Medicine, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan.;Department of Respiratory Medicine, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan.;Department of Respiratory Medicine, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan.;Department of Dermatology, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan.;Department of Neurology, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan.;Department of Respiratory Medicine, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan.",
"authors": "Fujisato|Shushi|S|;Urushibara|Takashi|T|;Kasai|Hajime|H|;Ishi|Daisuke|D|;Inafuku|Kazuhiro|K|;Fujinuma|Yoshikatsu|Y|;Shinozaki|Toshihide|T|",
"chemical_list": "D000998:Antiviral Agents; D005938:Glucocorticoids; D011239:Prednisolone",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3027034210.12659/AJCR.910521910521ArticlesA Fatal Case of Atypical Disseminated Herpes Zoster in a Patient with Meningoencephalitis and Seizures Associated with Steroid Immunosuppression Fujisato Shushi ABCDEF1Urushibara Takashi CDE1Kasai Hajime ABCDEF123Ishi Daisuke ABC1Inafuku Kazuhiro DE4Fujinuma Yoshikatsu DE5Shinozaki Toshihide CDE1\n1 Department of Respiratory Medicine, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan\n2 Department of Respirology, Graduate School of Medicine, Chiba University, Chiba City, Chiba, Japan\n3 Health Professional Development Center, Chiba University Hospital, Chiba City, Chiba, Japan\n4 Department of Dermatology, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan\n5 Department of Neurology, Kimitsu Chuo Hospital, Kisarazu, Chiba, JapanAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Hajime Kasai, e-mail: daikasai6075@yahoo.co.jp2018 01 10 2018 19 1162 1167 11 4 2018 06 6 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 69\n\nFinal Diagnosis: Disseminated herpes zoster\n\nSymptoms: Rash • seizures\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Infectious Diseases\n\nObjective:\nDiagnostic/therapeutic accidents\n\nBackground:\nHerpes zoster is caused by the reactivation of the varicella zoster virus (VZV) and usually presents with vesicular skin lesions with a dermatomal distribution. Disseminated herpes zoster (DHZ) infection is characterized by non-dermatomal skin eruptions, often with involvement of other organs, and occurs in immunocompromised patients.\n\nCase Report:\nA 69-year-old man who was treated with prednisolone for amiodarone-associated interstitial lung disease, presented with seizures and altered consciousness. He had an erythematous rash with raised vesicles involving the skin of the genital region, left thigh, and abdomen. Following a diagnosis of DHZ with herpes zoster meningoencephalitis, he was treated with intravenous acyclovir. However, his level of consciousness did not improve, and he died of respiratory failure due to aspiration pneumonia.\n\nConclusions:\nA diagnosis of DHZ should be considered in immunosuppressed patients treated with steroids who present with seizures. A detailed search for skin eruptions should be conducted to enable early diagnosis and treatment.\n\nMeSH Keywords:\nAcyclovirEncephalitis, Varicella ZosterFatal OutcomeHerpes ZosterSeizuresSteroids\n==== Body\nBackground\nHerpes zoster is caused by the reactivation of the varicella zoster virus (VZV) and usually presents with vesicular skin lesions with a dermatomal distribution. Disseminated herpes zoster (DHZ) infection is characterized by non-dermatomal skin eruptions and can occur in immunocompromised patients.\n\nIn immunocompromised patients who develop DHZ, associated complications can include pneumonia, hepatitis, encephalitis, or involvement of other organs [1]. DHZ can also occur without the presence of a skin rash [2]. DHZ may result in death because of delayed diagnosis in immunocompromised patients, including patients with bone marrow transplantation and acquired immunodeficiency syndrome (AIDS) [3]. Although cutaneous dissemination of VZV (shingles) is not usually life-threatening [4], cutaneous and visceral dissemination of VZV is associated with increased morbidity and mortality [3]. However, there have been few previously reported cases of patient mortality due to DHZ in patients with a history of steroid treatment [5,6]. This report presents a fatal case of DHZ in a patient on steroid therapy, who presented with seizures and disseminated skin lesions.\n\nCase Report\nIn August 2016, a 69-year-old man with chronic kidney disease and type 2 diabetes mellitus was admitted to our hospital with a diagnosis of amiodarone-induced interstitial pneumonia. He had been treated with amiodarone for paroxysmal atrial fibrillation. When amiodarone was discontinued, he was treated with high-dose intravenous methylpredniso-lone (1,000 mg daily) for three days, followed by prednisolone (60 mg daily). In his past medical history there was also a history of herpes encephalitis.\n\nOn day 40 after the initiation of steroid treatment, when the dose of prednisolone had been decreased to 40 mg daily, he developed seizures and a change in his level of consciousness. The seizures spontaneously ceased after a few minutes. However, he remained in a semi-comatose state. His vital signs included the following: a Glasgow Coma Scale score of 11/15 (E3, V3, M5); blood pressure, 137/59 mmHg; pulse rate, 116 beats/min; peripheral capillary oxygen saturation, 96% in room air; and body temperature, 37.4°C. He had no other neurological signs, such as neck or limb stiffness and no paralysis of the extremities. His main symptoms were seizures and impaired levels of consciousness. Laboratory findings included a creatinine concentration of 1.20 mg/dl and hemoglobin A1c (HbA1c) level of 9.3%, with no increased levels of inflammatory markers, no electrolyte abnormalities, and no hypoglycemia (Table 1).\n\nIn this patient, we initially suspected a diagnosis of symptomatic epilepsy caused by a history of herpes encephalitis, and head imaging with computed tomography (CT), which showed an area of low density in the left temporal lobe (Figure 1A). Therefore, he was placed under observation, without drug treatment, including the use of antiepileptic drugs. A day after the seizures began, while changing his protective underwear (adult diaper), a nurse detected an erythematous rash with raised vesicles on the genital region along the right side, in the distribution of the third to fourth sacral dermatomes (S3–S4) (Figure 2A). Although the patient was aware of the skin rash and had mild pain in the same area one week before the seizures occurred, he did not report it to the clinicians because he was embarrassed. Similar rashes were found on his left thigh and abdomen, and examination of his entire body showed that these lesions did not follow the distribution of the dermatomes, but were more widespread (Figure 2B, 2C).\n\nTherefore, a provisional diagnosis of disseminated herpes zoster (DHZ) was made. Analysis of cerebrospinal fluid (CSF) showed a white blood cell (WBC) count of 287/μl (proportion of segmented neutrophils, 80%), a CSF protein level of 481 mg/dl, and a CSF glucose level of 69 mg/dl (blood glucose value, 129 mg/dl). Bacterial cultures of the CSF and herpes simplex virus (HSV) polymerase chain reaction (PCR) were negative. Positive serum levels of varicella zoster virus (VZV) IgM and IgG and intrathecal IgG were detected. However, the antibody titer of HSV in the CSF showed negative findings. Based on these findings, a diagnosis of DHZ-induced meningoencephalitis was considered to be the most likely cause of the patient’s seizures and impaired levels of consciousness.\n\nTreatment immediately began with intravenous acyclovir, before confirmation of the diagnosis of DHZ (Figure 3). Although his consciousness level improved slightly after treatment began, his impaired levels of consciousness persisted for 14 days (Figure 3). Neurotoxicity due to acyclovir was considered as a potential cause, because of the clinical course of his cerebral symptoms. Acyclovir was discontinued after 14 days.\n\nSeven days after discontinuation of acyclovir treatment, his level of consciousness deteriorated. At this time, analysis of the CSF analysis showed a white blood cell count of 741 per μl (mononuclear cells, 94%), and a CSF protein level of 213 mg/dl. Also, a head CT showed bilateral low-density areas around the frontal lobes, which were suspected to be due to hematoma or cerebral edema (Figure 1B). A prolonged clinical course of meningoencephalitis due to DHZ was suspected, and treatment with acyclovir was resumed. However, his level of consciousness did not improve, and the patient died of respiratory failure due to aspiration pneumonia.\n\nDiscussion\nThe present case demonstrated several important clinical findings that might provide lessons regarding the importance of early diagnosis of disseminated herpes zoster (DHZ). First, the diagnosis of DHZ may be delayed if skin eruptions occur in a location that makes detection difficult, such as the genitals or pudendum. Second, as this case has demonstrated, DHZ can present with seizures due to meningoencephalitis as an initial symptom in immunosuppressed patients. Third, patients undergoing steroid therapy can be affected by DHZ, which may be accompanied by meningoencephalitis that is refractory to antiviral drugs and can be fatal.\n\nIn immunosuppressed patients presenting with seizures, DHZ should be considered in the differential diagnosis. As previously reported, there are varied neurologic complications that occur with herpes zoster infection, including Bell’s palsy, Ramsay Hunt syndrome, transverse myelitis, transient ischemic attacks (TIAs), and stroke [1]. Also, varicella zoster virus (VZV) is the third most common cause of viral meningitis, with 44% of VZV-associated meningitis cases presenting without skin rash [2]. In the present case, the skin rash occurred in the genital area of the patient, one week before the seizures began, which made the skin lesions difficult to detect. Also, in this case, we initially suspected symptomatic epilepsy caused by a past history of herpes encephalitis, which may have delayed the diagnosis of DHZ on this most recent presentation. To avoid delay in diagnosis, DHZ should be considered in immunosuppressed patients presenting with seizures, and a thorough physical examination of the skin, including the genital area, should be conducted to detect associated skin rashes.\n\nIn patients receiving steroid therapy, DHZ can be accompanied by meningoencephalitis that is refractory to antiviral drugs and can be fatal. Diseases that cause immunosuppression, including human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS), and human T-cell leukemia virus type 1 (HTVL-1), are risk factors for DHZ [7,8]. The risk of opportunistic infection is 1.6 times higher in patients receiving prednisolone (≥10 mg/day), 1.8 times higher in patients with diabetes mellitus, and patients taking steroids have a high risk of DHZ [9]. If DHZ is accompanied by disseminated intravascular coagulation (DIC), meningoencephalitis, and pneumonia, the mortality rate in cases with these comorbidities has been reported to be approximately 55% [10]. DHZ-induced meningoencephalitis has been previously reported in severely immunosuppressed patients [7,8]. In the present case, 40 mg oral prednisolone was administered daily following steroid pulse therapy, and the patient had a history of diabetes and chronic renal failure. A combination of these factors could have resulted in severe immunosuppression, resulting in accelerated progression of DHZ and death, despite acyclovir treatment.\n\nCombining molecular testing for HSV and VZV infection, including polymerase chain reaction (PCR) with antibody tests is useful for the diagnosis and exclusion of virus-induced neurologic disease. Although this patient had a history of herpes encephalitis, we diagnosed DHZ meningoencephalitis based on HSV PCR of the cerebrospinal fluid (CSF), and serum VZV antibody tests. However, in this patient, the presence of VZV IgG could have represented persistent titers from the previous disease, with a false positive VZV IgM, or reactivation of VZV IgM due to a systemic illness not due to DHZ. Therefore, caution should be undertaken when interpreting the results of routine antibody tests, which may show false-positive reactions or reactions due to prior infection. Also, the use of molecular diagnostic methods when examining the CSF, including PCR for the diagnosis of active HSV and VZV are useful for the confirmation or exclusion of a diagnosis of DHZ meningoencephalitis. The combination of serological and CSF studies using VZV PCR has previously been recommended for the identification of cases of VZV infection of the central nervous system infections in patients who present without a skin rash [11]. However, VZV PCR testing is not covered by health insurance for tests involving serum, skin vesicles, and CSF in Japan. Although HSV meningoencephalitis is not uncommon and treatment with acyclovir is effective, meningoencephalitis caused by DHZ occurs less frequently [12,13]. Therefore, in the present case, HSV PCR was performed for the analysis of the CSF and VZV PCR was not performed. Although a positive serum IgM and intrathecal IgG was consistent with the diagnosis of DHZ, VZV PCR of the CSF should be performed to obtain a definite diagnosis.\n\nConclusions\nIn conclusion, a case of disseminated herpes zoster (DHZ) has been presented associated with fatal meningoencephalitis. In immunosuppressed patients who present with seizures and impaired levels of consciousness, including patients who are treated with steroids, DHZ should be included in the differential diagnosis, and a thorough clinical examination should include examination for skin eruptions, for the early diagnosis and treatment of DHZ.\n\nConflict of interest\n\nNone.\n\nFigure 1. Computed tomography (CT) imaging of the head. (A) Head computed tomography (CT) performed after a seizure showing a low-density area in the left temporal lobe. (B) Bilateral low-density areas in the forehead region of the frontal lobes on head CT performed following discontinuation of acyclovir (arrow), which were suspected to be due to hematoma or edema.\n\nFigure 2. Disseminated erythematous rashes involving the skin of the genital areas, buttocks, left thigh, and abdomen. (A) An erythematous rash with raised vesicles involving the genital regions and involving the right third to fourth sacral (S3–S4) dermatomes. (B) An erythematous rash with raised vesicles is shown to involve the skin of the buttocks. (C) An erythematous rash with raised vesicles is shown to involve the skin of the left thigh and abdomen, which did not follow the distribution of a dermatome.\n\nFigure 3. The clinical course of the patient. CRP – C-reactive protein; CSF – cerebrospinal fluid; VZV – varicella zoster virus; HSV – herpes simplex virus; mono – monocyte; seg – segmented neutrophil; WBC – white blood cell.\n\nTable 1. Laboratory data after seizures.\n\nComplete blood count\tBlood chemistry\t\nWBC 10,900/μl\tAST 65 U/l\t\nRBC 399×104/μl\tALT 89 U/l\t\nHGB 14.9 g/dl\tLDH 574 U/l\t\nPLT 14.9×104/μl\tALP 281 U/l\t\n\tγ-GTP 66 U/l\t\n\tT-BIL 1.2 mg/dl\t\nImmunology\tTP 5.2 g/dl\t\nCRP 0.17 mg/dl\tALB 3.1 g/dl\t\n\tUN 28.6 mg/dl\t\n\tCRE 1.2 mg/dl\t\n\tNa 143 mmol/l\t\n\tK 3.3 mmol/l\t\n\tCl 95 mmol/l\t\n\tGlucose 106 mg/dl\t\n\tHbA1c 9.3 %\n==== Refs\nReferences:\n1. Cohen JI Herpes zoster N Engl J Med 2013 369 1766 67 \n2. Becerra JC Sieber R Martinetti G Infection of the central nervous system caused by varicella zoster virus reactivation: A retrospective case series study Int J Infect Dis 2013 17 e529 34 23566589 \n3. Koc Y Miller KB Schenkein DP Varicella zoster virus infections following allogeneic bone marrow transplantation: Frequency, risk factors, and clinical outcome Biol Blood Marrow Transplant 2000 6 44 49 10707998 \n4. Gomez E Chernev I Disseminated cutaneous herpes zoster in an immuno-competent elderly patient Infect Dis Rep 2014 6 5513 25276332 \n5. Nagel MA Lenggenhager D White T Disseminated VZV infection and asymptomatic VZV vasculopathy after steroid abuse J Clin Virol 2015 66 72 75 25866342 \n6. Nomdedéu J Nomdedéu J Martino R Ogilvie’s syndrome from disseminated varicella-zoster infection and infarcted celiac ganglia J Clin Gastroenterol 1995 20 157 59 7769201 \n7. Mabuchi T Yamaoka H Kato M Case of disseminated vesicles of herpes zoster developing one day before the onset of local eruption in a hospitalized immunocompromised patient Tokai J Exp Clin Med 2013 38 52 54 23868735 \n8. Fujii N Itoh Y Tomoda H Disseminated herpes zoster with multifocal neurologic involvement in an HTLV-1 carrier Intern Med 1993 32 854 56 8012086 \n9. Greenberg JD Reed G Kremer JM Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry Ann Rheum Dis 2010 69 380 86 19359261 \n10. Schiller GJ Nimer SD Gajewski JL Golde DW Abdominal presentation of varicella-zoster infection in recipients of allogeneic bone marrow transplantation Bone Marrow Transplant 1991 7 489 91 1843181 \n11. DeBiasi RL Kleinschmidt-DeMasters BK Weinberg A Tyler KL Use of PCR for the diagnosis of herpesvirus infections of the central nervous system J Clin Virol 2002 25 Suppl. 1 S5 11 12091076 \n12. Kamei S Takasu T Nationwide survey of the annual prevalence of viral and other neurological infections in Japanese inpatients Intern Med 2000 39 894 900 11065239 \n13. Wada-Isoe K Kusumi M Kai T Epidemiological study of acute encephalitis in Tottori Prefecture, Japan Eur J Neurol 2008 15 1075 79 18717727\n\n",
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"title": "A Fatal Case of Atypical Disseminated Herpes Zoster in a Patient with Meningoencephalitis and Seizures Associated with Steroid Immunosuppression.",
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{
"abstract": "Several aetiological theories have been proposed for the development of osteochondritis dissecans. Cartilage toxicity after fluoroquinolone use has been well documented in vitro. We present a case report of a 10-year-old child who underwent a prolonged 18-month course of ciprofloxacin therapy for chronic urinary tract infections. This patient later developed an osteochondritis dissecans lesion of the medial femoral condyle. We hypothesise that the fluoroquinolone therapy disrupted normal endochondral ossification, resulting in development of osteochondritis dissecans. The aetiology of osteochondritis dissecans is still unclear, and this case describes an association between fluoroquinolone use and osteochondritis dissecans development.",
"affiliations": "University of Utah School of Medicine, Salt Lake City, Utah.;St. Luke's Boise Medical Center, Boise, Idaho, USA Department of Orthopedics, University of Utah, Salt Lake City, Utah, USA.;Boise State University, Boise, Idaho, USA.;Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.",
"authors": "Jacobs|John C|JC|;Shea|Kevin G|KG|;Oxford|Julia Thom|JT|http://orcid.org/0000-0002-4850-3569;Carey|James L|JL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
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"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002648:Child; D002908:Chronic Disease; D004334:Drug Administration Schedule; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D010008:Osteochondritis Dissecans; D014552:Urinary Tract Infections",
"nlm_unique_id": "101526291",
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"pages": null,
"pmc": null,
"pmid": "25228675",
"pubdate": "2014-09-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "3992264;3117310;10682725;5908173;21785119;18226555;18632714;15562138;8740110;3968094;75656;14216462;2353417;11409663;9127853;9371369;19886258;7331787;20561273;11117292;9060073;19737988;622473;10843129;1015263;11685846;11280370;10064248;16142476;17210779;19352246;12966282;5909068;807740;16171175;10795030",
"title": "Fluoroquinolone use in a child associated with development of osteochondritis dissecans.",
"title_normalized": "fluoroquinolone use in a child associated with development of osteochondritis dissecans"
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{
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{
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] |
{
"abstract": "A 13-year-old girl presented to a private office for dental rehabilitation under general anesthesia. The patient had a previous uneventful anesthetic 5 years prior in the same office by another dental anesthesiologist. The patient was highly anxious and would not allow monitors placed prior to induction. After an uneventful mask induction with sevoflurane, nitrous oxide, and oxygen, monitors were placed and a 22-gauge intravenous cannula inserted. The initial rhythm on the electrocardiogram was trigeminy interspersed with normal sinus rhythm. The volatile anesthetic sevoflurane was discontinued immediately, and intravenous anesthesia was started but still the patient was consistently entering trigeminy. The patient was always hemodynamically stable and never hypoxic. An in-depth discussion of the case and discussion of ventricular dysrhythmias is presented.",
"affiliations": "Certified Specialist in Dental Anesthesia in Ontario, Canada (RCDSO).",
"authors": "Waxman|Bryan Neil|BN|",
"chemical_list": "D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D008738:Methyl Ethers; D000077149:Sevoflurane; D009609:Nitrous Oxide; D008874:Midazolam; D005283:Fentanyl; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.2344/0003-3006-62.3.110",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-3006",
"issue": "62(3)",
"journal": "Anesthesia progress",
"keywords": "Dental anesthesia; Management of pediatric cardiac arrhythmias; Pediatric cardiac arrhythmias; Trigeminy",
"medline_ta": "Anesth Prog",
"mesh_terms": "D000293:Adolescent; D000553:Ambulatory Care; D000766:Anesthesia, Dental; D000768:Anesthesia, General; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D018880:Atrial Premature Complexes; D002037:Bundle-Branch Block; D016854:Dental Anxiety; D003729:Dental Care; D004562:Electrocardiography; D005260:Female; D005283:Fentanyl; D006801:Humans; D006993:Hypnotics and Sedatives; D008738:Methyl Ethers; D008874:Midazolam; D009609:Nitrous Oxide; D011229:Preanesthetic Medication; D015742:Propofol; D000077149:Sevoflurane; D018879:Ventricular Premature Complexes",
"nlm_unique_id": "0043533",
"other_id": null,
"pages": "110-3",
"pmc": null,
"pmid": "26398127",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16487786",
"title": "A 13-Year-Old Girl in Trigeminy During Anesthesia for Outpatient Dental Surgery: A Case Report.",
"title_normalized": "a 13 year old girl in trigeminy during anesthesia for outpatient dental surgery a case report"
} | [
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"medicinalproduct": "SEVOFLURANE."
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],
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"reaction": [
{
"reactionmeddrapt": "Extrasystoles",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "3"
}
],
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},
"primarysource": {
"literaturereference": "WAXMAN BN. A 13-YEAR-OLD GIRL IN TRIGEMINY DURING ANESTHESIA FOR OUTPATIENT DENTAL SURGERY: A CASE REPORT. ANESTH-PROG 2015?62(3):110-3.",
"literaturereference_normalized": "a 13 year old girl in trigeminy during anesthesia for outpatient dental surgery a case report",
"qualification": "3",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20160125",
"receivedate": "20160125",
"receiver": {
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},
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"safetyreportid": 11949110,
"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160526"
}
] |
{
"abstract": "Background Bevacizumab (Bev) is generally well-tolerated, and Bev-associated intestinal perforation (BAP) is a rare albeit serious side effect in cases of non-small cell lung cancer (NSCLC). Therefore, the present study aimed to identify clinical predictors of BAP to help predict and manage the development of life-threatening intestinal complications among patients receiving Bev. Methods This retrospective study evaluated demographic, clinical, and treatment factors for patients with NSCLC who were treated with Bev between February 2010 and August 2015 at our center. Results We identified 314 regimens (208 patients; median age: 65 years; 115 women) for analysis, which included 119 first-line regimens, 74 s-line regimens, and 121 third-line or later regimens. BAP occurred in 7 cases (2.23% among all regimens and 3.37% among all patients), which generally occurred during first- or second-line treatment and was caused by ulcerative colitis (1 case), colon diverticulitis (1 case), and idiopathic perforations (5 cases). Univariate analyses revealed that BAP was significantly associated with deteriorating PS during the first cycle of chemotherapy (odd ratio [OR]: 11.07, 95% confidence interval [CI]: 2.37-51.63, p = 0.0022), grade ≥ 3 diarrhea (OR: 11.37, 95% CI: 2.37-54.50, p = 0.0024), febrile neutropenia (OR: 9.16, 95% CI: 1.98-42.49, p = 0.0047), and stomatitis (OR: 4.60, 95% CI: 1.01-21.04, p = 0.0492). Conclusions Among patients with NSCLC, BAP was associated with deteriorating PS during the first cycle of chemotherapy, grade ≥ 3 diarrhea, febrile neutropenia, and stomatitis. Therefore, careful observation is needed for patients with NSCLC who receive Bev in any line of treatment, especially if they develop serious side effects that affect their PS or mucous membrane.",
"affiliations": "Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemachi Chuo-ku, Osaka, 541-8567, Japan. moto19781205@yahoo.co.jp.;Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino, Japan.;Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino, Japan.;Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino, Japan.;Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino, Japan.;Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino, Japan.;Department of Surgery, Osaka Gyoumeikan Hospital, Osaka, Japan.;Department of Emergency & Critical Care Medicine, Kindai University Faculty of Medicine, Osaka, Japan.;Department of Pathology, Osaka Habikino Medical Center, Habikino, Japan.;Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino, Japan.",
"authors": "Tamiya|Motohiro|M|;Suzuki|Hidekazu|H|;Shiroyama|Takayuki|T|;Tanaka|Ayako|A|;Morishita|Naoko|N|;Okamoto|Norio|N|;Sakai|Kenichi|K|;Shigeoka|Hironori|H|;Kawahara|Kunimitsu|K|;Hirashima|Tomonori|T|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-018-0581-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "36(4)",
"journal": "Investigational new drugs",
"keywords": "Bevacizumab; Intestinal perforation; NSCLC; Prediction markers",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007416:Intestinal Perforation; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "696-701",
"pmc": null,
"pmid": "29536229",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": "15175435;24637999;18024860;22849580;17617521;17512451;10655437;21803880;24552320;23168366;22532266;16971205;23178954;19688063;18665327;23925664;10841143;16258101;16503384;19188680;18335169;18417314;19482548;18024857;17680315;16172168;17167137;20382413",
"title": "Clinical predictors of bevacizumab-associated intestinal perforation in non-small cell lung cancer.",
"title_normalized": "clinical predictors of bevacizumab associated intestinal perforation in non small cell lung cancer"
} | [
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] |
{
"abstract": "In this report, we present a challenging case of a 63-year-old Caucasian woman with an extreme stress response to blood pressure (BP) measurements. Office- and ambulatory BP measurements consistently found systolic BP above 200 mmHg. However, antihypertensive medication made her dizzy and extremely unwell, and she could barely tolerate treatment with a moderate dose of angiotensin-converting enzyme (ACE) inhibitor. Finger-cuff-based measurements (Finapres Finometer®) revealed extreme hypertension in relation to contact with medical professionals, but hypotension when the patient was seated alone unobserved. Months after, the patient suffered a hemorrhagic stroke possibly related to her extreme BP-fluctuations in stressful situations.",
"affiliations": "Department of Renal Medicine and the Clinic of Hypertension, Aarhus University Hospital, Aarhus, Denmark.;Department of Renal Medicine and the Clinic of Hypertension, Aarhus University Hospital, Aarhus, Denmark.;Department of Cardiology and the Clinic of Hypertension, Aarhus University Hospital, Aarhus, Denmark.",
"authors": "Nyvad|Jakob|J|;Reinhard|Mark|M|;Christensen|Kent L|KL|",
"chemical_list": "D000959:Antihypertensive Agents",
"country": "England",
"delete": false,
"doi": "10.1080/08037051.2019.1658517",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0803-7051",
"issue": "29(1)",
"journal": "Blood pressure",
"keywords": "White-coat hypertension; anxiety; arterial pressure; blood pressure; cardiovascular diseases; hypertension; stroke",
"medline_ta": "Blood Press",
"mesh_terms": "D000959:Antihypertensive Agents; D018660:Blood Pressure Monitoring, Ambulatory; D004244:Dizziness; D005260:Female; D006801:Humans; D008875:Middle Aged; D020521:Stroke; D059466:White Coat Hypertension",
"nlm_unique_id": "9301454",
"other_id": null,
"pages": "63-67",
"pmc": null,
"pmid": "31455097",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of an extreme white coat effect.",
"title_normalized": "a case of an extreme white coat effect"
} | [
{
"companynumb": "DK-PFIZER INC-2020090680",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
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"activesubstance": {
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},
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"medicinalproduct": "RAMIPRIL."
},
{
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},
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"drugdosagetext": "UNK (HALF OF MAXIMUM RECOMMENDED DOSE)",
"drugenddate": null,
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"drugindication": "WHITE COAT HYPERTENSION",
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"medicinalproduct": "RAMIPRIL."
}
],
"patientagegroup": null,
"patientonsetage": "63",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Dizziness",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Discomfort",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "NYVAD, J.. A CASE OF AN EXTREME WHITE COAT EFFECT. BLOOD PRESSURE. 2020?29 (1):10.1080/08037051.2019.1658517",
"literaturereference_normalized": "a case of an extreme white coat effect",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20200309",
"receivedate": "20200303",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17492579,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "To evaluate adherence to treatment, we developed and validated a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for baclofen quantification in hair.Twenty mg was washed twice with dichloromethane, incubated in phosphate buffer (pH 5) for 10 minutes at 95°C, then extracted by liquid-liquid extraction in alkaline condition. Baclofen-d4 was used as the internal standard. This method was applied to assess compliance in4 treated alcohol-dependent patients (3 dead and one living). Blood quantification of baclofen and ethanol were performed in the 4 cases. Hair ethylglucuronide (ethanol metabolite, EtG) measurement (2x3 cm) was associated in 1 patient. Baclofen quantification in hair was validated over the range 10-5000 pg/mg. The accuracy was within 96.0%-110.9% and the precision was less than 9.3%. Baclofen segmental (3x2cm) hair concentrations found in the living patient were 4420, 4260, and 4380 pg/mg, reflecting a regular exposure over the last 6 months and suggesting patient compliance. However, the high EtG level found in this patient in the analyzed segments (225 pg/mg and 215 pg/mg) showed excessive alcohol consumption during the same period, suggesting therapeutic failure. In the 3 deceased patients, the non-segmental analysis of hair showed baclofen concentrations of 15, 545, and 2475 pg/mg. The low concentrations in the 2 first cases are compatible either with a poor compliance or to a beginning of a treatment. This is the first measurement of baclofen in hair of alcohol dependent patients. It could be used as a monitoring biomarker to assess patient's compliance.",
"affiliations": "Department of Pharmacology and Toxicology, Versailles Saint-Quentin Medecine University, Raymond Poincaré Hospital, AP-HP, Garches, France.;Department of anesthesiology-intensive care, hôpital Necker, 149, rue de Sèvres, 75015, Paris, France.;Department of Pharmacology and Toxicology, Versailles Saint-Quentin Medecine University, Raymond Poincaré Hospital, AP-HP, Garches, France.;Department of Pharmacology and Toxicology, Versailles Saint-Quentin Medecine University, Raymond Poincaré Hospital, AP-HP, Garches, France.;Department of anesthesiology-intensive care, hôpital Necker, 149, rue de Sèvres, 75015, Paris, France.;Department of Forensic Medecine, Raymond Poincaré Hospital, AP-HP, Garches, France.;Department of Pharmacology and Toxicology, Versailles Saint-Quentin Medecine University, Raymond Poincaré Hospital, AP-HP, Garches, France.",
"authors": "Larabi|I A|IA|;Fabresse|N|N|http://orcid.org/0000-0001-9131-2306;Knapp|A|A|;Forcet|M|M|;Baud|F J|FJ|;Lorin de la Grandmaison|G|G|;Alvarez|J C|JC|http://orcid.org/0000-0001-5344-9475",
"chemical_list": "D015415:Biomarkers; D058786:GABA-B Receptor Agonists; D005965:Glucuronates; C093924:ethyl glucuronide; D000431:Ethanol; D001418:Baclofen",
"country": "England",
"delete": false,
"doi": "10.1002/dta.2308",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1942-7603",
"issue": "10(4)",
"journal": "Drug testing and analysis",
"keywords": "alcohol dependence; baclofen; ethyl glucuronide; hair; mass spectrometry",
"medline_ta": "Drug Test Anal",
"mesh_terms": "D000437:Alcoholism; D001418:Baclofen; D015415:Biomarkers; D002853:Chromatography, Liquid; D016903:Drug Monitoring; D000431:Ethanol; D005260:Female; D058786:GABA-B Receptor Agonists; D005965:Glucuronates; D006197:Hair; D006801:Humans; D057230:Limit of Detection; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "101483449",
"other_id": null,
"pages": "694-700",
"pmc": null,
"pmid": "28967184",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "LC-MS/MS method for quantification of baclofen in hair: A useful tool to assess compliance in alcohol dependent patients?",
"title_normalized": "lc ms ms method for quantification of baclofen in hair a useful tool to assess compliance in alcohol dependent patients"
} | [
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},
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{
"abstract": "The aim of this study is to investigate the efficacy and safety of nilotinib combined with multi-agent chemotherapy in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Thirty patients with Ph+ ALL were recruited. Standard induction chemotherapy was given for 4 weeks. Nilotinib was administered beginning on day 15 of induction. After achieving hematologic complete remission (HCR), patients received either seven courses of consolidation or hematopoietic cell transplantation (HCT). Nilotinib was continued 2 years after achieving HCR or before stem cell transplantation conditioning. HCR and molecular complete response (MCR), overall survival (OS), hematologic relapse-free survival (HRFS), molecular relapse-free survival (MRFS), toxicity, and nilotinib levels in the serum and cerebrospinal fluid were evaluated. All patients achieved HCR, and cumulative MCR rate was 83.3%. The median HRFS and OS were 18 and 47.5 months, respectively. Four-year HRFS and OS rates were 54% and 45%, respectively. The median MRFS and 4-year MRFS for the patients with MCR were 19 months and 45%, respectively. The molecular response of patients after induction cycle had no impact on HRFS, MRFS, or OS. The patients who achieved MCR after 3 and 6 months had superior HRFS. The HCT cohort in the first HCR had significantly lower rates of relapse and longer MRFS, HRFS, and OS. Most adverse events were reversible with dose reduction or transient interruption of nilotinib therapy. Only traces of nilotinib were detected in cerebrospinal fluid. Nilotinib combined with cytotoxic chemotherapy was effective and translated to a high HCR and MCR for patients with Ph+ ALL. It should be noted that nilotinib cannot cross the blood-brain barrier.",
"affiliations": "Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China.;Luekemia Center, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Science, Tianjin, 300020, China. wangjx@ihcams.ac.cn.",
"authors": "Liu|Bingcheng|B|;Wang|Ying|Y|;Zhou|Chunlin|C|;Wei|Hui|H|;Lin|Dong|D|;Li|Wei|W|;Liu|Kaiqi|K|;Zhang|Guangji|G|;Wei|Shuning|S|;Li|Yan|Y|;Gong|Benfa|B|;Liu|Yuntao|Y|;Gong|Xiaoyuan|X|;Mi|Yingchang|Y|;Wang|Jianxiang|J|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-019-03594-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "98(3)",
"journal": "Annals of hematology",
"keywords": "HRFS; MRFS; Nilotinib; OS; Ph+ ALL",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D060830:Consolidation Chemotherapy; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011446:Prospective Studies; D011743:Pyrimidines; D012074:Remission Induction; D016879:Salvage Therapy; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "633-645",
"pmc": null,
"pmid": "30635765",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Nilotinib combined with multi-agent chemotherapy in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: a single-center prospective study with long-term follow-up.",
"title_normalized": "nilotinib combined with multi agent chemotherapy in newly diagnosed philadelphia chromosome positive acute lymphoblastic leukemia a single center prospective study with long term follow up"
} | [
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"reaction": [
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute lymphocytic leukaemia recurrent",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LIIU B, WANG Y, ZHOU C, WEI H, LIN D, LI W ET AL.. NILOTINIB COMBINED WITH MULTI-AGENT CHEMOTHERAPY IN NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: A SINGLE-CENTER PROSPECTIVE STUDY WITH LONG-TERM FOLLOW-UP. ANNALS OF HEMATOLOGY. 2019?1-13",
"literaturereference_normalized": "nilotinib combined with multi agent chemotherapy in newly diagnosed philadelphia chromosome positive acute lymphoblastic leukemia a single center prospective study with long term follow up",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20190125",
"receivedate": "20190125",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15869884,
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"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
}
] |
{
"abstract": "D-penicillamine has been reported to cause antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis presenting as rapidly progressive glomerulonephritis or pulmonary-renal syndrome mostly in adults. We report a pediatric case of D-penicillamine induced ANCA-associated vasculitis that manifests as a pulmonary-renal syndrome with a mild renal manifestation. A 13-year-old girl who has been taking D-penicillamine for five years under the diagnosis of Wilson disease visited the emergency room because of hemoptysis and dyspnea. She had diffuse pulmonary hemorrhage, microscopic hematuria, and proteinuria. Myeloperoxidase ANCA was positive, and a renal biopsy revealed pauci-immune crescentic glomerulonephritis. Under the diagnosis of D-penicillamine-induced ANCA-associated vasculitis, D-penicillamine was switched to trientine, and the patient was treated with plasmapheresis, glucocorticoid, cyclophosphamide, and mycophenolate mofetil. Pulmonary hemorrhage improved rapidly followed by the disappearance of the hematuria and proteinuria five months later.",
"affiliations": "Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.;Department of Radiology, Seoul National University Children's Hospital, Seoul, Korea.;Department of Pathology, Seoul National University Hospital, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.",
"authors": "Kang|Sena|S|https://orcid.org/0000-0002-5891-6674;Cho|Myung Hyun|MH|https://orcid.org/0000-0002-3237-3173;Hyun|Hyesun|H|https://orcid.org/0000-0001-8525-1471;Kim|Ji Hyun|JH|https://orcid.org/0000-0001-8477-0157;Ko|Jae Sung|JS|https://orcid.org/0000-0002-3064-2974;Kang|Hee Gyung|HG|https://orcid.org/0000-0001-8323-5320;Cheong|Hae Il|HI|https://orcid.org/0000-0001-7556-1265;Kim|Woo Sun|WS|https://orcid.org/0000-0003-2184-1311;Moon|Kyung Chul|KC|https://orcid.org/0000-0002-1969-8360;Ha|Il Soo|IS|https://orcid.org/0000-0001-5428-6209",
"chemical_list": "D010396:Penicillamine",
"country": "Korea (South)",
"delete": false,
"doi": "10.3346/jkms.2019.34.e173",
"fulltext": "\n==== Front\nJ Korean Med SciJ. Korean Med. SciJKMSJournal of Korean Medical Science1011-89341598-6357The Korean Academy of Medical Sciences 3122298610.3346/jkms.2019.34.e173Case ReportPediatricsA Pediatric Case of a D-Penicillamine Induced ANCA-associated Vasculitis Manifesting a Pulmonary-Renal Syndrome https://orcid.org/0000-0002-5891-6674Kang Sena 1https://orcid.org/0000-0002-3237-3173Cho Myung Hyun 1*https://orcid.org/0000-0001-8525-1471Hyun Hyesun 1†https://orcid.org/0000-0001-8477-0157Kim Ji Hyun 1https://orcid.org/0000-0002-3064-2974Ko Jae Sung 1https://orcid.org/0000-0001-8323-5320Kang Hee Gyung 12https://orcid.org/0000-0001-7556-1265Cheong Hae Il 12https://orcid.org/0000-0003-2184-1311Kim Woo Sun 34https://orcid.org/0000-0002-1969-8360Moon Kyung Chul 5https://orcid.org/0000-0001-5428-6209Ha Il-Soo 121 Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.2 Kidney Institute, Seoul National University Medical Research Center, Seoul, Korea.3 Department of Radiology, Seoul National University Children's Hospital, Seoul, Korea.4 Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.5 Department of Pathology, Seoul National University Hospital, Seoul, Korea.Address for Correspondence: Il-Soo Ha, MD. Department of Pediatrics, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. ilsooha@snu.ac.kr*Present address: Department of Pediatrics, Korea Cancer Center Hospital, Seoul, Korea\n\n†Present address: Department of Pediatrics, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea\n\n10 6 2019 24 6 2019 34 24 e17327 2 2019 03 6 2019 © 2019 The Korean Academy of Medical Sciences.2019The Korean Academy of Medical SciencesThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.D-penicillamine has been reported to cause antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis presenting as rapidly progressive glomerulonephritis or pulmonary-renal syndrome mostly in adults. We report a pediatric case of D-penicillamine induced ANCA-associated vasculitis that manifests as a pulmonary-renal syndrome with a mild renal manifestation. A 13-year-old girl who has been taking D-penicillamine for five years under the diagnosis of Wilson disease visited the emergency room because of hemoptysis and dyspnea. She had diffuse pulmonary hemorrhage, microscopic hematuria, and proteinuria. Myeloperoxidase ANCA was positive, and a renal biopsy revealed pauci-immune crescentic glomerulonephritis. Under the diagnosis of D-penicillamine-induced ANCA-associated vasculitis, D-penicillamine was switched to trientine, and the patient was treated with plasmapheresis, glucocorticoid, cyclophosphamide, and mycophenolate mofetil. Pulmonary hemorrhage improved rapidly followed by the disappearance of the hematuria and proteinuria five months later.\n\nGraphical Abstract\n\n\nPenicillamineAntineutrophil Cytoplasmic AntibodiesVasculitisPulmonary-Renal SyndromeChild\n==== Body\nINTRODUCTION\nAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis characterized by the presence of ANCA and typical involvement of kidney and respiratory tract.1 D-penicillamine is one of the drugs that can induce drug-induced AAV.2 Rapidly progressive glomerulonephritis (RPGN) and pulmonary-renal syndrome (PRS) are primary manifestations of D-penicillamine-induced AAV.34567891011121314151617181920 Because most of them develop in adults, we could search only two cases of D-penicillamine-induced AAV diagnosed at age younger than 18 years,21 and both cases presented RPGN. Here, we report a case of D-penicillamine-induced AAV that developed in a 13-year-old girl and manifested a PRS without azotemia.\n\nCASE DESCRIPTION\nA 13-year-old female patient visited the emergency room for hemoptysis, fever, and dyspnea on September 8, 2017. She has been on D-penicillamine for five years under the diagnosis of Wilson disease with a well-controlled copper level. Urinalysis performed before the administration of D-penicillamine was normal. Since five months before admission, intermittent pain occurred at the ankle, foot, calf, and wrist. Two months prior to admission, urine test revealed microscopic hematuria (10-19 RBCs/HPF) and mild proteinuria (1+). Two weeks before admission, cough and fever developed followed by dyspnea and hemoptysis for a week before admission. She had no family history of autoimmune disease or Wilson disease.\n\nAt admission, blood pressure was 132/74 mmHg, the temperature was 36.5°C, pulse rate was 132/min, and respiratory rate was 24/min. Crackle sounds were heard at both lower lung fields, and heartbeats were regular without a murmur. Hemoglobin was 8.7 g/dL, reticulocyte count 2.5%, the white blood cell count was 9,670/µL, and platelet count was 344,000/µL. Serum hepatic enzymes were normal, and albumin level was 3.7 g/dL. Blood urea nitrogen and serum creatinine were 12 mg/dL and 0.62 mg/dL respectively and estimated GFR was 109.8 mL/min/1.73 m2. C-reactive protein level was 9.1 mg/dL, and erythrocyte sedimentation rate was 28 mm/hr. The patient had microscopic hematuria (5-9 RBCs/HPF) and proteinuria (urine protein creatinine ratio 1.05 mg/mg). Anti-myeloperoxidase (MPO) IgG titer was over 600 U/mL (reference < 20 U/mL) while anti-proteinase 3 (PR3) IgG titer was within normal limit. Complement levels were normal and antinuclear antibody, anti-double-stranded DNA antibody, rheumatoid factor, anti-cardiolipin antibody, anti-glomerular basement membrane antibody were all negative. There was no evidence of infection or hemolysis. Chest radiography and computed tomography suggested diffuse pulmonary hemorrhage (Fig. 1). The echocardiographic findings were not remarkable. Renal Doppler ultrasonography revealed normal size and shape of both kidneys and an equivocal increase in cortical echogenicity.\n\nFig. 1 Chest radiologic findings of the patient. (A) Bilateral extensive patchy consolidation at the plain film and (B) the multifocal patchy ground-glass opacity at chest computed tomography suggest diffuse pulmonary hemorrhage.\nUnder the tentative diagnosis of D-penicillamine-induced AAV, trientine was substituted for D-penicillamine. Because the patient's respiratory symptom aggravated, she was transferred to ICU and supported by a ventilator. Plasma exchange was performed for 3 days daily and methylprednisolone (1 g per day) was given intravenously for 3 days followed by the administration of IgG (0.7 g/kg) for 3 days.\n\nA renal biopsy disclosed cellular and fibrocellular crescents in 39% (16/41) of the glomeruli. Glomerular size and mesangial cellularity were mildly increased. Immunofluorescent and electron microscopic findings were not noteworthy except focal effacement of the foot processes. These findings were compatible with the pauci-immune crescentic glomerulonephritis (Fig. 2).\n\nFig. 2 Photomicrograph of the kidney biopsy. (A) Crescent formation is observed in 39% of the total 41 glomeruli by the light microscopy (PAS, ×40). (B) A representative crescent (arrow) is shown at a high power magnification (PAS, ×400).\nPAS = periodic acid–Schiff.\n\nAfter confirming the renal pathology, intravenous cyclophosphamide (750 mg/m2) was administered, followed by administration of oral glucocorticoids (prednisolone 60 mg/day) and mycophenolate mofetil (1,500 mg/day). Acute phase reactants dropped a few days later with the rapid improvement of the respiratory failure. Proteinuria and microscopic hematuria disappeared five months later. MPO-ANCA titer decreased more gradually and still positive in a low titer (8.1 IU/mL) at 17 months after the withdrawal of D-penicillamine.\n\nEthics statement\nThis study was approved by the Institutional Review Boards (IRB) of the Seoul National University Hospital (H-1901-133-1005) and an informed consent was received from the patient and a caregiver. The images are published under agreement of the patient.\n\nDISCUSSION\nAAV is an autoimmune small-vessel vasculitis characterized by ANCA, an autoantibody specific for neutrophil granule components, MPO or protease 3 (PR3).1 Drugs such as propylthiouracil, hydralazine, penicillamine, allopurinol, sulfasalazine, and levamisole have been described to induce AAV, the majority with MPO-AAV.22 D-penicillamine-induced AAV is reported to affect kidneys with or without concurrent involvement of the respiratory tract, therefore, leads to either RPGN345678910112021 or PRS.1213141516171819\n\nPRS describes a syndrome of respiratory failure in association with renal failure or a diffuse alveolar hemorrhage complicating acute glomerulonephritis.23 PRS often results in severe life-threatening systemic disease requiring urgent aggressive therapy and renal and lung biopsy reveals histological features of the glomerular crescents and pulmonary capillaritis.24 Serum creatinine is usually elevated in PRS, but it may not always be elevated.23 Among the 11 cases of penicillamine-associated PRS reported with the serum creatinine available, there was an adult woman who had normal serum creatinine.25 Our case also showed microscopic hematuria and proteinuria with normal renal function while renal biopsy revealed cellular or fibrocellular crescents in 39% of the glomeruli. McAdoo et al.26 analyzed 258 cases of necrotizing or crescentic glomerulonephritis and found that 14.7% of the patients represent preserved renal function. This silent crescentic glomerulonephritis with normal renal function is more likely to be identified in PRS because pulmonary manifestations facilitate earlier biopsy and diagnosis of the glomerulonephritis before renal function deteriorates. In our case, if the renal biopsy was performed later and the treatment was delayed, azotemia might have developed.\n\nMost of the reported AAV patients were adults. Only two cases of D-penicillamine-induced AAV are reported at the age younger than 18 years, and both pediatric cases presented as RPGN.21 Therefore, to the best of our knowledge, this is the first pediatric case of D-penicillamine-induced AAV that manifests a PRS.\n\nLoss of tolerance and development of autoimmunity to MPO and PR3 is the first step in the development of AAV. Mechanism of losing tolerance is unclear, though dysregulation of the adaptive immune response, neutrophil extracellular trap (NET), ANCA antigen on the surface of apoptotic neutrophil, and functional abnormality in regulatory T cell are implicated.1 Subsequently, T-cell helped activation of autoreactive B-cell produces ANCA. Finally, ANCA induces activation of circulating neutrophils that localize to vascular beds, degranulate and release NET resulting in endothelial injury.127\n\nHow individual drug triggers the AAV is not well understood. Because the molecular weight of most drugs is low, the formation of a bigger complex is required to provoke immune response.28 In animal experiments, penicillamine is reported to activate macrophages through binding to aldehyde-containing molecules and production of TNF-α, IL-6, and IL-23,2930 giving rise to induction of autoimmunity. Though mechanistic studies about penicillamine induced AAV is not sufficient, it can be compensated by investigations performed for other drug-induced AAVs, because the clinical manifestations are very similar.28 Propylthiouracil, another causative drug of AAV, is reported to be oxidized in the presence of activated neutrophils forming reactive drug metabolites that stimulate ANCA production.31 It was also reported that propylthiouracil induces abnormal conformation and impaired degradation of NET leading to the development of autoimmunity.32 In hydralazine-associated AAV, neutrophil apoptosis in response to hydralazine MPO binding is hypothesized to result in the production of autoantibodies.33\n\nThe prevalence of ANA in drug-associated AAV has been reported to vary from 17% to 80%. It was reported that the prevalence is higher in AAV induced by hydralazine and lower in the vasculitis associated with propylthiouracil.22 In authors review of the literature, ANA was present in 76% of the 17 reported cases of the D-penicillamine-induced AAV. Clinical significance of the ANA positivity in drug-induced AAV remains to be elucidated.\n\nBecause the diagnosis of drug-induced vasculitis is complicated by a variety of factors such as the dose and duration of medication, and frequency of diagnostic laboratory studies according to the physician's awareness of the disease, involved organs and clinical presentations may be diverse. Therefore, treatment should depend on the severity of clinical manifestations.28 The first step is to discontinue the offending agent. For those with active and significant organ involvement, additional immune suppression by glucocorticoid is necessary. For severe organ failure associated with alveolar hemorrhage or RPGN, cyclophosphamide or other immunosuppressants such as mycophenolate mofetil or rituximab may be added. Intravenous pulse methylprednisolone and plasmapheresis can be used in life-threatening cases. Supportive care would include ventilatory support and renal replacement for severe PRS.34\n\nDelayed diagnosis of drug-induced AAV may cause serious results. Therefore, it is preferable to avoid long-term use of AAV inducible medications such as propylthiouracil, hydralazine, penicillamine, allopurinol, sulfasalazine, and levamisole. When long-term use of these drugs is inevitable, it is desirable to monitor respiratory symptoms and signs, and urinalysis closely, and when suspected, check ANCA titer and chest radiography. However, it should be emphasized that though positive seroconversion of ANCA is a clue to the diagnosis of drug-induced AAV, positive ANCA titer only is not sufficient to diagnose the drug-induced AAV and begin treatment, because only a small proportion of the patients with positive ANCA develop clinical vasculitis.28\n\nIn this case, crescentic glomerulonephritis was found in the renal biopsy despite the mild renal manifestations and completely normal renal function. Therefore, when urinary abnormalities are found in a patient with suspected AAV and pulmonary hemorrhage, even if the renal function is normal, renal biopsy is highly recommended.\n\nAlthough anti-MPO antibody titer decreased steadily from over 600 to 8.1 IU/mL, the value was still above the normal range at 17 months after the withdrawal of D-penicillamine. This long-lasting ANCA activity is consistent with the finding in propylthiouracil (PTU)-induced AAV that anti-MPO titer was within the reference range only in six of the thirteen patients at a median follow-up of 38 months after discontinuation of PTU.35 Therefore, drug-induced ANCA seems to last for a substantial period after withdrawal of the triggering agent.\n\nDisclosure: The authors have no potential conflicts of interest to disclose\n\nAuthor Contributions:\nConceptualization: Kang HG, Ha IS.\n\nData curation: Kang S, Cho MH, Hyun H.\n\nFormal analysis: Kang S, Cho MH, Hyun H.\n\nValidation: Kim JH.\n\nWriting - original draft: Kang S.\n\nWriting - review & editing: Kim JH, Ko JS, Kang HG, Cheong HI, Kim WS, Moon KC.\n==== Refs\n1 Hutton HL Holdsworth SR Kitching AR ANCA-associated vasculitis: pathogenesis, models, and preclinical testing Semin Nephrol 2017 37 5 418 435 28863790 \n2 Hogan JJ Markowitz GS Radhakrishnan J Drug-induced glomerular disease: immune-mediated injury Clin J Am Soc Nephrol 2015 10 7 1300 1310 26092827 \n3 Banfi G Imbasciati E Guerra L Mihatsch MJ Ponticelli C Extracapillary glomerulonephritis with necrotizing vasculitis in D-penicillamine-treated rheumatoid arthritis Nephron 1983 33 1 56 60 6339966 \n4 Sadjadi SA Seelig MS Berger AR Milstoc M Rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis during treatment with high-dosage D-penicillamine Am J Nephrol 1985 5 3 212 216 4014326 \n5 Williams AJ Fordham JN Barnes CG Goodwin FJ Progressive proliferative glomerulonephritis in a patient with rheumatoid arthritis treated with D-penicillamine Ann Rheum Dis 1986 45 1 82 84 3954462 \n6 Devogelaer JP Pirson Y Vandenbroucke JM Cosyns JP Brichard S Nagant de Deuxchaisnes C D-penicillamine induced crescentic glomerulonephritis: report and review of the literature J Rheumatol 1987 14 5 1036 1041 3430507 \n7 Mathieson PW Peat DS Short A Watts RA Coexistent membranous nephropathy and ANCA-positive crescentic glomerulonephritis in association with penicillamine Nephrol Dial Transplant 1996 11 5 863 866 8671912 \n8 Hillis GS Khan IH Simpson JG Rees AJ Scleroderma, D-penicillamine treatment, and progressive renal failure associated with positive antimyeloperoxidase antineutrophil cytoplasmic antibodies Am J Kidney Dis 1997 30 2 279 281 9261042 \n9 Karpinski J Jothy S Radoux V Levy M Baran D D-penicillamine-induced crescentic glomerulonephritis and antimyeloperoxidase antibodies in a patient with scleroderma Am J Nephrol 1997 17 6 528 532 9426850 \n10 Nanke Y Akama H Terai C Kamatani N Rapidly progressive glomerulonephritis with D-penicillamine Am J Med Sci 2000 320 6 398 402 11149553 \n11 Bienaimé F Clerbaux G Plaisier E Mougenot B Ronco P Rougier JP D-Penicillamine-induced ANCA-associated crescentic glomerulonephritis in Wilson disease Am J Kidney Dis 2007 50 5 821 825 17954295 \n12 Gibson T Burry HC Ogg C Letter: Goodpasture syndrome and D-penicillamine Ann Intern Med 1976 84 1 100 1247260 \n13 Gavaghan TE McNaught PJ Ralston M Hayes JM Penicillamine-induced “Goodpasture's syndrome”: successful treatment of a fulminant case Aust N Z J Med 1981 11 3 261 265 6945838 \n14 Peces R Riera JR Arboleya LR López-Larrea C Alvarez J Goodpasture's syndrome in a patient receiving penicillamine and carbimazole Nephron 1987 45 4 316 320 3587472 \n15 Macarrón P García Díaz JE Azofra JA Martín de Francisco J Gonzalez E Fernandez G D-penicillamine therapy associated with rapidly progressive glomerulonephritis Nephrol Dial Transplant 1992 7 2 161 164 1314978 \n16 Endo H Hosono T Kondo H Antineutrophil cytoplasmic autoantibodies in 6 patients with renal failure and systemic sclerosis J Rheumatol 1994 21 5 864 870 8064727 \n17 Gaskin G Thompson EM Pusey CD Goodpasture-like syndrome associated with anti-myeloperoxidase antibodies following penicillamine treatment Nephrol Dial Transplant 1995 10 10 1925 1928 8592607 \n18 Derk CT Jimenez SA Goodpasture-like syndrome induced by D-penicillamine in a patient with systemic sclerosis: report and review of the literature J Rheumatol 2003 30 7 1616 1620 12858467 \n19 Sternlieb I Bennett B Scheinberg IH D-penicillamine induced Goodpasture's syndrome in Wilson's disease Ann Intern Med 1975 82 5 673 676 1094875 \n20 Ntoso KA Tomaszewski JE Jimenez SA Neilson EG Penicillamine-induced rapidly progressive glomerulonephritis in patients with progressive systemic sclerosis: successful treatment of two patients and a review of the literature Am J Kidney Dis 1986 8 3 159 163 3752071 \n21 Lee Y Lee ST Cho H D-penicillamine-induced ANA (+) ANCA (+) vasculitis in pediatric patients with Wilson's disease Clin Nephrol 2016 85 5 296 300 26784915 \n22 Choi HK Merkel PA Walker AM Niles JL Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of antimyeloperoxidase antibodies Arthritis Rheum 2000 43 2 405 413 10693882 \n23 West SC Arulkumaran N Ind PW Pusey CD Pulmonary-renal syndrome: a life threatening but treatable condition Postgrad Med J 2013 89 1051 274 283 23349383 \n24 Lee RW D'Cruz DP Pulmonary renal vasculitis syndromes Autoimmun Rev 2010 9 10 657 660 20472100 \n25 Matloff DS Kaplan MM D-Penicillamine-induced Goodpasture's-like syndrome in primary biliary cirrhosis--successful treatment with plasmapheresis and immunosuppressives Gastroenterology 1980 78 5 Pt 1 1046 1049 7380177 \n26 McAdoo SP Tanna A Randone O Tam FW Tarzi RM Levy JB Necrotizing and crescentic glomerulonephritis presenting with preserved renal function in patients with underlying multisystem autoimmune disease: a retrospective case series Rheumatology (Oxford) 2015 54 6 1025 1032 25431483 \n27 O'Sullivan KM Lo CY Summers SA Elgass KD McMillan PJ Longano A Renal participation of myeloperoxidase in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis Kidney Int 2015 88 5 1030 1046 26176828 \n28 Radić M Martinović Kaliterna D Radić J Drug-induced vasculitis: a clinical and pathological review Neth J Med 2012 70 1 12 17 22271809 \n29 Li J Uetrecht JP D-penicillamine-induced autoimmunity: relationship to macrophage activation Chem Res Toxicol 2009 22 9 1526 1533 19575532 \n30 Li J Mannargudi B Uetrecht JP Covalent binding of penicillamine to macrophages: implications for penicillamine-induced autoimmunity Chem Res Toxicol 2009 22 7 1277 1284 19462940 \n31 Jiang X Khursigara G Rubin RL Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils Science 1994 266 5186 810 813 7973636 \n32 Nakazawa D Tomaru U Suzuki A Masuda S Hasegawa R Kobayashi T Abnormal conformation and impaired degradation of propylthiouracil-induced neutrophil extracellular traps: implications of disordered neutrophil extracellular traps in a rat model of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis Arthritis Rheum 2012 64 11 3779 3787 22777766 \n33 Yokogawa N Vivino FB Hydralazine-induced autoimmune disease: comparison to idiopathic lupus and ANCA-positive vasculitis Mod Rheumatol 2009 19 3 338 347 19424772 \n34 Grau RG Drug-induced vasculitis: new insights and a changing lineup of suspects Curr Rheumatol Rep 2015 17 12 71 26503355 \n35 Yang J Yao LP Dong MJ Xu Q Zhang J Weng WW Clinical characteristics and outcomes of propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis in patients with Graves' disease: a median 38-month retrospective cohort study from a single institution in China Thyroid 2017 27 12 1469 1474 29088997\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1011-8934",
"issue": "34(24)",
"journal": "Journal of Korean medical science",
"keywords": "Antineutrophil Cytoplasmic Antibodies; Child; Penicillamine; Pulmonary-Renal Syndrome; Vasculitis",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D000293:Adolescent; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D005260:Female; D005921:Glomerulonephritis; D006470:Hemorrhage; D006527:Hepatolenticular Degeneration; D006801:Humans; D007668:Kidney; D008171:Lung Diseases; D010396:Penicillamine; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8703518",
"other_id": null,
"pages": "e173",
"pmc": null,
"pmid": "31222986",
"pubdate": "2019-06-24",
"publication_types": "D002363:Case Reports",
"references": "10693882;1094875;11149553;1247260;12858467;1314978;17954295;19424772;19462940;19575532;20472100;22271809;22777766;23349383;25431483;26092827;26176828;26503355;26784915;28863790;29088997;3430507;3587472;3752071;3954462;4014326;6339966;6945838;7380177;7973636;8064727;8592607;8671912;9261042;9426850",
"title": "A Pediatric Case of a D-Penicillamine Induced ANCA-associated Vasculitis Manifesting a Pulmonary-Renal Syndrome.",
"title_normalized": "a pediatric case of a d penicillamine induced anca associated vasculitis manifesting a pulmonary renal syndrome"
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"literaturereference": "KANG S, CHO M, HYUN H, JI K, KO J, KANG H, CHEONG H, KIM W, MOON K, HA I. A PEDIATRIC CASE OF A D?PENICILLAMINE INDUCED ANCA?ASSOCIATED VASCULITIS MANIFESTING A PULMONARY?RENAL SYNDROME. J KOREAN MED SCI. 2019 JUN 24?34(24): E173:1?7. DOI:10.3346/JKMS.2019.34.E173",
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{
"abstract": "BACKGROUND\nThere are no reports on cases of subconjunctival hemorrhage due to use of glycoprotein IIb/IIIa inhibitors. In this report, we present the case of a patient with bilateral subconjunctival hemorrhage after receiving abciximab.\n\n\nMETHODS\nA 40-year-old male patient underwent coronary angiography after acute anterior myocardial infarction and a coronary stent was placed. Abciximab was added to the therapy because of stent thrombosis. Bilateral subconjunctival hemorrhage was observed after the administration of the abciximab treatment. We treated our patient by stopping abciximab and administering artificial tears.\nFor the first time in the literature, we presented the case of a patient with bilateral subconjunctival hemorrhage after receiving abciximab, which was managed conservatively.",
"affiliations": "MD. Cardiology Specialist, Saglik Bilimleri University, Department of Cardiology, Trabzon Ahi Evren Cardiovascular and Thoracic Surgery Research and Application Center, Saglik Bilimleri University, Trabzon, Turkey.;MD. Associate Professor, Saglik Bilimleri University, Department of Cardiology, Trabzon Ahi Evren Cardiovascular and Thoracic Surgery Research and Application Center, Saglik Bilimleri University, Trabzon, Turkey.",
"authors": "Kul|Selim|S|;Sayın|Muhammet Raşit|MR|",
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"fulltext": "\n==== Front\nSao Paulo Med J\nSao Paulo Med J\nSao Paulo Med J\nSão Paulo Medical Journal\n1516-3180\n1806-9460\nAssociação Paulista de Medicina - APM\n\n29267537\n10.1590/1516-3180.2017.0182150717\nCase Report\nBilateral subconjunctival hemorrhage secondary to abciximab use: case report\nKul Selim I\nSayın Muhammet Raşit II\nI MD. Cardiology Specialist, Saglik Bilimleri University, Department of Cardiology, Trabzon Ahi Evren Cardiovascular and Thoracic Surgery Research and Application Center, Saglik Bilimleri University, Trabzon, Turkey.\nII MD. Associate Professor, Saglik Bilimleri University, Department of Cardiology, Trabzon Ahi Evren Cardiovascular and Thoracic Surgery Research and Application Center, Saglik Bilimleri University, Trabzon, Turkey.\nAddress for correspondence: Selim Kul. Sağlık Bilimleri Üniversitesi, Trabzon Ahi Evren Göğüs Kalp ve Damar Cerrahisi Araştırma ve Uygulama Merkezi, Kardiyoloji Kliniği. Soğuksu Mahallesi Vatan Caddesi No: 9. Ortahisar 61040 - Trabzon - Turkey. Tel. +90 462 2310461. Fax. +90 462 2310483. Cel. +90 532 6741632. E-mail: selimkul@gmail.com\nConflict of interest: None\n\n18 12 2017\n2019\n137 2 209211\n11 7 2017\n15 7 2017\n© 2022 by Associação Paulista de Medicina\n2022\nAssociação Paulista de Medicina\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons license.\nABSTRACT\n\nCONTEXT:\n\nThere are no reports on cases of subconjunctival hemorrhage due to use of glycoprotein IIb/IIIa inhibitors. In this report, we present the case of a patient with bilateral subconjunctival hemorrhage after receiving abciximab.\n\nCASE REPORT:\n\nA 40-year-old male patient underwent coronary angiography after acute anterior myocardial infarction and a coronary stent was placed. Abciximab was added to the therapy because of stent thrombosis. Bilateral subconjunctival hemorrhage was observed after the administration of the abciximab treatment. We treated our patient by stopping abciximab and administering artificial tears.\n\nCONCLUSİON:\n\nFor the first time in the literature, we presented the case of a patient with bilateral subconjunctival hemorrhage after receiving abciximab, which was managed conservatively.\n\nKEY WORDS:\n\nConjunctivitis, acute hemorrhagic\nAbciximab [supplementary concept]\nCoronary disease\n==== Body\npmcINTRODUCTION\n\nAbciximab, a Fab fragment of the chimeric human-murine monoclonal antibody 7E3, interferes with platelet aggregation by binding to the glycoprotein IIb/IIIa receptors of platelets.1 Although no randomized trial has tested the use of abciximab as a bailout therapy in cases of ST-elevated myocardial infarction (STEMI), it has been found to be beneficial in cases of large intraluminal thrombus, slow reflow or no reflow, and in relation to other thrombotic complications during angiography.2\n\nThe major side effect of abciximab is bleeding. The EPIC trial included patients undergoing high-risk angioplasty procedures, among whom 14% suffered major bleeding after receiving a bolus followed by infusion of abciximab, compared with 7% of the patients receiving placebo.3\n\nFor the first time in the literature (Table 1), we present the case of a patient with bilateral subconjunctival hemorrhage after receiving abciximab.\n\nTable 1: Strategies used for search in electronic databases on June 11, 2017\n\nDatabase\tSearch strategy\tReferences retrieved\t\nMEDLINE (via PubMed)\t(“Conjunctivitis, Acute Hemorrhagic”[Mesh]) AND (“abciximab” [Supplementary Concept])\t0\t\nEmbase (via Elsevier)\t(Abciximab OR Tirofiban OR Eptifibatide) AND (Subconjunctival Hemorrhage)\t0\t\n\nCASE REPORT\n\nA 40-year-old man was brought to the emergency department of our hospital with a history of chest pain for the last two hours. His past history was notable only for smoking as a cardiovascular risk factor. His vital signs included arterial blood pressure of 120/80 mmHg and a pulse rate of 66 bpm. His electrocardiogram was consistent with ST elevation in leads V1 to V6. His echocardiogram was notable for anterior and apical hypokinesia, with an ejection fraction of 40%. All his biochemical and blood count parameters were within normal limits.\n\nThe patient was diagnosed as presenting anterior myocardial infarction and was transferred to the catheter laboratory for primary percutaneous coronary intervention (PCI). He was administered loading doses of 600 mg, 300 mg and 8000 U of clopidogrel, acetylsalicylic acid and unfractionated heparin, respectively. A coronary angiogram showed 99% stenosis in the proximal portion of the left anterior descending artery (LAD) (Figure 1A). The left circumflex artery was free of any stenosis and the right coronary artery had a 30% non-significant lesion in its mid-segment. A 3.0 mm x 24 mm drug-eluting stent was placed at a pressure of 12 atm in the severely stenotic LAD segment, without predilatation (Figure 1B).\n\nFigure 1: A. Coronary angiogram showing 99% stenosis in the proximal portion of the left anterior descending artery (LAD). B. A 3.0 mm x 24 mm drug-eluting stent was placed at a pressure of 12 atm in the severely stenotic LAD segment, without predilatation. C. Coronary angiography showing thrombus in LAD stent.\n\nThe patient was then transferred to the coronary care unit for further observation. Thirty minutes later, the patient was defibrillated at 270 J due to an episode of ventricular fibrillation. Because his chest pain intensified, he was taken back to the catheter laboratory for a check on stent patency. Coronary angiography showed a thrombus in the LAD stent (Figure 1C).\n\nA decision was made to administer abciximab to prevent further thrombosis inside the stent lumen or elsewhere in the coronary circulation. Abciximab was administered as a bolus at a dose of 0.25 mg/kg, followed by infusion at a dose of 0.125 mcg/kg/min intravenously. However, 20 minutes after the start of the infusion, the patient developed subconjunctival hemorrhage in both eyes (Figure 2). Therefore, infusion of the drug was stopped, but administration of acetylsalicylic acid and clopidogrel was continued.\n\nFigure 2: Bilateral subconjunctival hemorrhage secondary to use of abciximab.\n\nAn ophthalmology consultation was obtained for the patient, and it was recommended that he should receive conservative treatment consisting of artificial tears. The chest pain did not recur in the coronary intensive care unit after administration of abciximab was stopped. He was transferred to the cardiology ward, and a few days later, a coronary angiogram showed absence of thrombus and the patient was discharged.\n\nHe returned to the cardiology outpatient clinic for a follow-up visit, at which it was noted that his conjunctival hemorrhage had been completely eliminated. He was asymptomatic, while continuing to take acetylsalicylic acid and clopidogrel two months later.\n\nDISCUSSION\n\nAnticoagulants and antiaggregant medications that prevent thrombosis and clot formation are central to management of patients undergoing percutaneous coronary intervention. Nevertheless, the risk of bleeding is inevitably increased through use of powerful antiplatelet and anticoagulant agents. Subconjunctival hemorrhage is one of the most common eye disorders, especially among individuals over the age of 50 years. Hypertension is one of the major risk factors of this condition. Anticoagulants in the form of low-dose heparin and warfarin have been linked to subconjunctival hemorrhage at an incidence of 1.5% to 5%.4,5 Dabigatran, a novel direct thrombin inhibitor with anticoagulant properties, has been reported to cause subconjunctival hemorrhage.6\n\nOur patient suffered bilateral subconjunctival hemorrhage. So far, no study has reported such an association for abciximab, tirofiban or eptifibatide. Our patient may have developed this complication due to abciximab, acetylsalicylic acid, clopidogrel or combined use of these three medications. We have not come across any report in the literature on a case of conjunctival hemorrhage due to use of clopidogrel. There has only been one case of conjunctival hemorrhage due to a high dose of aspirin.7 We used the usual doses of acetylsalicylic acid and clopidogrel. Since our patient’s subconjunctival hemorrhage regressed after abciximab was withdrawn, despite continuation of use of clopidogrel and acetylsalicylic acid during the follow-up, we consider that this complication was due solely to use of abciximab. Our patient suffered a rare bleeding complication due to abciximab, i.e. bilateral spontaneous subconjunctival hemorrhage. Even though subconjunctival hemorrhage may also occur as a result of rupture of small subconjunctival blood vessels, either idiopathically or after trauma or the Valsalva maneuver, our patient had neither of these causes.\n\nSubconjunctival hemorrhage usually has a benign course and is self-limiting. It is minimally symptomatic and does not necessitate any specific therapy; and this is particularly true for patients who are not using anticoagulants.\n\nCONCLUSION\n\nBilateral subconjunctival hemorrhage due to use of abciximab has not been previously reported in the literature. Bilateral subconjunctival hemorrhage was seen after abciximab use in our case for the first time in the literature. Bilateral subconjunctival hemorrhage was a rare complication due to use of abciximab in our patient. We treated our patient by stopping his use of abciximab and administering artificial tears and followed him up conservatively on an outpatient basis. We achieved the outcome of complete spontaneous healing. In cases of subconjunctival hemorrhage due to abciximab use, abciximab treatment must be discontinued and full recovery can be achieved by artificial tearing and conservative treatment.\n\nDepartment of Cardiology, Trabzon Ahi Evren Cardiovascular and Thoracic Surgery Research and Application Center, Saglik Bilimleri University, Trabzon, Turkey\n\nSources of funding: None\n==== Refs\nREFERENCES\n\n1 Ibbotson T McGavin JK Goa KL Abciximab: an updated review of its therapeutic use in patients with ischaemic heart disease undergoing percutaneous coronary revascularisation Drugs 2003 63 11 1121 1163 12749745\n2 Authors/Task Force membersWindecker S Kolh P Alfonso F 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Eur Heart J 2014 35 37 2541 2619 25173339\n3 EPIC Investigators Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty N Engl J Med 1994 330 14 956 961 8121459\n4 Schulman S Kearon C Kakkar AK Dabigatran versus warfarin in the treatment of acute venous thromboembolism N Engl J Med 2009 361 24 2342 2352 19966341\n5 Baetz BE Spinler SA Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases Pharmacotherapy 2008 28 11 1354 1373 18956996\n6 Nguyen TM Phelan MP Werdich XQ Rychwalski PJ Huff CM Subconjunctival hemorrhage in a patient on dabigatran (Pradaxa) Am J Emerg Med 2013 31 2 455.e3 455.e5\n7 Black RA Bensinger RE Bilateral subconjunctival hemorrhage after acetylsalicylic acid overdose Ann Ophthalmol 1982 14 11 1024 1025 7181333\n\n",
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"abstract": "A 49-year-old male became hypotensive, bradycardic, and suffered myocardial injury during induction of anesthesia with lidocaine, propofol, and rocuronium in the operating room. Coronary arteriography revealed coronary vasospasm in coronary arteries otherwise free of disease. In the ICU, the patient was again administered rocuronium for a procedure with subsequent hypotension, bradycardia, and ST elevation on telemetry that resolved with administration of diphenhydramine and hydrocortisone. An allergic reaction to rocuronium with coronary vasospasm is suspected, suggestive of the Type 1 variant of Kounis syndrome. This is the first report to describe a case of rocuronium-induced Type 1 Kounis syndrome.",
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"medicinalproduct": "ROCURONIUM BROMIDE."
}
],
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"patientonsetage": "49",
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Arteriospasm coronary",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Kounis syndrome",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FAGLEY, R.. ROCURONIUM-INDUCED CORONARY VASOSPASM - ^KOUNIS SYNDROME^. INTERNATIONAL JOURNAL OF CARDIOLOGY. 2009?137:E29-E32",
"literaturereference_normalized": "rocuronium induced coronary vasospasm kounis syndrome",
"qualification": "3",
"reportercountry": "US"
},
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"receivedate": "20190305",
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}
] |
{
"abstract": "Pembrolizumab is a humanized antibody that targets the programmed death-1 receptor expressed in T cells with high selectivity. This therapeutic is of great importance in cancer immunotherapy yet managing the potential immune-related adverse events remains a concern. Here, we report a rare case of mucous membrane pemphigoid in the oral mucosa, upper respiratory tract, and conjunctiva of a patient with ovarian adenocarcinoma without cutaneous manifestation, which persisted even after pembrolizumab discontinuation. A brief review of pembrolizumab-related bullous pemphigoid cases is presented and possible mechanisms underlying these lesions are discussed.",
"affiliations": "Hospital Israelita Albert Einstein.;Hospital Israelita Albert Einstein.;University of Florida College of Dentistry, Gainesville, FL.;Hospital Israelita Albert Einstein.;Oncology Division.;Oncology Division.;Department of Dermatology.;Department of Anatomic Pathology, Hospital Israelita Albert Einstein.;Oncology Division.;Department of General Pathology, School of Dentistry, University of São Paulo.;Oncology Division.",
"authors": "Bezinelli|Letícia Mello|LM|;Eduardo|Fernanda P|FP|;Migliorati|Cesar A|CA|;Ferreira|Mariana H|MH|;Taranto|Patrícia|P|;Sales|Diogo B|DB|;Santi|Claudia G|CG|;Macarenco|Ricardo S|RS|;Godoy|Claudia P V|CPV|;Corrêa|Luciana|L|;Buzaid|Antonio C|AC|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000280",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "42(9)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D018262:Adenocarcinoma, Clear Cell; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D010391:Pemphigoid, Bullous",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "359-362",
"pmc": null,
"pmid": "31246641",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Severe, Refractory Case of Mucous Membrane Pemphigoid After Treatment With Pembrolizumab: Brief Communication.",
"title_normalized": "a severe refractory case of mucous membrane pemphigoid after treatment with pembrolizumab brief communication"
} | [
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},
{
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}
],
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},
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"literaturereference_normalized": "a severe refractory case of mucous membrane pemphigoid after treatment with pembrolizumab brief communication",
"qualification": "3",
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},
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},
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"sendertype": "2"
},
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"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210717"
},
{
"companynumb": "BR-009507513-1908BRA000222",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
"drugadministrationroute": null,
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"drugdosagetext": "2 MILLIGRAM/KILOGRAM, Q3W",
"drugenddate": "2018",
"drugenddateformat": "602",
"drugindication": "OVARIAN CLEAR CELL CARCINOMA",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
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"drugstartdate": "201710",
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"drugstructuredosageunit": "007",
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"medicinalproduct": "PEMBROLIZUMAB."
}
],
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"patientonsetageunit": "801",
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"reaction": [
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pemphigoid",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2017"
}
},
"primarysource": {
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"literaturereference_normalized": "a severe refractory case of mucous membrane pemphigoid after treatment with pembrolizumab brief communication",
"qualification": "3",
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},
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},
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}
] |
{
"abstract": "After a 3-month leukopenic phase, a patient developed hematologic pictures of acute promyelocytic leukemia (APL). Treatment with chemotherapy and radiotherapy had been given 10 months previously for a non-Hodgkin's lymphoma (NHL) of diffuse large cell type arising in the Waldeyer's ring. A computed tomographic scan demonstrated a high density mass in the left frontal cerebrum, which was enhanced uniformly by the contrast material. Cytocentrifuge examination of cerebrospinal fluid also showed an excess of promyelocytes. From these observations, the mass was considered to be an infiltration of leukemic cells. The intracerebral mass and meningeal involvement were resolved concomitantly with a hematologic remission of APL after intrathecal injection of cytosine arabinoside and systemic combination chemotherapy. This is a particular case of APL previously undescribed, representing an unusual presentation with intracerebral APL mass as well as a rare posttherapeutic APL following NHL.",
"affiliations": null,
"authors": "Kanakura|Y|Y|;Yonezawa|T|T|;Hamaguchi|Y|Y|;Otsuka|A|A|;Matayoshi|Y|Y|;Kondoh|H|H|;Tamaki|T|T|;Katagiri|S|S|;Kanayama|Y|Y|;Nishiura|T|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/1097-0142(19870101)59:1<94::aid-cncr2820590121>3.0.co;2-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "59(1)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008228:Lymphoma, Non-Hodgkin; D008577:Meningeal Neoplasms",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "94-8",
"pmc": null,
"pmid": "3466663",
"pubdate": "1987-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute promyelocytic leukemia with an intracerebral mass and meningeal involvement after treatment of non-Hodgkin's lymphoma.",
"title_normalized": "acute promyelocytic leukemia with an intracerebral mass and meningeal involvement after treatment of non hodgkin s lymphoma"
} | [
{
"companynumb": "JP-PFIZER INC-2018161163",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
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},
{
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"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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},
{
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},
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},
{
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},
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"drugindication": "NON-HODGKIN^S LYMPHOMA",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "VINCRISTINE SULFATE."
}
],
"patientagegroup": null,
"patientonsetage": "43",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Central nervous system leukaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Second primary malignancy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute promyelocytic leukaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KANAKURA, Y.. ACUTE PROMYELOCYTIC LEUKEMIA WITH AN INTRACEREBRAL MASS AND MENINGEAL INVOLVEMENT AFTER TREATMENT OF NON-HODGKIN^S LYMPHOMA. CANCER. 1987?59:94-98",
"literaturereference_normalized": "acute promyelocytic leukemia with an intracerebral mass and meningeal involvement after treatment of non hodgkin s lymphoma",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20180423",
"receivedate": "20180423",
"receiver": {
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"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "We describe the case of an 8-year-old girl with common precursor B-cell acute lymphoblastic leukemia who presented with severe pancytopenia during maintenance therapy with methotrexate and 6-mercaptopurine. The bone marrow smear showed moderate hypocellularity and trilinear dysplastic changes consistent with a diagnosis of drug toxicity, with no evidence of lymphoblasts. Flow cytometric immunophenotyping was negative for leukemic cells. Blood cell counts normalized after treatment with folinic acid. Maintenance therapy was gradually restarted and she remained well at follow-up visits. Myelotoxicity from methotrexate and 6-mercaptopurine may represent an unpredictable incident during an otherwise uneventful maintenance therapy, and may occur independently of other organ toxicities.",
"affiliations": "*Department of Medical, Surgical and Health Sciences, University of Trieste ‡Institute for Maternal and Child Health IRCCS \"Burlo Garofolo,\" Trieste †San Camillo-Forlanini Hospital, Rome, Italy.",
"authors": "Chinello|Matteo|M|;Naviglio|Samuele|S|;Shardlow|Alison|A|;Severino|Alessandro|A|;Ventura|Alessandro|A|;Locasciulli|Anna|A|",
"chemical_list": "D015122:Mercaptopurine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000295",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(2)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001855:Bone Marrow Diseases; D002648:Child; D019468:Disease Management; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015122:Mercaptopurine; D008727:Methotrexate; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "156-7",
"pmc": null,
"pmid": "25493456",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dysplastic bone marrow changes during maintenance therapy for acute leukemia.",
"title_normalized": "dysplastic bone marrow changes during maintenance therapy for acute leukemia"
} | [
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"companynumb": "IT-ACCORD-027848",
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},
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"drugauthorizationnumb": "040716",
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"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
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"drugdosagetext": "ALSO RECEIVED INTRATHECAL METHOTREXATE AT THE DOSE OF 12 MG EVERY 6 WEEKS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA",
"drugintervaldosagedefinition": "803",
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{
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}
],
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
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"drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "2",
"drugrecurrence": [
{
"drugrecuraction": "Pancytopenia"
}
],
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"medicinalproduct": "MERCAPTOPURINE."
}
],
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"patientonsetage": "8",
"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Cough",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pancytopenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHINELLO M, NAVIGLIO S, SHARDLOW A, SEVERINO A, VENTURA A, LOCASCIULLI A. DYSPLASTIC BONE MARROW CHANGES DURING MAINTENANCE THERAPY FOR ACUTE LEUKEMIA. J PEDIATR HEMATOL ONCOL. 2014 DEC 9.",
"literaturereference_normalized": "dysplastic bone marrow changes during maintenance therapy for acute leukemia",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20141230",
"receivedate": "20141230",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10681446,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150529"
},
{
"companynumb": "PHHY2015IT036954",
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"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "090029",
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"drugenddate": null,
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"drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA",
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"medicinalproduct": "METHOTREXATE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
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"drugenddateformat": null,
"drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "6-MERCAPTOPURINE MONOHYDRATE"
}
],
"patientagegroup": null,
"patientonsetage": "8",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pancytopenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHINELLO M, NAVIGLIO S, SHARDLOW A, SEVERINO A, VENTURA A, LOCASCIULLI A.. DYSPLASTIC BONE MARROW CHANGES DURING MAINTENANCE THERAPY FOR ACUTE LEUKEMIA.. J-PEDIATR-HEMATOL-ONCOL. 2015;37(2):156-157",
"literaturereference_normalized": "dysplastic bone marrow changes during maintenance therapy for acute leukemia",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20150401",
"receivedate": "20150401",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10976883,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "BACKGROUND\nAcute porphyrias are rare disorders of the heme biosynthetic pathway and present with acute neurovisceral symptoms that can be induced by hormonal changes and medications. Women are far more likely to present with clinical symptoms than men, particularly during parts of their lifetime with changes in the level of female sex hormones such as ovulation, menstruation, and pregnancy. Treatment of ovulatory dysfunction and controlled ovarian hyperstimulation require the administration of hormones, which are considered porphyrinogenic. Women with acute hepatic porphyria have therefore been considered unsuitable for such treatments in the past.\n\n\nMETHODS\nWe report on nine women with acute hepatic porphyria who underwent in vitro fertilization (IVF), preceded by ovarian stimulation. Their mean age at the start of IVF was 33.2 years (range 27-38 years). Two women had been diagnosed with polycystic ovarian syndrome, two were treated for hyperprolactinemia, two had hypothyroidism, of which one also had type 1 diabetes, one had a uterus malformation, one had anovulatory cycles, and one used a sperm donor.\n\n\nRESULTS\nAll patients were able to undergo fertility treatment without experiencing severe porphyria attacks.\n\n\nCONCLUSIONS\nWomen with acute hepatic porphyria considering fertility treatments should be assessed individually for potential risks, treatment should be planned in close collaboration with a porphyria specialist, and biochemical activity should be monitored regularly during ovarian stimulation. As we gather more knowledge, we hope that the porphyrinogenicity of the stimulation agents is re-assessed and that more studies will shed light on the reproductive health of women living with acute hepatic porphyria.",
"affiliations": "Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.;Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.;Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.",
"authors": "Vassiliou|Daphne|D|https://orcid.org/0000-0003-1612-5986;Lindén Hirschberg|Angelica|A|;Sardh|Eliane|E|",
"chemical_list": "D000623:Porphobilinogen Synthase",
"country": "United States",
"delete": false,
"doi": "10.1111/aogs.14200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6349",
"issue": "100(9)",
"journal": "Acta obstetricia et gynecologica Scandinavica",
"keywords": "acute hepatic porphyria; assisted reproduction technologies; in vitro fertilization; porphyria; porphyrinogenicity",
"medline_ta": "Acta Obstet Gynecol Scand",
"mesh_terms": "D000328:Adult; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D010062:Ovulation Induction; D011085:Polycystic Ovary Syndrome; D000623:Porphobilinogen Synthase; D017094:Porphyrias, Hepatic; D011247:Pregnancy; D018873:Pregnancy Rate; D027724:Reproductive Techniques, Assisted; D013548:Sweden",
"nlm_unique_id": "0370343",
"other_id": null,
"pages": "1712-1721",
"pmc": null,
"pmid": "34060066",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment with assisted reproduction technologies in women with acute hepatic porphyria.",
"title_normalized": "treatment with assisted reproduction technologies in women with acute hepatic porphyria"
} | [
{
"companynumb": "SE-TOLMAR, INC.-21SE031164",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Subcutaneous injection",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "In vitro fertilisation",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"medicinalproduct": "ELIGARD"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
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"medicinalproduct": "ELIGARD"
},
{
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"activesubstancename": "ALFENTANIL"
},
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},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ARTICAINE"
},
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"drugdosageform": null,
"drugdosagetext": "UNK",
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"drugindication": "Anaesthesia",
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"medicinalproduct": "ARTICAINE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FOLLITROPIN ALFA"
},
"drugadditional": null,
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"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Ovarian hyperstimulation syndrome",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"medicinalproduct": "FOLLITROPIN ALFA"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROGESTERONE"
},
"drugadditional": null,
"drugadministrationroute": "067",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Prophylaxis of abortion",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PROGESTERONE"
}
],
"patientagegroup": null,
"patientonsetage": "37",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Abortion spontaneous",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Vassiliou D., Lind?n Hirschberg A., Sardh E.. Treatment with assisted reproduction technologies in women with acute hepatic porphyria. Acta Obstetricia et Gynecologica Scandinavica. 2021;100:9:1712-1721",
"literaturereference_normalized": "treatment with assisted reproduction technologies in women with acute hepatic porphyria",
"qualification": "1",
"reportercountry": "SE"
},
"primarysourcecountry": "SE",
"receiptdate": "20211122",
"receivedate": "20211101",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20020178,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Migration of intravitreal silicone to the retrolaminar optic nerve was detected pathologically in 1983, symptomatic migration to the subarachnoid space of the optic nerve was reported in 1994, and asymptomatic intraventricular silicone was first seen radiographically in 1999. Since then, little advance has been made in understanding this phenomenon despite numerous case reports. Although some authors have restricted their attention to cases of intraventricular silicone, we believe that these represent part of a clinical spectrum and that all cases with retrolaminar silicone should be considered. The pathophysiology of silicone migration may have significant implications for the management of patients after vitrectomy.\n\n\n\nTwo patients were evaluated by the authors. An internet-based literature review was conducted, beginning with the key search terms \"intraventricular, intracranial, subarachnoid, or optic nerve silicone,\" and \"complications of vitrectomy or intravitreal silicone.\" Further searches cascaded from the initial search results. An additional 24 cases of retrolaminar migration of silicone oil were found and summarized. The relevant anatomy and pathophysiology were reviewed, with attention to additional information from enucleation studies, as well as to gaps in the current understanding of this process.\n\n\n\nRetrolaminar migration of silicone oil may be more common than previously thought, especially in at-risk patient groups, and may be associated with visual and neurologic symptoms. Some impressions regarding the cause and significance of this syndrome seem incorrect. Although this process is likely linked to postoperative elevations of intraocular pressure, the exact mechanisms of silicone entry into the subarachnoid space remain undefined. A number of anatomic factors may influence the movement of silicone from the orbit and in the various compartments of the subarachnoid space and ventricular system, resulting in variability of clinical presentations and radiologic findings. Implications for clinical decision making and directions for further research are discussed.\n\n\n\nGreater awareness on the part of treating physicians, systematic study of at-risk populations, and advances in imaging technology will allow further insight into this phenomenon.",
"affiliations": "Brownwood Regional Medical Center (RB, CC), Brownwood, Texas; and Department of Ophthalmology (AG, VD, RNH), University of Texas Southwestern Medical Center, Dallas, Texas.",
"authors": "Boren|Rance A|RA|;Cloy|Carson D|CD|;Gupta|Ankur S|AS|;Dewan|Vinay N|VN|;Hogan|R Nick|RN|",
"chemical_list": "D012827:Silicone Oils",
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000440",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-8022",
"issue": "36(4)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D005260:Female; D005548:Foreign-Body Migration; D006801:Humans; D008297:Male; D009900:Optic Nerve; D009901:Optic Nerve Diseases; D012163:Retinal Detachment; D012827:Silicone Oils; D014821:Vitrectomy",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "439-447",
"pmc": null,
"pmid": "27636746",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Retrolaminar Migration of Intraocular Silicone Oil.",
"title_normalized": "retrolaminar migration of intraocular silicone oil"
} | [
{
"companynumb": "US-BAYER-2017-205625",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "3",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CORONARY ARTERY DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CLOPIDOGREL"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "999999",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CORONARY ARTERY DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ACETYLSALICYLIC ACID (} 100 MG)"
}
],
"patientagegroup": "6",
"patientonsetage": "82",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug administration error",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Haematoma",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Haemoglobin decreased",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Labelled drug-drug interaction medication error",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BOREN RA; CLOY CD; GUPTA AS; DEWAN VN; HOGAN RN. RETROLAMINAR MIGRATION OF INTRAOCULAR SILICONE OIL. JOURNAL OF NEURO-OPHTHALMOLOGY. 2016;36:439",
"literaturereference_normalized": "retrolaminar migration of intraocular silicone oil",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20171101",
"receivedate": "20171101",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14149727,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180321"
}
] |
{
"abstract": "Anti-tumor necrosis factor (TNF) therapy has been the major advance in the treatment of inflammatory bowel disease, especially Crohn's disease. But there is a higher risk of infections, especially tuberculosis (TB), in patients treated with anti-TNFα. The authors report a case of disseminated tuberculosis with the following features: pulmonary tuberculosis, left supra clavicular cervical and meditational lymphadenopathy, bilateral pleural effusion, peritoneal and splenic involvement. This disseminated tuberculosis was observed in a 39-year-old woman who was treated by infliximab for refractory Crohn's disease. The evolution with antituberculosis drugs was fatal, the death of the patient was due to hepatic encephalitis.\n\n\nCONCLUSIONS\nThe physicians should always be aware in the use of TNF-alpha blockers according to guidelines. Its recommended to realize a complete pretherapeutic assessment and it is necessary to follow-up the patients to detect possible reactivation of latent tuberculosis.",
"affiliations": "Service de pneumologie, hôpital militaire Avicenne, Marrakech, Maroc; Laboratoire PCIM, FMPM, université Cadi-Ayyad, Marrakech, Maroc. Electronic address: bouchentouf_rachid@yahoo.fr.;Service de pneumologie, hôpital militaire Avicenne, Marrakech, Maroc.;Service de pneumologie, hôpital militaire Avicenne, Marrakech, Maroc.",
"authors": "Bouchentouf|R|R|;Yasser|Z|Z|;Aitbenasser|M A|MA|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000995:Antitubercular Agents; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0761-8417",
"issue": "70(6)",
"journal": "Revue de pneumologie clinique",
"keywords": "Anti-TNF; Crohn's disease; Disseminated tuberculosis; Infliximab; Maladie de Crohn; Tuberculose disséminée",
"medline_ta": "Rev Pneumol Clin",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D000995:Antitubercular Agents; D003424:Crohn Disease; D017809:Fatal Outcome; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D014391:Tuberculosis, Miliary; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8406312",
"other_id": null,
"pages": "366-9",
"pmc": null,
"pmid": "25131370",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Disseminated tuberculosis following infliximab therapy for Crohn disease: a case report.",
"title_normalized": "disseminated tuberculosis following infliximab therapy for crohn disease a case report"
} | [
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{
"abstract": "Angioedema secondary to C1 inhibitor deficiency has been rarely reported to be associated with systemic lupus erythematosus. A genetic defect of C1 inhibitor produces hereditary angioedema, which is usually presented with cutaneous painless edema, but edema of the genital area, gastrointestinal and laryngeal tracts have also been reported. In lupus patients, angioedema may be the result of an acquired type of C1 inhibitor deficiency, most probably due to antibody formation directed against the C1 inhibitor molecule. Herein we report a new case of lupus nephritis that developed angioedema and a rapid course of disease progression with acute renal failure and alveolar hemorrhage without response to high dose steroid and plasmapheresis.",
"affiliations": "Department of Rheumatology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran; ; Department of Internal Medicine, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of Nephrology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran; ; Department of Internal Medicine, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of Internal Medicine, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of Internal Medicine, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of Internal Medicine, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.",
"authors": "Habibagahi|Zahra|Z|;Ruzbeh|Jamshid|J|;Yarmohammadi|Vahide|V|;Kamali|Malihe|M|;Rastegar|Mohammad Hassan|MH|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nIran J Med SciIran J Med SciIJMSIranian Journal of Medical Sciences0253-07161735-3688Shiraz University of Medical Sciences Shiraz, Iran ijms-40-372Case ReportRefractory Angioedema in a Patient with Systemic Lupus Erythematosus Habibagahi Zahra MD13Ruzbeh Jamshid MD23Yarmohammadi Vahide MD3Kamali Malihe MD3Rastegar Mohammad Hassan MD31 Department of Rheumatology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran;\n2 Department of Nephrology, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran;\n3 Department of Internal Medicine, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran\nCorrespondence: Zahra Habibagahi, MD; Department of Rheumatology and Internal Medicine, Internal Medicine, Zand Street, Shiraz, Iran Tel/Fax: +98 71 36474316 Email: zagahi@sums.ac.ir 7 2015 40 4 372 375 29 4 2013 8 9 2013 27 10 2013 © 2015: Iranian Journal of Medical Sciences\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAngioedema secondary to C1 inhibitor deficiency has been rarely reported to be associated with systemic lupus erythematosus. A genetic defect of C1 inhibitor produces hereditary angioedema, which is usually presented with cutaneous painless edema, but edema of the genital area, gastrointestinal and laryngeal tracts have also been reported. \n\nIn lupus patients, angioedema may be the result of an acquired type of C1 inhibitor deficiency, most probably due to antibody formation directed against the C1 inhibitor molecule. Herein we report a new case of lupus nephritis that developed angioedema and a rapid course of disease progression with acute renal failure and alveolar hemorrhage without response to high dose steroid and plasmapheresis. \n\nKeywords\nSystemic lupus erythematosusAngioedemaEnalapril\n==== Body\nIntroduction\n\nAngioedema usually leads to non-pitting edema of the face, lip, mouth, tongue, extremities, and genitalia.1 It can also affect airway and intestinal mucosa, causes airway obstruction and intestinal stenosis. Although angioedema is generally a benign and self-limited disease, but it may be life threatening in some situations with mortality rate from 15 to 33%.2,3\n\n\nAngioedema can occur in patients with decrease serum levels or abnormal function of regulatory complement protein, C1 inhibitor (C1-INH). Both hereditary and acquired forms of C1-INH deficiency have been defined.\n\nAngioedema must be suspected in any patient with typical clinical presentations and history of any new drug exposure or similar previous attacks. Family members with similar history must also be questioned to find hereditary forms of angioedema.\n\n\nFew cases of acquired angioedema have been reported in patients with systemic lupus erythematosus (SLE), some of them had an amnions course, which had to be intubated and ICU admitted due to airway obstruction.4,5\n\n\nCase Report\nAn 18-year-old girl, a new case of SLE for about 2 months, presented with facial and lower extremity edema in her last outpatient follow up. She had active urine sediment, serum creatinine of 1.4 mg/dl, and 24 hours urine protein of 2500 mg/day. Renal biopsy confirmed lupus nephritis, class IV, based on the International Society of Nephrology/Renal Pathology Society (ISN/RPS), with cellular crescent formation. She was admitted in internal medicine ward for further management.\n\nOn the day of admission, she was afebrile, not in respiratory distress, and her blood pressure was 160/95. She had periorbital edema, malar rash, and oral lesion on hard palate with normal tongue and uvula. The rest of the physical examination was unremarkable.\n\n\nWard laboratory test results revealed leukocyte count of 1.5×10\n9\n/L, absolute lymph count 0.720×10\n9\n/L, hemoglobin 8.0 g/dl, and platelet count 79×10\n9\n/L. ESR was 78 mm/hr, albumin 2.9 mg/dl with normal values of liver enzymes and alkaline phosphatase. The patient had serum creatinine 1.5 mg/dl. The results of serology tests were as follow: Antinuclear antibody (ANA) 1/360 with homogenous pattern, anti-double strand DNA antibody >240 IU/ml, anticardiolipin antibody 6.2 GPL units/ml (for the first time), and negative anti La, anti Ro, anti beta2glycoproteinI antibodies and lupus anticoagulant. Both C3 and C4 complement levels were low. Chest X-ray was normal.\n\n\nOn the evening of the day she received the second metylprednisolon pulse, developed sever, generalized sub mandibular and neck swelling progressed to stridor and hoarseness. She was afebrile, tachypnic, and had a normal appearing tongue, soft palate, and uvula. Breathing sounds and the other parts of physical examination had no significant change compared to the admission time. Serum level of C1-INH was low. She still had a normal chest X-ray.\n\nImipenem and vancomycin were started, after this event, enalapril was discontinued, and emergency intubation with fiberoptic bronchoscopy was performed by anesthesiologist due to low oxygen saturation. Severe epiglottis and vocal cord swelling were noted in the anesthesiologist report.\n\n\nIn the ICU, antibiotics were continued and she underwent mechanical respiration. Repeated bedside sonography and color Doppler imaging failed to show any collection, hematoma, or vascular thrombosis in the neck area. Few days later, creatinine rose and urine output decreased. Peripheral blood smear was not in favor of thrombotic thrombocytopenia. Dexamethazone (200 mg) and plasmapheresis were started immediately, but she developed bloody secretions from tracheal tube and bilateral coarse rales up to mid part of both lung fields. Chest X-ray showed diffuse bilateral infiltration, suspicious to pulmonary alveolar hemorrhage (figure 1). Finally, she developed cardiac arrest without any response to resuscitation.\n\n\nFigure 1 Chest X-ray AP: Bilateral diffuse alveolar infiltration.\n\nDiscussion\nAngioedema is defined as localized subcutaneous or submucosal swelling due to extravasation of fluid into interstitial tissues. It affects areas with loose connective tissue. \n\n\nAngioedema is classified into two major groups: mast cell mediated, the more common form, and kinin-mediated. Mast cell mediated angioedema is usually associated with urticaria, wheezing, and pruritus after exposure to an identifiable trigger. Kinin-mediated angioedema, however, occurs mostly in the absence of a specific trigger and without clinical signs of mast cell degranulation.4\n\n\n\nThe most well known cause of kinin-mediated angioedema is hereditary C1-INH deficiency. Patients in this group are healthy individuals without underlying disease, have a strong family history, and usually present earlier in life.6\n\n\n\nAcquired types of C1-INH deficiency resulted from autoantibodies to/or enhanced catabolism of C1-INH have also been described as a cause of angioedema.7 This form of angioedema, mostly reported in patients with autoimmune or lymphoproliferative disorders, characterized by adulthood onset and lack of family history.5\n\n\n\nAngiotensin converting enzyme inhibitors account for a type of kinin-mediated angioedema. These drugs inhibit bradykinin degradation by preventing angiotensin converting enzyme.8 ACE inhibitors also unmask C1 inhibitor deficiency.9 About 0.1–0.2% of patients may develop angioedema, between several hours to years after drug exposure.10 Although most of these cases have mild disease but fatal respiratory problems have also been described.11\n\n\nOur patient was a recently diagnosed case of lupus nephritis according to ACR classification criteria. She developed severe neck swelling and respiratory distress after receiving second metylprednisolon pulse. Our first diagnosis was the infections of the floor of the mouth. Although we did not perform CT scan of the neck, but no response to intravenous antibiotics and negative results of repeated neck sonography were not in favor of an infectious process. Color Doppler imaging also did not show vascular thrombosis, while low serum levels of C3 and C4 complement components, bloody secretions from endotracheal tube and increase in serum creatinine, were all in favor of a rapidly progressive active lupus with acute renal failure. The last chest X-ray in the ICU was compatible with diffuse alveolar hemorrhage, which completed this scenario. We explained low serum level of C1-INH and diffuse epiglottis and vocal cord swelling with acquired angioedema in a setting of an active lupus. Enalapril might also play a role. The patient had no family history or self-history of repeated similar attacks to support a hereditary phenomenon.\n\n\nAngioedema has been reported in a few cases of SLE. Like our patient, some of them had an intractable course, but most responded to aggressive treatment.5,12 Although most of the previously reported cases of SLE and angioedema had hereditary C1-INH deficiency, the age of presentation in the absence of family history was in favor of an acquired C1-INH deficiency angioedema in this case.13,14\n\n\n\nAutoantibodies against C1 inhibitor molecule may induce C1-INH deficiency/dysfunction, leads to hyperactivation of complement classic pathway usually in association with an active underlying autoimmune disease.15,16\n\n\n\nAntibodies against C1-INH molecule have not been invariably found in all patients with lupus and angioedema.17 Although these patients had low serum concentrations of C1-INH, but unlike our patient, they didn’t have any sign of disease activity.\n\n\nConclusion\nAcquired angioedema must be strongly in mind when a patient with lupus, irrespective of disease activity, develops acute neck swelling and shows signs of upper respiratory tract obstruction. Patients show different clinical presentations and variable responses to therapy. This heterogeneity may be due to different mechanisms of angioedema in this autoimmune disease. \n\n\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Nzeako UC Frigas E Tremaine WJ Hereditary angioedema: a broad review for clinicians Arch Intern Med 2001 161 2417 29 doi: 10.1001/archinte.161.20.2417. PubMed PMID: 11700154 11700154 \n2 Fay A Abinun M Current management of hereditary angioedema (C1 esterase inhibitor deficiency) J Clin Pathol 2002 55 266 70 PubMed PMID: 11919209; PubMed Central PMCID: PMC1769636 11919209 \n3 Markovic SN Inwards DJ Frigas EA Phyliky RP Acquired C1 esterase inhibitor deficiency Ann Intern Med 2000 132 144 50 doi: 10.7326/0003-4819-133-10-200011210-00025. PubMed PMID: 10644276 10644276 \n4 Lahiri M Lim AY Angioedema and systemic lupus erythematosus – A complementary association? Ann Acad Med Singapore 2007 36 142 5 Pubmed PMID: 17364082 17364082 \n5 Furlanetto V Jr Giassi Kde S Neves Fde S Zimmermann AF Castro GR Pereira IA Intractable acquired autoimmune angioedema in a patient with systemic lupus erythematosus Rev Bras Reumatol 2010 50 102 6 PubMed PMID: 21125146 21125146 \n6 Brown T Cicardi M Farkas H Bork K Kreuz W Zingala L Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema J Allergy Clin Immunol 2004 114 629 37 15356569 \n7 Cicardi M Zingale LC Pappalordo E Folcioni A Agostoni A Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies Medicine (Baltimore) 2003 82 274 81 doi: 10.1097/01.md.0000085055.63483.09. PubMed PMID: 12861105 12861105 \n8 Morimoto T Gandhi TK Fiskio JM Segar AC So JW Cook EF An evaluation of risk factors foe adverse drug events associated with angiotensin-converting enzyme inhibitors J Eval Clin Pract 2004 10 499 509 PubMed PMID: 15482412 15482412 \n9 Dykewics MS Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management Curr Opin Allergy Clin Immunol 2004 4 267 70 PubMed PMID: PMID:15238791 15238791 \n10 Hedner T Samuelsson O Lunde H Lindholm L Andren L Wiholm BE Angio-edema in relation to treatment with angiotensin converting enzyme inhibitors BMJ 1992 304 941 6 PubMed PMID: 1581715; PubMed Central PMCID: PMC1882283 1581715 \n11 Assadi FK Wang HE Lawless S McKay CP Hopp L Fattori D Angiotensin converting enzyme inhibitor-induced angioedema: a report of two cases Pediatr Nephrol 1999 13 917 9 doi: 10.1007/s004670050727. PubMed PMID: 10603148 10603148 \n12 Ko CH Ng J Kumar S Hurst M Life threatening angioedema in a patient with systemic lupus Clin Rheumatol 2006 25 917 8 PubMed PMID: 16547694 16547694 \n13 Koide M Shirahama S Tokura Y Takigawa M Hayakawa M Furukawa F Lupus erythematosus associated with C1 inhibitor deficiency J Dermatol 2002 29 503 7 doi: 10.1111/j.1346-8138.2002.tb00316.x. PubMed PMID: 12227484 12227484 \n14 Frigas E Nzeako UC Angioedema, pathogenesis, differential diagnosis, and treatment Clin Rev Allergy Immunol 2002 23 217 31 PubMed PMID: 12221866 12221866 \n15 Alsenz J Bork K Loos M Autoantibody mediated acquired deficiency of C1 inhibitor N Engl J Med 1987 316 1360 6 doi: 10.1056/NEJM198705283162202. PubMed PMID: 3494945 3494945 \n16 Hunsicker LG Ruddy S Carpenter CB Schur PH Merrill JP Müller-Eberhard HJ Metabolism of third complement component (C3) in nephritis. Involvement of the classic and alternate (properdin) pathways for complement activation N Engl J Med 1972 287 835 40 doi: 10.1056/NEJM197210262871701. PubMed PMID: 4627271 4627271 \n17 Nettis E Colanardi MC Loria MP Vacca A Acquired C1 inhibitor deficiency in a patient with systemic lupus erythematosus: a case report and review of the literature Eur J Clin Invest 2005 35 781 4 PubMed PMID: 16313255 16313255\n\n",
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"abstract": "Surgery is effective treatment for echinococcosis; however, there is a risk of hypertonic saline resorption and acute hypernatremia.\nWe report two cases of severe hypernatremia following hydatid cyst removal.\nA 17-year-old girl underwent surgical removal of hepatic hydatid cyst. Following the surgery, she developed seizures evolving to status epilepticus, and was sedated and mechanically ventilated. Blood chemistry showed hypernatremia. Fluid resuscitation with 5% dextrose infusions was started in combination with furosemide. Electrolytes were monitored frequently until plasma sodium levels normalized, 30 hours later. The patient was seizure free 48 hours later. The second patient is a 70-year-old man with hepatic hydatid cyst. After the surgery he became somnolent and confused due to severe hypernatremia. Intravenous administration of five percentage dextrose was initiated and high doses of furosemide. Sodium level normalized within 38 hours. The patient's mental status improved.\nA hospital protocol was established aiming to prevent hypernatremia and neurological complications.",
"affiliations": "University Clinic for Anaesthesiology, Reanimation and Intensive Care Medicine, Medical Faculty, Ss Cyril and Methodius University, Skopje, N Macedonia.;University Clinic for Anaesthesiology, Reanimation and Intensive Care Medicine, Medical Faculty, Ss Cyril and Methodius University, Skopje, N Macedonia.;University Clinic of Neurology, Medical Faculty, Ss Cyril and Methodius University, Skopje, N Macedonia.;University Surgical Clinic St Naum Ohridski,Medical Faculty, Ss Cyril and Methodius University, 1000 Skopje, N Macedonia.;University Clinic for Digestive Surgery, Medical Faculty, Ss Cyril and Methodius University, 1000, Skopje, N Macedonia.;University Clinic for Anaesthesiology, Reanimation and Intensive Care Medicine, Medical Faculty, Ss Cyril and Methodius University, Skopje, N Macedonia.;University Clinic for Anaesthesiology, Reanimation and Intensive Care Medicine, Medical Faculty, Ss Cyril and Methodius University, Skopje, N Macedonia.;University Clinic of Neurology, Medical Faculty, Ss Cyril and Methodius University, Skopje, N Macedonia.",
"authors": "Kuzmanovska|Biljana|B|;Kartalov|Andrijan|A|;Kuzmanovski|Igor|I|;Shosholcheva|Mirjana|M|;Jankulovski|Nikola|N|;Gavrilovska-Brzanov|Aleksandra|A|;Dimitrovski|Aleksandar|A|;Cvetkovska|Emilija|E|",
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"fulltext": "\n==== Front\nMed ArchMed ArchMedical ArchivesMedical Archives0350-199X1986-5961Academy of Medical Sciences of Bosnia and Herzegovina 10.5455/medarh.2019.73.356-358Case ReportHypernatremia-induced Neurologic Complications After Hepatic Hydatid Cyst Surgery: Pretreat to Prevent Kuzmanovska Biljana 1Kartalov Andrijan 1Kuzmanovski Igor 2Shosholcheva Mirjana 3Jankulovski Nikola 4Gavrilovska-Brzanov Aleksandra 1Dimitrovski Aleksandar 1Cvetkovska Emilija 21 University Clinic for Anaesthesiology, Reanimation and Intensive Care Medicine, Medical Faculty, Ss Cyril and Methodius University, Skopje, N Macedonia2 University Clinic of Neurology, Medical Faculty, Ss Cyril and Methodius University, Skopje, N Macedonia3 University Surgical Clinic St Naum Ohridski,Medical Faculty, Ss Cyril and Methodius University, 1000 Skopje, N Macedonia4 University Clinic for Digestive Surgery, Medical Faculty, Ss Cyril and Methodius University, 1000, Skopje, N MacedoniaCorresponding author:Gavrilovska-Brzanov Aleksandra MD, MSc, PhD, University Clinic for Anaesthesiology, Reanimation and Intensive Care Medicine, Medical Faculty, Ss Cyril and Methodius University, SkopjeN Macedonia+ 389 71 240 701gavrilovska.aleksandra@gmail.com\nORCID ID: https://www.orcid.org/0000-0001-9593-250210 2019 73 5 356 358 22 9 2019 18 10 2019 © 2019 Biljana Kuzmanovska, Andrijan Kartalov, Igor Kuzmanovski, Mirjana Shosholcheva, Nikola Jankulovski, Aleksandra Gavrilovska-Brzanov, Aleksandar Dimitrovski, Emilija Cvetkovska2019This 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.Introduction:\nSurgery is effective treatment for echinococcosis; however, there is a risk of hypertonic saline resorption and acute hypernatremia.\n\nAim:\nWe report two cases of severe hypernatremia following hydatid cyst removal.\n\nCase reports:\nA 17-year-old girl underwent surgical removal of hepatic hydatid cyst. Following the surgery, she developed seizures evolving to status epilepticus, and was sedated and mechanically ventilated. Blood chemistry showed hypernatremia. Fluid resuscitation with 5% dextrose infusions was started in combination with furosemide. Electrolytes were monitored frequently until plasma sodium levels normalized, 30 hours later. The patient was seizure free 48 hours later. The second patient is a 70-year-old man with hepatic hydatid cyst. After the surgery he became somnolent and confused due to severe hypernatremia. Intravenous administration of five percentage dextrose was initiated and high doses of furosemide. Sodium level normalized within 38 hours. The patient’s mental status improved.\n\nConclusion:\nA hospital protocol was established aiming to prevent hypernatremia and neurological complications.\n\nHypernatremiaHydatid cystNeurologic complications\n==== Body\n1. INTRODUCTION\nHuman echinococcosis is a zoonotic disease, which was traditionally found in parts of Europe, Africa, Asia, the Middle East, and Central and South America. With recent migration trends it becomes globally distributed, i.e. there is a relocation of patients with cystic echinococcosis from highly endemic to non-endemic countries, which are less experienced in its treatment (1). Treatment options for cystic echinococcosis (hydatid disease) include anthelminthic drugs, percutaneous aspiration, and surgery; however, surgery remains the most effective treatment and can lead to a complete cure. Hydatidectomy consists of puncture of the cyst and aspiration of the content, an introduction of a scolicidal agent (20% hypertonic sodium chloride - HS) and aspiration thereafter. The procedure carries the risk of hypertonic saline resorption and subsequent acute hypernatremia have been reported to cause a variety of neurological symptoms (2, 3).\n\n2. AIM\nWe report two cases of severe hypernatremia following hydatid cyst removal.\n\n3. CASE REPORTS\nWe report two notable cases of severe hypernatremia after hepatic hydatid cyst removal, as well as thereafter established preventive protocol and the impact of its implementation on postoperative sodium levels in 68 consecutive patients.\n\nEthical approval for this study (Ethics Committee No 21 ) was provided by the Ethics Committee of Anesthesia Department, Medical Faculty, Skopje, N Macedonia.\n\nA 17-year-old girl, ASA-Physical Status 1, with normal laboratory examinations, underwent surgical removal and hypertonic saline irrigation of large hepatic hydatid cyst (10 cm). In the perioperative period dextrose 5% / 500 ml and normal saline 0.9% / 1000 ml were intravenously used as perioperative hydration. The operation went uneventful. The cyst was punctured and partially aspirated, afterward 400 ml of scolicidal agent–HS 20% was introduced and after 5 minutes total aspiration was performed; further hydatidectomy was done and irrigation with HS 20% into the cyst cavity. Histopathological findings confirmed echinococcosis. Following the surgery, the patient was conscious and completely stable, but two hours later, she developed repeated generalized tonic-clonic seizures which evolved to status epilepticus. Intravenous diazepam was administered and because of ongoing seizure activity, thiopental was initiated. The patient was intubated and mechanically ventilated. Blood chemistry analysis showed hypernatremia of 166 mmol l-1 and plasma osmolality of 340 mOsm kg-1. Fluid resuscitation with 5% dextrose infusions was started immediately, and water via nasogastric tube in combination with natriuretic diuretics (Furosemide 1 mg kg-1). Electrolytes status was monitored every 4 hours until plasma sodium levels reached reference values, 30 hours after admission to ICU. Thiopental and mechanical ventilation were resumed within several hours after normalization of sodium plasma levels, and the patient was awake and seizure-free 48 hours after the beginning of seizures. CT scan of the brain on day 2 showed no significant abnormalities.\n\nThe second patient is a 70-year-old man, ASA-Physical Status 2, with normal baseline electrolyte status, who was subjected to a surgical treatment of large hepatic hydatid cyst (12 cm). Perioperative period was unremarkable; cyst was punctured and filled with scolicidal agent HS 20%. Total aspiration with hydatidectomy was performed. The patient perioperative received 500 ml of dextrose 5% and 1000 ml normal saline 0.9% intravenously. Although the patient awoke after the operation normally, in the following few hours his mental status deteriorated. He became somnolent, inattentive and confused. Neurological examination revealed an absence of any motor deficit or cranial nerve dysfunction. Blood chemistry tests showed severe hypernatremia of 170 mmol l-1 and plasma osmolality of 353 mOsm kg-1. Fluid resuscitation with 5% dextrose i.v. and water via nasogastric tube was applied, followed by high doses of furosemide (1.5 mg kg-1). Sodium level was evaluated every 4 hours, and it reached normal values within 48 hours. The patient’s mental status improved in the additional 3 days. His brain CT was within normal limits. The patient was discharged completely recovered 10 days after the surgery.\n\nHaving in mind these cases, a hospital protocol was established in order to prevent potential hypernatremia and subsequent neurological complications due to hypertonic saline irrigation during hydatidectomy. Accordingly, at the time of cyst irrigation with 20% HS, the patients receive 5% dextrose solution i.v. (10 ml kg -1 h-1), followed by diuretic (furosemide 0.5 mg kg-1) at the end of the surgery. Electrolyte status is monitored one hour after the surgery, and then twice a day if the sodium levels exceed the normal range. If hypernatremia occurs, infusion of 20 ml kg -1 h-1 of 5% dextrose solution is initiated for the first hour, followed by 10 ml kg -1h-1 until the normalization of plasma sodium levels, as well as 2000 ml of water via nasogastric tube in the following 24 hours, and furosemide (1 mg kg -1). It is worth noting that we also apply anaphylactic prophylaxis with chloropyramine hydrochloride 20 mg, and methylprednisolone 1 mg kg-1 one hour before the surgery, although its efficacy further needs to be established (4).\n\nAfter the introduction of the aforementioned protocol, a total of 68 patients with liver hydatid cysts were operated between January 2015 and December 2017. 60 patients had a single cyst, while seven had two cysts, and one patient had four hydatid cysts. Postoperative hypernatremia was observed in only eight patients (9%) out of 68 operated in three consecutive years. The sodium level in the first postoperative hour ranged between 143 - 153 mmol l-1, with a mean value of 146 mmol l-1. Its normalization was always achieved within 24 hours. Neurological complications in the hypernatremic patients were rare and mild, usually drowsiness and anxiety episodes that quickly resolved after the normalization of natremia.\n\n4. DISCUSSION\nThe standard first line procedure for treating patients with hydatid cyst is surgery, according to the World Health Organization (WHO) experts and expert consensus from 2010. The HS, from 3% to 30%, is recommended by WHO/OIE for irrigation of the hydatid cyst for preventing recurrence (5). Severe hypernatremia following hypertonic saline irrigation of hydatid cyst during surgery has been repeatedly reported in the literature (2-4, 6). Hypernatremia was also the major underlying complication in our patients. During the surgery the surrounding tissue of the lesion was cautiously protected and there was no fluid spillage. We assume that the HS might have been absorbed through the cyst walls or peritoneal membrane. Transfer of the fluid from intracellular to extracellular compartment results in pulmonary edema and brain dehydration. Associated clinical symptoms of central nervous system injury were described in a form of epileptic seizures and epileptic status, changes in mental status, irritability, lethargy or coma. Furthermore, two fatal outcomes due to epileptic status were reported (7, 8). Although neurological symptoms are dominant clinical feature in acute hypernatremia, CT scan of the brain might be presented as normal (9) and the diagnosis is based on clinical symptoms and laboratory findings. Normal findings in CT scans appeared in our cases as well. Raising awareness of these possible complications among anesthesiologists and surgeons, taking precautions to prevent hypernatremia during surgery, as well as close monitoring of plasma sodium levels and possible changes in patient’s mental status or other neurological signs and symptoms immediately after surgery, are crucial in the prevention of severe neurological complications. If hypernatremia occurs, normalization of the sodium levels should be done following guidelines for correction of acute and severe hypernatremia (8, 10). In the presented cases we follow the recommendations, because inappropriate extracellular osmotic tonicity correction could result in central nervous system swelling, which also contributes to this patient’s brain injury. Acute hypernatremia should be meticulously treated; correction rate of the serum sodium level limited from 8 mmol/L to 10 mmol/L, in the first 24 hours, and 18 mmol/l for the period of 48 hours. Serum sodium level corrections from 1 to 2 mmol/L are allowed in the early recovery period and usually improve clinical symptoms. Isotonic intravenous fluids could also restore hemodynamics. Intracellular fluid volume and osmolarity may be corrected by 5% dextrose infusion, and furosemide is recommended to prevent water intoxication resulting from inappropriate correction of electrolyte levels (10).\n\n5. CONCLUSION\nOur simple yet efficient protocol may lead to a reduction of acute hypernatremia after hydatid cyst removal, improved surgical outcome and patient safety, shorter hospital stay and lower healthcare costs.\n\nDeclaration of patient consent:\nThe authors certify that they have obtained all appropriate patient consent forms.\n\nAuthor’s contribution:\nEach author gave substantial contribution to the conception or design of the work and in the acquisition, analysis and interpretation of data for the work. Each author had role in drafting the work and revising it critically for important intellectual content. Each author gave final approval of the version to be published and they agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nConflicts of interest:\nThere are no conflicts of interest.\n\nFinancial support and sponsorship:\nNil.\n==== Refs\nREFERENCES\n1. Stojkovic M Weber TF Junghanss T Clinical management of cystic echinococcosis: state of the art and perspectives Curr Opin Infect Dis 2018 31 383 392 30124496 \n2. Albi A Baudin F Matmar M Severe hypernatremia after hypertonic saline irrigation of hydatid cysts Anesth Analg 2002 95 1806 1808 12456462 \n3. Cobanoglu U Postoperative hypernatremia in liver hydatid disease: a case report Turkiye Parazitol Derg 2008 32 167 170 18645953 \n4. Derbent A Ergun S Uyar M Pre-treatment of anaphylaxis, does it really work? Eur. J. Anaesthesiol 2005 22 955 956 16318672 \n5. Brunetti E Kern P Vuitton DA Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans Acta Tropica 2010 114 1 6 19931502 \n6. Rujun Z Renhua W Qingguo L Nanwei T Yuwei Z The association of hypernatremia and hypertonic saline irrigation in hepatic hydatid cysts. A case report and retrospective study Medicine 2017 9 96 37 e7889 28906370 \n7. Riengchan P Suankratay C Wilde H Hydatid disease of the liver: the first indigenous case in Thailand and review of the literature J Med Assoc Thai 2004 87 725 729 15279358 \n8. Krige JE Millar AJ Rode H Fatal hypernatraemia after hypertonic saline irrigation of hepatic hydatid cysts Pediatr Surg Int 2002 18 64 65 11793068 \n9. Ismail FY Szollics A Szolics M Clinical Semiology and Neuroradiologic Correlates of Acute Hypernatremic Osmotic Challenge in Adults: A Literature Review Am J Neuroradiol 2013 34 2225 2232 23413245 \n10. Hoorn EJ Tuut MK Hoorntje SJ Dutch guideline for the management of electrolyte disorders - 2012 revision Neth J Med 2013 71 153 165 23712815\n\n",
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"mesh_terms": "D000293:Adolescent; D000368:Aged; D003221:Confusion; D004444:Echinococcosis, Hepatic; D005260:Female; D005440:Fluid Therapy; D005665:Furosemide; D005947:Glucose; D006801:Humans; D006955:Hypernatremia; D007430:Intraoperative Care; D008297:Male; D011183:Postoperative Complications; D012462:Saline Solution, Hypertonic; D012640:Seizures; D000077260:Sleepiness; D049994:Sodium Potassium Chloride Symporter Inhibitors; D013226:Status Epilepticus; D007507:Therapeutic Irrigation",
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"abstract": "The elimination of metformin is exclusively through the kidneys and elevated plasma concentrations can cause lactic acidosis. We report a case of severe lactic acidosis (pH 6.60) occuring with ostensibly normal therapeutic doses of metformin in the setting of acute renal failure. Continuous veno-venous haemodiafiltration decreased plasma metformin concentrations from 266 lmol/L at presentation to 68 lmol/L, 21 h later. The patient improved rapidly.",
"affiliations": "Department of Anaesthesiology, Skåne University Hospital, Lund University, Malmö, Sweden.;Department of Intensive Care Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.;Department of Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.;Department of Nephrology and Transplantation, Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.",
"authors": "Pikwer|Andreas|A|;Vernersson|Einar|E|;Frid|Anders|A|;Sterner|Gunnar|G|",
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"fulltext": "\n==== Front\nNDT PlusNDT PlusndtplusckjNDT Plus1753-07841753-0792Oxford University Press 10.1093/ndtplus/sfr110II. Clinical ReportsCase ReportsExtreme lactic acidosis type B associated with metformin treatment Pikwer Andreas 1Vernersson Einar 2Frid Anders 3Sterner Gunnar 41 Department of Anaesthesiology, Skåne University Hospital, Lund University, Malmö, Sweden2 Department of Intensive Care Medicine, Skåne University Hospital, Lund University, Malmö, Sweden3 Department of Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden4 Department of Nephrology and Transplantation, Clinical Sciences, Skåne University Hospital, Lund University, Malmö, SwedenCorrespondence and offprint requests to: Andreas Pikwer; E-mail: andreas.pikwer@med.lu.se12 2011 14 9 2011 14 9 2011 4 6 399 401 16 5 2011 02 8 2011 © The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com2011This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comThe elimination of metformin is exclusively through the kidneys and elevated plasma concentrations can cause lactic acidosis. We report a case of severe lactic acidosis (pH 6.60) occuring with ostensibly normal therapeutic doses of metformin in the setting of acute renal failure. Continuous veno-venous haemodiafiltration decreased plasma metformin concentrations from 266 lmol/L at presentation to 68 lmol/L, 21 h later. The patient improved rapidly.\n\nlactic acidosismetformin\n==== Body\nBackground\nMetformin is widely used for the treatment of type 2 diabetes mellitus. It is eliminated exclusively through the kidneys, mostly by tubular secretion. Elevated plasma metformin may cause lactic acidosis, a rare but potentially fatal side effect. It has been shown that plasma metformin concentrations are only slightly increased in patients with impaired renal function down to an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73m2 [1].\n\nCase report\nA 55-year-old woman with diabetes mellitus type 2 presented to the emergency department (ED) with somnolence. She had consulted her family physician 1 day prior to this with a 3-week history of vomiting and fatigue. Laboratory investigations at this stage revealed a plasma creatinine of 1057 μmol/L compared to 115 μmol/L (eGFR 42 mL/min/1.73m2 according to Modification of Diet in Renal Disease formula) 6 months earlier. Her medications included metformin 1000 mg three times a day; simvastatin 20 mg once a day, atenolol 50 mg once a day and ramipril 10 mg once a day. The following day, the physician tried to contact the patient and when she did not answer the phone, ambulance personnel entered her apartment with the help of the police.\n\nOn ED presentation, she was found to be semi-conscious with a Glasgow Coma Score of 8. Her respiratory rate was 30 breaths/min, non-invasive blood pressure was immeasurable, invasive blood pressure was 45/30 mmHg, heart rate was 85 beats/min and urinary bladder temperature was 31.2°C. There were peaked T waves on the electrocardiogram. Initial arterial blood gas analysis showed a profound acidosis, with a pH of 6.60 (reference range 7.37–7.47), arterial partial pressure of carbon dioxide (PaCO2) 2.8 kPa (reference range 4.6–6.0 kPa), arterial partial pressure of oxygen (PaO2) 14.9 kPa (reference range 8.0–13.0 kPa) measured while the patient received 10 L/min O2 via resuscitation mask, base excess −29 mmol/L (reference range −3 to +3 mmol/L), a high lactate concentration of 20.0 mmol/L, a plasma creatinine of 1205 μmol/L and an increased plasma potassium concentration of 8.4 mmol/L. The anion gap was 37.4 mmol/L.\n\nThe patient was admitted to the intensive care unit (ICU) and treated with intravenous (i.v.) fluids, norepinephrine and dobutamin i.v. infusions (0.25 and 5.1 μg/kg/min, respectively), i.v. calcium chloride (180 mg), i.v. sodium bicarbonate (540 mmol), beta agonist inhalation and an i.v. loop diuretic. Continuous veno-venous haemodiafiltration (CVVHDF) was commenced and maintained for 21 h. Endotracheal intubation was not performed since she had by this time adequate airway and respiratory status.\n\nAt ICU admission, the plasma metformin was 266 μmol/L (therapeutic range <20 μmol/L), decreasing to 68 μmol/L at the end of the CVVHDF treatment (Figure 1). Thereafter, it slowly declined to reach normal therapeutic values after 3 days. The elimination half-time for metformin was ∼10 h during CVVHDF and ∼ 29 h after its cessation.\n\nFig. 1. Serum metformin levels and pH during and after CRRT (continuous renal replacement therapy). Therapeutic serum concentrations recommended to be <20 μmol/L.\n\nThe patient improved rapidly and was discharged to a medical ward after 45 h in the ICU. Plasma creatinine improved but remained elevated after 5 weeks, 156 μmol/L, with an eGFR of 27 mL/min/1.73m2. Metformin was discontinued and plasma glucose was normal with repaglinide 5 mg three times a day.\n\nDiscussion\nLactic acidosis is an uncommon but severe side effect of metformin treatment. The mechanism by which metformin causes raised lactate in the blood is unclear but it is suggested that metformin blocks the conversion of lactate and pyruvate to glucose giving rise to anaerobic acidosis (type B). Lactic acidosis is commonly associated with acute metformin intoxication. However, as demonstrated in this case, extreme lactic acidosis may develop in patients on therapeutic doses of metformin in the setting of acute renal failure induced by a prolonged episode of dehydration. In this patient, the pre-morbid history of moderately impaired renal function and angiotensin-converting enzyme inhibitor treatment may have contributed to acute renal failure. Lemyze et al. reported a very similar patient earlier. These authors also performed renal replacement therapy and measured metformin levels in their patient. They made the interesting observation that CVVHF was not enough to lower metformin levels. The levels fell only if dialysis was done or if CVVHF was augmented by dialysis CVVHDF. Our findings confirm this earlier study [2].\n\nMetformin is eliminated through renal excretion and reduced renal function will lead to accumulation of the drug. Plasma levels will only increase marginally down to a glomerular filtration rate of 30 mL/min/1.73m2 [1], probably because tubular secretion is a prominent mechanism for excretion. When renal function is further lowered, the plasma concentration of metformin will rise rapidly if the patient continues to take the drug. Metformin in plasma is a non-protein-bound water-soluble substance with low-molecular mass and is quickly cleared by haemodialysis. In the present case, the patient received treatment with CVVHDF for ∼21 h, which reduced the plasma metformin to 1/5 of the initial concentration. Conventional acute haemodialysis would probably have eliminated metformin more efficiently than CVVHDF, but in this case, the patient’s profound haemodynamic instability led us to choose CVVHDF as the treatment of choice.\n\nThis patient also received a loop diuretic. Theoretically and experimentally, loop diuretics may lessen the risk of hypoxic injury to the cells of the loop of Henle. This has not, however, been convincingly shown in clinical studies [3] and the risk of ototoxicity should be considered. The use of loop diuretic in our case may therefore be questioned, especially in the presence of dehydration-induced acute renal failure.\n\nAlthough CVVHDF also corrects acidosis, we chose to correct the metabolic acidosis simultaneously with intravenous infusions of sodium bicarbonate. While bicarbonate therapy for lactic acidosis has been described previously [4], one may appropriately question the wisdom of giving bicarbonate in this situation, given that bicarbonate therapy is not without risk. Our rationale was that extreme acidosis and hyperkalaemia were probable causes of circulatory shock, and the treating physician was concerned about the risk of imminent cardiac arrest and malignant arrhythmias, both of which would have been difficult to treat in the setting of severe acidosis. Nevertheless, the use of sodium bicarbonate in this setting is controversial and may potentially worsen intracellular acidosis, particularly in the setting of impaired ventilation. Other complications such as hypokalaemia, increased carbon dioxide production, hyperosmolality, volume overload and overshoot metabolic alkalosis, have also been described [5].\n\nMetformin-associated lactic acidosis has been defined as a lactate value >5 mmol/L and a bicarbonate level <22 mmol/L in a patient on metformin medication or after metformin overdose [6]. Determination of plasma metformin may be useful to differentiate metformin-induced lactic acidosis from other causes. If ketoacidosis and uraemia can be excluded, then intoxication with exogenous agents should be considered and metformin should be kept in mind [7].\n\nIn clinical practice, we have noted that p-metformin always exceeds 250 μmol/L in cases with severe lactic acidosis (pH < 7.2). This level is 10–15 times higher compared to therapeutic concentrations of metformin [1].\n\nTo conclude, we have presented a case with severe lactic acidosis successfully treated with supportive care and continuous haemodiafiltration. Physicians starting treatment with metformin should assess renal function and instruct the patient to stop taking the drug and consult their physician in any situation where dehydration may occur. Metformin intoxication should be suspected even with ostensibly normal doses in the setting of acute renal impairment.\n\nThe authors thank Michelle S. Chew, Associate Professor at the Department of Intensive Care Medicine, Skåne University Hospital Malmö, for reviewing and providing helpful feedback during the manuscript development process.\n\n\nConflict of interest statement. None declared.\n==== Refs\n1. Frid A Sterner GN Londahl M Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations Diabetes Care 2010 33 1291 1293 20215446 \n2. Lemyze M Baudry JF Collet F Life threatening lactic acidosis BMJ 2010 340 c857 20335644 \n3. Bagshaw SM Delaney A Haase M Loop diuretics in the management of acute renal failure: a systematic review and meta-analysis Crit Care Resusc 2007 9 60 68 17352669 \n4. Heaney D Majid A Junor B Bicarbonate haemodialysis as a treatment of metformin overdose Nephrol Dial Transplant 1997 12 1046 1047 9175069 \n5. Kraut JA Madias NE Metabolic acidosis: pathophysiology, diagnosis and management Nat Rev Nephrol 2010 6 274 285 20308999 \n6. Peters N Jay N Barraud D Metformin-associated lactic acidosis in an intensive care unit Crit Care 2008 12 R149 19036140 \n7. Chang CT Chen YC Fang JT High anion gap metabolic acidosis in suicide: don't forget metformin intoxication—two patients' experiences Ren Fail 2002 24 671 675 12380915\n\n",
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"abstract": "Fibrillary glomerulonephritis (FGN) is a rare glomerular disease. DNAJB9 as a new reliable diagnostic marker for the diagnosis of FGN was discovered recently. To investigate the clinicopathological features and prognosis of DNAJB9-positive FGN, we report on a case series in a single center in China.\n\n\n\nDNAJB9 immunohistochemistry was performed on renal biopsy samples from patients with FGN (n = 7), and non-FGN glomerular diseases (n = 27) were used as controls. The patients with DNAJB9-positive FGN were retrospectively analyzed.\n\n\n\nStrong DNAJB9 staining of glomerular extracellular deposits was observed in 6 cases of originally diagnosed FGN. One man and 5 women with a median age of 26 years were studied. The patients presented with renal insufficiency in 1 case, proteinuria in 6 cases, nephrotic syndrome in 3 cases, and microscopic hematuria in 2 cases. The histologic pattern was mesangial proliferative glomerulonephritis in 1 case and membranoproliferative glomerulonephritis in 5 cases. The glomerular deposits stained for polytypic IgG and both kappa and lambda in 3 cases, polytypic IgG without kappa or lambda in 1, monotypic IgG1-kappa in 1 and IgG1-lambda in 1. Extraglomerular deposits were identified in all cases. Congo red positivity was observed in 3 cases. All of the patients received renin-angiotensin-aldosterone system blockade and 5 of them received glucocorticoid and/or immunosuppression. At a median time of 36.2 months after biopsy, 2 cases had partial remission, 3 cases displayed no remission, and 1 case progressed to end-stage renal disease.\n\n\n\nExtraglomerular deposits in the FGN were common. Monotypic FGN was found in young patients with a favorable renal outcome.",
"affiliations": "National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China.;National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, East 305 Zhongshan Road, Nanjing, 210002, China. zengch_nj@hotmail.com.",
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] |
{
"abstract": "An 11-year-old immunocompetent girl presented with two and a half months of progressive right orbital cellulitis, which did not respond to multiple courses of antibiotics or prednisone. A panfungal polymerase chain reaction primer was positive for Saksenaea vasiformis, and she completed 5 months of oral posaconazole therapy after debridement. Saksenaea vasiformis is a rare cause of zygomycosis, and it typically causes skin and soft tissue infection in immunocompetent hosts, particularly after a traumatic injury. The diagnosis should be considered in cases with a protracted course that fail to respond to typical antibiotic therapy. Treatment includes surgical debridement, in additional to antifungal therapy with amphotericin B or posaconazole.",
"affiliations": "Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.;Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri.;Department of Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.;Department of Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.;Department of Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.;Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri.;Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.",
"authors": "Reich|Patrick|P|;Shute|Thomas|T|;Lysen|Colleen|C|;Lockhart|Shawn R|SR|;Kelly Keating|M|M|;Custer|Philip|P|;Orscheln|Rachel|R|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole",
"country": "England",
"delete": false,
"doi": "10.1093/jpids/piy021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-7193",
"issue": "7(3)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": null,
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": "D000935:Antifungal Agents; D002648:Child; D003131:Combined Modality Therapy; D003646:Debridement; D005260:Female; D006801:Humans; D007121:Immunocompetence; D009090:Mucorales; D009091:Mucormycosis; D054517:Orbital Cellulitis; D014230:Triazoles",
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "e169-e171",
"pmc": null,
"pmid": "29522137",
"pubdate": "2018-08-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Saksenaea vasiformis Orbital Cellulitis in an Immunocompetent Child Treated With Posaconazole.",
"title_normalized": "saksenaea vasiformis orbital cellulitis in an immunocompetent child treated with posaconazole"
} | [
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"companynumb": "US-009507513-1811USA008739",
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{
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"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
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"activesubstancename": "RIFAMPIN"
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"medicinalproduct": "RIFAMPIN."
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"activesubstancename": "POSACONAZOLE"
},
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"drugdosageform": "TABLET",
"drugdosagetext": "300 MILLIGRAM, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INFECTION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"medicinalproduct": "NOXAFIL"
}
],
"patientagegroup": null,
"patientonsetage": "11",
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"reaction": [
{
"reactionmeddrapt": "Product administered to patient of inappropriate age",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "REICH P, SHUTE T, LYSEN C, LOCKHART SR, KELLY KM, CUSTER P ET AL. SAKSENAEA VASIFORMIS ORBITAL CELLULITIS IN AN IMMUNOCOMPETENT CHILD TREATED WITH POSACONAZOLE. JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY. 2018?7 (3):E169-E171",
"literaturereference_normalized": "saksenaea vasiformis orbital cellulitis in an immunocompetent child treated with posaconazole",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20181127",
"receivedate": "20181127",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15662197,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190205"
}
] |
{
"abstract": "OBJECTIVE\nA regimen of cisplatin, doxorubicin, vincristine, and etoposide (PAVE) was designed for patients with small-cell lung cancer (SCLC) who were older than 65 years, with the following objectives compared with standard chemotherapy regimens: maintain efficacy, diminish toxicity, enhance compliance, and improve chemotherapy administration convenience at an acceptable cost.\n\n\nMETHODS\nThe PAVE regimen consisted of cisplatin 30 mg/m2 intravenously (i.v.) day 1; doxorubicin 40 mg/m2 i.v. day 1; vincristine 1.0 mg/m2 i.v. day 1; and etoposide 100 mg/m2 i.v. day 1 and orally days 3 and 5. Cycles were repeated every 3 weeks for four cycles. Patients with limited-stage disease and selected patients with extensive-stage disease received thoracic irradiation delivered concurrently with etoposide-cisplatin (EP) at the time of the second chemotherapy cycle.\n\n\nRESULTS\nSixty-six eligible patients were treated, which included 25 patients with limited-stage disease and 41 patients with extensive-stage disease. Median survival was 70 weeks and 5-year survival was 25% for limited-stage disease. Median survival was 46 weeks for extensive-stage disease. Only one treatment-related death occurred and severe toxicity was infrequent. The median delivered dose-intensity was according to protocol and the mean delivered total dose was 80% of intended.\n\n\nCONCLUSIONS\nThe treatment outcome achieved with PAVE in a phase II study of elderly patients compared favorably with published results of standard regimens in patient populations with better prognostic factors. Because the PAVE regimen can be delivered with good compliance, has acceptable toxicity, and is associated with logistic advantages compared with standard regimens, this protocol is suitable for further investigative trials in elderly patients with SCLC.",
"affiliations": "Lung Tumor Group, Vancouver Centre, British Columbia Cancer Agency, Canada.",
"authors": "Westeel|V|V|;Murray|N|N|;Gelmon|K|K|;Shah|A|A|;Sheehan|F|F|;McKenzie|M|M|;Wong|F|F|;Morris|J|J|;Grafton|C|C|;Tsang|V|V|;Goddard|K|K|;Murphy|K|K|;Parsons|C|C|;Amy|R|R|;Page|R|R|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.1998.16.5.1940",
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"issn_linking": "0732-183X",
"issue": "16(5)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D018288:Carcinoma, Small Cell; D002945:Cisplatin; D003131:Combined Modality Therapy; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D011379:Prognosis; D015996:Survival Rate; D014750:Vincristine",
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"abstract": "Autoimmune hepatitis (AIH) was the first liver disease for which an effective therapeutic intervention was carried out, using prednisolone; its usefulness was demonstrated in several clinical trials. Nevertheless, AIH still remains a difficult diagnosis in some cases, because it is necessary to dismiss other possible diagnoses, and perhaps due to it being a heterogeneous disease. The relationship between drug-induced liver injury (DILI) and AIH is complex and not fully understood. There are three possible scenarios: (1) DILI with a strong immunoallergic component mimicking AIH; (2) AIH mimicking a DILI due to drug exposure and (3) AIH triggered by exposure to an offending drug (drug-induced AIH). Drug-induced AIH is well described and documented for some drugs such as nitrofurantoin and minocycline. Histologically distinguishing DILI from AIH remains a challenge. We present an interesting case report which met serologic criteria and histological confirmation to establish AIH, but discontinuation of a suspected drug resolved hypertransaminasaemia.\nIdiosyncratic drug-induced liver injury is one of the most challenging liver disorders.Diagnosis of drug-induced liver injury is a complex question; this can evolve to severe hepatotoxicity if it is not diagnosed promptly.Usually, olmesartan and similar anti-hypertensive drugs are not considered drugs with the potential to cause liver damage.",
"affiliations": "Liver Unit, Clínica Universidad de Navarra, Madrid, Spain.;Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain.",
"authors": "de la Torre-Aláez|Manuel|M|;Iñarrairaegui|Mercedes|M|",
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"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2020_0014071407-1-10761-1-10-20191224ArticlesDrug Liver Injury Induced by Olmesartan Mediated by Autoimmune-Like Mechanism: A Case Report de la Torre-Aláez Manuel 1Iñarrairaegui Mercedes 2\n1 Liver Unit, Clínica Universidad de Navarra, Madrid, Spain\n2 Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain2020 03 1 2020 7 1 00140727 11 2019 30 11 2019 © EFIM 20202020This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseAutoimmune hepatitis (AIH) was the first liver disease for which an effective therapeutic intervention was carried out, using prednisolone; its usefulness was demonstrated in several clinical trials. Nevertheless, AIH still remains a difficult diagnosis in some cases, because it is necessary to dismiss other possible diagnoses, and perhaps due to it being a heterogeneous disease. The relationship between drug-induced liver injury (DILI) and AIH is complex and not fully understood. There are three possible scenarios: (1) DILI with a strong immunoallergic component mimicking AIH; (2) AIH mimicking a DILI due to drug exposure and (3) AIH triggered by exposure to an offending drug (drug-induced AIH). Drug-induced AIH is well described and documented for some drugs such as nitrofurantoin and minocycline. Histologically distinguishing DILI from AIH remains a challenge. We present an interesting case report which met serologic criteria and histological confirmation to establish AIH, but discontinuation of a suspected drug resolved hypertransaminasaemia.\n\nLEARNING POINTS\nIdiosyncratic drug-induced liver injury is one of the most challenging liver disorders.\n\nDiagnosis of drug-induced liver injury is a complex question; this can evolve to severe hepatotoxicity if it is not diagnosed promptly.\n\nUsually, olmesartan and similar anti-hypertensive drugs are not considered drugs with the potential to cause liver damage.\n\nOlmesartandrug-induced liver injuryautoimmune-like mechanismhypertransaminasaemia\n==== Body\nCASE DESCRIPTION\nThe patient was an 80-year-old woman with a history of hypertension being treated with olmesartan/amlodipine since 2015, dyslipidaemia, sigmoid diverticulosis and serous papillary peritoneal adenocarcinoma diagnosed on November 2015, treated by surgery and chemotherapy with carboplatin-paclitaxel, receiving 6 cycles (the last cycle was received in June 2016). A complete response was confirmed in December 2016, with tumour markers within the normal range and no findings suggestive of neoplasm in PET-CT.\n\nIn July 2017 the patient was referred to the Liver Unit due to alterations found during liver tests: aspartate aminotransferase (AST) 207 IU/L (N<33), alanine aminotransferase (ALT) 213 IU/L (N<33), gamma-glutamyl transpeptidase (GGTP) 21 IU/L (N<40), alkaline phosphatase (ALP) 116 IU/L (N<105), total bilirubin 0.5 mg/dl (N<1.2) and international normalized ratio 1.2.\n\nThese findings were discovered during follow-up of the tumoural disease. No tumour marker elevation or CT alterations were observed. Liver tests were normal before starting treatment with olmesartan. The patient did not take herbal products, or other potentially hepatotoxic drugs. She had not travelled outside Europe recently. She had no history of abusive alcohol consumption and her body mass index was 26.6 kg/m2. Physical examination was normal.\n\nNo fever, rash, eosinophilia, jaundice or coagulopathy was observed during follow-up, and she did not require hospitalization during the course of the disease.\n\nWe repeated the liver tests 1 week later, with alterations persisting at 5 times the upper limit of normal values. An extensive evaluation was carried out, which ruled out serological viral hepatitis (hepatitis A, B and C) and metabolic liver disease, as well as Wilson disease or haemochromatosis; there was a normal blood count, normal gamma globulin, thyroid and lipid profiles, and no other relevant biochemistry alterations. Testing for antinuclear antibodies (ANA) was positive with a higher titre of 1/2,560 and a homogeneous pattern; testing for ASMA, anti-LKM1 antibodies and AMA was negative.\n\nIn view of these findings and the persistent alterations seen in liver tests, we conducted a liver biopsy that showed the preserved architecture of liver parenchyma, with a portal polymorphic inflammatory infiltrate with occasional plasma cells (Fig. 1), lymphoplasmacytic patchy infiltrate in the lobule and mild portal fibrosis (Fig. 2). Occasional nuclear pseudoinclusions in hepatocytes were found. No signs suggestive of viral aetiology, abnormal iron deposits or Mallory’s hyaline were found with the corresponding techniques. Based on those results, we decided to stop olmesartan but without introducing prednisolone or other immunosuppressive therapy.\n\nTwo month after olmesartan withdrawal, liver tests, were decreased to the normal range (ALT 20 IU/L, AST 25 IU/L, GGTP 16 IU/L and ALP 106 IU/L). One year after, liver tests were still normal; the patient remains asymptomatic as shown in Fig. 3.\n\nDISCUSSION\nTreatment of arterial hypertension with olmesartan has been associated with the development of sprue-like enteropathy, characterized by diarrhoea, malabsorption, weight loss and varying degrees of duodenal mucosal atrophy[1–4]. Ianiro et al.[4] reviewed the literature and found 11 publications, for an overall number of 54 patients, who had developed sprue-like enteropathy associated with olmesartan. The duration of treatment was 3.3 years. Testing for anti-transglutaminase and anti-endomysial antibodies was found to be negative. The presence of anti-enterocyte antibodies was tested in 21 patients, with a positive result in only 3 patients. After discontinuation of olmesartan, clinical remission occurred in 100% of patients.\n\nThe underlying physiopathological mechanisms of olmesartan-associated enteropathy are unknown, although several studies suggest that cell-mediated immunity damage may play a role[1, 4].\n\nThe FDA communicated the risk of enteropathy induced by olmesartan in July 2013. Although an association with enteropathy is more common with olmesartan, enteropathy with other angiotensin II receptor blockers (ARBs) has been reported[2].\n\nThe first report we found in the literature regarding the implications of autoimmune-like chronic hepatitis mediated by treatment with olmesartan was published by Barge et al.[5] in April 2017. These authors described a 61-year-old woman with anorexia, asthenia and weight loss of 10 kg without diarrhoea, with abnormal liver test results and ANA-positive titres. Elastography and biopsy results were compatible with fibrosis and autoimmune hepatitis. Three months after olmesartan withdrawal, the clinical and analytical evolution was favourable. Treatment with immunosuppressive drugs was not started. A second biopsy was performed, showing regression of fibrosis and resolution of interface hepatitis. In this case, it was suggested that the mechanism of hepatic injury was autoimmune, on the basis of the findings and reports in the literature with respect to enteropathy mediated by immunity damage.\n\nIdiosyncratic drug-induced liver injury is 1 of the most challenging liver disorders faced by hepatologists that has been known. An important effort exists to understand the mechanism of liver damage and to identify drugs or other potential toxic agents due to the frequency this is seen in clinical practice. Even some scientific societies are developing new recommendations on this issue. For example, it’s worth noting the efforts from the European Association for the Study of the Liver (EASL), which published its new guidelines this year to summarize the available scientific evidence[6].\n\nIt is accepted that the diagnosis of drug-induced liver injury is a complex question and this can evolve to a severe hepatotoxicity if it is not diagnosed promptly. For that, we think it is important for clinicians to know potential liver-toxic drugs.\n\nOur case report is an interesting liver toxicity case due to an anti-hypertensive drug used in clinical practice and the possible immunomediated mechanism of damage associated with this. Usually, olmesartan and similar anti-hypertensive drugs are not considered to be drugs with the potential for liver damage.\n\nWe attempt to demonstrate this relationship with liver test result evolution after withdrawal of the drug, autoimmune serologic testing and pathologic findings. Hypertransaminasaemia was resolved without the need for treatment with corticosteroids or other immunosuppressive drugs. We also propose once we have reviewed our case, based on analytical evolution, serological data and liver biopsy, that an autoimmune mechanism may play a role in liver damage. In our case, the clinical manifestations were not as evident as in the case of Barge et al.[5].\n\nIn our opinion, treatment with olmesartan should be considered in the case of a patient with unexplained mild to moderate hypertransaminasaemia and serologic data suggestive of an autoimmune phenomenon with no other signs suggestive of autoimmune hepatitis, once other aetiological causes and other toxic agents have been excluded. We think that this case will be of interest to clinicians who usually attend patients with abnormal liver test results such as internists or hepatologists.\n\nAcknowledgements\nWe appreciate the histological images provided by Dra. Marta Abengozar from the Department of Pathology of Clínica Universidad de Navarra in Pamplona.\n\nConflicts of Interests: The Authors declare that there are no competing interest\n\nFigure 1 Histological results from liver biopsy showing an inflammatory infiltrate in the portal space with some plasmatic cells. These are the typical findings in patients with autoimmune hepatitis (images have been provided by Dra. M. Abengozar, Department of Pathology, Clínica Universidad de Navarra)\n\nFigure 2 Histological results from liver biopsy showing portal fibrosis using Masson’s trichrome stain (images have been provided by Dra. M. Abengozar, Department of Pathology, Clínica Universidad de Navarra)\n\nFigure 3 Evolution of liver test results (AST/GOT and ALT/GPT). This shows when the patient started and finished treatment with olmesartan and the follow-up after 1 year\n==== Refs\nREFERENCES\n1 Rubio-Tapia A Herman M Ludvigsson JF Kelly DG Mangan TF Wu TT Murray JA Severe Spruelike enteropathy associated with olmesartan Mayo clinic proceedings 2012 8 87 8 732 8 22728033 \n2 Basson M Mezzarobba M Weill A Ricordeau P Allemand H Alla F Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study Gut 2016 65 10 1664 1669 26250345 \n3 Naik D Martelli M Hernandez Gonzalo D Sharma A Pannu D An atypical case of chronic diarrhoea: olmesartan-induced sprue-like enteropathy BMJ Case Rep 2015 2015 bcr2015212318 \n4 Ianiro G Bibbo S Montalto M Ricci R Gasbarrinina A Cammarota G Systematic review: Sprue-like enteropathy associated with olmesartan Aliment Pharmacol Ther Syst 2014 40 16 23 \n5 Barge S Ziol M Nault J Autoimmune-like chronic hepatitis induced by olmesartan Hepatology 2017 66 2086 2088 28437842 \n6 European Association for the Study of the Liver EASL Clinical Practice Guidelines: drug-induced liver injury J Hepatol 2019 70 6 1222 1261 logical results from liver biopsy. 30926241\n\n",
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{
"abstract": "Bisphosphonate use has been identified as a contributory factor in atypical subtrochanteric fracture of the femur. These fractures are commonly treated with an intramedullary device. We present a case of implant failure of an intrameduallary device caused by non-union of an atypical subtrochanteric fracture.",
"affiliations": "Department of Trauma & Orthopaedics, Connolly Hospital, Dublin, Ireland.",
"authors": "O'Neill|Barry James|BJ|;O'hEireamhoin|Sven|S|;Morrissey|David I|DI|;Keogh|Peter|P|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019386:Alendronate",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D019386:Alendronate; D050071:Bone Density Conservation Agents; D020878:Device Removal; D005260:Female; D005264:Femoral Fractures; D005594:Fracture Fixation, Intramedullary; D006620:Hip Fractures; D006801:Humans; D008875:Middle Aged; D011475:Prosthesis Failure; D011859:Radiography; D012086:Reoperation",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24700046",
"pubdate": "2014-04-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10999794;1661297;23071416;10979796;11344052;19419297;19224071;18222447;22187839;19884427;20335571;17463107;15598694;11095442;21343577;23409846;10780852;7477143;17190893;11277260;8610169;20415309;18843515",
"title": "Implant failure caused by non-union of bisphosphonate-associated subtrochanteric femur fracture.",
"title_normalized": "implant failure caused by non union of bisphosphonate associated subtrochanteric femur fracture"
} | [
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{
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{
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] |
{
"abstract": "A 21-year-old male presented with two weeks of ascending numbness involving all 4 limbs, and imbalance when walking. Examination revealed diminished vibration and proprioception at the fingers, toes, and ankles, a high steppage gait and a positive Romberg sign. He had no weakness in any muscle groups. Laboratory data included vitamin B12 218 pg/mL (normal range: 200-800 pg/mL), homocysteine 87 μmol/L (normal range: 2.2-13.2 μmol/L), and non-reactive RPR. Magnetic resonance imaging of the cervical spine revealed abnormal T2-weighted hyperintensity along the posterior columns extending from C2 to C7.",
"affiliations": "Department of Neurology, University of Southern California , Los Angeles, CA , USA.",
"authors": "Arshi|B|B|;Shaw|S|S|",
"chemical_list": "D013287:Illicit Drugs; D006710:Homocysteine; D009609:Nitrous Oxide; D014805:Vitamin B 12",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2014.953170",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "52(8)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "CNS and psychological; CNS/Psychological; Metabolic",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D006710:Homocysteine; D006801:Humans; D006987:Hypesthesia; D013287:Illicit Drugs; D019570:Inhalation Exposure; D008279:Magnetic Resonance Imaging; D008297:Male; D009609:Nitrous Oxide; D011434:Proprioception; D013116:Spinal Cord; D014805:Vitamin B 12; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "905-6",
"pmc": null,
"pmid": "25200456",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subacute ascending numbness.",
"title_normalized": "subacute ascending numbness"
} | [
{
"companynumb": "US-ALSI-201400214",
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{
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"activesubstancename": "NITROUS OXIDE"
},
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"medicinalproduct": "NITROUS OXIDE."
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],
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"reaction": [
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "22.0",
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{
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"reactionoutcome": "6"
}
],
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},
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"literaturereference": "LITERATURE REFERENCE: ARSHI B, SHAW S. SUBACUTE ASCENDING NUMBNESS. CLIN TOXICOL (PHILA). 2014?OCT?52(8):905-6.",
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},
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{
"abstract": "Terminal complement inhibition therapy with eculizumab (a humanized monoclonal antibody to C5) has revolutionized the treatment of patients with thrombotic microangiopathy (TMA). Successful responders are often placed on long-standing therapy to prevent disease recurrence in the native kidney or allograft. The tissue deposition of eculizumab in patients with C3 glomerulopathy has been described but no studies have yet investigated tissue deposition of eculizumab in cases where it was indicated for thrombotic microangiopathy which, unlike C3 glomerulopathy, does not usually show immune-type electron dense deposits. To evaluate this, we reviewed biopsies from 13 patients who received eculizumab for TMA treatment or prevention of recurrence. We found IgG2, IgG4, and kappa positivity within arterioles corresponding to eculizumab deposits, with similar distribution to C5b-9, in all but one patient. In that patient eculizumab therapy had been discontinued 24 months prior to biopsy. Deposits in arterioles could be seen as early as one day after infusion and after a single dose of eculizumab, and were detected up to 162 days after therapy discontinuation. This may play a role in controlling local complement activation-associated vascular changes in these patients. Thus, IgG subclass staining by immunofluorescence is important to avoid misdiagnoses of immune-complex or monoclonal immunoglobulin deposition disease in patients with TMA who received eculizumab.",
"affiliations": "Department of Pathology, The Ohio State University, Columbus, Ohio, USA. Electronic address: Clarissa.Cassol@osumc.edu.;Department of Pathology, The Ohio State University, Columbus, Ohio, USA.;Department of Pathology, The Ohio State University, Columbus, Ohio, USA.;Department of Pathology, The Ohio State University, Columbus, Ohio, USA.;Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.;Department of Pathology, The Ohio State University, Columbus, Ohio, USA. Electronic address: Tibor.Nadasdy@osumc.edu.",
"authors": "Cassol|Clarissa A|CA|;Brodsky|Sergey V|SV|;Satoskar|Anjali A|AA|;Blissett|Angela R|AR|;Cataland|Spero|S|;Nadasdy|Tibor|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; D015938:Complement Membrane Attack Complex; C481642:eculizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.kint.2019.05.008",
"fulltext": null,
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"issn_linking": "0085-2538",
"issue": "96(3)",
"journal": "Kidney international",
"keywords": "IgG subclasses; eculizumab; thrombotic microangiopathy",
"medline_ta": "Kidney Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D001160:Arterioles; D001706:Biopsy; D003167:Complement Activation; D051056:Complement Inactivating Agents; D015938:Complement Membrane Attack Complex; D005260:Female; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies; D055502:Secondary Prevention; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "0323470",
"other_id": null,
"pages": "761-768",
"pmc": null,
"pmid": "31345584",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Eculizumab deposits in vessel walls in thrombotic microangiopathy.",
"title_normalized": "eculizumab deposits in vessel walls in thrombotic microangiopathy"
} | [
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"abstract": "Heavy chain disease (HCD) is a rare B-cell proliferative neoplasm that is characterised by the production of truncated monoclonal immunoglobulin heavy chains without light chains. Gamma HCD is a subgroup of HCD. A 67-year-old man was admitted to our hospital with dyspnoea and lower leg oedema. Based on the results of heart catheterisation, he was diagnosed with pulmonary hypertension. Laboratory tests revealed an elevated level of IgG, and serum immunoelectrophoresis showed that IgG was a monoclonal gamma heavy chain without light chains. Finally, he was diagnosed with gamma HCD complicated by pulmonary hypertension. Bortezomib and dexamethasone therapy was initiated, but became refractory within 8 months. Therefore, the treatment was switched to lenalidomide and dexamethasone therapy, and the disease has been stably controlled for more than 2 years. To the best of our knowledge, this is the first case of gamma HCD being successfully treated by lenalidomide and dexamethasone therapy.",
"affiliations": "Hematology, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, Japan ashitaharerukana21@gmail.com.;Hematology, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, Japan.",
"authors": "Shibata|Sho|S|;Fukunaga|Akiko|A|",
"chemical_list": "D007074:Immunoglobulin G; D007155:Immunologic Factors; D000069286:Bortezomib; D003907:Dexamethasone; D000077269:Lenalidomide",
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"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-2020-236162\n10.1136/bcr-2020-236162\nCase Report\n1506\n1333\n175\nGamma heavy chain disease complicated by pulmonary hypertension, which was successfully treated with lenalidomide\nShibata Sho Fukunaga Akiko Hematology, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, Japan\nCorrespondence to Dr Sho Shibata; ashitaharerukana21@gmail.com\n2020 \n30 11 2020 \n30 11 2020 \n13 11 e23616202 11 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/.Heavy chain disease (HCD) is a rare B-cell proliferative neoplasm that is characterised by the production of truncated monoclonal immunoglobulin heavy chains without light chains. Gamma HCD is a subgroup of HCD. A 67-year-old man was admitted to our hospital with dyspnoea and lower leg oedema. Based on the results of heart catheterisation, he was diagnosed with pulmonary hypertension. Laboratory tests revealed an elevated level of IgG, and serum immunoelectrophoresis showed that IgG was a monoclonal gamma heavy chain without light chains. Finally, he was diagnosed with gamma HCD complicated by pulmonary hypertension. Bortezomib and dexamethasone therapy was initiated, but became refractory within 8 months. Therefore, the treatment was switched to lenalidomide and dexamethasone therapy, and the disease has been stably controlled for more than 2 years. To the best of our knowledge, this is the first case of gamma HCD being successfully treated by lenalidomide and dexamethasone therapy.\n\noncologyhaematology (incl blood transfusion)special-featureunlocked\n==== Body\nBackground\nHeavy chain disease (HCD) is a rare B-cell proliferative neoplasm that is characterised by the production of truncated monoclonal immunoglobulin heavy chains without light chains. HCD has been divided into three categories based on the type of monoclonal heavy chain isotype (α, γ and μ).1 Gamma HCD, also known as Franklin’s disease, was initially reported by Franklin et al in 1964,2 and is a very rare disease; only approximately 150 cases have been reported to date.3 Tumour cells are assumed to be derived from postgerminal centre B cells with the ability to differentiate into plasma cells.3 The tumour cells of gamma HCD typically involve the lymph nodes, bone marrow, liver, spleen, peripheral blood and other extranodal sites. Involved tissues generally show the polymorphous proliferation of lymphocytes, plasmacytoid lymphocytes and plasma cells.4 Most patients present with systemic symptoms, lymphadenopathy and splenomegaly. Almost 25% of patients have a history of autoimmune disease, such as rheumatoid arthritis, autoimmune haemolytic anaemia or thrombocytopenic purpura.5 6 Several studies have reported the diversity of the clinical manifestations and haematopathological features of gamma HCD, and its clinical course varies, ranging from indolent to progressive.\n\nThere is currently no standard therapy for gamma HCD, and some cases have been treated with chemotherapy using the cyclophosphamide, vincristine and prednisone (CVP regimen), cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP regimen), melphalan and bortezomib. Lenalidomide, an immunomodulatory drug (IMiD), has not yet been used in the treatment of gamma HCD. We herein present a case of gamma HCD complicated by pulmonary hypertension that showed a clinical response to lenalidomide.\n\nCase presentation\nA 67-year-old man was admitted to our hospital with dyspnoea and lower leg oedema for 1 month. He had a history of type 2 diabetes. On examination, his blood pressure was 163/88 mm Hg, pulse 97/min and respiratory rate 26/min with an O2 saturation of 88% in room air, and he had splenomegaly and no palpable lymphadenopathy. X-ray of the chest revealed an elevated cardiothoracic ratio of 65%. Echocardiography showed an elevated tricuspid regurgitation pressure gradient (TRPG) of 75 mm Hg, and, thus, right heart catheterisation was performed. The examination revealed a mean pulmonary artery pressure of 54 mm Hg, and pulmonary artery wedge pressure (PAWP) of 18 mm Hg, which was consistent with pulmonary hypertension. Treatment was initiated with a phosphodiesterase 5 inhibitor and prostacyclin analogue; however, no improvements were observed.\n\nInvestigations\nLaboratory tests indicated an elevated level of IgG (4850 mg/dL) and he was referred to our department. Other laboratory data showed a white blood cell count of 3.0×109/L, haemoglobin level of 92 g/L, platelet count of 79×109/L, lactate dehydrogenase level of 343 IU/L, serum creatinine level of 0.88 mg/dL and interleukin-2 receptor level of 983 U/mL. There were no tumour cells in his peripheral blood. His serum IgA level decreased to 64 mg/dL, his IgM level was normal (48 mg/dL) and the serum-free light chain ratio (κ/λ) was normal. Serum protein electrophoresis revealed the presence of the M protein (figure 1). In serum immunoelectrophoresis, serum formed an M-bow in response to anti-IgG antiserum, but not in response to anti-κ antiserum or anti-λ antiserum. Serum also formed an M-bow in response to anti-IgG Fc antiserum. (figure 2) Bence Jones protein was not detected by urine immunoelectrophoresis. Bone marrow aspiration showed approximately 10% abnormal plasmacytoid cells (figure 3), and bone marrow biopsy revealed that cells expressed CD138, but not kappa or lambda chains (figure 4). A flow cytometric analysis of bone marrow revealed no population with cytoplasmic immunoglobulin light chain restrictions in the lymphocyte fraction. A PCR analysis and Southern blotting demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene (figure 5). No cytogenetic abnormality was indicated in G-banding. CT revealed splenomegaly and no lymphadenopathy. No fluorodeoxyglucose (FDG) uptake was observed on whole-body positron emission tomography (PET)/CT.\n\nFigure 1 Serum protein electrophoresis revealed the presence of the M protein in β and γ fractions. The shape of the M peak was not typical.\n\nFigure 2 In serum immunoelectrophoresis, serum formed an M-bow in response to anti-IgG antiserum, but not to anti-κ antiserum or anti-λ antiserum. in addition, serum formed an M-bow in response to anti-IgG Fc antiserum. N, normal serum; PS, patient’s sample.\n\nFigure 3 The bone marrow aspirate contained approximately 10% abnormal plasmacytoid cells. (A) May Giemsa staining, ×200. (B）May Giemsa staining, ×1000.\n\nFigure 4 Pathology of bone marrow. Immunohistochemically, tumour cells were positive for CD138, and negative for kappa and lambda. (A) H&E staining, ×400. (B) CD138 staining, ×400. (C) CD138 staining, ×200. (D) lambda staining, ×200. (E）kappa staining,×200.\n\nFigure 5 Southern blotting with an immunoglobulin heavy chain JH gene probe demonstrated the clonal rearrangement of the immunoglobulin heavy chain JH gene.\n\nTreatment\nThe patient was diagnosed with gamma HCD complicated by pulmonary hypertension (group 5, pulmonary hypertension due to unclear multifactorial mechanisms, according to the Nice classification).7\n\nThe patient was started on BD therapy (bortezomib 1.3 mg/m2/day on days 1, 4, 8 and 11, and dexamethasone 20 mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12). After the initiation of BD therapy, his serum IgG level and TRPG immediately decreased with the attenuation of clinical manifestations. However, after eight cycles of BD therapy, his IgG level increased to 2500 mg/dL. We decided that BD therapy became refractory and switched the treatment to RD therapy (lenalidomide 25 mg/day on days 1–21, dexamethasone 20 mg/day on days 1, 8, 15 and 22). RD therapy successfully decreased his serum IgG level to the normal range, along with TRPG of 14 mm Hg. After RD therapy, the M protein was still detected by serum protein electrophoresis, whereas splenomegaly was attenuated and abnormal plasmacytoid cells disappeared from bone marrow. The patient developed grade 4 neutropaenia and grade 3 thrombocytopenia. Therefore, we reduced the dose of lenalidomide to 20 mg/day from the fifth course of treatment. Despite grade 4 neutropaenia, no signs of infection were observed. He has been treated with RD therapy for 2 years on an outpatient basis with a stable disease status for gamma HCD and pulmonary hypertension (figure 6).\n\nFigure 6 The clinical course. Bortezomib had a temporary effect, but became refractory within 8 months. Therefore, lenalidomide was administered. His serum IgG level and tricuspid regurgitation pressure gradient (TRPG) by echocardiography rapidly decreased, and the disease has been stably controlled for more than 2 years. The response to treatment was parallel in IgG and TRPG.\n\nDiscussion\nThe patient did not present with systemic symptoms, lymphadenopathy, such as lymphoma, or autoimmune disease. The main symptoms were dyspnoea and oedema, which were caused by pulmonary hypertension. To the best of our knowledge, there has been no reported case of gamma HCD complicated by pulmonary hypertension. Pulmonary hypertension occurs in several haematological disorders, such as sickle cell disease, thalassemia and myeloproliferative neoplasms (MPN).8 In the Nice classification, pulmonary hypertension is classified into one of five groups based on its aetiology, with cases caused by haematological disorders being placed into group 5, pulmonary hypertension due to unclear multifactorial mechanisms.7 The pathology by which haematological disorders develop pulmonary hypertension remains unclear and multifactorial. In haemolytic disorders, one of the mechanisms is assumed to involve haemolysis, resulting in increased free haemoglobin, and significant reductions in NO bioavailability due to free haemoglobin developing endothelial dysfunction, which leads to pulmonary hypertension.9 In MPN, bone marrow-derived circulating cells may play an important role in its pathogenesis.10\n\nSome cases of pulmonary hypertension are complicated by multiple myeloma, and the aetiology may not involve a single mechanism, but rather a combination of mechanisms, such as immunoglobulin light chain (AL) amyloid deposition, high cardiac output states, or renal disease.11 AL amyloidosis often involves the heart, and elevated left atrial pressure may cause pulmonary hypertension. Furthermore, a previous case report of pulmonary hypertension was due to pulmonary vascular amyloid deposition in a patient with multiple myeloma.12 High cardiac output states also promote left atrial hypertension. Renal disease causes volume overload and secondary hypertension. In the present case, biopsy was not performed, PAWP was slightly elevated, and there was no serious renal impairment; therefore, the mechanisms responsible for pulmonary hypertension remained unclear. Since the response to treatment was parallel in gamma HCD and pulmonary hypertension, we presumed that pulmonary hypertension was affected by the pathological condition of gamma HCD.\n\nGamma HCD is a very rare and heterogeneous disease, for which there is currently no standard therapy. In some patients, the clinical course is indolent and observation may be a treatment option. Some reported cases have been successfully treated with chemotherapy using the CVP regimen, CHOP regimen, melphalan and prednisone.4 5 13\n\nRituximab monotherapy and combination therapy were previously reported to be effective when tumours expressed CD20.14 A previous case of gamma HCD with plasma cell dyscrasia was shown to respond to treatment with bortezomib and dexamethasone.15 Bortezomib is a proteasome inhibitor that is used in the treatment of multiple myeloma and mantle cell lymphoma. In the present case, abnormal plasmacytoid cells involved the bone marrow; therefore, we initially attempted to treat the patient with bortezomib. Bortezomib had a temporary effect, but became refractory within 8 months. We then attempted to treat the patient with lenalidomide, which is classified as IMiD, and a derivative of thalidomide. Lenalidomide is a standard treatment for multiple myeloma, and the incorporation of lenalidomide improves the prognosis of multiple myeloma. Furthermore, its efficacy has been demonstrated for B-cell lymphoma, particularly mantle cell lymphoma, follicular lymphoma and non-germinal centre diffuse large B-cell lymphoma.16 After the administration of lenalidomide, serum protein electrophoresis detected the M protein; however, its level decreased and abnormal plasmacytoid cells disappeared from bone marrow. Lenalidomide was effective for not only gamma HCD, but also pulmonary hypertension. The only adverse events observed were grade 4 neutropaenia and grade 3 thrombocytopenia, which were ameliorated by a reduction in the dose of lenalidomide administered. The patient has been treated with RD therapy for 2 years on an outpatient basis with a stable disease status. In conclusion, to the best of our knowledge, this is the first case report of gamma HCD that demonstrated a clinical response to lenalidomide and dexamethasone therapy, and we concluded that lenalidomide has potential as an effective treatment option for this very rare disease. Moreover, this case was characteristic in that gamma HCD was complicated by pulmonary hypertension.\n\nLearning points\nGamma heavy chain disease (HCD) is a rare B-cell proliferative neoplasm that is characterised by the production of truncated monoclonal immunoglobulin heavy chains without light chains.\n\nLenalidomide has potential as an effective new treatment option for gamma HCD.\n\nGamma HCD can cause pulmonary hypertension.\n\nContributors: AF was attending physician. SS analysed test results and literature and was involved in the treatment. SS wrote this paper.\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\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Wahner-Roedler DL , Kyle RA \nHeavy chain diseases\n. Best Pract Res Clin Haematol \n2005 ;18 :729 –46\n. 10.1016/j.beha.2005.01.029 16026747 \n2 Franklin EC , Lowenstein J , Bigelow B , et al \nHeavy chain disease- a new disorder of serum gamma-globulins : report of the first case\n. Am J Med \n1964 ;37 :332 –50\n. 10.1016/0002-9343(64)90191-3 14209281 \n3 Cook JR , Harris NL , Isaacson PG , et al \nHeavy chain diseases; who classification of tumours of haematopoietic and lymphoid tissues, world Health organization . 4 edn \nFrance : International Agency for Research on Cancer , 2017 : 237 –40\n.\n4 Bianchi G , Anderson KC , Harris NL , et al \nThe heavy chain diseases: clinical and pathologic features\n. Oncology \n2014 ;28 :45 –53\n.24683718 \n5 Wahner-Roedler DL , Witzig TE , Loehrer LL , et al \nGamma-heavy chain disease: review of 23 cases\n. Medicine \n2003 ;82 :236 –50\n. 10.1097/01.md.0000085058.63483.7f 12861101 \n6 Fermand JP , Brouet JC , Danon F , et al \nGamma heavy chain \"disease\": heterogeneity of the clinicopathologic features. Report of 16 cases and review of the literature\n. Medicine \n1989 ;68 :321 –35\n.2509855 \n7 Simonneau G , Gatzoulis MA , Adatia I , et al \nUpdated clinical classification of pulmonary hypertension\n. J Am Coll Cardiol \n2013 ;62 :D34 –41\n. 10.1016/j.jacc.2013.10.029 24355639 \n8 Mathew R , Huang J , Wu JM , et al \nHematological disorders and pulmonary hypertension\n. World J Cardiol \n2016 ;8 :703 –18\n. 10.4330/wjc.v8.i12.703 28070238 \n9 Morris CR , Gladwin MT , Kato GJ \nNitric oxide and arginine dysregulation: a novel pathway to pulmonary hypertension in hemolytic disorders\n. Curr Mol Med \n2008 ;8 :620 –32\n. 10.2174/156652408786241447 18991648 \n10 Yan L , Chen X , Talati M , et al \nBone marrow-derived cells contribute to the pathogenesis of pulmonary arterial hypertension\n. Am J Respir Crit Care Med \n2016 ;193 :898 –909\n. 10.1164/rccm.201502-0407OC 26651104 \n11 Krishnan U , Mark TM , Niesvizky R , et al \nPulmonary hypertension complicating multiple myeloma\n. Pulm Circ \n2015 ;5 :590 –7\n. 10.1086/682430 26401262 \n12 Hashimoto H , Kurata A , Mizuno H , et al \nPulmonary arterial hypertension due to pulmonary vascular amyloid deposition in a patient with multiple myeloma\n. Int J Clin Exp Pathol \n2015 ;8 :15391 –5\n.26823900 \n13 Munshi NC , Digumarthy S , Rahemtullah A \nCase records of the Massachusetts General Hospital. Case 13-2008. A 46-year-old man with rheumatoid arthritis and lymphadenopathy\n. N Engl J Med \n2008 ;358 :1838 –48\n. 10.1056/NEJMcpc0800959 18434654 \n14 Takano H , Nagata K , Mikoshiba M , et al \nCombination of rituximab and chemotherapy showing anti-tumor effect in gamma heavy chain disease expressing CD20\n. Am J Hematol \n2008 ;83 :938 –9\n. 10.1002/ajh.21284 18839436 \n15 Arnason JE , Mendez LM \nInduction therapy for gamma-heavy chain disease with bortezomib and dexamethasone: a case report\n. Blood \n2012 ;120 :5051\n10.1182/blood.V120.21.5051.5051 \n16 Garciaz S , Coso D , Schiano de Colella J-M , et al \nLenalidomide for the treatment of B-cell lymphoma\n. Expert Opin Investig Drugs \n2016 ;25 :1103 –16\n. 10.1080/13543784.2016.1208170\n\n",
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"title": "Gamma heavy chain disease complicated by pulmonary hypertension, which was successfully treated with lenalidomide.",
"title_normalized": "gamma heavy chain disease complicated by pulmonary hypertension which was successfully treated with lenalidomide"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-288837",
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
},
{
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}
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},
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"literaturereference": "SHIBATA S, FUKUNAGA A. GAMMA HEAVY CHAIN DISEASE COMPLICATED BY PULMONARY HYPERTENSION, WHICH WAS SUCCESSFULLY TREATED WITH LENALIDOMIDE. BMJ CASE REP. 2020?13 (11):NO PAGINATION",
"literaturereference_normalized": "gamma heavy chain disease complicated by pulmonary hypertension which was successfully treated with lenalidomide",
"qualification": "3",
"reportercountry": "JP"
},
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"receiptdate": "20210405",
"receivedate": "20210405",
"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
},
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"seriousnessdeath": null,
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"transmissiondate": "20210717"
}
] |
{
"abstract": "OBJECTIVE\nThe aim of this study was to compare the efficacy and safety of induction therapy using the interleukin-2 receptor antagonist (IL-2RA) with antithymocyte globulin (ATG) under a tacrolimus-based immunosuppression regimen in kidney transplantation from donors after cardiac death.\n\n\nMETHODS\nIt was a single-centre, retrospective, cohort study design to evaluate the efficacy and safety of IL-2RA vs. ATG induction therapy in adult renal transplant recipients from donors after cardiac death. The primary end-point was the incidence of biopsy-proven acute rejection (BPAR) at 6 months, and the secondary end-point included the incidence of delayed graft function (DGF), the renal function, and the patient and graft survival at 6 months. The safety end-point was the incidence of infectious complications.\n\n\nRESULTS\nA total of 132 patients (n = 37 in the IL-2RA group and n = 95 in the ATG group) were enrolled from March 2013 to April 2014. The BPAR at 6 months was similar between the two groups (IL-2RA vs. the ATG group, 5.4% vs. 12.6%, respectively, p = 0.228). There were no differences in the DGF, renal function at 1 and 3 months, and the patient and graft survival at 6 months between the two groups, but the renal function at 6 months in the IL-2RA group was superior to that of the ATG group (p = 0.02). The IL-2RA group experienced less infection than the ATG group (p = 0.025).\n\n\nCONCLUSIONS\nThe efficacy of IL2-RA and ATG induction under a tacrolimus-based immunosuppression regimen in low-risk DCD transplantation did not differ, but the safety of the IL2-RA induction was better than that of the ATG induction.",
"affiliations": "Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China.;Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China.;Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China.;Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China.;Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China.;Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China.;Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang, China.",
"authors": "Peng|W|W|;Liu|G|G|;Xie|W|W|;Huang|H|H|;Wu|J|J|;Shou|Z|Z|;Chen|J|J|",
"chemical_list": "D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1111/ijcp.12663",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1368-504X",
"issue": null,
"journal": "International journal of clinical practice. Supplement",
"keywords": null,
"medline_ta": "Int J Clin Pract Suppl",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2; D012189:Retrospective Studies; D016559:Tacrolimus; D014019:Tissue Donors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9712380",
"other_id": null,
"pages": "23-8",
"pmc": null,
"pmid": "26177071",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Interleukin-2 receptor antagonist compared with antithymocyte globulin induction therapy in kidney transplantation from donors after cardiac death.",
"title_normalized": "interleukin 2 receptor antagonist compared with antithymocyte globulin induction therapy in kidney transplantation from donors after cardiac death"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201704892",
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"occurcountry": "CN",
"patient": {
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"medicinalproduct": "PREDNISONE."
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"activesubstancename": "METHYLPREDNISOLONE"
},
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},
{
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},
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"drugstructuredosageunit": "007",
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"medicinalproduct": "ANTI-THYMOCYTE GLOBULIN (RABBIT) NOS"
}
],
"patientagegroup": "5",
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"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
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"reactionmeddraversionpt": "20.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PENG W,LIU G,XIE W,WU J,SHOU Z. INTERLEUKIN-2 RECEPTOR ANTAGONIST COMPARED WITH ANTITHYMOCYTE GLOBULIN INDUCTION THERAPY IN KIDNEY TRANSPLANTATION FROM DONORS AFTER CARDIAC DEATH. INT-J-CLIN-PRACT 2015;.",
"literaturereference_normalized": "interleukin 2 receptor antagonist compared with antithymocyte globulin induction therapy in kidney transplantation from donors after cardiac death",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20170612",
"receivedate": "20170612",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170830"
}
] |
{
"abstract": "We retrospectively compared the outcomes of 20 patients receiving Venetoclax + low-dose Cytarabine + Actinomycin D (ACTIVE) with 29 patients receiving FLAG-Ida as salvage therapy for relapsed or refractory AML (R/R AML) after alloSCT. The groups were statistically balanced according to age, performance status, cytogenetics, and previous treatment. The overall response rate (CR + CRp + MLFS) of ACTIVE was 75% (15/20) in comparison to 66% (19/29) in the FLAG-Ida group (p = 0.542). The cumulative CR + CRp rate was significantly higher in the ACTIVE group compared to FLAG-Ida (70% (14/20) vs. 34% (10/29), respectively, p = 0.02). All three patients failing previous Venetoclax therapy and five out of seven patients with previous FLAG-Ida exposure achieved a CR/CRp after ACTIVE induction. ACTIVE patients survived longer compared to FLAG-Ida patients (13.1 vs. 5.1 months, respectively, p = 0.032). The treatment-related mortality was 0% in the ACTIVE group and 34% (10/29) in the FLAG-Ida patients (p = 0.003). The cumulative incidence of relapse did not differ between the two treatment groups. ACTIVE appears to have comparable antileukemic activity and lower toxicity compared to FLAG-Ida resulting in improved survival. Patients with Venetoclax or FLAG-Ida exposure responded to ACTIVE.",
"affiliations": "Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania. andrius.zucenka@santa.lt.;Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.;Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.;Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.;Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.;Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.;Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.;Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.;Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.;Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.",
"authors": "Zucenka|Andrius|A|http://orcid.org/0000-0002-5520-1534;Vaitekenaite|Vilmante|V|;Maneikis|Kazimieras|K|;Davainis|Linas|L|;Pileckyte|Regina|R|;Trociukas|Igoris|I|;Peceliunas|Valdas|V|;Zvirblis|Tadas|T|;Staras|Vytautas|V|;Griskevicius|Laimonas|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41409-021-01416-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "56(11)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": null,
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "2804-2812",
"pmc": null,
"pmid": "34274954",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Venetoclax-based salvage therapy followed by Venetoclax and DLI maintenance vs. FLAG-Ida for relapsed or refractory acute myeloid leukemia after allogeneic stem cell transplantation.",
"title_normalized": "venetoclax based salvage therapy followed by venetoclax and dli maintenance vs flag ida for relapsed or refractory acute myeloid leukemia after allogeneic stem cell transplantation"
} | [
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"companynumb": "LT-PFIZER INC-202100969945",
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},
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"drugdosagetext": "UNK, CYCLIC",
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"abstract": "Myelomatous pleural effusion (MPE), as a presentation of extramedullary infiltration of multiple myeloma (MM), is rare and currently associated with poor outcomes without effective therapy. The potential value of cytokine detection in pleural effusion to MPE has not been reported to date.\nWe herein report a case of refractory and relapsed multiple myeloma that developed bilateral MPE due to disease progression caused by intolerance to various chemotherapy regimens. Cytomorphology and flow cytometry were adopted for diagnosis confirmation. Chemotherapy containing immunomodulators combined with thoracic catheterization drainage was applied to the patient, showing a certain therapeutic effect. During the course of disease, the change of cytokine profile in pleural effusion was monitored by cytometric bead array (CBA) technology, revealing that cytokines related to tumor load such as interleukin 6 (IL-6) and interleukin 10 (IL-10) in pleural effusion decreased with the improvement of disease, while other cytokines such as interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 17A (IL-17A), tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), granzyme A, granzyme B, perforin and granulysin increased with the improvement of disease.\nThere is a prospect that cytokine level in pleural effusion may indicate treatment response of MPE, and in light of this case, immunomodulators may be utilized in treating patients suffering MPE. Due to limitations of our single case, we urge more groups to evaluate the potential role of cytokine profile in MPE.",
"affiliations": "Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China.;Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China.;Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China.;Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China.;Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China.;Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China.;Department of Respiration, Peking University First Hospital, Beijing, People's Republic of China.;Department of Pathology, Peking University First Hospital, Beijing, People's Republic of China.;Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China.;Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China.",
"authors": "Xu|Junhui|J|;Gao|Liang|L|;Yan|Miao|M|;Wang|Bingjie|B|;Song|Zhengyang|Z|0000-0002-8014-7103;Liu|Huihui|H|;Sun|Kunyan|K|;Nong|Lin|L|0000-0002-1331-2420;Wang|Mangju|M|;Cen|Xinan|X|",
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"doi": "10.2147/OTT.S324810",
"fulltext": "\n==== Front\nOnco Targets Ther\nOnco Targets Ther\nott\nott\nOncoTargets and therapy\n1178-6930\nDove\n\n324810\n10.2147/OTT.S324810\nCase Report\nPotential Role of Pleural Fluid Cytokine Profile in Myelomatous Pleural Effusions\nXu et al\nXu et al\nXu Junhui 1 2 *\nGao Liang 1 *\nYan Miao 1\nWang Bingjie 1\nhttp://orcid.org/0000-0002-8014-7103\nSong Zhengyang 1\nLiu Huihui 1\nSun Kunyan 3\nhttp://orcid.org/0000-0002-1331-2420\nNong Lin 4\nWang Mangju 1\nCen Xinan 1\n1 Department of Hematology, Peking University First Hospital, Beijing, People’s Republic of China\n2 Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, People’s Republic of China\n3 Department of Respiration, Peking University First Hospital, Beijing, People’s Republic of China\n4 Department of Pathology, Peking University First Hospital, Beijing, People’s Republic of China\nCorrespondence: Mangju Wang; Xinan Cen Department of Hematology, Peking University First Hospital, No. 8 Xi Shi Ku Street, Xi Cheng District, Beijing, 100034, People’s Republic of ChinaTel +86-10-83575746 Email wang_m_j@163.com; cenxn@bjmu.edu.cn\n* These authors contributed equally to this work\n\n24 8 2021\n2021\n14 45454550\n14 6 2021\n08 8 2021\n© 2021 Xu et al.\n2021\nXu et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nBackground\n\nMyelomatous pleural effusion (MPE), as a presentation of extramedullary infiltration of multiple myeloma (MM), is rare and currently associated with poor outcomes without effective therapy. The potential value of cytokine detection in pleural effusion to MPE has not been reported to date.\n\nCase Presentation\n\nWe herein report a case of refractory and relapsed multiple myeloma that developed bilateral MPE due to disease progression caused by intolerance to various chemotherapy regimens. Cytomorphology and flow cytometry were adopted for diagnosis confirmation. Chemotherapy containing immunomodulators combined with thoracic catheterization drainage was applied to the patient, showing a certain therapeutic effect. During the course of disease, the change of cytokine profile in pleural effusion was monitored by cytometric bead array (CBA) technology, revealing that cytokines related to tumor load such as interleukin 6 (IL-6) and interleukin 10 (IL-10) in pleural effusion decreased with the improvement of disease, while other cytokines such as interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 17A (IL-17A), tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), granzyme A, granzyme B, perforin and granulysin increased with the improvement of disease.\n\nConclusion\n\nThere is a prospect that cytokine level in pleural effusion may indicate treatment response of MPE, and in light of this case, immunomodulators may be utilized in treating patients suffering MPE. Due to limitations of our single case, we urge more groups to evaluate the potential role of cytokine profile in MPE.\n\nKeywords\n\nmyelomatous pleural effusions\ncytokine\nIFN-γ\nIL-2\nimmunomodulator\nBeijing Municipal Science Technology This study was funded by the Beijing Municipal Science Technology Commission (No. Z191100006619026). The funder had no role in the study except for financial support.\n==== Body\nBackground\n\nMM is characterized by abnormal proliferation of monoclonal plasma cells secreting large amounts of monoclonal immunoglobulin or light chains inside bone marrow and finally leads to anemia, hypercalcemia, bone destruction, kidney injury, etc. Incidence of pleural effusion in MM patients is approximately 6%,1 and the possible mechanisms include hypoalbuminemia, congestive heart failure caused by amyloidosis cardiomyopathy, renal dysfunction, pleural invasion, etc.2 Among them, we name the pleural effusion caused by pleural invasion as MPE, which is a type of extramedullary invasion with poor prognosis and treatment response.1 Other than tuberculous pleural effusion, a high level of adenosine deaminase (ADA) was also reported in one-third of MPE, which indicates MPE patients’ varied immunocompetence based on ADA’s important role in lymphatic system differentiation and maturation.3 In some cases, reports of chemotherapy combined with intrathoracic injection of IL-2 or interferon α (IFN-α) attained a proven curative effect, achieving a remission duration of up to 30 months.4,5 All these phenomena imply that the immune system plays an important role in the development of MPE. We applied CBA technology (LEGENDplex™ Human CD8/NK Panel) to monitor cytokine profile in pleural effusion to explore the important role of cytokines during the disease course of an MPE patient.\n\nThe LEGENDplex™ Human CD8/NK Panel (Biolegend, cat.740267) is a multiplex bead-based assay, using fluorescence-encoded beads suitable for use on various flow cytometers. This panel allows simultaneous quantification of 13 human proteins with high detection sensitivities and broad dynamic ranges, including IL-2, IL-4, IL-10, IL-6, IL-17A, TNF-α, soluble Fas (sFas), soluble Fas Ligand (sFasL), IFN-γ, granzyme A, granzyme B, perforin and granulysin.\n\nCase Presentation\n\nThe patient was a 70-year-old female who visited Beijing Hospital in 2014 for weakness, amaurosis and profuse sweating. The hemoglobin concentration was 63g/L (6.3g/dL). The white blood cell count was 6.49×109/L. The platelet count was 100×109/L. The laboratory chemistry profile showed total protein 110g/L, albumin 36g/L, calcium 2.32 mmol/L, creatinine 74 umol/L. The immunoglobulin profile showed IgA 80g/L, IgG 4.15g/L, IgM 0.04g/L. The serum and urine immunofixation electrophoresis demonstrated IgA-Kappa (IgA-κ) monoclonal gammopathy and the β2-microglobulin was 8.89mg/L. Bone marrow aspiration showed monotypic plasma cells accounted for 60%. The final diagnosis was IgA-κ type multiple myeloma, International staging system (ISS) III and Durie-Salmon stage (D-S) IIIB. She had no significant medical history other than a myomectomy. She consecutively received six cycles of chemotherapy with different combinations of drugs, containing bortezomib, thalidomide, lenalidomide, ixazomib, cyclophosphamide, and dexamethasone. But this patient still suffered repeated disease progress due to drug intolerance. In November 2019, she was diagnosed with relapsed and refractory MM (r/rMM). Daratumumab was then initiated. After a transient improvement, the disease progressed again in May 2020, impelling bortezomib to be used again. In June 2020, the patient developed bilateral pleural effusion when the frequency of daratumumab was reduced (Figure 1A, June 8, 2020, chest Computerized Tomography (CT)). Diagnostic thoracentesis showed bloody effusion with features suggestive of an exudate (specific gravity 1.030, nucleated cells count 11,530/mm3, mononuclear cell 88%, total protein 36.7g/L, albumin 23.5g/L, lactate dehydrogenase (LDH) 463 U/L, ADA 40.1 U/L). Microbiological examination including fungus and mycobacterium tuberculosis did not reveal any pathogens, and the next-generation sequencing (NGS) technology disclosed no pathogen either. Cytological analysis and flow cytometry analysis revealed a large number of abnormal plasma cells. On June 9, 2020, we detected the cytokine profile in peripheral blood and right-sided pleural effusion using CBA technology and the results are listed in Table 1. Subsequently, consecutive thoracic drainage was performed in combination with Daratumumab, liposomal Adriamycin, Thalidomide and Dexamethasone (DATD). The right-sided pleural effusion then decreased after 1 week. On June 15, 2020, we detected the cytokine profile in right-sided pleural effusion second time and the results are listed in Table 1. Due to the DATD intolerance, the chemotherapy regimen was changed to pomalidomide and dexamethasone. The disease remained stable. In July 2020, patient ceased taking pomalidomide due to myelosuppression. As a result, the left-sided pleural effusion began to increase slowly (Figure 1B: July 15, 2020, chest CT). The patient developed dyspnea in August 2020 with chest CT (Figure 1C, August 17, 2020) signifying the obvious increase of left-sided pleural effusion. Again, a microbiological examination of left-sided effusion found no pathogens. Cytological analysis and flow cytometry analysis revealed a large number of abnormal plasma cells. On August 17, 2020, the cytokine profile in left-sided pleural effusion was detected by CBA technology, and the results are listed in Table 1. The chemotherapy of liposomal Adriamycin plus dexamethasone was chosen together with respiratory support, left-sided thoracic catheterization drainage and antibiotics therapy. However, after a temporary improvement, the patient’s disease continuously progressed. Chest CT was examined in September (Figure 1D, September 3, 2020), disclosing ground-glass opacity and consolidation in the right lung, diffuse ground-glass opacity in the left lung, the progression of lesions in upper lobe and decrease of bilateral pleural effusion. The patient died of exacerbation of pulmonary infection and respiratory failure on September 8, 2020.Table 1 The Cytokine Concentrations are as Follows\n\nTime\tSample\tIL-2 pg/mL\tIL-4 pg/mL\tIL-10 pg/mL\tIL-6 pg/mL\tIL-17A pg/mL\tTNF-α pg/mL\tIFN-γ pg/mL\tGranzyme-A pg/mL\tGranzyme-B pg/mL\tPerforin pg/mL\tGranulysin pg/mL\t\n9 June 2020\tPeripheral blood\t<8.17\t1.48\t85.23\t12.00\t<1.28\t<1.80\t<3.43\t20.88\t9.13\t986.97\t655.00\t\n9 June 2020\tRight pleural effusion\t<8.17\t<1.18\t1488.16\t4884.91\t<1.28\t2.37\t<3.43\t57.52\t721.32\t1108.74\t550.25\t\n15 June 2020\tRight pleural effusion\t1301.42\t7.56\t1.62\t2685.95\t795.89\t22.75\t15.22\t319.46\t1141.92\t3517.97\t1668.17\t\n17 August 2020\tLeft pleural effusion\t15.05\t0.83\t1027.33\t11,088.80\t<1.28\t5.54\t9.32\t100.27\t435.53\t243.55\t945.15\t\nAbbreviations: IL-2, interleukin 2; IL-4, interleukin 4; IL-10, interleukin 10; IL-6, interleukin 6; IL-17A, interleukin 17A; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ.\n\nFigure 1 Changes in chest CT findings during the course of the disease. (A) Taken on 8 June 2020, Initial stage: Chest CT showed bilateral pleural effusion as well as left interlobar effusion and no manifestation of acute inflammation and space-occupying lesions. (B) Taken on 15 July 2020, Remission stage: slowly increasing tendency of the left pleural effusion and no increasing in right pleural effusion. (C) Taken on 17 August 2020, Relapse stage: obvious increase of left pleural effusion and decrease of right pleural effusion. (D) Taken on 3 September 2020, Terminal stage: Ground-glass opacity and consolidation in the right lung, diffuse ground-glass opacity in the left lung, the progression of lesions in upper lobe and decrease of bilateral pleural effusion.\n\nDiscussion\n\nWhen MPE occurs as the initial symptom of MM, it is easy to be misdiagnosed as tuberculous (TB) pleural effusion because both are exudative and around one-third of MPE also have a higher ADA level.1 Furthermore, a certain proportion of myeloma plasma cells look like lymphocytes due to their intrinsic cytomorphological heterogeneity. The sensitivity of purified protein derivative (PPD) test, T-spot TB, mycobacterium tuberculosis culture, polymerase chain reaction (PCR) and NGS technology to make the diagnosis of tuberculosis pleural effusion is comparatively low.6 The invasive nature imposes restriction on the application of pleural biopsy, although its sensitivity has been proven. The ADA is not suitable as a differentiating criterion due to its increased level in MPE although it has both high sensitivity and specificity.6 It has been reported that IFN-γ is significantly higher in TB pleural effusion than in malignant patients.7 The sensitivity and specificity of IFN-γ over 140pg/mL in differentiating the two kinds of pleural effusion are reported to be as high as 89–99% and 92–98%, respectively.6 As a distinctive cytokine of Th1 cells, IFN-γ in peripheral blood and pleural effusion is significantly elevated by activated macrophages after the infection. Nevertheless, this patient was immunosuppressed; thus, her IFN-γ level either in peripheral blood or pleural effusion was below the measurable range. There may be a great difference of IFN-γ level between MPE and tuberculous pleural effusion, which drew a large prospect for IFN-γ to be used in identification. Various cytokines interact with each other as a network, so their ratio may better define the pleural effusion’s nature than the absolute concentration. The ratio of IL-4/IL-5, IL-4/TNF-α, IL-2/TNF-α, and IL-10/TNF-α is lower and IFN-γ/IL-2, IL-4, IL-5, IL-10, TNF-α in TB pleural effusion is higher than non-TB pleural effusion.7 However, whether the ratio of these cytokines can be used as a differentiating index needs larger sample size to verify further. The next question is whether cytokines can be used to distinguish MPE from other malignant pleural effusion and miscellaneous pleural effusion. Different cytokine-pairs with significant correlation were observed in different kinds of pleural effusion.7 The correlation between IFN-γ and IL-2 or IL-4 is unique in malignant pleural effusion, and correlation between TNF-α and IL-10 or IL-4 only exists in miscellaneous ones.7 Similarly, in our patient we revealed that the concentration of IL-2, IL-4, IL-17A, TNF-α, IFN-γ, granzyme A, granzyme B, perforin and granulysin elevated simultaneously when MPE went into remission, which indicates a positive correlation among these cytokines. In contrast, IL-6 and IL-10 decreased at the same time. In MPE, there may be a specific negative correlation between the increased cytokines and decreased ones. However, whether this negative correlation can distinguish MPE from other types of pleural effusion requires further study. Nevertheless, cytokine profile in pleural effusion may provide potential biomarkers when it is difficult for routine methods to make the distinguishment.\n\nMPE is usually an advanced manifestation of MM and its median survival time is only 2.8–4.0 months even under active treatment.1 The lack of Th1 cytokines such as IL-2 as a sign of impaired or depressed fetal/neonatal immune response has been demonstrated to be significantly related to the prevalence of adverse outcomes in fetal pleural effusion.8 At present, multi-drug chemotherapy combined with repeated thoracentesis drainage or pleurodesis is strongly recommended.1 The right-sided pleural effusion of this patient was significantly reduced after the application of DATD regimen combined with thoracentesis drainage. Moreover, no progress occurred during maintenance treatment of pomalidomide. We revealed concentration of cytokines in pleural effusion is closely related to disease deterioration and improvement. The changes in these cytokines may represent the strength of the immune status in the chest cavity. The detection of cytokines in pleural effusion may become a barometer to predict the variation tendency of pleural effusion.\n\nIL-2 is an important immunoregulatory cytokine in various diseases.9 A previous study reported that chemotherapy combined with IL-2 immunotherapy showed good curative effect in two cases of MPE with overall survival of up to 30 months.4 The lack of IL-2 was observed in fetal pleural effusion because of fetuses’ impaired or depressed immune system.8 Our patient showed a higher IL-2 concentration in remission of pleural effusion and a lower IL-2 level in relapse, which indicated the potential value of IL-2 in MPE control. Due to the fact that IL-2 down-regulates the expression level of programmed cell death protein 1 (PD-1) and promotes the secretion of both granzyme B and IFN - γ, it can enhance tumor killing ability.9 IL-2 reverses T cell exhaustion based on these biological activities, which is probably related to its positive effect in treatment. In our case, both granzyme B and IFN-γ in pleural effusion increased in pace with IL-2’s increase, which fully verified this mechanism. However, more evidence is required to determine whether IL-2 can treat MPE. Additionally, which medication drives the cytokine variation in pleural effusion? Immunomodulators are suspected to be the answer to a large extent. Immunomodulators, including thalidomide, lenalidomide and pomalidomide, can induce T lymphocytes to secrete IL-2 through cereblon (CRBN) signaling pathway, and further inhibit the proliferation of myeloma cells,10 which is capable to state the reason why IL-2 returned to its initial level and why the pleural effusion significantly progressed after discontinuation of immunomodulators. Therefore, immunomodulators may inhibit the formation of pleural effusion through regulating immune environment inside thoracic cavity. As we all know, MPE is a special subtype of extramedullary disease (EMD). The effectiveness of different kinds of immunomodulators in EMD has been discussed in the published literature. No treatment response was observed in MM patients with extramedullary disease when taking thalidomide.11,12 Although it is considered that lenalidomide is a more potentially effective immunomodulator than thalidomide, there were few published data on the effectiveness of lenalidomide.13,14 A retrospective study demonstrated the efficacy and tolerability of pomalidomide/cyclophosphamide/dexamethasone combination in a group of patients with EMD.15 Our case showed the patient’s disease remained stable during the use of pomalidomide. After stopping pomalidomide, her pleural effusion progressed again. It seemed immunomodulators may play a certain role in the control of MPE. Therefore, we suggest that immunomodulators may be utilized in treating patients suffering MPE.\n\nConclusion\n\nTo date, this is the first report describing the potentially important role of cytokines in myeloma pleural effusion. Our case indicates that a possible value of IFN-γ to be applied in differentiating tuberculous pleural effusion from MPE. In addition, the concentration of various cytokines in pleural effusion may be used as a potential barometer to forecast the outcome of MPE. Finally, our work may provide evidence to include immunotherapy in the treatment of MPE. We are collecting more patients with MPE to perform cytokine measurements. We anticipate more valuable results and findings in the future. We also urge more groups to further evaluate the potential role of cytokine profile in MPE.\n\nAcknowledgments\n\nWe thank her close relatives for allowing us to publish his case.\n\nData Sharing Statement\n\nAll data generated or analysed during this study are included in this published article.\n\nEthics Approval and Consent to Participate\n\nInstitutional approval was not required to publish the case details.\n\nConsent for Publication\n\nThis patient’s relatives provided written informed consent for the publication of the case details and images.\n\nAuthor Contributions\n\nAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas. All authors took part in drafting, revising or critically reviewing the article; gave final approval for the version to be published; have agreed on the journal to which the article has been submitted; and have agreed to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors declare that they have no conflicts of interest.\n==== Refs\nReferences\n\n1. YanamandraU, DeoP, SahuKK, et al. Clinicopathological profile of myelomatous pleural effusion: single-center real-world experience and review of literature. Clin Lymphoma Myeloma Leuk. 2019;19 :183–189.e1. doi:10.1016/j.clml.2018.12.003 30704934\n2. KintzerJS, RosenowEC, KyleRA. Thoracic and pulmonary abnormalities in multiple myeloma. A review of 958 cases. Arch Intern Med. 1978;138 :727–730. doi:10.1001/archinte.1978.03630290039015 646535\n3. ChoYU, ChiHS, ParkCJ, JangS, SeoEJ, SuhC. Myelomatous pleural effusion: a case series in a single institution and literature review. Korean J Lab Med. 2011;31 :225–230.22016674\n4. ZhongY, ZhangJ, WangH. Myelomatous pleural effusion involvement in 23 patients with multiple myeloma: a single-center clinical analysis. Thorac Cancer. 2015;6 :359–362. doi:10.1111/1759-7714.12220 26273384\n5. MakinoS, YamaharaS, NagakeY, KamuraJ. Bence-Jones myeloma with pleural effusion: response to alpha-interferon and combined chemotherapy. Int Med. 1992;31 :617–621. doi:10.2169/internalmedicine.31.617\n6. Villena GarridoV, Cases ViedmaE, Fernández VillarA, et al. Recommendations of diagnosis and treatment of pleural effusion. Update. Arch Bronconeumol. 2014;50 :235–249. doi:10.1016/j.arbr.2014.04.007 24698396\n7. AoeK, HirakiA, MurakamiT, et al. Relative abundance and patterns of correlation among six cytokines in pleural fluid measured by cytometric bead array, Int. J Mol Med. 2003;12 (2 ):193–198.\n8. ImaiK, KotaniT, TsudaH, KobayashiT, UshidaT, MoriyamaY. Determination of the cytokine levels in fetal pleural effusion and their association with fetal/neonatal findings. Cytokine. 2020;127 :154945. doi:10.1016/j.cyto.2019.154945 31805478\n9. HanL, JiangQ, YaoW, FuT, ZengQ. Thoracic injection of low-dose interleukin-2 as an adjuvant therapy improves the control of the malignant pleural effusions: a systematic review and meta-analysis base on Chinese patients. BMC Cancer. 2018;18 :725. doi:10.1186/s12885-018-4581-5 29980186\n10. LindnerS, KrönkeJ. The molecular mechanism of thalidomide analogs in hematologic malignancies. J Mol Med. 2016;94 :1327–1334. doi:10.1007/s00109-016-1450-z 27492707\n11. RosiñolL, CibeiraMT, BladéJ, et al. Extramedullary multiple myeloma escapes the effect of thalidomide. Haematologica. 2004;89 :832–836.15257935\n12. WuP, DaviesF, BoydK, et al. The impact of extramedullary disease at presentation in the outcome of myeloma. Leuk Lymphoma. 2009;50 :230–235. doi:10.1080/10428190802657751 19197724\n13. RichardsonPG, BloodE, MitsiadesCS, et al. A randomized Phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108 :3458–3464. doi:10.1182/blood-2006-04-015909 16840727\n14. KumarS, FlinnIW, RichardsonPG, et al. Novel three- and four-drug combination regimens of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for previously untreated multiple myeloma: results from the multicenter, randomized, phase 2 EVOLUTION study. Blood. 2006;116 :621(abstr 621).\n15. Hagihara M, Ide S, Ohara S, Uchida T, Inoue M, Hua J. omalidomide/cyclophosphamide/dexamethasone combination therapy for relapsed/refractory multiple myeloma accompanied by extramedullary. lesions Rinsho Ketsueki. 2020;61 (1 ):20–26.\n\n",
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"abstract": "BACKGROUND\nToxic epidermal necrolysis and Stevens-Johnson syndrome are acute life-threatening skin reactions. AZD9291 has been developed as a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) with activity against T790M mutation.\n\n\nMETHODS\nHerein we report a 68-year-old woman who developed a large area of skin necrosis and was diagnosed with toxic epidermal necrolysis after AZD-9291 ingestion. To the best of our knowledge, this is the first case reported in patients with EGFR T790M mutation in non-small cell lung cancer (NSCLC). Cabozantinib combined with erlotinib had clinically meaningful effectiveness, with additional toxicity that was generally manageable.\n\n\nCONCLUSIONS\nTreatment with AZD-9261 is effective in regressing the growth of the NSCLC and can bring some hope to despairing patients. We hope that more research will be carried out on the association between severe rashes and EGFR-TKIs, and more safe and effective drugs can be developed.",
"affiliations": "Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China.;Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China.;Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China.;Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China.;Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China. zhanghm@shutcm.edu.cn.",
"authors": "Li|Wen|W|;He|Xiang|X|;Liu|Hui|H|;Zhu|Jiong|J|;Zhang|Hui-Min|HM|",
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"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i29.pg8846\n10.12998/wjcc.v9.i29.8846\nCase Report\nSuccessful treatment after toxic epidermal necrolysis induced by AZD-9291 in a patient with non-small cell lung cancer: A case report\nLi W et al. Toxic epidermal necrolysis AZD-9291 non-small cell lung cancer\nLi Wen Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China\n\nHe Xiang Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China\n\nLiu Hui Department of Oncology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China\n\nZhu Jiong Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China\n\nZhang Hui-Min Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, Shanghai 201203, China. zhanghm@shutcm.edu.cn\n\nAuthor contributions: Li W contributed by collecting and assembling data; Li W and He X conceived, designed the research, analyzed and interpreted data; Zhang HM and He X funded the research; Li W and Liu H provided study materials or patients; All authors wrote the paper.\n\nSupported by National Natural Science Foundation of China, No. 81974570 .\n\nCorresponding author: Hui-Min Zhang, Director, Doctor, Department of Dermatology, Shuguang Hospital Affiliated to Shanghai University of TCM, No. 528 Zhangheng Road, Shanghai 201203, China. zhanghm@shutcm.edu.cn\n\n16 10 2021\n16 10 2021\n9 29 88468851\n12 5 2021\n18 6 2021\n18 8 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. See: http://creativecommons.org/Licenses/by-nc/4.0/\nBACKGROUND\n\nToxic epidermal necrolysis and Stevens-Johnson syndrome are acute life-threatening skin reactions. AZD9291 has been developed as a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) with activity against T790M mutation.\n\nCASE SUMMARY\n\nHerein we report a 68-year-old woman who developed a large area of skin necrosis and was diagnosed with toxic epidermal necrolysis after AZD-9291 ingestion. To the best of our knowledge, this is the first case reported in patients with EGFR T790M mutation in non-small cell lung cancer (NSCLC). Cabozantinib combined with erlotinib had clinically meaningful effectiveness, with additional toxicity that was generally manageable.\n\nCONCLUSION\n\nTreatment with AZD-9261 is effective in regressing the growth of the NSCLC and can bring some hope to despairing patients. We hope that more research will be carried out on the association between severe rashes and EGFR-TKIs, and more safe and effective drugs can be developed.\n\nToxic epidermal necrolysis\nAZD-9291\nOsimertinib\nEpidermal growth factor receptor - tyrosine kinase inhibitors\nNon-small cell lung cancer\nCase report\n==== Body\npmc Core Tip: To the best of our knowledge, this is the first case reported in a patient with epidermal growth factor receptor T790M mutation in non-small cell lung cancer. Cabozantinib combined with erlotinib had clinically meaningful effectiveness, with additional toxicity that was generally manageable.\n\nINTRODUCTION\n\nToxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are acute life-threatening skin reactions. Both are rare, with TEN and SJS affecting approximately 1 or 2/1000000 annually. The average reported mortality rate of SJS is 1%-5%, and that of TEN is 25%-35%. The diseases are characterized by mucosal skin blistering and shedding, along with sudden signs of high fever and systemic toxicity[1]. SJS is diagnosed when the epidermal detachment covers 10% of the body surface area, TEN is diagnosed when 30% is affected, and SJS/TEN overlap when 10%-30% is affected[2].\n\nDrugs are assumed or identified as the main cause of SJS/TEN in most cases. Medications most often used for SJS/TEN include B-Lactams, nonsteroidal anti-inflammatory drugs, anticonvulsants, barbiturates, and allopurinol[3]. It is rarely reported with targeted antitumor drugs, especially AZD-9291, which is a representative third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). AZD-9291 was shown to have superior efficacy and less toxicity, and to be especially suited for patients with EGFR T790M mutation[4]. To the best of our knowledge, there is only one previously reported case of AZD-9291precipitating SJS/TEN in patients with advanced EGFR mutation-positive non-small cell lung cancer (NSCLC)[5]. We report a 68-year-old woman who developed extensive skin necrosis after taking AZD-9291, and was diagnosed with TEN.\n\nCASE PRESENTATION\n\nChief complaints\n\nThe patient was a 68-year-old woman with a medical history of postoperative treatment of NSCLC with bone metastasis 1 year 8 mo before presentation.\n\nHistory of present illness\n\nA review of the patient’s medical history revealed nothing significant other than lung cancer and hypertension.\n\nHistory of past illness\n\nA review of the patient’s medical history revealed nothing significant other than lung cancer and hypertension.\n\nPersonal and family history\n\nThe patient had no significant personal or family history.\n\nPhysical examination\n\nThe patient presented with multiple erythematous papules mainly on the face and thigh on day 74. Seventy-eight days later, the patient developed several oral blisters and scattered erythema papules that rapidly developed into mucosal erosion and systemic epidermal abscission including the skin on the face and back (Figure 1). The large area of exfoliation involved 30% of the body surface area. Nikolsky’s sign was positive. Despite the severity of the disease, the patient’s general condition is acceptable.\n\nFigure 1 Appearance of the drug eruptions in our patient. A: Facial findings on day 74 after AZD-9291 treatment; B, C, and D: Improvement of the skin rash after 14 d of treatment.\n\nLaboratory examination\n\nRoutine laboratory examination revealed normal alanine aminotransferase (ALT 22 U/L, normal limits 13-69 U/L). Laboratory markers of systemic involvement indicated anemia, leucopenia, hypoalbuminemia, and hyponatremia. More importantly, there was no short-term drug or diet exposure before the outbreak. In addition, the interval between the first administration of AZD-9291 and the onset of disease was consistent with hypersensitivity latency. Bacterial cultures of blood, urine, and blisters revealed no evidence of bacterial infection. A drug lymphocyte-stimulation test was positive for AZD-9291, with a stimulation index of 2.6. As the above information was indicative enough, and the patient refused to have a pathological examination, biopsy was not performed.\n\nImaging examination\n\nChest computed tomography (CT) showed pulmonary lesions in posterior segment of right upper lobe, and peripheral lung cancer with multiple pulmonary metastases. Multiple metastases of the thoracic vertebrae, sternum, and ribs were considered (Figure 2A and B), which were similar to previous CT images (Figure 2C and D). Follow-up was recommended.\n\nFigure 2 Chest computed tomography changes. A and B: Chest computed tomography findings on day 128 of AZD-9291 use; C and D: Chest computed tomography on day 45 of AZD-9291 use.\n\nFINAL DIAGNOSIS\n\nWe concluded that AZD-9291 had caused TEN.\n\nTREATMENT\n\nAZD-9291 was immediately discontinued. Emergency routine blood and blood chemistry examination indicated a low leukocyte count, hypoalbuminemia, and electrolyte disorder, suggesting that we needed to maintain the leukocyte level and correct the electrolyte disorder by administering albumin. The patient was treated with 10 g/d human immunoglobulins for 5 d and 60 mg/d of methylprednisolone for 5 d as steroid pulse therapy, followed thereafter by 40 mg/d for 3 d. Blisters and sites with exudate were coated with ethacridine lactate solution once a day. Erosive areas were treated with chloramphenicol dexamethasone ointment and covered with oil gauze once a day. During treatment, secretions were regularly collected to detect infection. Erosive genital mucosa was treated with medical colloidal dispersant several times a day. Blood scabs involving the eyes, nose and oral mucosa were regularly cleaned to prevent adhesion. The patient recovered from TEN after 2 wk of intensive therapy. Prednisolone was tapered off and finally discontinued over 1 mo. No recurrences were observed.\n\nAfter she stopped taking the AZD-9291, the patient received oral erlotinib 150 mg daily plus oral cabozantinib 60 mg daily. A mild rash on the face was considered an adverse event, and the dose of cabozantinib was reduced to 20 mg on day 10. The patient is still being treated with erlotinib plus cabozantinib without acquired resistance or SJS/TEN recurrence 12 mo after TEN.\n\nOUTCOME AND FOLLOW-UP\n\nChest CT follow-up after discharge showed that the lung tumor size was similar to before. Until the submission of this report, the tumor was still the same as before. What’s more, no new metastatic lesions have been found.\n\nDISCUSSION\n\nSJS and TEN are difficult to resolve because of rapid progression. Therefore, early diagnosis and prompt withdrawal of the culprit drugs are of great importance. Histological workup of fresh cryosections and conventional formalin-fixed sections of the skin and direct immune fluorescence staining should be additionally performed. The skin should be treated conservatively to prevent the loss of fluid and occurrence of infection.\n\nLung cancer is the most common cancer-related mortality worldwide, with about 80%-85% of patients suffering from NSCLC[6]. EGFR mutations are present in approximately 10% of Caucasian NSCLC patients and 30% of Asian NSCLC patients[7]. EGFR-TKIs are key drugs, with clinical benefit to NSCLC patients harboring EGFR mutations. Despite an initial favorable response, the vast majority of patients will experience disease progression and acquire resistance to EGFR-TKIs[8]. T790M as the secondary mutation in EGFR is the most common mechanism of acquired resistance[9]. AZD9291 has been developed as third-generation EGFR-TKI with activity against T790M mutation. AZD-9291, also known as osimertinib, is a selective inhibitor of EGFR-TKI sensitization and EGFR T790M mutation with obvious curative effect and a low incidence of serious side effects.\n\nThe incidence of cutaneous adverse events, which are common during treatment with EGFR-TKIs, is less frequent with AZD-9291 compared with first and second generation EGFR-TKIs, afatinib, gefitinib, or erlotinib. Adverse effects consist mainly of diarrhea, rash, dry skin, pruritus, and nausea. It was reported that the severity of rash is positively correlated with the EGFR-TKI titer. A meta-analysis of the relationship between EGFR-TKI-related rash severity and efficacy found that patients with rash had longer progression-free survival than patients without rash[9]. Perhaps, rash can be regarded as a response marker that may be related to prolonged survival time. However, when severe epidermal ablation and necrosis occur, the drug must be discontinued. It is very beneficial to accurately evaluate the severity of drug reactions and promptly take corrective treatment measures.\n\nCONCLUSION\n\nThis is the second report of TEN associated with AZD-9291. The patient discontinued AZD-9291 because of TEN. CT of the lung was basically unchanged from previous images, and there seemed to be less hydrothorax. Compared with the other reported case, this patient has longer survival. The patient in our study received oral erlotinib 150 mg daily plus cabozantinib 20 mg daily. Erlotinib is approved for the treatment of all patients with advanced NSCLC but is most active in the treatment of EGFR with mutant EGFR.\n\nCabozantinib-based regimens are used as second-line or third-line treatment of advanced NSCLC patients with wild-type EGFR. This case is consistent with the reports that, in NSCLC patients with EGFR T790M mutation, cabozantinib combined with erlotinib has clinically meaningful results, with additional toxicity that was generally manageable. On the other hand, compared with the previously reported case, the woman in our study used AZD-929 longer. Perhaps the patient benefit can be attributed to the longer time of use of AZD-929. In the Asian population, first-line treatment with osimertinib showed clinical improvement of progression-free survival (PFS) compared with standard EGFR-TKIs, with an overall safety profile consistent with that seen in the phase III FLAURA study population[10]. That is to say, AZD-9261 treatment inhibited the growth of NSCLC and can bring some hope to despairing patients. We hope to conduct more research on the relationship between severe rashes and EGFR-TKIs in order to develop safer and more effective drugs.\n\nInformed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.\n\nConflict-of-interest statement: The authors declare that they have no conflicting interests.\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, 2021\n\nFirst decision: June 15, 2021\n\nArticle in press: August 18, 2021\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Sugimura H S-Editor: Wang LL L-Editor: Filipodia P-Editor: Xing YX\n==== Refs\n1 Isvy-Joubert A Ingen-Housz-Oro S Vincent R Haddad C Valeyrie-Allanore L Chosidow O Race JM Wolkenstein P Severe cutaneous adverse reactions to drugs: from patients to the national office for compensation of medical accidents Dermatology 2014 228 338 343 24662107\n2 Chen CB Wu MY Ng CY Lu CW Wu J Kao PH Yang CK Peng MT Huang CY Chang WC Hui RC Yang CH Yang SF Chung WH Su SC Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies Cancer Manag Res 2018 10 1259 1273 29844705\n3 Roujeau JC Kelly JP Naldi L Rzany B Stern RS Anderson T Auquier A Bastuji-Garin S Correia O Locati F Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis N Engl J Med 1995 333 1600 1607 7477195\n4 Ramalingam SS Vansteenkiste J Planchard D Cho BC Gray JE Ohe Y Zhou C Reungwetwattana T Cheng Y Chewaskulyong B Shah R Cobo M Lee KH Cheema P Tiseo M John T Lin MC Imamura F Kurata T Todd A Hodge R Saggese M Rukazenkov Y Soria JC FLAURA Investigators Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC N Engl J Med 2020 382 41 50 31751012\n5 Wang J Cheng X Lu Y Zhou B A case report of toxic epidermal necrolysis associated with AZD-9291 Drug Des Devel Ther 2018 12 2163 2167\n6 Dubey AK Gupta U Jain S Epidemiology of lung cancer and approaches for its prediction: a systematic review and analysis Chin J Cancer 2016 35 71 27473753\n7 Cancer Genome Atlas Research Network Comprehensive molecular profiling of lung adenocarcinoma Nature 2014 511 543 550 25079552\n8 Kobayashi S Boggon TJ Dayaram T Jänne PA Kocher O Meyerson M Johnson BE Eck MJ Tenen DG Halmos B EGFR mutation and resistance of non-small-cell lung cancer to gefitinib N Engl J Med 2005 352 786 792 15728811\n9 Liu HB Wu Y Lv TF Yao YW Xiao YY Yuan DM Song Y Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis PLoS One 2013 8 e55128 23383079\n10 Cho BC Chewaskulyong B Lee KH Dechaphunkul A Sriuranpong V Imamura F Nogami N Kurata T Okamoto I Zhou C Cheng Y Cho EK Voon PJ Lee JS Mann H Saggese M Reungwetwattana T Ramalingam SS Ohe Y Osimertinib vs Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA Asian Subset J Thorac Oncol 2019 14 99 106 30240852\n\n",
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"abstract": "Burkitt's lymphoma (BL) is an aggressive non-Hodgkin's B-cell lymphoma with an extremely short doubling time that often presents in extra nodal sites or as an acute leukaemia. Nowadays, with the rapid response to chemotherapy and the diffuse nature of BL, there is no established role for radiation therapy (RT) even in localized disease. Regarding the relapsed/refractory BL, the treatment recommendations remain undefined. We present a 56-year-old woman, diagnosed with BL refractory to 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), who had disease progression on R-DHAP (rituximab, dexamethasone, high dose cytarabine and cisplatin) with intrathecal methotrexate, then a partial response on RICE (rituximab, ifosfamide, carboplatin and etoposide). Patient received high dose chemotherapy and autologous haematopoietic stem cell transplantation. Then, she was treated with hyperfractionated involved-field RT regimen. Currently, the patient remains disease free for around 2 years after remission. We acknowledge that RT is not a standard treatment of BL, especially in patients who attain complete response (CR) after first-line multi-agent chemotherapy or even in those who have a CR after second-line chemotherapy pre-transplant. Yet, the use of a superfractionated regimen of consolidative radiation could be justified in the treatment of recurrent/refractory localized BL who do not achieve a CR even with second-line salvage chemotherapy. Radiation therapy in this context, given that it is a well-tolerated treatment, is a modality worthy of being re-considered in relapsed/refractory BL. Copyright © 2016 John Wiley & Sons, Ltd.",
"affiliations": "Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon.",
"authors": "Charafeddine|Khalil|K|;Hilal|Lara|L|;Bazarbachi|Ali|A|;Salame|Nassima|N|;Youssef|Bassem|B|",
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],
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"literaturereference": "CHARAFEDDINE K, HILAL L, BAZARBACHI A, SALAME N, YOUSSEF B. HYPERFRACTIONATED RADIATION THERAPY IN BURKITT^S LYMPHOMA: A RECONSIDERATION ASPECT. HEMATOL ONCOL. 2016;MAY 17:EPUB AHEAD OF PRINT",
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}
] |
{
"abstract": "A young woman presenting respiratory infections, polyarthritis, severe neutropenia, and increased serum IgM was treated with intravenous immunoglobulin (IVIG) with good clinical and laboratory outcome followed by a loss of efficacy. The increased serum IgM associated to recurrent infections and autoimmune manifestations suggested the diagnosis of a hyper-IgM syndrome (HIGMs). The frequency of peripheral T cells, the expression of CD40 on the patients' B cells and CD40L on T cells and the activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG) at mRNA level was comparable to controls. In contrast, the frequency of B cells was one half of the healthy control and all cells showed an atypical phenotype. Although AID and UNG were normal, class-switch recombination was not very efficient because circulating switched memory were reduced and, once stimulated with CpG, generated less antibody-secreting cells than controls. An increase in serum B Lymphocytes stimulator (BLyS) was also found. The patient presented a peculiar clinical and immunological phenotype fitting for many aspects of both HIGM4 and Common Variable Immunodeficiency (CVID). These findings underline the need to better explore the complex link between these two diseases.",
"affiliations": "Research Center, Ospedale Pediatrico Bambino Gesù, Laboratory of Flow-cytometry and B cell development, IRCSS, Rome, Italy.",
"authors": "Rosado|M M|MM|;Picchianti Diamanti|A|A|;Cascioli|S|S|;Ceccarelli|S|S|;Caporuscio|S|S|;D'Amelio|R|R|;Carsetti|R|R|;Lagana|B|B|",
"chemical_list": "D015415:Biomarkers; D007075:Immunoglobulin M; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors",
"country": "England",
"delete": false,
"doi": "10.1177/039463201102400416",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0394-6320",
"issue": "24(4)",
"journal": "International journal of immunopathology and pharmacology",
"keywords": null,
"medline_ta": "Int J Immunopathol Pharmacol",
"mesh_terms": "D000328:Adult; D001402:B-Lymphocytes; D015415:Biomarkers; D017074:Common Variable Immunodeficiency; D018899:CpG Islands; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome; D007075:Immunoglobulin M; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D016130:Immunophenotyping; D009503:Neutropenia; D010641:Phenotype; D011237:Predictive Value of Tests; D012141:Respiratory Tract Infections; D013601:T-Lymphocytes; D015854:Up-Regulation",
"nlm_unique_id": "8911335",
"other_id": null,
"pages": "983-91",
"pmc": null,
"pmid": "22230404",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hyper-IgM, neutropenia, mild infections and low response to polyclonal stimulation: hyper-IgM syndrome or common variable immunodeficiency?",
"title_normalized": "hyper igm neutropenia mild infections and low response to polyclonal stimulation hyper igm syndrome or common variable immunodeficiency"
} | [
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},
{
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},
{
"reactionmeddrapt": "Product use issue",
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},
{
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},
{
"reactionmeddrapt": "Polyarthritis",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Asthenia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nail infection",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Respiratory tract infection",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CARSETTI R. HYPER-IGM, NEUTROPENIA, MILD INFECTIONS AND LOW RESPONSE TO POLYCLONAL STIMULATION: HYPER-IGM SYNDROME OR COMMON VARIABLE IMMUNODEFICIENCY. INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY. 2011?24(4):983-91",
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"qualification": "3",
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},
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"receiptdate": "20160325",
"receivedate": "20160325",
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
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"transmissiondate": "20160526"
}
] |
{
"abstract": "We report a 23-month old girl who presented with bilateral epiphora who underwent bilateral lacrimal probing and syringing, during which a cocaine adrenaline solution was used. Two hours after the procedure she developed acute pulmonary oedema secondary to myocardial ischaemia. The patient was treated with intravenous glyceryltrinitrate and milrinone infusions; cardiac enzymes and left ventricular function normalised over the subsequent 72 hours. Topical administration of cocaine and adrenaline solution may have dangerous systemic cardiac effects and should always be used judiciously.",
"affiliations": null,
"authors": "McGovern|E|E|;Moylett|E|E|;McMahon|C J|CJ|",
"chemical_list": "D000779:Anesthetics, Local; D002317:Cardiovascular Agents; D009184:Mydriatics; D005996:Nitroglycerin; D003042:Cocaine; D020105:Milrinone; D004837:Epinephrine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0332-3102",
"issue": "108(3)",
"journal": "Irish medical journal",
"keywords": null,
"medline_ta": "Ir Med J",
"mesh_terms": "D000287:Administration, Topical; D000779:Anesthetics, Local; D002317:Cardiovascular Agents; D003042:Cocaine; D003941:Diagnostic Techniques, Ophthalmological; D004837:Epinephrine; D005260:Female; D006801:Humans; D007223:Infant; D007766:Lacrimal Apparatus Diseases; D020105:Milrinone; D009184:Mydriatics; D017202:Myocardial Ischemia; D005996:Nitroglycerin; D016896:Treatment Outcome",
"nlm_unique_id": "0430275",
"other_id": null,
"pages": "89-90",
"pmc": null,
"pmid": "25876303",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Myocardial ischaemia following cocaine and adrenaline exposure in a child during an ophthalmological procedure.",
"title_normalized": "myocardial ischaemia following cocaine and adrenaline exposure in a child during an ophthalmological procedure"
} | [
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{
"abstract": "The study was conducted to assess serious infectious complications in five hand allograft recipients (four males, one female, age 40 ± 10 years), transplanted between 2006 and 2010. All donors and recipients were positive but one for cytomegalovirus (CMV) immunoglobulin G. All recipients received immunosuppressive therapy basiliximab, tacrolimus, mycophenolate mofetil and methylprednisolone. Until May 2013, there were four cases of severe infections requiring hospitalization. One patient developed CMV infection on the 28th postoperative day. Despite therapy with ganciclovir and prophylaxis with valganciclovir, reinfection episodes occurred both 4 weeks and 7 months later. The female recipient developed CMV infection 8 months after hand transplantation. After 3 weeks of ganciclovir treatment, the polymerase chain reaction results remained negative. We found that the CD4/CD8 T lymphocytes ratio differs in those two patients who had developed CMV disease in the past in comparison to the three remaining hand transplant recipients (mean 0.46 versus 1.7, respectively). Moreover, the ratio of patients who were CD4-8 negative to total T lymphocytes in CMV recovered patients was two-fold higher compared to the remaining recipients (10.0 versus 4.4, respectively). The female recipient was also hospitalized because of acute tonsillitis 25 months after hand transplantation, and successfully treated with amoxicillin clavulanate. The third recipient was hospitalized because of severe acute pain involving right lower limb, especially foot, 74 months after hand transplantation. After 48 hours, a painful vesicular rash occurred on the plantar as well as dorsal surface of right foot and herpes zoster was diagnosed. Immunosuppressive therapy after hand transplantation may be complicated by serious infections. CMV disease was associated with persistent alterations in T lymphocyte subsets.",
"affiliations": "Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland. Electronic address: dorotakaminska@interia.pl.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Subdepartment of Replantation of Limbs St. Hedwig District Hospital in Trzebnica, Trzebnica, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Subdepartment of Replantation of Limbs St. Hedwig District Hospital in Trzebnica, Trzebnica, Poland.;Subdepartment of Replantation of Limbs St. Hedwig District Hospital in Trzebnica, Trzebnica, Poland.",
"authors": "Kamińska|D|D|;Kościelska-Kasprzak|K|K|;Myszka|M|M|;Banasik|M|M|;Chełmoński|A|A|;Boratyńska|M|M|;Jabłecki|J|J|;Klinger|M|M|",
"chemical_list": "D000998:Antiviral Agents; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "46(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D064591:Allografts; D000998:Antiviral Agents; D003586:Cytomegalovirus Infections; D005260:Female; D063987:Hand Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D011044:Poland; D011183:Postoperative Complications; D012189:Retrospective Studies; D016176:T-Lymphocyte Subsets; D016559:Tacrolimus; D014184:Transplantation, Homologous; D063986:Vascularized Composite Allotransplantation",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2887-9",
"pmc": null,
"pmid": "25380943",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Significant infections after hand transplantation in a Polish population.",
"title_normalized": "significant infections after hand transplantation in a polish population"
} | [
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],
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}
],
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},
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"literaturereference": "KAMINSKA D,KOSCIELSKA-KASPRZAK K,MYSZKA M,BANASIK M,CHELMONSKI A,BORATYNSKA M,JABLECKI J,KLINGER M. SIGNIFICANT INFECTIONS AFTER HAND TRANSPLANTATION IN A POLISH POPULATION. TRANSPLANTATION PROCEEDINGS 2014?8:2887-2889.",
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},
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"receiptdate": "20151124",
"receivedate": "20151124",
"receiver": {
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},
"reporttype": "1",
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160304"
},
{
"companynumb": "PL-APOTEX-2015AP014675",
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"occurcountry": "PL",
"patient": {
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{
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"drugindication": "ANTIBIOTIC PROPHYLAXIS",
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"reaction": [
{
"reactionmeddrapt": "Herpes zoster",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Post herpetic neuralgia",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KAMINSKA D, KOSCIELSKA-KASPRZAK K, MYSZKA M, BANASIK M, CHELMONSKI A, BORATYNSKA M, ET AL.. SIGNIFICANT INFECTIONS AFTER HAND TRANSPLANTATION IN A POLISH POPULATION.. TRANSPLANT-PROC. 2014?46(8):2887-9",
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"receiptdate": "20151123",
"receivedate": "20151123",
"receiver": {
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},
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] |
{
"abstract": "Calcitriol acts synergistically with carboplatin in preclinical models of adenocarcinoma of the prostate. The authors sought to test high-dose oral calcitriol in combination with carboplatin in patients with metastatic androgen-independent prostate cancer. Seventeen patients received oral calcitriol (0.5 microg/kg) on day 1 and intravenous carboplatin (AUC 7 or AUC 6 in patients with prior radiation) on day 2, repeated every 4 weeks. PSA response was the primary end point and was defined as a 50% reduction confirmed 4 weeks later. Palliative response (2-point reduction or normalization of pain on the present pain intensity [PPI] scale without increased analgesic consumption) was also examined. One of 17 patients (6%, 95% CI, 0-28) achieved a confirmed PSA response. Four patients (24%, 95% CI, 7-49) had PSA reductions ranging from 24 to 38%. Of the 15 patients with a PPI > or = 1 point on entry, 3 (18%, 95% CI, 4-48) met criteria for palliative response. Treatment-related toxicity was mild and generally similar to that expected with single-agent carboplatin. Despite encouraging preclinical evidence, the addition of oral calcitriol to carboplatin in this study was not associated with an increase in the response rate when compared with the reported activity of carboplatin alone.",
"affiliations": "Department of Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA. beert@ohsu.edu",
"authors": "Beer|Tomasz M|TM|;Garzotto|Mark|M|;Katovic|Nina M|NM|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin; D002117:Calcitriol",
"country": "United States",
"delete": false,
"doi": "10.1097/01.coc.0000136020.27904.9c",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "27(5)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D002117:Calcitriol; D016190:Carboplatin; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D011471:Prostatic Neoplasms; D016879:Salvage Therapy",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "535-41",
"pmc": null,
"pmid": "15596926",
"pubdate": "2004-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "High-dose calcitriol and carboplatin in metastatic androgen-independent prostate cancer.",
"title_normalized": "high dose calcitriol and carboplatin in metastatic androgen independent prostate cancer"
} | [
{
"companynumb": "US-VALIDUS PHARMACEUTICALS LLC-US-2019VAL000545",
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{
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},
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"medicinalproduct": "CALCITRIOL."
},
{
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"activesubstancename": "CARBOPLATIN"
},
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"medicinalproduct": "CARBOPLATIN."
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oedema",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pain",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BEER T, GARZOTTO M AND KATOVIC N. HIGH-DOSE CALCITRIOL AND CARBOPLATIN IN METASTATIC ANDROGEN-INDEPENDENT PROSTATE CANCER. AMERICAN JOURNAL OF CLINICAL ONCOLOGY. 2004?27(5):535-41",
"literaturereference_normalized": "high dose calcitriol and carboplatin in metastatic androgen independent prostate cancer",
"qualification": "3",
"reportercountry": "US"
},
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},
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},
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"seriousnesslifethreatening": null,
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}
] |
{
"abstract": "Dexmedetomidine is an alpha(2)-agonist indicated for sedation in critically ill patients and procedural sedation in nonintubated patients. It is a distinctive sedative because it does not cause respiratory depression, but it may cause hypotension and bradycardia. We describe a 74-year-old man who was receiving dexmedetomidine for agitation and experienced progressive bradycardia. The patient experienced a postoperative myocardial infarction 3 days after repair of an abdominal aortic aneurysm. A dexmedetomidine infusion was started at 0.11 microg/kg/hour, without a loading dose, for agitation; the patient's heart rate was 123 beats/minute and blood pressure was 147/70 mm Hg, both within normal limits. Over the next 6 hours, the dexmedetomidine infusion rate was increased to a maximum of 0.7 microg/kg/hour; the patient's heart rate progressively decreased to 21 beats/minute, followed by pulseless electrical activity. After 2 minutes of chest compressions and an intravenous bolus of atropine 0.4 mg, the patient regained a pulse. Dexmedetomidine was discontinued, and the patient's heart rate and blood pressure returned to within normal limits. The patient was discharged home 7 days later without any cardiac or neurologic sequelae. Clinicians need to be educated about the potential for dexmedetomidine to cause bradycardia progressing to pulseless electrical activity, and patients need to be closely monitored. Patients who receive dexmedetomidine and develop a greater than 30% decrease in heart rate may be at high risk for severe bradycardia leading to pulseless electrical activity. We urge caution when using dexmedetomidine, especially in patients with significant cardiac disease.",
"affiliations": "Department of Pharmacy, The Ohio State University Medical Center, Ohio 43210, USA. Gerlach.6@osu.edu",
"authors": "Gerlach|Anthony T|AT|;Murphy|Claire V|CV|",
"chemical_list": "D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine",
"country": "United States",
"delete": false,
"doi": "10.1592/phco.29.12.1492",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "29(12)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000368:Aged; D001919:Bradycardia; D020927:Dexmedetomidine; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006801:Humans; D006993:Hypnotics and Sedatives; D007262:Infusions, Intravenous; D008297:Male; D011595:Psychomotor Agitation",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "1492",
"pmc": null,
"pmid": "19947809",
"pubdate": "2009-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dexmedetomidine-associated bradycardia progressing to pulseless electrical activity: case report and review of the literature.",
"title_normalized": "dexmedetomidine associated bradycardia progressing to pulseless electrical activity case report and review of the literature"
} | [
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] |
{
"abstract": "Management of immune thrombocytopenia (ITP) during pregnancy can be challenging because treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess the safety and efficacy of off-label use of Tpo-RAs during pregnancy, a multicenter observational and retrospective study was conducted. Results from 15 pregnant women with ITP (pregnancies, n = 17; neonates, n = 18) treated with either eltrombopag (n = 8) or romiplostim (n = 7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks (range, 1-39 weeks); the indication for starting Tpo-RAs was preparation for delivery in 10 (58%) of 17 pregnancies, whereas 4 had chronic refractory symptomatic ITP and 3 were receiving eltrombopag when pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA-related fetal or neonatal complications were observed, except for 1 case of neonatal thrombocytosis. Response to Tpo-RAs was achieved in 77% of cases, mostly in combination with concomitant ITP therapy (70% of responders). On the basis of these preliminary findings, temporary off-label use of Tpo-RAs for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and is likely to be helpful, especially before delivery.",
"affiliations": "Department of Internal Medicine, National Reference Center for Immune Cytopenias, Henri Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Creteil, Créteil, France.;Department of Haematology, S. Bortolo Hospital, Vicenza, Italy.;Department of Hematology, Hospital Universitario de Burgos, Burgos, Spain.;Department of Haematology, Sultan Qaboos University, Muscat, Oman.;Institut d'Hématologie de Basse-Normandie, Centre Hospitalier Universitaire de Caen Normandie, Caen, France.;Department of Research, Østfold Hospital Trust, Sarpsborg, Norway.;Section for Hematology, Department of Medicine, Haukeland University Hospital, Bergen, Norway.;Department of Internal Medicine, La Timone University Hospital, Assistance Publique-Hôpitaux de Marseille, Aix Marseille Université, Marseille, France.;Immuno-Hematology, Hôpital Claude Huriez, Lille, France; and.;Weill Cornell Medicine, New York, NY.;Department of Internal Medicine, National Reference Center for Immune Cytopenias, Henri Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Creteil, Créteil, France.",
"authors": "Michel|Marc|M|;Ruggeri|Marco|M|;Gonzalez-Lopez|Tomas Jose|TJ|;Alkindi|Salam|S|;Cheze|Stéphane|S|;Ghanima|Waleed|W|;Tvedt|Tor Henrik Anderson|THA|;Ebbo|Mikael|M|;Terriou|Louis|L|;Bussel|James B|JB|;Godeau|Bertrand|B|",
"chemical_list": "D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; C082218:MPL protein, human; D013926:Thrombopoietin; C488777:romiplostim; C520809:eltrombopag",
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2020007594",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "136(26)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000328:Adult; D001565:Benzoates; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006834:Hydrazines; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D016553:Purpura, Thrombocytopenic, Idiopathic; D011720:Pyrazoles; D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D012189:Retrospective Studies; D013926:Thrombopoietin",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3056-3061",
"pmc": null,
"pmid": "32814348",
"pubdate": "2020-12-24",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study.",
"title_normalized": "use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy results from a multicenter study"
} | [
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"companynumb": "FR-AMGEN-FRASP2019208302",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
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"drugindication": "IMMUNE THROMBOCYTOPENIA",
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],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Premature delivery",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
}
],
"summary": null
},
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"literaturereference": "MICHEL M.? RUGGERI M.? GONZALEZ LOPEZ T. ET AL.. USE OF THROMBOPOIETIN RECEPTOR AGONISTS FOR IMMUNE THROMBOCYTOPENIA IN PREGNANCY: RESULTS FROM A MULTICENTER STUDY. BLOOD. 2020?1?12",
"literaturereference_normalized": "use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy results from a multicenter study",
"qualification": "3",
"reportercountry": "ES"
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"receiptdate": "20200901",
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{
"abstract": "BACKGROUND\nCombined chemotherapy with carboplatin and paclitaxel is first-line treatment for lung and ovarian cancer. Drug-induced antibodies to carboplatin are rare but can cause severe, even fatal, hemolysis. Paclitaxel-induced immune hemolysis has not been reported. We describe a case of immune-mediated hemolysis associated with antibodies to carboplatin and paclitaxel in a woman with ovarian cancer who had received multiple chemotherapeutic agents over 7 years, including several courses of these two drugs. She required many transfusions. During a chemotherapy infusion the patient became hypotensive, was pale, and had rigors and red urine. The nadir hematocrit was 12.4%; peak bilirubin and lactate dehydrogenase were 16.3 mg/dL and 1188 units/L, respectively.\n\n\nMETHODS\nBlood samples collected within hours after chemotherapy and 2 days later were tested for antibodies to carboplatin and paclitaxel.\n\n\nRESULTS\nThe direct antiglobulin test was positive with anti-IgG (3+) and anti-C3 (2+). The plasma collected shortly after chemotherapy agglutinated carboplatin-treated red blood cells (RBCs); untreated and paclitaxel-treated RBCs both reacted at the antiglobulin test most likely due to circulating carboplatin, paclitaxel, or both drugs. Serum collected 2 days later agglutinated (titer 2) and sensitized (titer 128) carboplatin-treated RBCs; untreated and paclitaxel-treated RBCs were nonreactive. An acid eluate reacted weakly in the presence of polyethylene glycol with carboplatin-treated RBCs. The serum reacted with untreated and enzyme-treated RBCs in the presence of soluble carboplatin and paclitaxel.\n\n\nCONCLUSIONS\nAnti-carboplatin and the first example of anti-paclitaxel were detected in this patient's sample.",
"affiliations": "American Red Cross Blood Services, Southern California Region, Pomona, California.;Bloodworks Northwest and the 2Departments of Hematology and Laboratory Medicine, University of Washington Medical Center, Seattle, Washington.;Bloodworks Northwest and the 2Departments of Hematology and Laboratory Medicine, University of Washington Medical Center, Seattle, Washington.;Swedish Medical Center, Seattle, Washington.",
"authors": "Leger|Regina M|RM|;Jain|Shweta|S|;Nester|Theresa A|TA|;Kaplan|Henry|H|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1111/trf.13255",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "55(12)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D000970:Antineoplastic Agents; D016190:Carboplatin; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D017239:Paclitaxel",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "2949-54",
"pmc": null,
"pmid": "26264449",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced immune hemolytic anemia associated with anti-carboplatin and the first example of anti-paclitaxel.",
"title_normalized": "drug induced immune hemolytic anemia associated with anti carboplatin and the first example of anti paclitaxel"
} | [
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"abstract": "OBJECTIVE\nThe aim was to evaluate long-term drug retention, discontinuation, efficacy and safety of CT-P13 and reference infliximab in patients with rheumatoid arthritis (RA) enrolled in the Korean College of Rheumatology Biologics (KOBIO) registry.\n\n\nMETHODS\nPatients included adults with RA who received CT-P13 or reference infliximab between December 2012 and December 2017. Drug retention, efficacy (Disease Activity Score in 28 joints [DAS28]-erythrocyte sedimentation rate [ESR] or DAS28-C-reactive protein [CRP] and American College of Rheumatology [ACR] core set measure), and adverse events (AEs) were assessed over 4-years' follow-up.\n\n\nRESULTS\nData from 199 RA patients (CT-P13: n = 147; reference infliximab: n = 52) were analyzed. Median treatment duration was 1.22 years for CT-P13 and 1.40 years for reference infliximab (p = 0.67). Overall, 82% of patients received first-line therapy. Drug retention of CT-P13 versus reference infliximab was comparable for the overall population (p = 0.84) and for first-line (p = 0.66) and subsequent treatment lines (p = 0.96). Treatment changes or discontinuations occurred in 65.2% of patients with CT-P13 and 69.6% with reference infliximab. The most common reason for treatment changes or discontinuing treatment was lack of efficacy (CT-P13: 31.9%; reference infliximab: 34.8%). CT-P13 demonstrated comparable improvements in DAS28-ESR, DAS28-CRP and ACR responses to reference infliximab. Overall, 19 grade 3 AEs were reported for CT-P13 and eight for reference infliximab.\n\n\nCONCLUSIONS\nLong-term data from patients with RA treated in routine clinical practice in Korea showed that CT-P13 had a comparable drug retention rate to reference infliximab, with similar efficacy and an acceptable safety profile. CLINICALTRIALS.\nNCT01965132.",
"affiliations": "Department of Rheumatology, Ajou University School of Medicine, Suwon, Republic of Korea.;Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea.;Division of Rheumatology, Seoul Metropolitan Government-Seoul National University Hospital Boramae Medical Center, Seoul, Republic of Korea.;Department of Internal Medicine (Division of Rheumatology), Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea.;Celltrion Healthcare Co. Ltd., Incheon, Republic of Korea.;Celltrion Healthcare Co. Ltd., Incheon, Republic of Korea.;Division of Rheumatology, Seoul Metropolitan Government-Seoul National University Hospital Boramae Medical Center, Seoul, Republic of Korea. kideb1@gmail.com.",
"authors": "Kim|Hyoun-Ah|HA|http://orcid.org/0000-0003-2609-3367;Lee|Eunyoung|E|;Lee|Sun-Kyung|SK|;Park|Yong-Beom|YB|;Lee|Young Nam|YN|http://orcid.org/0000-0003-2776-4708;Kang|Hee Jung|HJ|;Shin|Kichul|K|http://orcid.org/0000-0002-6749-7598",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D059451:Biosimilar Pharmaceuticals; C000591237:CT-P13; D000069285:Infliximab",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40259-019-00393-y",
"fulltext": "\n==== Front\nBioDrugs\nBioDrugs\nBiodrugs\n1173-8804 1179-190X Springer International Publishing Cham \n\n31734899\n393\n10.1007/s40259-019-00393-y\nOriginal Research Article\nRetention Rate and Safety of Biosimilar CT-P13 in Rheumatoid Arthritis: Data from the Korean College of Rheumatology Biologics Registry\nhttp://orcid.org/0000-0003-2609-3367Kim Hyoun-Ah 1 Lee Eunyoung 23 Lee Sun-Kyung 4 Park Yong-Beom 5 http://orcid.org/0000-0003-2776-4708Lee Young Nam 6 Kang Hee Jung 6 http://orcid.org/0000-0002-6749-7598Shin Kichul kideb1@gmail.com 4 1 grid.251916.80000 0004 0532 3933Department of Rheumatology, Ajou University School of Medicine, Suwon, Republic of Korea \n2 grid.251916.80000 0004 0532 3933Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea \n3 grid.411261.10000 0004 0648 1036Office of Biostatistics, Ajou Research Institute for Innovative Medicine, Ajou University Medical Center, Suwon, Republic of Korea \n4 grid.484628.4 0000 0001 0943 2764Division of Rheumatology, Seoul Metropolitan Government-Seoul National University Hospital Boramae Medical Center, Seoul, Republic of Korea \n5 grid.415562.10000 0004 0636 3064Department of Internal Medicine (Division of Rheumatology), Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea \n6 Celltrion Healthcare Co. Ltd., Incheon, Republic of Korea \n16 11 2019 \n16 11 2019 \n2020 \n34 1 89 98\n© The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Objective\nThe aim was to evaluate long-term drug retention, discontinuation, efficacy and safety of CT-P13 and reference infliximab in patients with rheumatoid arthritis (RA) enrolled in the Korean College of Rheumatology Biologics (KOBIO) registry.\n\nMethods\nPatients included adults with RA who received CT-P13 or reference infliximab between December 2012 and December 2017. Drug retention, efficacy (Disease Activity Score in 28 joints [DAS28]–erythrocyte sedimentation rate [ESR] or DAS28–C-reactive protein [CRP] and American College of Rheumatology [ACR] core set measure), and adverse events (AEs) were assessed over 4-years’ follow-up.\n\nResults\nData from 199 RA patients (CT-P13: n = 147; reference infliximab: n = 52) were analyzed. Median treatment duration was 1.22 years for CT-P13 and 1.40 years for reference infliximab (p = 0.67). Overall, 82% of patients received first-line therapy. Drug retention of CT-P13 versus reference infliximab was comparable for the overall population (p = 0.84) and for first-line (p = 0.66) and subsequent treatment lines (p = 0.96). Treatment changes or discontinuations occurred in 65.2% of patients with CT-P13 and 69.6% with reference infliximab. The most common reason for treatment changes or discontinuing treatment was lack of efficacy (CT-P13: 31.9%; reference infliximab: 34.8%). CT-P13 demonstrated comparable improvements in DAS28-ESR, DAS28-CRP and ACR responses to reference infliximab. Overall, 19 grade 3 AEs were reported for CT-P13 and eight for reference infliximab.\n\nConclusion\nLong-term data from patients with RA treated in routine clinical practice in Korea showed that CT-P13 had a comparable drug retention rate to reference infliximab, with similar efficacy and an acceptable safety profile.\n\nClinicalTrials.gov identifier\nNCT01965132.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s40259-019-00393-y) contains supplementary material, which is available to authorized users.\n\nhttp://dx.doi.org/10.13039/100010780Celltrion Healthcareissue-copyright-statement© Springer Nature Switzerland AG 2020\n==== Body\nKey Points\n\nPatients with rheumatoid arthritis (RA) enrolled in the Korean College of Rheumatology Biologics (KOBIO) registry were managed according to routine clinical practice, providing a comprehensive and accurate real-world assessment.\t\nLong-term data from the KOBIO registry showed that, in Korean patients with RA, CT-P13 had a comparable drug retention rate to reference infliximab, with similar efficacy and an acceptable safety profile.\t\nThe comparability of CT-P13 and reference infliximab with regard to safety, tolerability and efficacy, combined with the lower price of CT-P13, offers the opportunity for substantial cost-savings without compromising on quality of treatment or patient outcomes.\t\n\n\n\nIntroduction\nCT-P13, a chimeric monoclonal antibody against tumor necrosis factor (TNF), is a biosimilar of infliximab reference product [1]. CT-P13 was the first biosimilar monoclonal antibody to be approved by the European Medicines Agency in 2013 for the same indications as reference infliximab, including rheumatoid arthritis (RA) (in combination with methotrexate), ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis and psoriasis [1, 2]. As of July 2019, CT-P13 has been approved in 91 countries worldwide.\n\nSupporting clinical evidence for the approval of CT-P13 came from two randomized clinical trials [3]: PLANETAS, involving patients with ankylosing spondylitis [4], and PLANETRA, involving RA patients with an inadequate response to methotrexate [5]. The PLANETAS [4, 6] and PLANETRA [5, 7] studies showed that CT-P13 and reference infliximab had equivalent pharmacokinetic profiles, comparable efficacy, and no clinically important differences in safety profiles up to week 54. In the PLANETRA extension study, comparable efficacy and tolerability were observed in those patients who switched from reference infliximab to CT-P13 for an additional year and in those who received CT-P13 for 2 years [8]. Additional support regarding the comparable efficacy and safety of CT-P13 and reference infliximab comes from a randomized, double-blind trial in Japanese RA patients with an inadequate response to methotrexate [9]. Results from the extension phase of this study demonstrated that treatment with CT-P13, either long-term or after switching from reference infliximab, was well tolerated with persistent efficacy [10]. Furthermore, results from the 52-week randomized, double-blind, non-inferiority, phase IV NOR-SWITCH trial involving patients with a range of inflammatory diseases, including RA, demonstrated that switching to CT-P13 was not inferior to continued treatment with reference infliximab, with similar drug discontinuation rates [11].\n\nAs well as demonstrating the equivalence of CT-P13 and reference infliximab under clinical study conditions, it is important to show that long-term patient outcomes are comparable in the real-world clinical setting. Several real-world studies have shown that the efficacy and safety of CT-P13 are maintained during long-term treatment in patients with inflammatory rheumatologic diseases, including RA [12–17]. Although data from the DANBIO registry showed that the adjusted 1-year retention rate of CT-P13 was slightly lower than reference infliximab in a historic cohort, this difference may represent a nocebo effect [15], where patients can have worsening symptoms induced by a negative attitude towards an intervention (including switching to a biosimilar) [18]. In a recent real-life study of patients with rheumatic disease who had switched from reference infliximab to CT-P13, comparison with a historic reference infliximab cohort revealed an initial nocebo effect [14]. However, with longer follow-up, retention rates of reference infliximab and CT-P13 appeared to be identical, which confirms the safety, efficacy and acceptability of switching in the long-term [14]. These findings highlight the need for long-term follow-up data in real-world studies.\n\nThe Korean College of Rheumatology Biologics (KOBIO) registry is an ongoing, multi-center, prospective, observational study designed to collect real-world data on patients being treated with biologic disease-modifying antirheumatic drugs (DMARDs) in Korea [19–21]. The aim of this analysis from the KOBIO registry was to evaluate drug retention rates, discontinuations, efficacy and safety of CT-P13 and reference infliximab in Korean patients with RA who were followed for up to 4 years. In addition, we also investigated outcomes in patients receiving CT-P13 or reference infliximab as first-line or subsequent therapy.\n\nMaterials and Methods\nStudy Population\nData were collected through KOBIO, a nationwide registry in Korea established in December 2012 to capture data on the use of biologic agents (ClinicalTrials.gov identifier: NCT01965132) [21]. The KOBIO registry was established as an inception cohort, enrolling patients with a diagnosis of RA, ankylosing spondylitis or psoriatic arthritis at the time of initiating, restarting or changing a biologic [19–21].\n\nPatients aged ≥ 18 years were eligible for inclusion in the KOBIO registry if they had RA that required treatment with a biologic or non-biologic DMARD, as deemed by their rheumatologist [21]. Patients already on biologic therapy at screening were excluded from the registry. Participation in the registry did not require any additional visits or laboratory tests outside routine clinical practice.\n\nThis analysis presents data from patients with RA who had received CT-P13 or reference infliximab, concurrent with methotrexate per the label, between December 2012 and December 2017. Patients were excluded from this analysis if they did not receive treatment with CT-P13 or reference infliximab.\n\nAll patient treatments were determined by the treating physician, including the selection of biologic, dosing and treatment duration. The present analysis was conducted according to the principles of the Declaration of Helsinki. All patients provided written consent to participate in the registry, and the data collection form and study protocol were approved by institutional review boards (Ajou University Hospital; AJIRB-MED-MDB-17-505) or local ethics committees at each participating center.\n\nData Collection and Outcomes Measured\nData were collected annually from participating hospitals using standardized case report forms. The following baseline data were collected for this analysis: age, gender, body mass index, smoking history, disease duration, disease activity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor positivity, anti-cyclic citrullinated peptide positivity, previous DMARD use, corticosteroid use and line of therapy.\n\nThe primary outcome measure for this analysis was drug retention (i.e., time to treatment discontinuation or changing to another biologic). Data were collected on treatment dates and lines of therapy, treatment changes and reasons for changing, and discontinuations and reasons for discontinuation. Discontinuation was defined as permanent discontinuation of biologic therapy.\n\nEfficacy was assessed using the Disease Activity Score in 28 joints (DAS28)-ESR or DAS28-CRP score, and the American College of Rheumatology (ACR) core set measure. The response rates were reported using per-protocol analysis. The DAS28 scale ranges from 0 to 9.4, where a score < 2.6 indicates remission, ≥ 2.6 to < 3.2 low disease activity, ≥ 3.2 to ≤ 5.1 moderate disease activity, and > 5.1 highly active disease [22]. ACR20 indicates a 20% improvement in both tender and swollen joint counts and three out of five other measures within the ACR core set of disease activity measures [23]. ACR50 and ACR70 correspond to 50% and 70% improvement, respectively. The number of patients with adverse events (AEs), defined using the Medical Dictionary for Regulatory Activities (version 17.0), during treatment with biologics was evaluated. AEs were also assessed after changing biologic or after discontinuation of biologic therapy. Those patients who did not have a documented time to discontinuation were included in the analyses of baseline demographics, efficacy and safety, but were excluded from analysis of drug retention rate.\n\nStatistical Analyses\nDrug retention rates were analyzed using Kaplan–Meier survival curves and were compared statistically using a log-rank test. Confidence bands were calculated using the method of Hall and Wellner [24]. Baseline demographics and disease characteristics were compared between treatment groups using a Chi squared test of homogeneity for categorical variables and t test for continuous variables. Efficacy measured by DAS28 score was compared statistically with p values calculated using a two-sided Wilcoxon rank-sum test. All statistical analyses were performed using SAS statistical software (version 9.4, SAS Institute), and p values < 0.05 were considered statistically significant.\n\nResults\nPatient Characteristics\nData from 199 patients with RA enrolled in the KOBIO registry between December 2012 and December 2017 were analyzed, of whom 147 patients were treated with CT-P13 and 52 patients with reference infliximab. Data are presented for the number of enrolled patients, although missing data, such as ESR, CRP or questionnaire answers meant that for some parameters, data were not available for all patients. In addition, 12 patients treated with CT-P13 and eight patients treated with reference infliximab were lost to follow-up and were excluded from some analyses.\n\nPatient baseline demographics and characteristics were similar between groups (Table 1). Patients had a mean age of 51.8 years [standard deviation (SD) ± 12.2 years]. Mean DAS28-CRP (5.0, SD ± 1.2) and DAS28-ESR (5.7, SD ± 1.1) scores at baseline were consistent with a patient population with moderate-to-severely active RA [22]. The mean duration of disease at baseline was 7.4 years (SD ± 7.6 years), indicative of a patient population with long-established RA. At baseline, almost all patients (96.5%) had been previously treated with DMARDs and concurrent corticosteroid use was reported in 87.9% of patients. The majority of patients (82.4%) received first-line infliximab therapy (CT-P13: n = 124/147, 84.4%; reference infliximab: n = 40/52, 76.9%), with second or subsequent lines of therapy received by 17.6% of patients (CT-P13: n = 23/147, 15.6%; reference infliximab: n = 12/52, 23.1%).Table 1 Baseline patient characteristics\n\nCharacteristic\tAll patients (N = 199)\tCT-P13 (N = 147)\tReference infliximab (N = 52)\tP value\t\nAge, years\t51.8 (12.2)\t51.3 (12.4)\t53.3 (11.5)\t0.30\t\nDisease duration, years\t7.4 (7.6)\t7.7 (7.6)\t6.5 (7.7)\t0.35\t\nMale, n (%)\t28 (14.1)\t18 (12.2)\t10 (19.2)\t0.21\t\nBMI, kg/m2\t22.9 (4.0)\t23.0 (4.2)\t22.8 (3.3)\t0.75\t\nSmoking history, n (%)\t0.55\t\n Ex-smoker\t13 (6.5)\t9 (6.1)\t4 (7.7)\t–\t\n Current smoker\t14 (7.0)\t12 (8.2)\t2 (3.8)\t–\t\n Never\t172 (86.4)\t126 (85.7)\t46 (88.5)\t–\t\nTender joint count\t9.9 (8.2)\t9.9 (7.5)\t9.8 (10.1)\t0.92\t\nSwollen joint count\t7.5 (6.2)\t7.7 (5.9)\t6.9 (7.2)\t0.45\t\nESR, mm/h\t52.6 (27.4)\t53.8 (28.1)\t49.1 (25.3)\t0.29\t\nCRP, mg/dL\t2.9 (5.3)\t3.1 (6.0)\t2.4 (2.4)\t0.24\t\nDAS28-ESR\t5.7 (1.1)\t5.7 (1.2)\t5.5 (1.1)\t0.29\t\nDAS28-CRP\t5.0 (1.2)\t5.0 (1.2)\t4.9 (1.1)\t0.43\t\nRheumatoid factor (positivity), n (%)\t163 (81.9)\t117 (79.6)\t46 (88.5)\t0.12\t\nAnti-CCP (positivity), n (%)\t139 (69.8)\t99 (67.3)\t40 (76.9)\t0.055\t\nPrevious DMARD use, n (%)\t192 (96.5)\t142 (96.6)\t50 (96.2)\t0.88\t\nMethotrexate dose, mg/week, median (IQR)\t15 (10─15)\t15 (12.5─15)\t15 (10─15)\t0.59\t\nCorticosteroid use, n (%)\t175 (87.9)\t127 (86.4)\t48 (92.3)\t0.26\t\nCorticosteroid dose, dose equivalent for prednisolone in mg/day, median (IQR)\t5 (2.5─7.5)\t5 (2.5─7.5)\t6 (4─8)\t0.013\t\nInfliximab treatment line, n (%)\t0.23\t\n 1st line\t164 (82.4)\t124 (84.4)\t40 (76.9)\t–\t\n ≥ 2nd line\t35 (17.6)\t23 (15.6)\t12 (23.1)\t–\t\nData presented are mean (standard deviation), unless otherwise indicated\n\nBMI body mass index, CCP cyclic citrullinated peptide, CRP C-reactive protein, DAS28 disease activity score in 28 joints, DMARD disease-modifying antirheumatic drug, ESR erythrocyte sedimentation rate, IQR interquartile range\n\n\n\nTreatment Duration and Drug Retention\nTreatment duration is shown in Supplementary Table 1 (see the electronic supplementary material, Online Resource 1). Overall, the median duration of treatment was 1.22 years (range 0.54–2.31) with CT-P13 and 1.40 years (range 0.43–3.16) with reference infliximab (p = 0.67). Irrespective of treatment group, duration of first-line therapy was longer than subsequent lines of therapy (Supplementary Table 1 in Online Resource 1). The median treatment duration in patients receiving first-line or subsequent CT-P13 therapy was 1.32 (range 0.58–2.47) and 0.83 years (range 0.35–1.97), respectively, and in those receiving first-line or subsequent reference infliximab therapy, it was 1.65 (range 0.43–3.16) and 0.58 years (range 0.42–3.42), respectively.\n\nOverall, there was no difference in drug retention with CT-P13 and reference infliximab (log-rank p = 0.84; Fig. 1a). Drug retention was also similar between CT-P13 and reference infliximab groups in patients who received first-line therapy (p = 0.66; Fig. 1b) and subsequent treatment lines (p = 0.96; Fig. 1c). After 4 years’ follow-up, the retention rate was 17.5% for CT-P13 and 33.6% for reference infliximab in the overall patient population. In patients receiving first-line therapy, the retention rate was 15.7% for CT-P13 and 35.4% for reference infliximab.Fig. 1 Drug retention in a all patients, b patients treated with first-line therapy and c patients treated with second-line or subsequent therapy. Shading indicates 95% Hall-Wellner bands. + indicates censored patients\n\n\n\nTreatment Changes and Discontinuations\nReasons for changing to another agent or discontinuing treatment are presented in Table 2. Overall, the rate of treatment changes or discontinuations was similar between the CT-P13 and reference infliximab groups (65.2% vs 69.6%, respectively). The most common reason for treatment changes or discontinuations was lack of efficacy (CT-P13: 31.9%; reference infliximab: 34.8%). Treatment changes or discontinuations due to an AE were reported in 20.0% of patients in the CT-P13 group and 23.9% of patients in the reference infliximab group. A similar proportion of patients in the CT-P13 group and reference infliximab groups changed or discontinued therapy after achieving clinical remission (3.0% and 4.3%, respectively).Table 2 Reasons for discontinuation of therapy or changing to another biologic\n\n\tCT-P13 (N = 135)\tReference infliximab (N = 46)\t\nChanged, n (%)\tDiscontinued treatment, n (%)\tTotal, n (%)\tChanged, n (%)\tDiscontinued treatment, n (%)\tTotal, n (%)\t\nLack of efficacy\t35 (25.9)\t8 (5.9)\t43 (31.9)\t14 (30.4)\t2 (4.3)\t16 (34.8)\t\nAE\t18 (13.3)\t9 (6.7)\t27 (20.0)\t4 (8.7)\t7 (15.2)\t11 (23.9)\t\nClinical remission\t–\t4 (3.0)\t4 (3.0)\t–\t2 (4.3)\t2 (4.3)\t\nOther reasons\t6 (4.4)a\t8 (5.9)b\t14 (10.4)\t–\t2 (4.3)c\t2 (4.3)\t\nUnspecified\t–\t–\t–\t–\t1 (2.2)\t1 (2.2)\t\nTotal\t59 (43.7)\t29 (21.5)\t88 (65.2)\t18 (39.1)\t14 (30.4)\t32 (69.6)\t\nAE adverse event\n\naReasons include removal of prescription code for CT-P13 (n = 6)\n\nbReasons include patient’s decision (n = 5), planning for pregnancy (n = 2) and scheduled surgery (n = 1)\n\ncReasons include patient’s decision (n = 1) and planning for pregnancy (n = 1)\n\n\n\nA similar proportion of patients in each treatment group changed biologic therapy (CT-P13: 43.7%; reference infliximab: 39.1%) or discontinued treatment (CT-P13: 21.5%; reference infliximab: 30.4%; Table 2). Of those patients who changed biologic therapy in the CT-P13 and reference infliximab groups, the most commonly cited reason was lack of efficacy (Table 2). AEs were the most commonly cited reason for discontinuing treatment with CT-P13 or reference infliximab (Table 2). AEs leading to treatment discontinuation or changing to another biologic are shown in Supplementary Table 2 (Online Resource 1). Infusion-related reactions were the most common AEs resulting in treatment changes (CT-P13: 12 events; reference infliximab: two events) and treatment discontinuation (CT-P13: three events; reference infliximab: three events).\n\nSimilar proportions of patients receiving first-line CT-P13 or reference infliximab changed biologic (44.2% and 42.9%, respectively) or discontinued treatment (20.4% and 22.9%, respectively; Supplementary Table 3, Online Resource 1). Reasons for discontinuing treatment or changing to another biologic by line of therapy are presented in Supplementary Table 3 (Online Resource 1). Overall, 15 out of 22 patients (68.2%) in the CT-P13 group and nine out of 11 patients (81.8%) in the reference infliximab group changed or discontinued treatment during second-line or subsequent therapy.\n\nThe drugs received following treatment with CT-P13 and reference infliximab are summarized in Supplementary Table 4 (Online Resource 1). Tocilizumab was the most commonly substituted drug following first-line treatment with CT-P13 and reference infliximab (34.0% and 73.3%, respectively). Adalimumab was also commonly used following first-line treatment with CT-P13 (26.0%), but was not substituted after first-line reference infliximab.\n\nEfficacy\nCT-P13 demonstrated similar efficacy to reference infliximab with comparable improvements observed over time (Figs. 2 and 3). Over the 4-year observation period, treatment with either CT-P13 or reference infliximab resulted in a substantial reduction in disease activity from baseline, assessed by DAS28-ESR and DAS28-CRP (Fig. 2). After 2 years of treatment with either CT-P13 or reference infliximab, DAS28-ESR and DAS28-CRP scores corresponded to low disease activity/disease remission, and disease control was maintained up to 4 years after initiating treatment. ACR20 response rates in the first year of treatment were 57.3% with CT-P13 and 45.8% with reference infliximab, and increased in the second year of treatment (CT-P13: 82.1%; reference infliximab: 62.1%; Fig. 3). ACR50 and ACR70 response rates showed a pattern consistent with ACR20 responses, where the proportion of patients responding increased between the first and second years of treatment and were numerically higher in the CT-P13 group compared with the reference infliximab group (Fig. 3).Fig. 2 Efficacy measured by a DAS28-ESR and b DAS28-CRP scores. DAS28-CRP disease activity score in 28 joints–C-reactive protein, DAS28-ESR disease activity score in 28 joints–erythrocyte sedimentation rate\n\nFig. 3 ACR response by duration of follow-up. ACR American College of Rheumatology, ACR20 20% response as defined by ACR, ACR50 50% response as defined by ACR, ACR70 70% response as defined by ACR\n\n\n\nSafety\nOverall, 19 grade 3 AEs were reported in the CT-P13 group and eight in the reference infliximab group (Table 3). There were four grade 3 AEs considered to be related to CT-P13 (one infusion/injection reaction; one infection, not specified; one case of mononeuritis multiplex; and one case of skin rash). No drug-related grade 3 AEs were reported with reference infliximab. Infusion-related reactions were the most commonly reported AEs (CT-P13: 16 events; reference infliximab: seven events), followed by infection (CT-P13: 11 events; reference infliximab: four events). There were no cases of tuberculosis reported with either treatment. Two cases of malignant solid tumors (one case of malignant melanoma and one case of thyroid cancer) were reported with CT-P13. Three cases of malignancy (one case of lymphoma and two cases of oral cavity mass) were reported with reference infliximab. Of these malignancies, only lymphoma was deemed related to treatment. One death was reported in each group, due to pneumonia (CT-P13 group) and cardiac arrest (reference infliximab group).Table 3 Summary of adverse events of interest\n\nAE, number of events\tCT-P13 (N = 147)\tReference infliximab (N = 52)\t\nAE, grade 3\t19\t8\t\nDrug-related AE, grade 3\t4\t0\t\nInfusion-related reaction\t16\t7\t\nInfection\t11\t4\t\nTuberculosis\t0\t0\t\nMalignancy\t2\t3\t\nAE adverse event\n\n\n\nDiscussion\nThis prospective, registry-based, observational study presents real-life data on the long-term retention, efficacy and safety of CT-P13 compared with reference infliximab in Korean patients with RA. Our analysis showed that drug retention was comparable in patients treated with CT-P13 and reference infliximab, irrespective of treatment line. CT-P13 provided similar long-term clinical benefit to reference infliximab. Treatment with both CT-P13 and reference infliximab resulted in a substantial reduction in DAS28-ESR and DAS28-CRP scores over the 4-year observation period. Furthermore, DAS28-ESR and DAS28-CRP scores corresponded to low disease activity/disease remission after 2 years of treatment with either CT-P13 or reference infliximab, and disease control was maintained up to 4 years after initiating treatment.\n\nFor observational registries, drug survival may be regarded as a reliable indicator of overall treatment effectiveness [25]. Registry-based studies in patients with RA who received first-line reference infliximab, including the Swedish Biologics Register ARTIS [26] and a local Italian registry [25], have reported drug survival rates of 38–44.3% after 5 years. The Danish DANBIO registry reported a drug survival rate of 41% for reference infliximab after 2 years [27]. The reference infliximab retention rates found in our study were similar to previous reports, with a retention rate of 33.6% in the overall patient population and 35.4% in patients receiving first-line therapy, after 4 years’ follow-up. The main reason for drug discontinuation in the observational registry studies was lack of efficacy and AEs [25–27], which is consistent with our study. Our analysis demonstrated that drug retention was comparable in patients treated with CT-P13 and reference infliximab irrespective of treatment line. This is consistent with the data reported by Germain et al., who observed similar treatment retention rates among patients with rheumatic disease who had switched from reference infliximab to CT-P13 (56%, median follow-up 120 weeks), compared with a historic reference infliximab cohort (67%, median follow-up 131 weeks; p = 0.052) [14].\n\nIn the current study, the efficacy of CT-P13 and reference infliximab (in combination with methotrexate) was comparable when measured using the continuous disease activity measure of DAS28 and the dichotomous measure of ACR20 response in a patient population with highly active disease of long duration. We observed 1-year ACR20 response rates of 57.3% and 45.8% with CT-P13 and reference infliximab, respectively. Similarly, the PLANETRA randomized controlled study showed that CT-P13 and reference infliximab were comparable in terms of efficacy, although higher ACR20 response rates of 74.7% and 71.3% were achieved after 54 weeks of combined treatment with methotrexate plus CT-P13 or reference infliximab, respectively [7]. These higher response rates may reflect the fact that clinical trials have strict inclusion criteria and enrolled patients may not always be representative of the entire real-world patient population. Indeed, analysis of data from the German RABBIT registry has shown that only 21–33% of patients with RA treated with reference infliximab in RABBIT would have been eligible for major trials, with ineligible patients having lower response rates but similar absolute improvement [28].\n\nCT-P13 was well tolerated during our study and displayed a long-term safety profile consistent with that of reference infliximab, with no clinically important differences. Consistent with the 54-week PLANETRA phase 3 clinical study [7], infusion-related reactions were the most commonly reported AEs in our analysis (CT-P13: 16 events; reference infliximab: seven events). Although it is established that patients with RA are at an increased risk of lymphoma compared with the general population, TNF inhibitor (TNFi) treatment does not appear to increase lymphoma risk [29–31]. The case of lymphoma deemed to be related to CT-P13 reported in our analysis does not raise safety concerns due to the known increased risk of lymphoma in patients with RA; however, the incidence of lymphoma in patients treated with TNFis should continue to be closely monitored. TNFis are associated with an increased risk of serious infections in RA [31], and infections are the most common serious AEs associated with CT-P13 and reference infliximab during post-marketing spontaneous reporting [32, 33]. In the current study, one serious infection was reported in the CT-P13 group (pneumonia). Reassuringly, this study reported no cases of active tuberculosis infection with either infliximab product.\n\nIn addition to offering efficacy and safety comparable with reference infliximab, the introduction of CT-P13 for the treatment of RA offers the potential for substantial cost-savings, given the high contribution of medication to overall treatment costs for RA [34, 35]. Introduction of lower-priced infliximab biosimilars, including CT-P13, might increase patient access to treatment, particularly in those countries where reference infliximab is not recommended due to cost constraints [35–37]. In addition, the NOR-SWITCH study has provided support for non-medical switching from reference infliximab to CT-P13 [11, 38]. In 2014, the Norwegian health authorities recommended CT-P13 for patients initiating infliximab treatment; as a result, the cost saving in Norway for CT-P13 versus reference infliximab increased from 39% in 2014 to 69% in 2015 [11]. Such cost savings could significantly impact CT-P13 uptake and, consequently, healthcare budgets in many countries [11, 38]. Direct medical costs for both patients and the payer were reduced following the introduction of biosimilar infliximab in the South Korean healthcare market, which could potentially be used to increase patient access to biologics [39]. Moreover, the introduction of infliximab biosimilars in the United Kingdom resulted in substantial cost-savings in the first 2 years of use [40], and considerable budget reductions are predicted for the roll out of infliximab biosimilars in other European countries [35, 41]. While treatment with intravenous CT-P13 is effective and well tolerated, a subcutaneous formulation of CT-P13 is being developed for self-administration [42, 43], offering the potential for improved patient compliance and reduced costs to healthcare systems [44].\n\nThrough the KOBIO registry, patients were managed according to routine clinical practice, providing a comprehensive and accurate real-world assessment. Strengths of our analysis include the prospective nature of data collection in the KOBIO registry, the long follow-up period, and the relatively large patient population. The main limitation of the current study is related to its observational design, which relies on passive reporting of safety events and may lead to under-estimation of incidence. Few patients included in this analysis received infliximab as second-line or subsequent therapy, precluding analysis of the reasons for discontinuing therapy in this population. Furthermore, the generalizability of our results to other countries may be influenced by the stringent Korean National Health Insurance reimbursement criteria for TNFi eligibility [45]; hence, the patient population in this analysis may not be representative of patient populations undergoing infliximab treatment in other countries and, subsequently, outcomes may vary.\n\nConclusion\nIn conclusion, long-term data from this nationwide cohort of Korean patients with RA treated in routine clinical practice showed that CT-P13 had a comparable drug retention rate to reference infliximab, with similar efficacy and an acceptable safety profile. The proven comparability of CT-P13 and reference infliximab safety, tolerability and efficacy, and the lower price of CT-P13, offers the opportunity for substantial cost-savings without compromising on quality of treatment or patient outcomes.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (PDF 399 kb)\n\n \n\nAcknowledgements\nMedical writing support (including development of a draft outline and subsequent drafts in consultation with the authors, assembling tables and figures, collating author comments, copyediting, fact checking and referencing) was provided by Julianna Solomons, PhD, at Aspire Scientific (Bollington, UK), and funded by Celltrion Healthcare Co., Ltd. (Incheon, Republic of Korea).\n\nAuthor contributions\nHAK, EL, YNL, HJK, and KS made a substantial contribution to the conception or design of the study; and all authors made a substantial contribution to the acquisition, analysis, and interpretation of the data and manuscript development, and gave final approval of the manuscript for submission.\n\nCompliance with Ethical Standards\nFunding\nThis study was supported by Celltrion Healthcare Co., Ltd.\n\nConflict of interest\nYoung Nam Lee and Hee Jung Kang are employees of Celltrion Healthcare Co., Ltd. Hyoun-Ah Kim, Eunyoung Lee, Sun-Kyung Lee, Yong-Beom Park, and Kichul Shin have no conflicts to declare.\n\nResearch including human participants\nThe present analysis was conducted according to the principles of the Declaration of Helsinki. The data collection form and study protocol were approved by institutional review boards (Ajou University Hospital; AJIRB-MED-MDB-17-505) or local ethics committees at each participating center.\n\nInformed consent\nAll patients provided written consent to participate in the registry.\n\nData availability statement\nAll available data are reported in the manuscript and supplementary file.\n==== Refs\nReferences\n1. European Medicines Agency. European Public Assessment Report: Remsima. 2013. https://www.ema.europa.eu/documents/assessment-report/remsima-epar-public-assessment-report_en.pdf. Accessed 05 Feb 2019.\n2. McKeage K A review of CT-P13: an infliximab biosimilar BioDrugs. 2014 28 3 313 321 10.1007/s40259-014-0094-1 24723086 \n3. 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Avouac J Molto A Abitbol V Etcheto A Salcion A Gutermann L Systematic switch from innovator infliximab to biosimilar infliximab in inflammatory chronic diseases in daily clinical practice: the experience of Cochin University Hospital, Paris, France Semin Arthritis Rheum. 2018 47 5 741 748 10.1016/j.semarthrit.2017.10.002 29102156 \n14. Germain V, Scherlinger M, Barnetche T, Schaeverbeke T, Federation Hospitalouniversitaire Acronim. Long-term follow-up after switching from originator infliximab to its biosimilar CT-P13: the weight of nocebo effect. Ann Rheum Dis. 2018 (E-pub ahead of print).\n15. Glintborg B Sorensen IJ Loft AG Lindegaard H Linauskas A Hendricks O A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry Ann Rheum Dis 2017 76 8 1426 1431 10.1136/annrheumdis-2016-210742 28473425 \n16. 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Development of a subcutaneous formulation of CT-P13 (infliximab): maintenance subcutaneous administration may elicit lower immunogenicity compared to intravenous treatment. Arthritis Rheumatol. 2018;70(Abstract 2514).\n44. Viola M Sequeira J Seica R Veiga F Serra J Santos AC Subcutaneous delivery of monoclonal antibodies: how do we get there? J Control Release 2018 286 301 314 10.1016/j.jconrel.2018.08.001 30077735 \n45. Hur JW Choe JY Kim DW Kim HA Kim SH Kim WU Rheumatoid arthritis patients fulfilling Korean National Health Insurance reimbursement guidelines for anti-tumor necrosis factor-alpha treatment and comparison to other guidelines Rheumatol Int 2015 35 11 1817 1823 10.1007/s00296-015-3353-7 26342296\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1173-8804",
"issue": "34(1)",
"journal": "BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy",
"keywords": null,
"medline_ta": "BioDrugs",
"mesh_terms": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D059451:Biosimilar Pharmaceuticals; D001799:Blood Sedimentation; D057915:Drug Substitution; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012042:Registries; D056910:Republic of Korea; D012219:Rheumatology; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "9705305",
"other_id": null,
"pages": "89-98",
"pmc": null,
"pmid": "31734899",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": "26343027;24285495;23687259;26342296;27586879;28721016;26395836;30269270;30077735;27919202;28331376;24832837;24723086;27502891;7779114;25736355;30352888;29667324;28473425;29127626;24961712;28298374;29998827;28243760;28822981;29102156;29352847;22473918;28502609;30762274;23687260;26795209;17075823;27038608;27130908;28903543;26556048;20039405",
"title": "Retention Rate and Safety of Biosimilar CT-P13 in Rheumatoid Arthritis: Data from the Korean College of Rheumatology Biologics Registry.",
"title_normalized": "retention rate and safety of biosimilar ct p13 in rheumatoid arthritis data from the korean college of rheumatology biologics registry"
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"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "103772",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RHEUMATOID ARTHRITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "REMICADE"
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Lymphoma",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KIM H, LEE E, ?LEE S, PARK Y, LEE Y, KANG H, SHIN K. RETENTION RATE AND?SAFETY OF?BIOSIMILAR CT-P13 IN?RHEUMATOID ARTHRITIS: DATA FROM?THE?KOREAN COLLEGE OF?RHEUMATOLOGY BIOLOGICS REGISTRY. BIODRUGS. 2020??34(1):89-98.",
"literaturereference_normalized": "retention rate and safety of biosimilar ct p13 in rheumatoid arthritis data from the korean college of rheumatology biologics registry",
"qualification": "3",
"reportercountry": "KR"
},
"primarysourcecountry": "KR",
"receiptdate": "20200221",
"receivedate": "20200221",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 17447612,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "OBJECTIVE\nTo describe management of anterior migration of a fluocinolone acetonide(FAc) intravitreal implant.\n\n\nMETHODS\nA retrospective case report. A 61-year-old man with diabetic macular edema and prior vitrectomy had anterior migration of a FAc implant. Anterior segment photos and optical coherence tomography were performed.\n\n\nRESULTS\nApproximately 3 months after FAc implant was administered, it was noted to have migrated into the anterior chamber. Vision, intraocular pressure, and optical coherence tomography imaging initially remained stable, and no evidence of detectable corneal edema developed in 30 months of follow-up. However, at 36 months of follow-up, after second FAc implant injection, mild corneal edema developed,suspected to be related to the migrating implants.\n\n\nCONCLUSIONS\nAnterior migration of a FAc implant may lead to less rapid and severe corneal decompensation compared with other steroid implants. Despite this, delayed corneal edema may occur. Careful monitoring of the cornea and intraocular pressure is recommended in cases of anterior FAc migration.",
"affiliations": "Department of Ophthalmology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.;Department of Ophthalmology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.;Department of Ophthalmology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.",
"authors": "Gunzenhauser|Robert C|RC|;Greven|Margaret A|MA|;John|Vishak J|VJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000897",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": null,
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31339874",
"pubdate": "2019-07-17",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "ANTERIOR MIGRATION OF INTRAVITREAL FLUOCINOLONE ACETONIDE IMPLANTS: A CASE REPORT.",
"title_normalized": "anterior migration of intravitreal fluocinolone acetonide implants a case report"
} | [
{
"companynumb": "US-ROCHE-3013290",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "4",
"drugadministrationroute": "050",
"drugauthorizationnumb": "125085",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Infusion, Solution",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Diabetic retinal oedema",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BEVACIZUMAB"
}
],
"patientagegroup": null,
"patientonsetage": "61",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "No adverse event",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Gunzenhauser R, Greven M and John V. ANTERIOR MIGRATION of INTRAVITREAL FLUOCINOLONE ACETONIDE IMPLANTS: A CASE REPORT. Retinal Cases and Brief Reports 2022 Jan 01;16 (1):67-9.",
"literaturereference_normalized": "anterior migration of intravitreal fluocinolone acetonide implants a case report",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20220419",
"receivedate": "20220419",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 20727676,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220720"
}
] |
{
"abstract": "Vemurafenib is a specific inhibitor of the V600E mutated BRAF protein kinase used for the treatment of unresectable or metastatic melanoma harboring this mutation. Multiple predictable side effects have been described with use of this targeted therapy, and implicate BRAF and mitogen activated protein kinase (MAPK) signaling pathways in their pathogenesis. Herein, we report the novel finding of an interface dermatitis in radiation recall and a keratosis pilaris-like clinical reaction in a patient treated with vemurafenib.",
"affiliations": "Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA.",
"authors": "Braunstein|Inbal|I|;Gangadhar|Tara C|TC|;Elenitsas|Rosalie|R|;Chu|Emily Y|EY|",
"chemical_list": "D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib",
"country": "United States",
"delete": false,
"doi": "10.1111/cup.12318",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": "41(6)",
"journal": "Journal of cutaneous pathology",
"keywords": "dermatopathology; melanoma; radiation therapy",
"medline_ta": "J Cutan Pathol",
"mesh_terms": "D000015:Abnormalities, Multiple; D000328:Adult; D000970:Antineoplastic Agents; D007644:Darier Disease; D003875:Drug Eruptions; D005138:Eyebrows; D006801:Humans; D007211:Indoles; D008297:Male; D008545:Melanoma; D012878:Skin Neoplasms; D013449:Sulfonamides; D000077484:Vemurafenib",
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "539-43",
"pmc": null,
"pmid": "24517243",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vemurafenib-induced interface dermatitis manifesting as radiation-recall and a keratosis pilaris-like eruption.",
"title_normalized": "vemurafenib induced interface dermatitis manifesting as radiation recall and a keratosis pilaris like eruption"
} | [
{
"companynumb": "US-ROCHE-1356903",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "202429",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MALIGNANT MELANOMA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "960",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VEMURAFENIB"
}
],
"patientagegroup": null,
"patientonsetage": "37",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Keratosis pilaris",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Recall phenomenon",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dermatitis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Wound dehiscence",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BRAUNSTEIN I, GANGADHAR T, ELENITSAS R, AND CHU E. VEMURAFENIB INDUCED INTERFACE DERMATITIS MANIFESTING AS RADIATION RECALL AND A KERATOSIS PILARIS LIKE ERUPTION. J CUTAN PATHOL 2014 FEB 12;:-.",
"literaturereference_normalized": "vemurafenib induced interface dermatitis manifesting as radiation recall and a keratosis pilaris like eruption",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20161219",
"receivedate": "20161219",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13041661,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170207"
}
] |
{
"abstract": "OBJECTIVE\nRecently, there have been an increased number of reports on levetiracetam (LEV) induced cutaneous adverse drug reactions (CADRs). We aimed to identify and critically evaluate all the descriptive studies on LEV induced-CADRs and to describe the possible clinical manifestations, management, and treatment outcomes of the condition.\n\n\nMETHODS\nPubMed and grey literature databases were searched from inception to June 2019 without any restriction. We also performed a bibliographic search for additional studies. Only descriptive studies on LEV-induced CADRs were included for our review. Study selection, data abstraction and quality assessment were performed by two contributors independently and disagreements were settled through consensus or through discussion with a third reviewer.\n\n\nRESULTS\nData from 24 out of 88 studies, which included 25 patients (12 female and 13 male) aged from 40 weeks to 73 years, were reviewed. Patients received between 500 mg/day to 3000 mg/day of LEV. Drug reaction with eosinophilia and systemic symptoms syndrome, Steven-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis, generalised hyperpigmentation and leucocytoclastic vasculitis were observed among the included patients. Immediate cessation of LEV, providing supportive care and use of topical antihistamines and anti-inflammatory drugs appeared to be the mainstay of management, and all patients were found to have recovered.\n\n\nCONCLUSIONS\nClinicians should be aware of the possible CADRs induced by LEV to avoid the development of a potentially fatal condition. Immediate withdrawal of the drug and supporting care seem to be effective in the management of the CADRs.\nInternational Prospective Register for Systematic Reviews (PROSPERO) number CRD42019141002.",
"affiliations": "Department of Pharmacy Practice, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, BG Nagara, Karnataka, 571448, India. Electronic address: muhammedrashid2@gmail.com.;Department of Pharmacy Practice, Jaya College of Pharmacy, Thiruninravur, Chennai, Tamil Nadu, 602024 India. Electronic address: ashapharmd523@gmail.com.;Department of Pharmacy Practice, Indo-Soviet Friendship College of Pharmacy, Moga, Punjab, 142001 India. Electronic address: manikchhabra57@gmail.com.;Department of Pharmacy Practice, Sarada Vilas College of Pharmacy, Mysuru, Karnataka, 570004, India. Electronic address: ananthkashyap77@gmail.com.",
"authors": "Rashid|Muhammed|M|;Rajan|Asha K|AK|;Chhabra|Manik|M|;Kashyap|Ananth|A|",
"chemical_list": "D000927:Anticonvulsants; D006633:Histamine Antagonists; D000077287:Levetiracetam",
"country": "England",
"delete": false,
"doi": "10.1016/j.seizure.2020.01.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "75()",
"journal": "Seizure",
"keywords": "Adverse drug reaction; Cutaneous reactions; Seizure disorder; Systematic review; levetiracetam",
"medline_ta": "Seizure",
"mesh_terms": "D000927:Anticonvulsants; D003875:Drug Eruptions; D004827:Epilepsy; D006633:Histamine Antagonists; D006801:Humans; D000077287:Levetiracetam; D028761:Withholding Treatment",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "101-109",
"pmc": null,
"pmid": "31931437",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Levetiracetam and cutaneous adverse reactions: A systematic review of descriptive studies.",
"title_normalized": "levetiracetam and cutaneous adverse reactions a systematic review of descriptive studies"
} | [
{
"companynumb": "IN-DEXPHARM-20200103",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATOVAQUONE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ATOVAQUONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEUCOVORIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "TOXOPLASMOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVETIRACETAM."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACYCLOVIR"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ACYCLOVIR."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFADIAZINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SULPHADIAZINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PYRIMETHAMINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PYRIMETHAMINE"
}
],
"patientagegroup": "5",
"patientonsetage": "57",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Mental impairment",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RASHID M, RAJAN A, CHHABRA M, KASHYAP A. LEVETIRACETAM AND CUTANEOUS ADVERSE REACTIONS: A SYSTEMATIC REVIEW OF DESCRIPTIVE STUDIES. SEIZURE. 2020?75:101-109.",
"literaturereference_normalized": "levetiracetam and cutaneous adverse reactions a systematic review of descriptive studies",
"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20200204",
"receivedate": "20200204",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 17364822,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "OBJECTIVE\nTo assess whether extracorporeal treatment (ECTR) improves outcome of patients with metformin-associated lactic acidosis (MALA) and to evaluate the clinical applicability of the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) criteria for starting ECTR in metformin poisoning.\n\n\nMETHODS\nPatients with metformin serum concentrations above 2 mg/l who were admitted in the Deventer Teaching Hospital between January 2000 and July 2019 and complied with the definition of MALA (pH < 7.35 and lactate concentration > 5 mmol/l) were included. Mortality and clinical parameters of patients treated with ECTR or not were compared. In addition, treatment of MALA in clinical practice was verified against the criteria of EXTRIP.\n\n\nRESULTS\nForty-two patients were included. Lactate (13.8 versus 10.5 mmol/l, p = 0.01), creatinine (575 versus 254 umol/l, p < 0.01)), metformin (29.4 versus 8.6 mg/l, p < 0.01) concentrations, and vasopressor requirement (72% versus 23%, p < 0.01) were significantly higher in the ECTR-group. Blood pH (7.05 versus 7.19, p = 0.03) and bicarbonate (6 versus 11 mmol/l, p < 0.01) were significantly lower. Mortality, length of hospital stay, and mechanical ventilation requirement were not statistically different. In 83% of patients, treatment of MALA was in accordance with the EXTRIP criteria.\n\n\nCONCLUSIONS\nAlthough there was no statistical benefit in mortality shown from ECTR, ECTR might be lifesaving in MALA, considering the ECTR-group was significantly sicker than the non-ECTR-group. The majority of patients were treated in line with the EXTRIP criteria. Severity of lactic acidosis and renal impairment were the main indications for initiating ECTR.",
"affiliations": "Department of Clinical Pharmacy, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, P.O. Box 5001, 7400 GC, Deventer, The Netherlands. i.vanberlo-vandelaar@dz.nl.;Department of Internal Medicine, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE, Deventer, The Netherlands.;Department of Research and Innovation, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE, Deventer, The Netherlands.;Department of Intensive Care, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE, Deventer, The Netherlands.;Unit of PharmacoTherapy, -Epidemiology &-Economics, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.;Department of Clinical Pharmacy, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, P.O. Box 5001, 7400 GC, Deventer, The Netherlands.",
"authors": "van Berlo-van de Laar|Inge R F|IRF|https://orcid.org/0000-0003-3643-6706;Vermeij|Cornelis G|CG|;van den Elsen-Hutten|Marjo|M|;de Meijer|Arthur|A|;Taxis|Katja|K|;Jansman|Frank G A|FGA|",
"chemical_list": "D008687:Metformin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-020-02857-5",
"fulltext": "\n==== Front\nEur J Clin Pharmacol\nEur. J. Clin. Pharmacol\nEuropean Journal of Clinical Pharmacology\n0031-6970 1432-1041 Springer Berlin Heidelberg Berlin/Heidelberg \n\n2857\n10.1007/s00228-020-02857-5\nPharmacokinetics and Disposition\nExtracorporeal treatment of metforminassociated lactic acidosis in clinical practice: a retrospective cohort study\nhttps://orcid.org/0000-0003-3643-6706van Berlo-van de Laar Inge R.F. i.vanberlo-vandelaar@dz.nl 1 Vermeij Cornelis G. 2 van den Elsen-Hutten Marjo 3 de Meijer Arthur 4 Taxis Katja 5 Jansman Frank G.A. 15 1 grid.413649.d0000 0004 0396 5908Department of Clinical Pharmacy, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, P.O. Box 5001, 7400 GC Deventer, The Netherlands \n2 grid.413649.d0000 0004 0396 5908Department of Internal Medicine, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, The Netherlands \n3 grid.413649.d0000 0004 0396 5908Department of Research and Innovation, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, The Netherlands \n4 grid.413649.d0000 0004 0396 5908Department of Intensive Care, Deventer Hospital, Nico Bolkesteinlaan 75, 7416 SE Deventer, The Netherlands \n5 grid.4830.f0000 0004 0407 1981Unit of PharmacoTherapy, -Epidemiology &-Economics, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands \n13 3 2020 \n13 3 2020 \n2020 \n76 6 815 820\n29 11 2019 5 3 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Purpose\nTo assess whether extracorporeal treatment (ECTR) improves outcome of patients with metformin-associated lactic acidosis (MALA) and to evaluate the clinical applicability of the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) criteria for starting ECTR in metformin poisoning.\n\nMethods\nPatients with metformin serum concentrations above 2 mg/l who were admitted in the Deventer Teaching Hospital between January 2000 and July 2019 and complied with the definition of MALA (pH < 7.35 and lactate concentration > 5 mmol/l) were included. Mortality and clinical parameters of patients treated with ECTR or not were compared. In addition, treatment of MALA in clinical practice was verified against the criteria of EXTRIP.\n\nResults\nForty-two patients were included. Lactate (13.8 versus 10.5 mmol/l, p = 0.01), creatinine (575 versus 254 umol/l, p < 0.01)), metformin (29.4 versus 8.6 mg/l, p < 0.01) concentrations, and vasopressor requirement (72% versus 23%, p < 0.01) were significantly higher in the ECTR-group. Blood pH (7.05 versus 7.19, p = 0.03) and bicarbonate (6 versus 11 mmol/l, p < 0.01) were significantly lower. Mortality, length of hospital stay, and mechanical ventilation requirement were not statistically different. In 83% of patients, treatment of MALA was in accordance with the EXTRIP criteria.\n\nConclusions\nAlthough there was no statistical benefit in mortality shown from ECTR, ECTR might be lifesaving in MALA, considering the ECTR-group was significantly sicker than the non-ECTR-group.\n\nThe majority of patients were treated in line with the EXTRIP criteria. Severity of lactic acidosis and renal impairment were the main indications for initiating ECTR.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s00228-020-02857-5) contains supplementary material, which is available to authorized users.\n\nKeywords\nMetforminLactic acidosisExtracorporeal treatmentRenal impairmentUniversity of Groningenissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nMetformin is the most commonly prescribed oral antidiabetic drug in non-insulin-dependent type 2 diabetes mellitus (NIDDM). Metformin inhibits gluconeogenesis, facilitates cellular glucose uptake, and decreases insulin resistance [1]. Metformin treatment is associated with a lower incidence of cardiovascular events and mortality in NIDDM [2]. Although metformin is considered to be a safe and well tolerated drug, its use may rarely be complicated by lactic acidosis [1, 3–6]. The most widely accepted mechanism how metformin causes hyperlactatemia and metabolic acidosis is by partial inhibition of oxidative phosphorylation complex 1 of the mitochondrial electron transport chain. Another possible mechanism in which metformin may elevate plasma lactate levels is through inhibition of pyruvate carboxylase which results in both accelerated lactate production and reduced lactate metabolism [1, 3–5]. There appears to be a clear relationship between metformin accumulation and lactic acidosis, although some authors have pointed out that several such patients had other confounding risk factors for lactic acidosis [3–5, 7].\n\nMetformin-associated lactic acidosis (MALA) is a serious adverse event with a high mortality rate of up to 50% [1, 4]. The incidence of MALA varies from 0 to 138 per 100.000 patient years and may increase in the coming years due to the increase in the number of type 2 diabetes mellitus patients and the use of metformin [4, 6, 8, 9]. Several studies suggest that starting timely treatment might reduce MALA-related morbidity and mortality [8–14]. Extracorporeal treatments (ECTRs) may be necessary to remove metformin, clear lactate, and correct acid-base abnormalities [1, 11]. Calello et al. [1] formulated specific recommendations for starting ECTR in metformin poisoning based on a systematic literature search: the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) criteria [15], which have been included in the treatment guidelines for metformin intoxication by the Dutch Poisons Information Centre (DPIC) [16]. However, the evidence levels of the EXTRIP criteria are low and their validity in clinical practice has not been assessed yet. We therefore evaluated the treatment of MALA patients in clinical practice. The aim of this study was firstly to assess whether ECTR improves outcome of MALA patients. Secondly, we aimed to evaluate whether the EXTRIP criteria for starting ECTR in MALA are applicable in clinical practice, i.e., to what extent patients who received ECTR and those who did not fulfill the EXTRIP criteria for starting ECTR [1].\n\nMethods\nA retrospective single-center cohort study was conducted at the Deventer Teaching Hospital in the Netherlands. Laboratory data were searched for patients who had their metformin serum concentrations measured between January 2000 and July 2019. In these patients, serum metformin concentration measurement had been requested because of a clinical suspicion of MALA, based on documented metformin use and concurrent illness leading to an emergency department visit. In the Deventer Teaching Hospital, the metformin assay is routinely available 24 h a day. Results are available for clinical decisions within 4 h. Patients were included if they met the MALA definition: pH < 7.35 and lactate > 5.0 mmol/l in association with metformin exposure [1]. Only patients with serum metformin concentrations above the lower limit of quantification of our analysis method, i.e., 2 mg/l, were included. The following patient data were extracted from the medical records: age, gender, admission diagnosis, ECTR treatment (or not), reasons for initiating ECTR (or not), decreased consciousness, vasopressor requirement, mechanical ventilation requirement, length of hospital stay, mortality (defined as in-hospital mortality), and laboratory results on admission: serum concentrations of creatinine, lactate, bicarbonate and metformin, and blood pH. In the Deventer Teaching Hospital, ECTR is readily and unrestrictedly available for treatment of MALA patients.\n\nPatients were divided into an ECTR and non-ECTR group, and the concentrations of lactate, creatinine, bicarbonate and metformin, blood pH, decreased consciousness, vasopressor and mechanical ventilation requirement, length of hospital stay, and mortality were compared. In case of normal distribution of continuous data, the independent sample t test was used. The non-parametric Mann-Whitney test was used for not normally distributed and ordinal data. The Chi square test was used to compare nominal data between groups. In all tests, a p value < 0.05 was considered statistically significant. Data analysis was performed with SPSS version 24.0.\n\nIn the ECTR and non-ECTR group, we assessed whether patients met the EXTRIP criteria for starting ECTR depicted in Table 1. Impaired kidney function is defined by the EXTRIP nephrology sub-committee as (1) advanced stage G3b, G4, or G5 chronic kidney disease (i.e., eGFR < 45 mL/min/1.73 m2), (2) kidney disease: Improving Global Outcomes (KDIGO) stage 2 or 3 acute kidney injuries, (3) in the absence of a baseline serum creatinine, 176 μmol/L in adults and 132 μmol/L in elderly/low muscle mass patients, and (4) the presence of oligo/anuria regardless of serum creatinine concentration.Table 1 EXTRIP criteria for starting ECTR in metformin poisoning [1]\n\nIndications\t\nECTR is recommended if:\n\n• Lactate concentration greater than 20 mmol/l\n\n• Blood pH less than or equal to 7.0\n\n• Standard therapy (supportive measures, bicarbonate, etc.) fails\n\nECTR is suggested if:\n\n• Lactate concentration is 15–20 mmol/l\n\n• Blood pH 7.0–7.1\n\nComorbid conditions that lower the threshold for initiating ECTR:\n\n• Impaired kidney function\n\n• Shock\n\n• Decreased level of consciousness\n\n• Liver failure\n\n\t\nEXTRIP Extracorporeal Treatments in Poisoning Workgroup\n\nECTR Extracorporeal treatment\n\n\n\nIn those patients who were not treated according to the EXTRIP criteria, the reasons for initiating ECTR or not were evaluated.\n\nResults\nIn our hospital pharmacy laboratory database, we identified 160 patients who had serum metformin concentrations measured. Of these, 42 patients met the inclusion criteria of MALA and were included in the study. Forty patients (95%) had renal impairment on admission and 29 patients (69%) were treated with ECTR. ECTR was conducted in the intensive care unit. ECTR modalities used were continuous veno venous hemofiltration (CVVH) (19 patients), hemodialysis (HD) (7 patients), or a sequential combination of CVVH and HD (3 patients). The patient characteristics and the results of the comparison between the ECTR and non-ECTR groups are listed in Table 2. The main admission diagnoses were dehydration, sepsis, shock, and myocardial infarction. Detailed information of the patient characteristics per patient is given in Online Resource 1 (ECTR-group) and Online Resource 2 (non-ECTR-group).Table 2 Results: patient characteristics and comparison clinical parameters ECTR versus non-ECTR group\n\nPatient characteristics\tECTR N = 29\nMean ± sd (range)\tNon-ECTR N = 13\nMean ± sd (range)\tStatistical analysis\t\nGender\t6 M 23 F\t5 M 8 F\t\t\nAge (years)\t71 ± 9 (52–87)\t77 ± 11 (58–89)\t\t\npH\t7.05 ± 0.18 (6.61–7.34)\t7.19 ± 0.18 (6.85–7.33)\tp = 0.027\t\nLactate (mmol/l)\t13.8 ± 4.9 (5.8–23.2)\t10.5 ± 2.8 (6.7–18)\tp = 0.033\t\nBicarbonate (mmol/l)\t6 ± 3 (2–13)\t11 ± 4 (2–17)\tp < 0.01\t\nMetformin concentration (mg/l)\t29.4 ± 20.3 (2.3–100)\t8.6 ± 11.2 (2.2–37)\tp < 0.01\t\nCreatinine (umol/l)\t575 ± 268 (113–1039)\t254 ± 192 (70–720)\tp < 0.01\t\nDecreased consciousness N (%)\t9 (31%)\t3 (23%)\tp = 0.699\t\nVassopressor requirement N (%)\t21 (72%)\t3 (23%)\tp < 0.01\t\nMechanical ventilation requirement N (%)\t6 (21%)\t1 (8%)\tp = 0.296\t\nLength of stay (days)\t17.3 ± 23.6 (2–120)\t7.8 ± 9.0 (1–32)\tp = 0.067\t\nMortality N (%)\t11 (38%)\t6 (46%)\tp = 0.616\t\nECTR Extracorporeal Treatment\n\n\n\nThirty-five of the 42 (83%) patients were treated in line with the EXTRIP criteria.\n\nOf the 29 patients in the ECTR-group, 28 (97%) fulfilled the EXTRIP criteria to receive ECTR. Clinical reasons for starting ECTR in these patients were severe metabolic acidosis, renal failure, hyperkalaemia, and high metformin concentrations. Ninety-seven percent of the ECTR group met the criterion of impaired renal function of Calello et al. [1] in which the threshold for initiating ECTR could be lowered. One patient (patient no. 27, Online Resource 1) did not fulfill the EXTRIP criteria. This patient was admitted because of an intentional overdose and did not meet the criterion of impaired renal function of Calello et al. [1]. ECTR was started because of the combination high serum metformin concentration and lactic acidosis in order to eliminate metformin and to correct the acidosis.\n\nOf the 13 patients in the non-ECTR group, in 7 (54%) of the patients treatment, (non-ECTR) was in line with the EXTRIP criteria. One patient (patient no. 6, Online Resource 2) did not fulfill the EXTRIP criteria for starting ECTR, and in 6 patients, ECTR was not necessary because they recovered after starting supportive care.\n\nFor the other 6 (46%) patients, ECTR should have been considered according to the EXTRIP criteria. Supportive care was started in these patients but they died shortly after the start of the treatment. Four patients died within 1 day from cardiac arrest. In one patient, a conservative policy was started because of the very bad prognosis due to comorbidity and she died 1 day after admittance. One patient (patient no.10, Online Resource 2) did not recover with supportive care and died 1 month after admission probably from sepsis. There were no data available in this patients’ medical record whether ECTR was considered.\n\nDiscussion\nThis retrospective cohort study shows a lower but not statistically different mortality in MALA patients treated with ECTR compared to those who were not. The overall mortality of 40% in our study is in line with the mortality reported in previous studies, ranging from 20 to 50% [7, 8, 12–14, 17–21]. Blood pH, lactate, creatinine, and serum metformin concentration in the ECTR group in this study are similar to that reported in the literature [9, 13, 20–22]. The significantly higher lactate and creatinine concentrations in the ECTR group compared to the non-ECTR group have also been reported in other studies [9, 12, 19].\n\nPatients in the ECTR group were sicker than patients in the non-ECTR group considering the degree of lactic acidosis, kidney function, and vasopressor requirement while having a lower but not statistically different, mortality. As hyperlactatemia in general and in MALA patients is associated with increased mortality [8, 11, 23–25], this at least comparable outcome suggests there might be a benefit for ECTR. This is also suggested by Peters et al. [19]. Our study was probably underpowered to show a statistical difference. We also compared the length of hospital stay (17.3 versus 7.8 days, p = 0.067), but in this study, this parameter is less suitable as outcome measure compared to mortality because of the large range in the ECTR group (2–120 days) and the high percentage patients who died within 1–2 days in the non-ECTR group.\n\nTo evaluate whether the EXTRIP criteria for initiating ECTR in patients with MALA are applicable in clinical practice, we compared the indications for starting ECTR in this study with the recommendations of Calello et al. [1]. Overall, 83% of our patients were treated in line with the EXTRIP criteria. In the ECTR group, 97% and in the non-ECTR group 54% of the patients fulfilled the EXTRIP criteria. Severity of lactic acidosis and kidney function were the main indications for initiating ECTR in this study. This is also shown in the EXTRIP criteria [1] and the study of Corcia et al. [9]. Moreover, in accordance with Corchia et al. [9], we identified hyperkalaemia as a reason for starting ECTR. In contrast, hemodynamic instability and shock, as proposed by Corcia et al. [9] and EXTRIP [1, 15] for initiating ECTR, were not recorded in the patients’ medical records in this study. Calello et al. [1] have not formulated a threshold for metformin serum concentration because at the time of formulation of these recommendations, there was much uncertainty regarding the value of metformin concentrations in relation to the prognosis and the limited availability of the metformin assays. Some studies have shown a correlation between metformin concentration and mortality [8, 9, 20] while others have not [17, 21, 25, 26]. Despite the uncertainty concerning its prognostic value, measuring metformin serum concentrations could be of diagnostic value in MALA and may assist in its management [9, 22, 26]. However, establishing a specific threshold for metformin serum concentrations is not possible based on the results of this study.\n\nThe EXTRIP criteria include lowering thresholds of pH and lactate for initiating ECTR in impaired kidney function, shock, decreased level of consciousness, and liver failure but this is not quantified. The majority of the ECTR group in this study had impaired renal function, and the mean pH and lactate concentration were 7.05 and 13.8 mmol/l respectively. In clinical practice, comorbidity is common, and it is not always clear whether there is metformin accumulation, showing the heterogeneity regarding the EXTRIP criteria and real-life scenarios. Because of this heterogeneity, formulating more concise criteria for initiating ECTR in MALA patients is very difficult. The main reasons for not initiating ECTR in this study were recovery after starting supportive care or death shortly after admission. Six patients who met the EXTRIP criteria were not treated with ECTR and died. At the time of admission of these patients, the EXTRIP criteria were not implemented in our hospital. Four out of these six patients died within 1 day from cardiac arrest and there was no renal indication for starting ECTR. Additionally, in the non-ECTR group, 54% of patients had serum metformin concentrations lower than 5 mg/l which is in line with the ‘normal’ value of serum metformin concentrations in therapeutic use [4, 27]. Therefore, it is debatable whether metformin was the cause of MALA in these patients. Lalau et al. [4] suggested adding serum metformin concentration higher than 5 mg/l as criterion to MALA to distinguish it from metformin unrelated lactic acidosis (MULA). However, we used the definition of MALA pH < 7.35 and lactate >5 mmol/l in association with metformin exposure as formulated by Calello et al. [1] because we wanted to evaluate Calello’s recommendations in clinical practice. In addition, we validated metformin exposure by only including patients with verifiable serum metformin concentrations to avoid discussion about metformin exposure.\n\nThe present study is one of the largest cohort studies regarding the management of MALA. The strength of our study is that metformin concentrations, lactate, blood pH, and kidney function were measured simultaneously on admission and during subsequent treatment. Furthermore, only patients with verified metformin serum concentrations were included. Lalau et al. [4] presented the lack of these combined data as major methodological flaw in most studies on MALA. However, we did not measure metformin concentrations in erythrocytes, which probably better reflects metformin tissue effects, and we have no information on last intake so we cannot refer to peak versus trough concentrations [4]. A limitation of our study is that other causes of lactic acidosis were not ruled out which could have influenced the mortality in this study. Other limitations include the retrospective and monocentric design and selection bias. We selected patients based on serum metformin concentration measurement. MALA patients without serum metformin concentration measurement could have been missed. Finally, as presented in the EXTRIP guidelines, metformin and lactate clearance are lower with continuous renal replacement therapy (CRRT) than with intermittent HD. As such, the predominant use of CVVH in our study might have weakened the results in favor for ECTR.\n\nFor clinical practice, we recommend that clinicians be alert to MALA in the emergency department when patients are admitted with lactic acidosis in combination with metformin use. ECTR might be lifesaving in the treatment of MALA and should therefore be considered at an early stage. The EXTRIP-criteria are a good starting point for the decision to start ECTR but each individual patient needs to be evaluated separately. Severity of lactic acidosis and renal impairment are the main indications for initiating ECTR. Knowledge of the metformin concentrations may be a valuable additional parameter for the diagnosis and management of MALA. Therefore, we recommend implementing metformin assays as routine investigation with 24-h availability in hospitals treating MALA patients.\n\nConclusion\nAlthough there was no statistical difference in mortality between the treatment with or without ECTR, ECTR might be lifesaving in treating MALA. Patients in the ECTR group were sicker compared to the non-ECTR group considering the degree of lactic acidosis, kidney function, and vasopressor requirement and had at least a comparable mortality. In 83% of the patients, treatment was in line with the EXTRIP criteria. Severity of lactic acidosis and renal impairment were the main indications for initiating ECTR. Measuring serum metformin concentrations may assist in the diagnosis and management of MALA.\n\nElectronic supplementary material\n\nESM 1 (PDF 64 kb)\n\n \nESM 2 (PDF 34 kb)\n\n \n\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nData and/or code availability\nThe datasets generated during and/or analyzed during this study are available from the corresponding author on reasonable request.\n\nAuthors’ contribution\nAll authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Inge van Berlo-van de Laar, Marjo van den Elsen-Hutten, and Cornelis Vermeij. The first draft of the manuscript was written by Inge van Berlo-van de Laar and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nCompliance with ethical standards\nConflict of interest\nAuthor Frank Jansman has been a member of advisory boards of Amgen and Genzyme.\n\nAll other authors declare that they have no conflicts of interest.\n\nEthics approval\nThis study was assessed by the Medical Ethical Committee of Isala Hospital (Zwolle, the Netherlands) and approved as a non-interventional study.\n==== Refs\nReferences\n1. Calello DP Liu KD Wiegand TJ Roberts DM Lavergne V Gosselin S Hoffman RS Nolin TD Ghannoum M Extracorporeal Treatments in Poisoning Workgroup Extracorporeal treatment for metformin poisoning: systematic review and recommendations from the extracorporeal treatments in poisoning workgroup Crit Care Med 2015 43 8 1716 1730 10.1097/CCM.0000000000001002 25860205 \n2. 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UMC Utrecht Nationaal Vergiftigingen Informatie Centrum, Utrecht. Available from: https://www.vergiftigingen.info/f?p=300:STOFMONOGRAFIE:10568776339678::NO. Accessed 1 June 2019 \n17. Seidowsky A Nseir S Houdret N Fourrier F Metformin-associated lactic acidosis: a prognostic and therapeutic study Crit Care Med 2009 37 7 2191 2196 10.1097/CCM.0b013e3181a02490 19487945 \n18. Greco P Reolisti G Maggiore U Feriolo E Fani F Loratelli C Sustained low-efficiency dialysis for metformin associated lactic acidosis in patients with acute kidney injury J Nephrol 2019 32 2 297 306 10.1007/s40620-018-00562-2 30523561 \n19. Peters N Jay N Barraud D Cravoisy A Nace L Bollaer PE Metformin-associated lactic acidosis in an intensive care unit Crit Care 2008 12 6 R149 10.1186/cc7137 19036140 \n20. Friesecke S Abel P Roser M Felix SB Runge S Outcome of severe lactic acidosis associated with metformin accumulation Crit Care 2010 14 R226 10.1186/cc9376 21171991 \n21. Vecchio S Giampretti A Petrolini M Lonati D Protti A Papa P Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy Clin Toxicol 2014 52 129 135 10.3109/15563650.2013.860985 \n22. Duong JK Furlong TJ Roberts DM Graham GG Greenfield JR Williams KM Day RO The role of metformin in metformin-associated lactic acidosis (MALA): case series and formulation of a model of pathogenesis Drug Saf 2013 36 733 746 10.1007/s40264-013-0038-6 23549904 \n23. van den DPA N Brouwers MCG Stassen PM Prognostic value of plasma lactate levels in a retrospective cohort presenting at a university hospital emergency department BMJ Open 2017 7 e011450 10.1136/bmjopen-2016-011450 \n24. Kjelland CB Djogovic D The role of serum lactate in the acute care setting J Intensive Care Med 2010 25 5 286 300 10.1177/0885066610371191 20622256 \n25. Yeh HC Ting IW Tsai CW Wu JY Kuo CC Serum lactate level and mortality in metformin associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports and case series BMC Nephrol 2017 18 1 229 10.1186/s12882-017-0640-4 28693440 \n26. Kajbaf F Lalau JD The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis BMC Pharmacol Toxicol 2013 14 22 10.1186/2050-6511-14-22 23587368 \n27. Kajbaf F De Broe ME Lalau JD Therapeutic concentrations of metformin: a systematic review Clin Pharmacokinet 2016 55 4 439 459 10.1007/s40262-015-0323-x 26330026\n\n",
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"abstract": "Non-arteritic anterior ischemic optic neuropathy is a result of an infarction of the small vessel at the anterior portion of the optic disc and causes acute, unilateral, painless visual loss. There is no generally accepted treatment method for this condition but some medical and surgical treatments are recommended. Earlier studies show that visual acuity recovery was better with corticosteroid medication compared to non-treated patients. However corticosteroids may cause side effects such as cataract, increased intraocular pressure and rarely central serous chorioretinopathy. This case report presents a patient with central serous chorioretinopathy secondary to corticosteroid medication.",
"affiliations": "Beyoglu Eye Training and Research Hospital, Istanbul, Turkey.;Beyoglu Eye Training and Research Hospital, Istanbul, Turkey.;Beyoglu Eye Training and Research Hospital, Istanbul, Turkey.;Beyoglu Eye Training and Research Hospital, Istanbul, Turkey.",
"authors": "Alkin|Zeynep|Z|;Yilmaz|Ihsan|I|;Ozkaya|Abdullah|A|;Yazici|Ahmet Taylan|AT|",
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"fulltext": "\n==== Front\nSaudi J OphthalmolSaudi J OphthalmolSaudi Journal of Ophthalmology1319-4534Elsevier S1319-4534(15)00017-X10.1016/j.sjopt.2015.01.002Case ReportSteroid-induced central serous chorioretinopathy in a patient with non-arteritic anterior ischemic optic neuropathy Alkin Zeynep Yilmaz Ihsan ihsanyilmaz.dr@gmail.com⁎Ozkaya Abdullah Yazici Ahmet Taylan Beyoglu Eye Training and Research Hospital, Istanbul, Turkey⁎ Corresponding author at: Bereketzade Cami Sokak No: 2, Beyoglu, Istanbul, Turkey. Tel.: +90 532 345 59 72. ihsanyilmaz.dr@gmail.com21 1 2015 Jul-Sep 2015 21 1 2015 29 3 232 234 5 11 2014 10 12 2014 14 1 2015 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Non-arteritic anterior ischemic optic neuropathy is a result of an infarction of the small vessel at the anterior portion of the optic disc and causes acute, unilateral, painless visual loss. There is no generally accepted treatment method for this condition but some medical and surgical treatments are recommended. Earlier studies show that visual acuity recovery was better with corticosteroid medication compared to non-treated patients. However corticosteroids may cause side effects such as cataract, increased intraocular pressure and rarely central serous chorioretinopathy. This case report presents a patient with central serous chorioretinopathy secondary to corticosteroid medication.\n\nKeywords\nIschemic optic neuropathyCentral serous chorioretinopathyCorticosteroid\n==== Body\nIntroduction\nCorticosteroid medication for treatment of non-arteritic anterior ischemic optic neuropathy is controversial. It may cause a central serous chorioretinopathy (CSCR) and threaten the patients’ visual acuity. As a treatment cutting of the corticosteroid medication should be advised. This case reports a 54-year-old male with CSCR secondary to corticosteroid medication which is used for treating patients’ non-arteritic anterior ischemic optic neuropathy (NAION). The corticosteroid treatment induced central serous chorioretinopathy in patients’ healthy eye and reduced visual acuity.1–4 The corticosteroid treatment was stopped. Two months after that visual acuity turned back to normal and central serous chorioretinopathy disappeared.\n\nCase report\nA 54-year-old male was referred to us with decreased visual acuity in his right eye (RE). The best-corrected visual acuity (BCVA) was 0.05 in RE and 0.8 in left eye (LE). Ocular history was unremarkable. The patient had a systemic hypertension which was under control medically. Slit lamp examinations of anterior segment were normal in both eyes. Intraocular pressure (IOP) measurements were performed via Goldmann applanation tonometer and IOP was 14 mmHg in RE, 13 mmHg in LE. Relative afferent pupillary defect was present in RE. Dilated fundus examination revealed splinter hemorrhages and edema at the optic discs in RE. Fundus examination was normal in LE. Perimetry was performed via Humphrey 30–2 threshold test and there was a lower altitudinal visual field defect in RE. Fundus fluorescein angiography (FA) showed hyperfluorescence at the optic disc in RE and normal angiographic findings in LE (Fig. 1a and b). Optic disc appearance, visual fields, FA and optical coherence tomography of discs were suggestive of non-arteritic anterior ischemic optic neuropathy (NA-NAION) in RE. Patient was diagnosed with NA-AION and methylprednisolone was administered with a dose of 1 gr/day intravenously for 3 days. Then, steroid treatment continued with 1 mg/kg/day orally for a week.\n\nSix days after initiating the corticosteroid treatment, the patient complained decreased visual acuity in his LE. BCVA was 0.05 in RE and 0.1 in LE. Relative afferent pupillary defect was still present in RE. Anterior segment and IOP measurements were normal in both eyes. Fundus examination showed decreased edema at the optic disc in RE. Additionally, there was an elevation in the macula in LE. Late-phase FA demonstrated granular hyperfluorescence just located nasally to the fovea surrounded by serous detachment in LE in addition to decreased hyperfluorescence at the optic disc in RE (Fig. 2a and b). Indocyanine green angiography (ICG) showed focal hyperfluorescence in mid-phase at the same location as in FA in LE (Fig. 2c). Spectral-domain optical coherence tomography revealed subretinal fluid in the macula in LE (Fig. 3). Central macular thickness (CMT) was 610 μm. The patient was diagnosed with acute CSC.\n\nAfter the patient diagnosed steroid-induced CSCR, corticosteroid treatment was stopped abruptly. One month later, BCVA was 0.5 in LE. CMT was decreased to 414 μm in LE. Two months after the cessation of corticosteroid treatment, BCVA improved to 0.8 in LE and 0.1 in RE. There was no subretinal fluid and CMT was 279 μm in LE (Fig. 4).\n\nDiscussion\nCentral serous chorioretinopathy is characterized by serous detachment of the neurosensory retina due to defect in the retinal pigment epithelium.1,2 CSCR most commonly affects males between 20 and 50 years. Early studies showed that CSCR is related to psychological stress, endogenous hypercortisolism and use of corticosteroid medicines.3 It has been shown that corticosteroid treatment given through various routes such as oral, inhaled, epidural, intra-articular may cause CSCR.4 Exact mechanism for steroid induced CSCR has not been fully understood yet; however, it may result from inhibition of collagen synthase, increasing permeability of choroidal capillary, and dysfunction of ionic pump in the retina pigment epithelium.5,6\n\nEarlier studies showed that many CSCR may resolve spontaneously and just observational therapy was needed for 3–4 months.7 Some of CSCR cases may resolve with the successful treatment of underlying pathology or mechanism.8 Vayalambrone et al. reported a 32-year-old Afro-Caribbean male patients with multi-focal CSCR secondary to latent tuberculosis. After the empiric antituberculous therapy, the patient had a significant visual improvement with resolution of the serous detachment.8 Similarly, in our patient after stopping underlying mechanism, which was a corticosteroid used, CSCR was resolved. After two months from stopping corticosteroid treatment visual acuity backed to 0.8 in LE, which was the same with patient’s previous visual acuity.\n\nThere were similar results reported in the literature.9,10 Shah et al reported a 24 year-old male with CSCR secondary to prednisolone (60 mg/day) for treating left sided facial palsy.9 The dose of prednisolone was reduced to 40 mg and used for seven days then stopped.9 They reported that visual disturbances abated gradually within one week after prednisolone was withdrawn.9 Loo et al. reported 3 patients with CSCR secondary to corticosteroid medication for different diseases.10 They reported that two of those cases resolved with tapering of corticosteroids and one case was treated by focal laser photocoagulation.10 There are still some CSCR cases may not improve on conventional observational approach. Photodynamic therapy may be used for these cases.11 Shibata et al. used photodynamic therapy for treating two patients with CSCR and they reported that successful results were achieved.11\n\nThere are new approaches for the treatment of NAION such as local steroid application.12 As systemic steroid might trigger CSCR in the fellow healthy eye as presented, local (intravitreal) steroid application for the diseased eye would have been more appropriate.12\n\nConclusion\nThis case showed that systemic corticosteroid treatment may cause visual acuity loss due to CSCR and stopping the corticosteroid administration may be appropriate treatment.\n\nConflict of interest\nThe authors declared that there is no conflict of interest.\n\nPeer review under responsibility of Saudi Ophthalmological Society, King Saud University.\n\nFigure 1 Fundus fluorescein angiogram of both eyes (a, b). A hyperfluorescence at the inferior half of the optic disc in RE (a) and normal angiogram in LE (b).\n\nFigure 2 Fundus fluorescein angiography scans showed decreased hyperfluorescence at the inferior half of the optic disc in RE (a) and a central serous chorioretinopathy in LE (b). Arrow indicates the border of the pigment epithelial detachment and star indicates hyperfluorescence spots. Indocyanine green angiography scans showed focal hyperfluorescence coherent to fundus fluorescein angiography scan in LE (4c).\n\nFigure 3 Spectral domain optical coherence tomography shows serous macular detachment as hyporeflective space between neurosensory retina and RPE in LE.\n\nFigure 4 Spectral-domain optical coherence tomography scans two months after the corticosteroid treatment were stopped. The CSCR was resolved.\n==== Refs\nReferences\n1 Grixti A. Kumar V. Steroid induced central serous chorioretinopathy in giant cell arteritis Case Rep Ophthalmol Med 2013 2013 924037 23840998 \n2 Fardin B. Weissgold D.J. Central serous chorioretinopathy after inhaled steroid use for post-mycoplasmal bronchospasm Br J Ophthalmol 86 9 2002 1065 1066 12185142 \n3 Tsai D.C. Chen S.J. Huang C.C. Chou P. Chung C.M. Huang P.H. Epidemiology of idiopathic central serous chorioretinopathy in Taiwan, 2001–2006: a population-based study PLoS One 8 6 2013 e66858 23826160 \n4 Balakrishnan S. Apsingi S. Manjure S.B. Sudden loss of visual acuity following intra-articular steroid injection in to the knee joint: a case report Cases J 1 2008 428 19116023 \n5 Cassel G.H. Brown G.C. Annesley W.H. Central serous chorioretinopathy: a seasonal variation? Br J Ophthalmol 68 1984 724 726 6477852 \n6 Siaudvytyte L. Diliene V. Miniauskiene G. Balciuniene V.J. Photodynamic therapy and central serous chorioretinopathy Med Hypothesis Discov Innov Ophthalmol 1 4 2012 67 71 24600627 \n7 Ponce C.M. Mohidat H.M. Garcia C.A. Central serous chorioretinopathy after blunt trauma BMJ Case Rep 2012 \n8 Vayalambrone D. Ivanova T. Misra A. Atypical central serous retinopathy in a patient with latent tuberculosis BMJ Case Rep 2012 \n9 Shah S.P. Desai C.K. Desai M.K. Dikshit R.K. Steroid-induced central serous retinopathy Indian J Pharmacol 43 5 2011 607 608 22022013 \n10 Loo J.L. Lee S.Y. Ang C.L. Can long-term corticosteroids lead to blindness? A case series of central serous chorioretinopathy induced by corticosteroids Ann Acad Med Singapore 35 2006 496 499 16902727 \n11 Shibata A. Ohkuma Y. Hayashi T. Tsuneoka H. Efficacy of reduced-fluence photodynamic therapy for serous retinal pigment epithelial detachment with choroidal hyperpermeability Clin Ophthalmol 7 2013 2123 2126 24204113 \n12 Alten F. Clemens C.R. Heiduschka P. Eter N. Intravitreal dexamethasone implant [Ozurdex] for the treatment of nonarteritic anterior ischaemic optic neuropathy Doc Ophthalmol 129 3 2014 203 207 25274269\n\n",
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"keywords": "Central serous chorioretinopathy; Corticosteroid; Ischemic optic neuropathy",
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] |
{
"abstract": "We describe the casuistry of a homozygous familial hypercholesterolemia female patient with a biallelic missense variant (NM_000527.4:c.1775G>A, p.Gly592Glu) in the LDLR gene, severe hypertriglyceridemia and late manifestation of coronary heart disease not earlier than at the age of 45 years. An atypical phenotype led to a delayed diagnosis.",
"affiliations": "Department of Clinical Biochemistry, St. Anne's University Hospital, Pekarska 53, 656 91 Brno, Czechia; Department of Laboratory Methods, Masaryk University, Komenskeho nam. 2, 602 00 Brno, Czechia. Electronic address: ondrej.kyselak@fnusa.cz.;Department of Clinical Biochemistry, St. Anne's University Hospital, Pekarska 53, 656 91 Brno, Czechia; Department of Laboratory Methods, Masaryk University, Komenskeho nam. 2, 602 00 Brno, Czechia. Electronic address: vladimir.soska@fnusa.cz.;Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine (IKEM), Videnska 1958, 140 21 Prague, Czechia. Electronic address: jan.kovar@medicon.cz.;Centre for Molecular Biology and Gene Therapy, University Hospital Brno, Cernopolni 9, 613 00 Brno, Czechia. Electronic address: tichy.lukas@fnbrno.cz.;Centre for Cardiovascular Surgery and Transplantation, Pekarska 53, 656 91 Brno, Czechia; Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czechia. Electronic address: hana.grombirikova@cktch.cz.;Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine (IKEM), Videnska 1958, 140 21 Prague, Czechia. Electronic address: jahb@ikem.cz.;Centre for Cardiovascular Surgery and Transplantation, Pekarska 53, 656 91 Brno, Czechia; Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czechia. Electronic address: tomas.freiberger@cktch.cz.",
"authors": "Kyselak|Ondrej|O|;Soska|Vladimir|V|;Kovar|Jan|J|;Tichy|Lukas|L|;Grombirikova|Hana|H|;Hubacek|Jaroslav A|JA|;Freiberger|Tomas|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacl.2021.04.006",
"fulltext": null,
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"issn_linking": "1876-4789",
"issue": "15(3)",
"journal": "Journal of clinical lipidology",
"keywords": "Combined hyperlipidemia; Delayed diagnosis; Homozygous familial hypercholesterolemia; LDLR gene variant; Polygenic score; Severe hypertriglyceridemia",
"medline_ta": "J Clin Lipidol",
"mesh_terms": null,
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "435-440",
"pmc": null,
"pmid": "33975813",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A case of homozygous familial hypercholesterolemia with an atypical phenotype and delayed clinical symptoms.",
"title_normalized": "a case of homozygous familial hypercholesterolemia with an atypical phenotype and delayed clinical symptoms"
} | [
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],
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"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Aortic stenosis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Coronary artery disease",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FREIBERGER T.? KYSELAK O.? SOSKA V. ET. AL.. A CASE OF HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA WITH AN ATYPICAL PHENOTYPE AND DELAYED CLINICAL SYMPTOMS. JOURNAL OF CLINICAL LIPIDOLOGY. 2021?15 (3):435?440",
"literaturereference_normalized": "a case of homozygous familial hypercholesterolemia with an atypical phenotype and delayed clinical symptoms",
"qualification": "3",
"reportercountry": "CZ"
},
"primarysourcecountry": "CZ",
"receiptdate": "20210713",
"receivedate": "20210705",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19493592,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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}
] |
{
"abstract": "OBJECTIVE\nHematopoietic cell transplant patients are exposed to numerous classes of medications. Transplant practitioners must vigilantly monitor for drug interactions especially involving immunosuppressants. We report a hematopoietic cell transplant patient receiving sirolimus who developed supratherapeutic serum concentrations after initiating mirabegron.\n\n\nCONCLUSIONS\nA 31-year-old, 98 kg female received a second umbilical cord blood transplant four years after the first transplant for relapsed acute myeloid leukemia. Mycophenolate mofetil and sirolimus were utilized for graft versus host disease prophylaxis. The patient was receiving sirolimus 2 mg daily and the serum concentration on day 26 post-transplant (day + 26) was within therapeutic range (6.7 μg/L, goal range 3-12 μg/L). Her post-transplant course was complicated by BK viruria-associated cystitis for which she was started on mirabegron. Six days after starting the new medication (day + 33), the sirolimus serum concentration increased to 19.2 μg/L. Thus mirabegron was discontinued and sirolimus was held. Sirolimus was restarted once the serum concentration was within goal and subsequently stabilized with a combination of 1 mg and 2 mg daily for a total weekly dose of 10 mg. The proposed mechanisms of interaction include: (1) sirolimus inhibition of organic anion transporting polypeptide leading to increased mirabegron in the intestinal lumen; (2) mirabegron inhibition of P-glycoprotein leading to increased absorption of sirolimus and; (3) increased sirolimus absorption leading to increased sirolimus serum concentrations.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first report of a potential drug interaction between sirolimus and mirabegron. Transplant specialists should be aware of this potential interaction when considering the concurrent use of these medications.",
"affiliations": "Department of Pharmacy, University of Minnesota Medical Center, Minneapolis, USA.;Department of Pharmacy, University of Minnesota Medical Center, Minneapolis, USA.",
"authors": "Engle|Jeff A|JA|;Fair|Christina|C|",
"chemical_list": "D000083:Acetanilides; D007166:Immunosuppressive Agents; D013844:Thiazoles; C520025:mirabegron; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.1177/1078155217726161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "24(8)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Sirolimus; drug interaction; hematopoietic cell transplant; mirabegron",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000083:Acetanilides; D000328:Adult; D004347:Drug Interactions; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D020123:Sirolimus; D013844:Thiazoles",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "627-631",
"pmc": null,
"pmid": "28814193",
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"abstract": "A 62-year-old male with the previous history of uncontrolled diabetes and hypertension on irregular treatment presented with a history of fever, dysuria, and urinary retention with progressive painful loss of vision over a period of 2 days. His eye examination showed hypopyon, and he was diagnosed to have rapidly progressive endogenous endophthalmitis. He was started on vancomycin and piperacillin-tazobactam empirically. His blood and urine cultures grew methicillin-resistant Staphylococcus aureus (MRSA). Transesophageal echocardiography ruled out infective endocarditis. Intravitreal injection of vancomycin and ceftazidime was given. Vitreous culture also grew MRSA. A workup for possible source revealed multiple prostatic abscesses on the transrectal ultrasound. Antibiotic was changed to daptomycin in view of high vancomycin minimum inhibitory concentration. His vision was improved at the time of discharge.",
"affiliations": "Department of Critical Care Medicine, Apollo First Med Hospital, Chennai, Tamil Nadu, India.;Department of Critical Care Medicine, Apollo First Med Hospital, Chennai, Tamil Nadu, India.;Department of Infectious Diseases, Apollo First Med Hospital, Chennai, Tamil Nadu, India.;Department of Critical Care Medicine, Apollo Hospitals, Chennai, Tamil Nadu, India.;Department of Critical Care Medicine, Apollo First Med Hospital, Chennai, Tamil Nadu, India.",
"authors": "Bhavsar|Mrugank M|MM|;Devarajan|T V|TV|;Nembi|P Senthur|PS|;Ramakrishnan|Nagarajan|N|;Mani|Ashwin K|AK|",
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"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-21-17210.4103/ijccm.IJCCM_375_16Case ReportMetastatic Endogenous Endophthalmitis: A Rare Presentation with Methicillin-resistant Staphylococcus aureus Prostatic Abscess Bhavsar Mrugank M. Devarajan T. V. Nembi P. Senthur 1Ramakrishnan Nagarajan 2Mani Ashwin K. Department of Critical Care Medicine, Apollo First Med Hospital, Chennai, Tamil Nadu, India1 Department of Infectious Diseases, Apollo First Med Hospital, Chennai, Tamil Nadu, India2 Department of Critical Care Medicine, Apollo Hospitals, Chennai, Tamil Nadu, IndiaAddress for correspondence: Dr. Ashwin K. Mani, Department of Critical Care Medicine, Apollo First Med Hospital, 154, PH Road, Chennai - 600 010, Tamil Nadu, India. E-mail: ashwin.mani@gmail.com3 2017 21 3 172 175 Copyright: © 2017 Indian Journal of Critical Care Medicine2017This 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.A 62-year-old male with the previous history of uncontrolled diabetes and hypertension on irregular treatment presented with a history of fever, dysuria, and urinary retention with progressive painful loss of vision over a period of 2 days. His eye examination showed hypopyon, and he was diagnosed to have rapidly progressive endogenous endophthalmitis. He was started on vancomycin and piperacillin-tazobactam empirically. His blood and urine cultures grew methicillin-resistant Staphylococcus aureus (MRSA). Transesophageal echocardiography ruled out infective endocarditis. Intravitreal injection of vancomycin and ceftazidime was given. Vitreous culture also grew MRSA. A workup for possible source revealed multiple prostatic abscesses on the transrectal ultrasound. Antibiotic was changed to daptomycin in view of high vancomycin minimum inhibitory concentration. His vision was improved at the time of discharge.\n\nKeywords\nEndophthalmitismethicillin-resistant Staphylococcus aureusprostatic abscesstransrectal ultrasoundvancomycin\n==== Body\nINTRODUCTION\nMethicillin-resistant Staphylococcus aureus (MRSA) bacteremia continues to be a significant cause of morbidity and mortality in intensive care settings. The most critical determinants of survival and reduction of complications are early identification of bloodstream infection, combined with the initiation of timely and appropriate antibiotic therapy. Early recognition, prompt initiation of appropriate antibiotics, and rapid microbiological diagnosis are, therefore, key components of effective clinical management. We report a patient with a rare presentation of rapidly progressive endogenous endophthalmitis due to MRSA bacteremia secondary to prostatic abscess.\n\nCASE REPORT\nA 62-year-old male with poorly controlled diabetes and hypertension presented with pain and decreased left eye vision for 2 days which was rapidly worsening and leading to complete loss of vision on presentation to us. Patient also had associated symptoms such as low-grade fever and dysuria for the past 1 week. On further evaluation, patient was noted to be febrile (100.4°F), tachycardic, dehydrated, and had evidence of prostatic hypertrophy per rectal examination [Figure 2]. Local examination of the left eye revealed hypopyon with complete loss of vision (visual acuity – R/E – 6/60, L/E – only light perception). Fundoscopic examination revealed multiple vitreous exudates and findings suggestive of endogenous endophthalmitis. Preliminary investigations revealed leukocytosis (white blood cells count 14,100), elevated erythrocyte sedimentation rate (48 mm/h), and poorly controlled diabetes (HbA1C of 11). Urine routine showed plenty of pus cells with blood glucose level 268. Primary diagnosis was urinary tract infection and endogenous endophthalmitis. Patient was started on piperacillin-tazobactam and vancomycin empirically with pending cultures. Urine culture showed Gram-positive cocci (GPCs) and blood culture and sensitivity confirmed MRSA with vancomycin minimum inhibitory concentration (MIC) was 0.5. Patient was continued on vancomycin. A transesophageal echocardiography revealed normal left ventricular function and no evidence of valvular disease or vegetations suggestive of endocarditis. Abdominal ultrasound showed Grade 1 prostatomegaly [Figure 1]. Transrectal ultrasound (TRUS) revealed multiple small prostatic abscesses. Urologist was consulted, and conservative management was suggested. Patient was posted for vitrectomy and intravitreal injection of antibiotics, but on the day of surgery in spite of adequate sugar control, patient's sugar level was 470 mg/dl, so vitrectomy was deferred, and only intravitreal injection of vancomycin and ceftazidime was given. Vitreous fluid culture also grew MRSA. Postprocedure after 1 week, fundus examination showed subretinal abscess which was not seen in the first examination [Figure 4]. There were also features of early retinal detachment. However, the patient's vision improved to 6/24 in the left eye. The bacteremia failed to clear in spite of adequate therapy with vancomycin. The repeat blood culture showed MRSA with higher MIC (vancomycin MIC >2) by E-test. Antibiotic was changed to daptomycin. After starting daptomycin, the subsequent blood cultures were negative. The patient's vision improved with antibiotics, and vitrectomy was not performed. He was discharged with daptomycin to continue for 4 weeks. At the time of discharge, patient vision was 6/60. Patient was on regular follow-up with infectious disease specialist and ophthalmologist as an outpatient, and antibiotic therapy was continued. After completion of 4-week antibiotics, ophthalmic examination showed no hypopyon [Figure 3], and there was also significant vision improvement from 6/60 to 6/18. Follow-up of TRUS showed resolved prostatic abscesses. Patient's urinary symptoms had completely resolved too. Urine analysis was normal, and urine cultures did not show significant growth. Once daptomycin therapy was completed, the patient was initiated on oral cotrimoxazole for which MRSA strain was sensitive and was advised to complete the course of treatment for prostatic abscess. After 2 months from discharge, patient underwent retinal reattachment surgery as a sequel of subretinal abscess with endogenous endophthalmitis [Figure 5]. Patient's current vision is 6/60 in the left eye.\n\nFigure 1 Prostate ultrasound showing abscess.\n\nFigure 2 Left eye hypopyon.\n\nFigure 3 Left eye – after completion of treatment.\n\nFigure 4 Fundus examination - subretinal abscess.\n\nFigure 5 Resolving abscess.\n\nDISCUSSION\nIntraocular colonization by bacteria can occur after trauma (exogenous endophthalmitis) or systemic dissemination (endogenous or metastatic endophthalmitis). Endogenous bacterial endophthalmitis is perhaps the rarest form and may be caused by organisms such as Escherichia coli, Staphylococcus aureus, and Klebsiella[1] In an immunocompromised patient, the sources are the gastrointestinal tract (hepatic abscess and appendicitis), genitourinary tract (renal abscess and infected stones), and the heart, ear, etc. Metastatic bacterial endophthalmitis from a genitourinary source is rare.[2]\n\nS. aureus bacteremia is common and increasing worldwide and is associated with substantial morbidity and mortality. It is often associated with a local focus of infection that has gained access to the bloodstream. MRSA is a significant cause of both healthcare-associated and community-acquired infections.[34]\n\nThe inability to rapidly identify and characterize infecting organisms means that initial antibiotic therapy is often empirical. This may result in inappropriate treatment, which is associated with extended overall duration of hospitalization, increased risk of patient mortality, and increased overall cost of treatment, particularly for patients infected with MRSA. However, with the emergence and increasing prevalence of community-associated methicillin-resistant strains, the choices of standard empirical antibiotic therapy are often reconsidered to cover resistant organisms. From a clinical standpoint, given the morbidity and mortality associated with delayed treatment of MRSA infection, it would be necessary to include MRSA coverage in empirical antibiotic regimens in settings where a significant proportion of patients hospitalized for community-acquired S. aureus infection have methicillin-resistant strains. This may of course be deescalated if culture is returned as methicillin sensitive strains (MSSA).\n\nA recent review study demonstrated key clinical principles in the management of S. aureus bacteremia; all infective foci must be identified and removed as soon as possible, and long-term antimicrobial therapy is required for those with persistent bacteremia or a deep, irremovable focus. The best drugs, dose, mode of delivery, and duration of therapy remained uncertain, a situation compounded by emerging S. aureus strains that are resistant to old and new antibiotics.[5]\n\nClinical outcomes could be inferior in patients with MRSA having vancomycin MIC >1. Teicoplanin would not be effective in patient with higher MIC for vancomycin. Linezolid is an option, but it is not approved therapy for MRSA bacteremia and prolonged duration of therapy associated with toxicities such as cytopenia and neuropathy. Hence, daptomycin was chosen.\n\nIn our case report, our primary focus is that an unusual presentation of MRSA prostatic abscesses associated with rapidly progressing endogenous endophthalmitis should not be missed and aggressive intervention must be needed to prevent permanent loss of vision. In previous case reports, vitrectomy was done, few patients developed retinal detachment, and few patients lost vision and required enucleation.[6789] In our case report, patient with endogenous endophthalmitis from MRSA bacteremia was managed without vitrectomy.\n\nNew management strategies are required including the use of techniques that allow the rapid identification of S. aureus bacteremia which enables the administration of appropriate antibiotic therapy and the identification of new drugs that enables effective empirical treatment against both susceptible and resistant S. aureus.\n\nCONCLUSION\nRapidly progressive endogenous endophthalmitis should lead to suspicion for bacteremia and a diligent workup for a possible source. The management of these patients can be complex and requires a multidisciplinary effort. Early diagnosis of primary foci along with metastatic spread needed to manage the patient and prevent loss of vision.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Bhat S Fassaludeen M Thomas A Cherian J Metastatic bacterial endophthalmitis from a prostatic abscess BJU Int 2003 92 Suppl 3 e21 19125478 \n2 Sadiq MA Hassan M Agarwal A Sarwar S Toufeeq S Soliman MK Endogenous endophthalmitis: Diagnosis, management, and prognosis J Ophthalmic Inflamm Infect 2015 5 32 26525563 \n3 Bader M Hinthorn D Bajracharya H Desai S Kumar V MRSA bacteremia with prostate abscess and endophthalmitis Infect Med 2005 22 379 81 \n4 David MZ Daum RS Community-associated methicillin-resistant Staphylococcus aureus : Epidemiology and clinical consequences of an emerging epidemic Clin Microbiol Rev 2010 23 616 87 20610826 \n5 Thwaites GE Edgeworth JD Gkrania-Klotsas E Kirby A Tilley R Török ME Clinical management of Staphylococcus aureus bacteraemia Lancet Infect Dis 2011 11 208 22 21371655 \n6 Ness T Schneider C Endogenous endophthalmitis caused by methicillin-resistant Staphylococcus aureus (MRSA) Retina 2009 29 831 4 19516121 \n7 Newman DO Lisa A Waller S Fernando M Jessica R Endogenous invasive community acquired methicillin-resistant Staphylococcus aureus endophthalmitis: Observations in two cases Kans J Med 2011 7 106 10 \n8 Nishida T Ishida K Niwa Y Kawakami H Mochizuki K Ohkusu K An eleven-year retrospective study of endogenous bacterial endophthalmitis J Ophthalmol 2015 2015 261310 25802752 \n9 Ho V Ho LY Ranchod TM Drenser KA Williams GA Garretson BR Endogenous methicillin-resistant Staphylococcus aureus endophthalmitis Retina 2011 31 596 601 21343874\n\n",
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"abstract": "A patient was admitted to the medical emergency department by his family physician. His complaints were weakness and fatigue for more than one week. Four days before admission, he went to his general practitioner for these complaints and also for painful elbows. His physician prescribed diclofenac and esomeprazole. Upon presentation, he had high systolic/diastolic blood pressure (>180/>90 mm Hg, measured repeatedly), and otherwise normal parameters. He had gained 6.5 kg in body weight. Clinical examination was normal, except for very mild bilateral malleolar edema. Routine blood tests showed a strongly elevated serum creatinine, hyperkalemia, and elevated lactate dehydrogenase. Haptoglobin levels were normal. Urinalysis showed a normal sediment, urine and blood cultures remained sterile. Ophthalmoscopy was completely normal, as was a routine chest X-ray. Renal ultrasound demonstrated kidneys with a diameter of 13 cm. Due to uncontrollable hypertension, our patient was hospitalized at the intensive care department where intravenous nifedipine was started, with good instantaneous control of blood pressure. Because of increasing potassium levels acute hemodialysis was started within 24 h after admission. Differential diagnosis consisted of diclofenac- or esomeprazole-induced interstitial nephritis or rapidly progressive glomerulonephritis. A renal biopsy was performed within 72 h after admission. The kidney biopsy showed an overwhelming inflammatory cell infiltrate consisting of a monoclonal lymphocytic cell population. However, the numerous mitotic figures, polyploidy, and prominent nucleoli present, were indicative of a lymphoma. Additional stainings confirmed a non-Hodgkin diffuse large-cell B-cell lymphoma. Treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, and prednisolone) was initiated with very good clinical and biochemical response, yet only mild recovery of kidney function. Occasionally the kidney is involved as an extranodal non-Hodgkin lymphoma (NHL) localization. However, a primary presentation of acute kidney failure due to lymphoma localization is extremely rare. Our case demonstrates that early renal biopsy is indispensable for fast and adequate diagnosis and treatment.",
"affiliations": "a Cardiology Department , OLV Hospital , Aalst , Belgium.;b Internal Medicine, Service of Haematology , University Hospitals Leuven , Leuven , Belgium.;c Laboratory of Nephrology , KU Leuven - University of Leuven, University Hospitals Leuven , Leuven , Belgium.;c Laboratory of Nephrology , KU Leuven - University of Leuven, University Hospitals Leuven , Leuven , Belgium.;d Department of Pathology , University Hospitals Leuven , Leuven , Belgium.;d Department of Pathology , University Hospitals Leuven , Leuven , Belgium.;c Laboratory of Nephrology , KU Leuven - University of Leuven, University Hospitals Leuven , Leuven , Belgium.",
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"abstract": "Human papillomavirus-related small cell carcinoma of the head and neck is an extremely rare, aggressive subtype with poor outcomes. Therapeutic options are limited and are largely adopted from small cell lung cancer treatment paradigms.\n\n\n\nThis report describes a 69-year old male who was diagnosed of HPV-related oropharyngeal cancer with mixed small cell and squamous cell pathology which was clinically aggressive and progressed through multimodal platinum-based therapies. Upon manifestation of worsening metastatic disease, the patient was initiated on a combination of ipilimumab and nivolumab. Within 2 months of starting immunotherapy, a robust partial response was observed. During the treatment course, the patient developed immune-related adverse effects including new diabetes mellitus, colitis, and hypothyroidism. The disease-specific survival was 26 months.\n\n\n\nCombination immunotherapy may be an attractive option for HPV-related small cell head and neck cancers resistant to other treatment modalities and thus warrants further evaluation.",
"affiliations": "Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St, CRB1 Rm#186, Baltimore, MD, 21287, USA.;Department of Pathology, Johns Hopkins University School of Medicine, 410 N Broadway, Rm#2249, Baltimore, MD, 21287, USA.;Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St, CRB1 G86, Baltimore, MD, 21287, USA.;Department of Oncology, Johns Hopkins University School of Medicine, 1550 Orleans St, CRB2 5m44, Baltimore, MD, 21287, USA. Hkang30@jhmi.edu.",
"authors": "Ho|Won Jin|WJ|;Rooper|Lisa|L|;Sagorsky|Sarah|S|;Kang|Hyunseok|H|0000-0001-5758-8202",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D007328:Insulin; D000074324:Ipilimumab; D000077594:Nivolumab; D013974:Thyroxine; D011241:Prednisone; D008775:Methylprednisolone",
"country": "England",
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"doi": "10.1186/s40425-018-0348-4",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 34810.1186/s40425-018-0348-4Case ReportA robust response to combination immune checkpoint inhibitor therapy in HPV-related small cell cancer: a case report Ho Won Jin Who10@jhmi.edu 1Rooper Lisa rooper@jhmi.edu 2Sagorsky Sarah Sboneri1@jhmi.edu 3http://orcid.org/0000-0001-5758-8202Kang Hyunseok Hkang30@jhmi.edu 41 0000 0001 2171 9311grid.21107.35Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St, CRB1 Rm#186, Baltimore, MD 21287 USA 2 0000 0001 2171 9311grid.21107.35Department of Pathology, Johns Hopkins University School of Medicine, 410 N Broadway, Rm#2249, Baltimore, MD 21287 USA 3 0000 0001 2171 9311grid.21107.35Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St, CRB1 G86, Baltimore, MD 21287 USA 4 0000 0001 2171 9311grid.21107.35Department of Oncology, Johns Hopkins University School of Medicine, 1550 Orleans St, CRB2 5m44, Baltimore, MD 21287 USA 9 5 2018 9 5 2018 2018 6 3325 1 2018 29 4 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\nHuman papillomavirus-related small cell carcinoma of the head and neck is an extremely rare, aggressive subtype with poor outcomes. Therapeutic options are limited and are largely adopted from small cell lung cancer treatment paradigms.\n\nCase presentation\nThis report describes a 69-year old male who was diagnosed of HPV-related oropharyngeal cancer with mixed small cell and squamous cell pathology which was clinically aggressive and progressed through multimodal platinum-based therapies. Upon manifestation of worsening metastatic disease, the patient was initiated on a combination of ipilimumab and nivolumab. Within 2 months of starting immunotherapy, a robust partial response was observed. During the treatment course, the patient developed immune-related adverse effects including new diabetes mellitus, colitis, and hypothyroidism. The disease-specific survival was 26 months.\n\nConclusion\nCombination immunotherapy may be an attractive option for HPV-related small cell head and neck cancers resistant to other treatment modalities and thus warrants further evaluation.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s40425-018-0348-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nImmunotherapyHPVSmall cell cancerOropharyngealissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nHuman papillomavirus (HPV)-related small cell cancer of the head and neck (H&N) is extremely rare and has previously been reported as a distinct morphological variant [1, 2]. While HPV-related H&N squamous cell cancers have been associated with more favorable treatment response and survival rates when compared with HPV-negative cancers [3, 4], HPV-related H&N cancers with small cell morphology tend to progress aggressively with many cases demonstrating less than 15 months of disease-specific survival [1, 2, 5].\n\nGiven the rarity of this subtype, there are no preceding clinical trials providing for evidence-based guidelines for therapy. Thus, the treatment paradigm for small cell H&N cancers is largely derived from experience with small cell lung cancers (SCLC). Despite the adoption of platinum-based regimen, in combination with radiation therapy when appropriate, treatment outcomes for small cell H&N cancers overall remain poor without clear options for subsequent lines of therapy [6, 7]. Notably, immunotherapy in recent years have demonstrated promise in treating recurrent or metastatic H&N squamous cell cancers [8] as well as SCLC [9], the treatment options for which have historically been very limited.\n\nHere, we present a case of metastatic H&N small cell cancer associated with HPV responding to combination immunotherapy after failing platinum-based chemotherapy with radiation.\n\nCase presentation\nA 69-year old male patient who has a 30-pack-year smoking history presented with a left-sided neck mass which was increasing in size for several weeks. Fine needle aspiration (FNA) revealed a high grade basaloid carcinoma with myoepithelial and focal neuroendocrine features. He underwent direct laryngoscopy and left selective neck dissection levels II-IV which revealed pT1pN2bM0 glossopharyngeal sulcus carcinoma with mixed squamous cell and small cell pathology (focally positive for CD56, synaptophysin, and chromogranin) positive for high-risk HPV (Fig. 1). Genomic profiling of the tumor was performed via FoundationOne™. The following genomic alterations were detected: KRAS G12C, TSC2 T1181 M, EP300 R1055*, LRP1B loss exons 8–9 and loss exons 12–20, CREBBP S302 N, MED12 A1753V, PALB2 D255N, PIK3R2 E342D, STAT4 T446I, microsatellite stable disease, and tumor mutation burden of 5.59 Mut/Mb; no clearly actionable mutations were identified.Fig. 1 Hematoxylin and eosin stained sections demonstrated a population of tumor cells with minimal cytoplasm, a high nuclear-cytoplasmic ratio, speckled chromatin, nuclear molding, and prominent mitotic and apoptotic figures, consistent with small cell carcinoma (a, 400×). These cells demonstrated patchy positivity for the neuroendocrine marker synaptophysin (b, 400×) and diffuse, strong nuclear and cytoplasmic positivity for p16 (c, 400×) by immunohistochemistry as well as punctate nuclear reactivity for high-risk HPV by RNA in-situ hybridization (d, 400×), supporting the diagnosis of HPV-related small cell carcinoma\n\n\n\nBased on multidisciplinary tumor board review, decision was made to pursue chemoradiation over transoral robotic surgery/radical tonsillectomy. Adopting the treatment paradigm for small cell lung carcinomas, the patient underwent four cycles of cisplatin and etoposide with concurrent intensity-modulated radiation therapy for a total of 70Gy. During follow up, only minimally progressive changes were observed on the post-treatment scan and a three-month follow up scan. Subsequently, however, marked disease progression was noted in another 3 months with several new pulmonary nodules and a new hepatic metastasis confirmed by fine-needle aspiration. Despite four more cycles of palliative cisplatin and etoposide, post-treatment imaging demonstrated worsening pulmonary and hepatic disease (Fig. 2a-d).Fig. 2 CT scans of the chest and abdomen show numerous bilateral pulmonary nodules measuring up to 43 mm (a-c) and liver lesions with a prominent 20 mm lesion (d) prior to immunotherapy initiation. All lesions are markedly improved (e-h) by four months after treatment with ipilimumab and nivolumab has started\n\n\n\nExtrapolating the data from CheckMate 032 study involving patients with recurrent SCLC after failing platinum-based first-line therapy [9], combination immunotherapy regimen with ipilimumab 1 mg/kg every 6 weeks and nivolumab 240 mg every 2 weeks was initiated. To note, upon immunohistochemical analysis, the tumor demonstrated 20% positivity for PD-L1 expression via clone 22C3 antibody (Fig. 3). Further characterization of the tumor-infiltrating lymphocytes by immunohistochemistry revealed a robust presence of CD4+ cells, CD8+ cells, and Foxp3+ cells (Table 1). After one dose of ipilimumab and three doses of nivolumab, significant interval improvement in disease was noted on CT scans with decreased size of most metastatic lesions. After an additional dose of ipilimumab and nivolumab, the patient developed grade 3 immune-related colitis, hypothyroidism, and diabetes mellitus type I and was intermittently hospitalized. He was treated with high-dose steroid taper, which consisted of intravenous methylprednisolone 2 mg/kg IV for 1 week, followed by decreasing dose of oral prednisone every 4 days starting from 1 mg/kg for the next 4 weeks. He was also treated with levothyroxine, and insulin, and further immunotherapy was held thereafter. A repeat scan at 4 months from treatment initiation demonstrated complete resolution of a 20 mm hepatic lesion, complete resolution of pulmonary lesions that measured up to 23 mm, and 67% decrease in a pulmonary target lesion from 43 mm to 14 mm, all of which were consistent with continued partial response (2E-H). Unfortunately, he developed progression of disease in liver and lungs at 6-month restaging scans; progression-free survival was 6 months. He was re-challenged with single agent nivolumab with prophylactic vedolizumab, and tolerated four doses of the treatment well without worsening of immune-related colitis. However, he developed progression of disease with growing nodules in cervical LN, mediastinum, lungs, and liver as well as a singular brain lesion on the first restaging scan. The brain lesion was resected for palliation and diagnosis, confirming metastatic spread with positive PD-L1 expression and tumor-infiltrating lymphocytes (Table 1). The patient’s performance status rapidly declined in the following 2 months, was enrolled in hospice, and he passed away soon thereafter. Disease-specific survival at the time of death was at 26 months.Fig. 3 20% of tumor cells demonstrated membranous staining for PD-L1, consistent with low expression (400×)\n\nTable 1 Immunohistochemical analysis of tumor specimens\n\n\tPD-L1\tCD4/HPF\tCD8/HPF\tFOXP3/HPF\tCD8/FOXP3\tCD8/CD4\t\nNeck primary (pre-treatment)\t20%\t75\t111\t31\t3.58\t1.48\t\nMetastatic brain (post-treatment)\t10%\t53\t69\t9\t7.67\t1.3\t\nHPF high-power field; immunohistochemistry methods described in Additional file 1\n\n\n\nDiscussion\nLiterature review of HPV-related small cell cancers of H&N: A rare and aggressive disease\nSmall cell cancers of extrapulmonary primary have been reported to represent as much as 5% of all small cell carcinoma cases [10]. The existing treatment paradigms for SCLC have been accepted by many institutions as the first line approach for extrapulmonary small cell cancers [1, 2, 5–7, 10]. In fact, a single institutional review of 120 patients with extrapulmonary small cell cancer including H&N small cell cancers demonstrated sustained durable responses with multimodal therapy; 5-year survival of 25.4% for limited stage patients, a rate superior to most series of patients with limited stage SCLC [10]. However, as our patient also eventually progressed after platinum-based treatments with distant metastasis, the overall prognosis remains dismal even for HPV-positive cancers. Among five HPV-related oropharyngeal small cell cancer cases previously reviewed at Johns Hopkins Hospital by Bishop and Westra, three patients had disease-specific survival of only 6 to 15 months despite having been treated with chemoradiation (except for one patient who received chemotherapy only). The remaining two patients who underwent chemoradiation, one with surgical resection and one without, had reported follow up duration of 20 months and 5 months, respectively [1]. Kraft et al. also described their institutional experience, in which among four cases of HPV-related oropharyngeal small cell cancer with follow up information, three cases had total follow-up duration of 9 to 14 months, all ending with progression of disease in the setting of multimodal treatment regimens [2]. In another case series, two patients who were treated with carboplatin-etoposide and radiotherapy, as well as surgery in one patient, died due to progression with 15 and 29 months of disease-specific survival, respectively [5].\n\nRationale behind the immunotherapy for HPV-related small cell cancer of the H&N\nRecently, immunotherapy has emerged as a new attractive treatment modality in oncology. In small cell cancers of the lung, CheckMate 032 showed that nivolumab, a PD-1 inhibitor, with or without ipilimumab, a CTLA-4 inhibitor, provides durable responses for some patients who have failed one or more platinum-containing therapy [9]. In the field of H&N cancers, positive results from a nonrandomized trial exploring the use of pembrolizumab, also a PD-1 antibody, in patients with advanced solid tumors led to the first approval of a checkpoint inhibitor in the treatment of H&N squamous cell cancers [11]. Subsequently, CheckMate 141 demonstrated that nivolumab was preferable to standard single-agent options (methotrexate, docetaxel, or cetuximab) in platinum-refractory H&N squamous cell cancers with higher rate of overall survival and lower rate of treatment-related adverse effects [8]. Now several clinical trials are underway for H&N cancers to explore combinatorial approaches to inhibit not only PD-1/PD-L1 signaling but also in conjunction with anti-CTLA-4 agents. These efforts have thus provided the grounds for trialing our patient with combination immunotherapy.\n\nHowever, the exact mechanism by which the combination of nivolumab and ipilimumab have provided their therapeutic efficacy in our case of HPV-associated H&N small cell cancer is not clear. In principle, inhibiting immunoregulatory pathways induces antitumor immune responses within the tumor microenvironment, but it remains largely speculative whether the intrinsic microenvironmental characteristics associated with the histologic phenotype or HPV status have actually contributed to the therapeutic effect seen in our case. As for small cell cancers, Antonia et al. observed that PD-L1 expression in SCLC was overall less prevalent than in squamous cell lung cancers but that PD-L1 expression status did not necessarily predict tumor responses to PD-1 inhibition [9]. In fact, in our case, there was 20% positivity for PD-L1 expression. Thus, whether the mixed morphology involving squamous phenotype had any bearing on the overall response of the tumor to the immunotherapy is unknown. However, with regards to HPV status in the H&N cancers, HPV-related H&N squamous cell cancers were associated with better responses to nivolumab than HPV-negative tumors [8]. Furthermore, an immune-landscape analysis demonstrated that HPV-positive H&N tumors possess significantly higher CTLA-4 expression and presence of infiltrating regulatory T cells than HPV-negative H&N tumors [12]. Based on our immunohistochemical analysis, both the pre-treatment tissue from the neck and the post-treatment tissue from the brain demonstrated positive PD-L1 expression and substantial presence of CD8+ cells. Prior studies have shown that CD8/Foxp3 and CD8/CD4 ratios are significantly greater in HPV+ than HPV- HNSCC, suggesting a relatively heightened immunologic microenvironment in HPV+ disease [13, 14]. While studies have demonstrated that higher presence of CD8+ cells correlate with a more favorable prognosis in both HNSCC and SCLC, there is only limited evidence that pre-treatment presence of CD8+ T-cells predicts response to checkpoint inhibitor therapy [15, 16].\n\nTaken together, we suspect that such a highly immune-mediated tumor environment, especially as related to HPV infection, may have provided the context in which inhibition of both CTLA-4 and PD-1/PD-L1 pathways led to significant antitumor effects.\n\nInsights from the genomic profile\nGenomic analysis of SCLC revealed that inactivating mutations in TP53 and RB1 affect the vast majority of all tumors, suggesting the notion that the loss of function in these two genes is obligatory in the carcinogenesis of SCLC [17]. Among other genes recurrently mutated in SCLC, mutations in CREBBP and EP300 histone acetyletransferases have also been identified [17]. Given that the fundamental oncogenic process of HPV infection features viral oncoproteins E6 and E7 interfering with the function of p53 and Rb proteins, respectively [18], it was not entirely unexpected that the genomic sequencing of our patient’s HPV-related tumor did not reveal mutations in TP53 and RB1. Notably, the cancer was positive for mutations in CREBBP and EP300. These observed alterations together are consistent with and provide a potential molecular basis for the small cell phenotype seen in our case.\n\nTumor mutational burden and DNA repair deficiencies have been suggested as predictive biomarkers for immune checkpoint inhibitor therapy; tumors that have higher mutational load and/or poor DNA repair mechanisms presents more neoantigens, thereby becoming more susceptible to recognition by the immune system [19]. Furthermore, while HPV viral antigens may serve as neo-epitopes, a recent report has suggested that immune activation against nonviral tumor antigens rather than canonical viral antigens in fact plays a major role in anti-tumor activity [20]. Le et al. demonstrated that tumors with mismatch repair (MMR) deficiency regardless of their tissue of origin are sensitive to immune checkpoint inhibition [21]. In this study, neuroendocrine tumors were among the tumors that had higher rate (> 5%) of MMR deficiency. Also notable, in cataloguing the somatic mutational signatures of cancers, Alexandrov et al. previously observed that both SCLC and head and neck cancers possess relatively higher mutational burdens among 30 human cancer types compared [22]. Interestingly, genomic profiling of our patient’s cancer identified a mutation in PALB2, a gene intimately involved in DNA repair machinery, suggesting a potential genetic basis for immunotherapy response. However, the assay also detected low tumor mutational burden in the cancer, when estimated by targeted comprehensive genomic profiling [23]. Overall, it remains unclear what impact these genetic characteristics truly had on the observed response to immunotherapy.\n\nPotential significance of immune-related adverse events\nLastly, our patient developed multiple immune-related adverse events (IRAE). To date, it has not been determined whether a particular type of IRAE or the severity of IRAE portends significant treatment response, but correlations have been observed in other cancers. For example, in melanoma, multiple reports have associated cutaneous IRAE such as vitiligo with better immunotherapy-related treatment outcomes [24, 25], leading to the hypothesis that there may be lineage-specific epitopes shared by both the normal cells and tumor cells of the same tissue origin [26]. Additional studies to characterize and understand the potentially meaningful relationships between treatment outcomes and IRAE would be valuable.\n\nVedolizumab is a monoclonal antibody against integrin α4β7, which is primarily expressed on a subset of CD4+ T cells and mediates homing of these cells to GI tract [27]. It is approved for treatment of inflammatory bowel disease, and a case series have suggested that it is effective and well tolerated for patients with steroid refractory immune related colitis [28]. We chose to use vedolizumab prophylactically before re-challenge with nivolumab, as it is not expected to have profound systemic immune suppressive effects. Our patient did not develop immune related colitis, although he was taken off because of progression of disease.\n\nConclusion\nIn this report, we have described a patient with HPV-related H&N small cell cancer, an aggressive and rare variant of HPV-related H&N cancers, who has demonstrated significant response to combination immunotherapy with ipilimumab and nivolumab after having progressed through the most adopted treatment approach involving radiation and combination chemotherapy with platinum and etoposide. Thus, immunotherapy regimens based on PD-L1 and/or CTLA-4 inhibition may be an effective approach to treating HPV-related H&N small cell cancers and should be considered for patients who are refractory to first lines of therapy. Taking into account the rarity of this cancer, additional experience and larger-scale studies focused on molecular characteristics of small cell cancers, HPV-related cancers, or the relevant tumor microenvironment features may be more productive in further establishing the utility of immunotherapeutic approaches and any potential predictive markers.\n\nAdditional file\n\nAdditional file 1: Methods for immunohistochemistry analysis. (DOCX 12 kb)\n\n \n\n\nAbbreviations\nCREBBPCREB binding protein\n\nCTLA-4Cytotoxic T-lymphocyte associated protein 4\n\nEP300E1A binding protein p300\n\nH&NHead and neck\n\nHPVHuman papillomavirus\n\nIRAEImmunotherapy related adverse effects\n\nMMRMismatch repair\n\nPD-1/PD-L1Programmed cell death protein 1/programmed death-ligand 1\n\nRB1 (Rb)Retinoblastoma 1\n\nSCLCSmall cell lung cancer\n\nTP53 (p53)tumor protein p53\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s40425-018-0348-4) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nWe appreciate Dr.Cheng Ting Lin for review of radiographic images.\n\nAuthors’ contributions\nWH, LR, and HK reviewed and analyzed the case. SS, LR, and HK were key clinical members for patient care. WH performed literature review. WH and HK were major contributors in manuscript preparation. All authors contributed to critical revision of the manuscript. All authors approved the prepared manuscript for submission.\n\nEthics approval and consent to participate\nCase reports exempt and did not need ethics approval.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of his individual details and accompanying images in this manuscript. The consent form is included in the patient’s chart and is available for review by the Editor-in-Chief.\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. Bishop JA Westra WH Human papillomavirus-related small cell carcinoma of the oropharynx Am J Surg Pathol 2011 35 1679 1684 10.1097/PAS.0b013e3182299cde 21997688 \n2. Kraft S Faquin WC Krane JF HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior Am J Surg Pathol 2012 36 321 330 10.1097/PAS.0b013e31823f2f17 22301491 \n3. Ang KK Harris J Wheeler R Weber R Rosenthal DI Nguyen-Tan PF Westra WH Chung CH Jordan RC Lu C Human papillomavirus and survival of patients with oropharyngeal cancer N Engl J Med 2010 363 24 35 10.1056/NEJMoa0912217 20530316 \n4. Fakhry C Zhang Q Nguyen-Tan PF Rosenthal D El-Naggar A Garden AS Soulieres D Trotti A Avizonis V Ridge JA Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma J Clin Oncol Off J Am Soc Clin Oncol 2014 32 3365 3373 10.1200/JCO.2014.55.1937 \n5. Bates T McQueen A Iqbal MS Kelly C Robinson M Small cell neuroendocrine carcinoma of the oropharynx harbouring oncogenic HPV-infection Head Neck Pathol 2014 8 127 131 10.1007/s12105-013-0471-y 23838856 \n6. Hatoum GF Patton B Takita C Abdel-Wahab M LaFave K Weed D Reis IM Small cell carcinoma of the head and neck: the university of Miami experience Int J Radiat Oncol Biol Phys 2009 74 477 481 10.1016/j.ijrobp.2008.08.014 19004574 \n7. Iqbal MS Paleri V Moor J Dobrowsky W Kelly C Kovarik J Small cell neuroendocrine carcinoma of larynx: case series and literature review J Laryngol Otol 2015 129 910 915 10.1017/S0022215115001668 26173932 \n8. Ferris RL Blumenschein G Jr Fayette J Guigay J Colevas AD Licitra L Harrington K Kasper S Vokes EE Even C Nivolumab for recurrent squamous-cell carcinoma of the head and neck N Engl J Med 2016 375 1856 1867 10.1056/NEJMoa1602252 27718784 \n9. Antonia SJ Lopez-Martin JA Bendell J Ott PA Taylor M Eder JP Jager D Pietanza MC Le DT de Braud F Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial Lancet Oncol 2016 17 883 895 10.1016/S1470-2045(16)30098-5 27269741 \n10. Brennan SM Gregory DL Stillie A Herschtal A Mac Manus M Ball DL Should extrapulmonary small cell cancer be managed like small cell lung cancer? Cancer 2010 116 888 895 10.1002/cncr.24858 20052730 \n11. Seiwert TY Burtness B Mehra R Weiss J Berger R Eder JP Heath K McClanahan T Lunceford J Gause C Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial Lancet Oncol 2016 17 956 965 10.1016/S1470-2045(16)30066-3 27247226 \n12. Mandal R Senbabaoglu Y Desrichard A Havel JJ Dalin MG Riaz N Lee KW Ganly I Hakimi AA Chan TA Morris LG The head and neck cancer immune landscape and its immunotherapeutic implications JCI Insight 2016 1 e89829 10.1172/jci.insight.89829 27777979 \n13. Krupar R Robold K Gaag D Spanier G Kreutz M Renner K Hellerbrand C Hofstaedter F Bosserhoff AK Immunologic and metabolic characteristics of HPV-negative and HPV-positive head and neck squamous cell carcinomas are strikingly different Virchows Arch 2014 465 299 312 10.1007/s00428-014-1630-6 25027580 \n14. Russell S Angell T Lechner M Liebertz D Correa A Sinha U Kokot N Epstein A Immune cell infiltration patterns and survival in head and neck squamous cell carcinoma Head Neck Oncol 2013 5 24 24723971 \n15. Gibney GT Weiner LM Atkins MB Predictive biomarkers for checkpoint inhibitor-based immunotherapy Lancet Oncol 2016 17 e542 e551 10.1016/S1470-2045(16)30406-5 27924752 \n16. Eerola AK Soini Y Paakko P A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma Clin Cancer Res 2000 6 1875 1881 10815910 \n17. George J Lim JS Jang SJ Cun Y Ozretic L Kong G Leenders F Lu X Fernandez-Cuesta L Bosco G Comprehensive genomic profiles of small cell lung cancer Nature 2015 524 47 53 10.1038/nature14664 26168399 \n18. Chung CH Gillison ML Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications Clin Cancer Res 2009 15 6758 6762 10.1158/1078-0432.CCR-09-0784 19861444 \n19. Schumacher TN Schreiber RD Neoantigens in cancer immunotherapy Science (New York, NY) 2015 348 69 74 10.1126/science.aaa4971 \n20. Stevanovic S Pasetto A Helman SR Gartner JJ Prickett TD Howie B Robins HS Robbins PF Klebanoff CA Rosenberg SA Hinrichs CS Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer Science 2017 356 200 205 10.1126/science.aak9510 28408606 \n21. Le DT Durham JN Smith KN Wang H Bartlett BR Aulakh LK Lu S Kemberling H Wilt C Luber BS Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade Science (New York, NY) 2017 357 409 413 10.1126/science.aan6733 \n22. Alexandrov LB Nik-Zainal S Wedge DC Aparicio SA Behjati S Biankin AV Bignell GR Bolli N Borg A Borresen-Dale AL Signatures of mutational processes in human cancer Nature 2013 500 415 421 10.1038/nature12477 23945592 \n23. Chalmers ZR Connelly CF Fabrizio D Gay L Ali SM Ennis R Schrock A Campbell B Shlien A Chmielecki J Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden Genome Med 2017 9 34 10.1186/s13073-017-0424-2 28420421 \n24. Nakamura Y Tanaka R Asami Y Teramoto Y Imamura T Sato S Maruyama H Fujisawa Y Matsuya T Fujimoto M Yamamoto A Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study J Dermatol 2017 44 117 122 10.1111/1346-8138.13520 27510892 \n25. Sanlorenzo M Vujic I Daud A Algazi A Gubens M Luna SA Lin K Quaglino P Rappersberger K Ortiz-Urda S Pembrolizumab cutaneous adverse events and their association with disease progression JAMA Dermatol 2015 151 1206 1212 10.1001/jamadermatol.2015.1916 26222619 \n26. Lo JA Fisher DE Flaherty KT Prognostic significance of cutaneous adverse events associated with Pembrolizumab therapy JAMA Oncol 2015 1 1340 1341 10.1001/jamaoncol.2015.2274 26270186 \n27. Berlin C Berg EL Briskin MJ Andrew DP Kilshaw PJ Holzmann B Weissman IL Hamann A Butcher EC Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1 Cell 1993 74 185 195 10.1016/0092-8674(93)90305-A 7687523 \n28. Bergqvist V Hertervig E Gedeon P Kopljar M Griph H Kinhult S Carneiro A Marsal J Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis Cancer Immunol Immunother 2017 66 581 592 10.1007/s00262-017-1962-6 28204866\n\n",
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"abstract": "Acute mediastinitis (AM) is a rare but life-threatening disease. Here, we report a case of AM secondary to endobronchial tuberculosis (EBTB) and pseudomembranous Aspergillus tracheobronchitis (PMATB) co-infection. EBTB was confirmed by tissue culture for Mycobacterium tuberculosis and GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) detection (simultaneous detection of M. tuberculosis and resistance to rifampin) using endobronchial biopsies; PMATB was confirmed by histopathology. Even with antibiotic treatment and systemic support treatment, the patient died of massive hemoptysis on day 10 after admission. When immunocompromised hosts have AM, especially with central airway involvement, EBTB and aspergillosis should be considered potential causes. Bronchoscopy is helpful for rapid diagnosis and administering precise treatment.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China.;Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China.;Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China.;Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China.;Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China.",
"authors": "Liang|Chao-Nan|CN|;Zhao|Hong-Wen|HW|;Kang|Jian|J|;Hou|Gang|G|https://orcid.org/0000-0003-3438-1764;Yin|Yan|Y|",
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"fulltext": "\n==== Front\nJ Int Med Res\nJ. Int. Med. Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n10.1177/0300060520918469\n10.1177_0300060520918469\nCase Report\nAcute mediastinitis associated with tracheobronchial tuberculosis and aspergillosis: a case report and literature review\nLiang Chao-nan Zhao Hong-wen Kang Jian https://orcid.org/0000-0003-3438-1764Hou Gang Yin Yan Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China\nYan Yin and Gang Hou, Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang 110001, Liaoning, China. Emails: yinyan1b@126.com; hougangcmu@163.com\n20 5 2020 \n5 2020 \n48 5 030006052091846922 9 2019 2 3 2020 © The Author(s) 20202020SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Acute mediastinitis (AM) is a rare but life-threatening disease. Here, we report a case of AM secondary to endobronchial tuberculosis (EBTB) and pseudomembranous Aspergillus tracheobronchitis (PMATB) co-infection. EBTB was confirmed by tissue culture for Mycobacterium tuberculosis and GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) detection (simultaneous detection of M. tuberculosis and resistance to rifampin) using endobronchial biopsies; PMATB was confirmed by histopathology. Even with antibiotic treatment and systemic support treatment, the patient died of massive hemoptysis on day 10 after admission. When immunocompromised hosts have AM, especially with central airway involvement, EBTB and aspergillosis should be considered potential causes. Bronchoscopy is helpful for rapid diagnosis and administering precise treatment.\n\nBronchoscopyinterventional pulmonologyco-infectionMycobacterium tuberculosisendobronchial tuberculosisAspergillus tracheobronchitisedited-statecorrected-prooftypesetterts2\n==== Body\nIntroduction\nAcute mediastinitis (AM) is a rare but life-threatening disease with a mortality rate of up to 80%.1 In general, esophageal rupture and postoperative complications are the most common causes of AM.2 Tracheal perforation, direct extension of an infection from the lungs, and descending infection from the neck are also common causes of AM.3 Overall, the bacteriologic findings in mediastinitis secondary to extension of an infection from head and neck sources indicate polymicrobial infections. Tuberculosis and fungal infections, such as histoplasmosis and aspergillosis, are the most common infections in chronic mediastinitis4,5 but rarely cause AM. Rapid and accurate confirmation of pathogens is crucial to determining both the treatment and prognosis of AM. Here, we report a case of tracheobronchial tuberculosis (TBTB) and pseudomembranous Aspergillus tracheobronchitis (PMATB) co-infection presenting as AM in a female with uncontrolled diabetes mellitus (DM). Optimal management of combined TB and DM is important but challenging in terms of achieving good disease outcomes and avoiding toxicity, drug interactions, and other issues.6,7 Although we confirmed the pathogens and administered antibiotics in a timely manner, we could not rescue the patient. To the best of our knowledge, such a case has not been reported in the literature.\n\nCase report\nThis research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent to use the patient’s information and images for publication was provided by a relative of the patient.\n\nA 63-year-old female patient was admitted due to dyspnea and productive cough that had lasted for 6 days. The patient was febrile, and her highest temperature was 38.6°C. She had been diagnosed with type 2 DM, hypertension, and coronary heart disease six years prior and had uncontrolled hyperglycemia and hypertension. On admission, her vital signs were as follows: temperature, 35.5°C; respiration rate, 20 breaths/minute; pulse, 108 beats/minute; and blood pressure, 256/113 mmHg. Blood gas analysis showed type I respiratory failure (pH, 7.44; PaCO2, 34 mmHg; PaO2, 52 mmHg; and SpO2, 88%). Laboratory data revealed a white blood cell count of 18.31 × 109/L, a neutrophil count of 17.27 × 109/L, a C-reactive protein level of 123.1 mg/L, a procalcitonin level of 0.61 ng/mL (0–0.05 ng/mL), an immunoglobulin E level of 332 IU/mL (0.00–100.00 IU/mL), a glucose level of 17.91 mmol/L, and a plasma glycosylated hemoglobin level of 14.90%. The level of (1,3)-β-d-glucan was normal. Liver and renal functions were normal. The human immunodeficiency virus antibody test was negative. Sputum smears were positive for gram-positive cocci, Gram-negative bacilli, and fungal spores but negative for Mycobacterium tuberculosis (MTB).\n\nHigh-resolution computed tomography (CT) revealed stenosis of the right main bronchus, infiltrative and patchy shadows in the bilateral lungs, atelectasis of the right middle lobe, bilateral pleural effusion, pericardial effusion, increased attenuation of mediastinal fat, localized mediastinal fluid, free gas bubbles in the mediastinum, and mediastinal lymph node enlargement (Figure 1a–f).\n\nFigure 1. The details of chest computed tomography (CT), bronchoscopy, and pathology. Panels a–f: Chest CT revealed the fullness of the mediastinum and increased attenuation of mediastinal fat, localized mediastinal fluid, free gas bubbles in the mediastinum, and mediastinal lymph node enlargement (d, e, f). Panels show inflammatory infiltration of the bilateral lungs, especially in the right middle lobe (a–f), atelectasis of the right middle lobe (c, f), bilateral pleural effusion, and pericardial effusion. Panels g to i reveal diffusive pseudomembranous tracheobronchitis of the trachea and right and left bronchus. Panels J and K show hematoxylin and eosin staining of the biopsy of membrane of the right bronchus (j: 100×, k: 400×), which revealed septate and branching fungal hyphae, consistent with the features of Aspergillus, and some underlying necrotic lung tissue.\n\nInitial empirical antibiotic therapy included meropenem (1.0 g, q8h, iv) and moxifloxacin (400 mg, qd, iv). We controlled the patient’s blood glucose and blood pressure to acceptable levels. To further evaluate the tracheobronchial lesion, we performed a bronchoscopy, which revealed stenosis of the lower segment of the trachea and bilateral main bronchi, which were covered with yellowish-white mucus and secretions (Figure 1g–i). Eight biopsies were obtained using forceps, one for bacterial culture, one for fungal culture, one for tuberculous bacteria culture (BACTEC MGIT 960 System; Becton Dickinson, Oxford, UK), one for GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) detection, and four for pathological examination. Histopathology of the samples suggested hyphae typical of Aspergillus with necrotic and inflammatory cell infiltration (Figure 1j, k). GeneXpert MTB/RIF detection confirmed the existence of MTB (MTB detected at a high level, with no rifampicin resistance detected) and tissue culture was positive for MTB. Because of the policy regarding MTB control and treatment, the patient had to be transferred to a hospital specializing in patients with tuberculosis. Thus, on day 6 after admission to our hospital, the patient was transferred to a hospital for systemic treatment, including anti-tuberculosis and anti-fungal therapy. Anti-tuberculosis treatment was initiated orally with isoniazid 300 mg/day, rifampicin 450 mg/day, ethambutol 750 mg/day, and pyrazinamide 500 mg tid; anti-aspergillosis treatment was initiated with voriconazole (4 mg/kg, q12h). Unfortunately, the patient’s condition deteriorated rapidly, and she died suddenly from massive hemoptysis on day 4 after transfer from our hospital.\n\nDiscussion and conclusion\nAM is rare and associated with a high mortality if not treated in a timely manner. Chills, high fever, tachycardia, and sepsis are common clinical symptoms of AM,2 but they are nonspecific. CT findings are very important for recognizing AM, including increased attenuation of mediastinal fat, localized mediastinal fluid, free gas bubbles in the mediastinum, mediastinal lymph node enlargement, pleural and/or pericardial effusion and lung infiltrate.3 In our case, we observed mediastinal fat attenuation, free gas bubbles in the mediastinum, and pericardial and pleural effusion, which are typical radiologic manifestations of AM.\n\nRapid confirmation of pathogens is crucial in AM. Bronchial biopsy, which is a relatively safe and noninvasive technique, can quickly provide high-quality tissue samples when the infection involves the central airways. The GeneXpert MTB/RIF assay is an innovative tool for rapidly diagnosing TBTB and rifampicin resistance.8 In our case, we performed bronchial biopsy and identified MTB using the GeneXpert MTB/RIF assay on the same day, but the MTB-positive tissue culture result was not reported until 4 days after the patient had died.\n\nTracheal fistulae caused by TBTB have been reported, and anti-tuberculosis therapy has proven to be effective.9 Of note, tracheal fistulae are an uncommon complication of Aspergillus tracheobronchitis (ATB).10 The AM in our patient might have been caused by a tracheobronchial mediastinal fistula due to TBTB or PMATB, but we could not confirm the position of the fistula because of the existence of a pseudomembrane. Involvement of the full tracheobronchial layer in ATB that may lead to mediastinitis has been identified as a poor prognostic factor in previous study.11 Bronchoscopy in our patient showed the lower segment of the trachea, carina, the left mainstem bronchus, right mainstem bronchus and the bronchus intermedius were covered with yellowish-white mucus and secretions, and both the right mainstem bronchus and the bronchus intermedius were narrowed, consistent with the bronchoscopic manifestations of TBTB and PMATB. Aspergillus can colonize the airways of patients with underlying lung disease, such as tuberculosis, but the patient in this case died of massive hemoptysis. This was indirect evidence of AM caused by Aspergillus because invasive Aspergillus infections can lead to vascular invasion and infarction, which can then result in transmural necrosis.12 Diabetes mellitus is a moderate-to-strong risk factor for the development of TBTB and ATB. Moreover, treatment failure and death are more frequent in diabetic patients.13 Reversal of predisposing factors, such as hyperglycemia, is crucial for the treatment of invasive fungal infections.\n\nIn conclusion, when AM occurs in an immunocompromised host, especially with central airway involvement, endobronchial tuberculosis and aspergillosis should be considered potential causes. Bronchoscopy should be performed in a timely manner to facilitate a rapid definite diagnosis and administration of precise treatment.\n\nAuthor contributions\nGH and YY made substantial contributions to the conception or design of the work. All authors contributed to the acquisition of data for the work. GH, C-NL and H-WZ helped to collect the data of the case. YY and C-NL wrote the manuscript. GH, YY, and JK interpreted data. GH performed the bronchoscopy. All authors revised the paper critically for important intellectual content and approved the final version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iD\nGang Hou https://orcid.org/0000-0003-3438-1764\n==== Refs\nReferences\n1 Vagvolgyi A Vadasz P Heiler Z , et al\n[Surgical treatment of acute descending necrotising mediastinitis]\n. Magy Seb \n2012 ; \n65 : 383 –387\n. DOI: 10.1556/MaSeb.65.2012.5.9.23086825 \n2 Akman C Kantarci F Cetinkaya S. \nImaging in mediastinitis: a systematic review based on aetiology\n. Clin Radiol \n2004 ; \n59 : 573 –585\n. DOI: 10.1016/j.crad.2003.12.001.15208062 \n3 Carrol CL Jeffrey RB JrFederle MP , et al\nCT evaluation of mediastinal infections\n. J Comput Assist Tomogr \n1987 ; \n11 : 449 –454\n. DOI: 10.1097/00004728-198705000-00015.3571587 \n4 Zhang C Yao M Yu Z , et al\nRare fibrosing granulomatous mediastinitis of tuberculosis with involvement of the transverse sinus\n. J Thorac Cardiovasc Surg \n2007 ; \n133 : 836 –837\n. DOI: 10.1016/j.jtcvs.2006.11.023.17320609 \n5 Chatterjee D Bal A Singhal M , et al\nFibrosing mediastinitis due to Aspergillus with dominant cardiac involvement: report of two autopsy cases with review of literature.\n\nCardiovasc Pathol \n2014 ; \n23 : 354 –357\n. DOI: 10.1016/j.carpath.2014.05.005.24998315 \n6 van Crevel R Koesoemadinata R Hill PC , et al\nClinical management of combined tuberculosis and diabetes\n. Int J Tuberc Lung Dis \n2018 ; \n22 : 1404 –1410\n. DOI: 10.5588/ijtld.18.0340.30606312 \n7 Bao J Hafner R Lin Y , et al\nCurbing the tuberculosis and diabetes co-epidemic: strategies for the integration of clinical care and research\n. Int J Tuberc Lung Dis \n2018 ; \n22 : 1111 –1112\n. DOI: 10.5588/ijtld.18.0482.30236174 \n8 Zhang Q Zhang Q Sun BQ , et al\nGeneXpert MTB/RIF for rapid diagnosis and rifampin resistance detection of endobronchial tuberculosis\n. Respirology \n2018 ; \n23 : 950 –955\n. DOI: 10.1111/resp.13316.29691960 \n9 Kim M Kang ES Park JY , et al\nFistula formation between right upper bronchus and bronchus intermedius caused by endobronchial tuberculosis: a case report\n. Tuberc Respir Dis (Seoul) \n2015 ; \n78 : 286 –288\n. DOI: 10.4046/trd.2015.78.3.286.26175787 \n10 Rummens P Bruyneel M Lungarella M , et al\nAspergillus tracheobronchitis, bronchopleural fistula and empyema after lobectomy for aspergilloma\n. Med Mycol Case Rep \n2014 ; \n6 : 25 –28\n. DOI: 10.1016/j.mmcr.2014.07.006.25379394 \n11 Wu N Huang Y Li Q , et al\nIsolated invasive Aspergillus tracheobronchitis: a clinical study of 19 cases\n. Clin Microbiol Infect \n2010 ; \n16 : 689 –695\n. DOI: 10.1111/j.1469-0691.2009.02923.x.19689467 \n12 Pornsuriyasak P Murgu S Colt H. \nPseudomembranous aspergillus tracheobronchitis superimposed on post-tuberculosis tracheal stenosis\n. Respirology \n2009 ; \n14 : 144 –147\n. DOI: 10.1111/j.1440-1843.2008.01389.x.19144060 \n13 Dooley KE Chaisson RE. \nTuberculosis and diabetes mellitus: convergence of two epidemics\n. Lancet Infect Dis \n2009 ; \n9 : 737 –746\n. DOI: 10.1016/S1473-3099(09)70282-8.19926034\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "48(5)",
"journal": "The Journal of international medical research",
"keywords": "Aspergillus tracheobronchitis; Bronchoscopy; Mycobacterium tuberculosis; co-infection; endobronchial tuberculosis; interventional pulmonology",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000995:Antitubercular Agents; D001228:Aspergillosis; D001230:Aspergillus; D001980:Bronchi; D001999:Bronchoscopy; D060085:Coinfection; D048909:Diabetes Complications; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D025301:Hyphae; D016867:Immunocompromised Host; D008480:Mediastinitis; D008482:Mediastinum; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D013183:Sputum; D014057:Tomography, X-Ray Computed; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "300060520918469",
"pmc": null,
"pmid": "32431185",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15208062;30606312;25379394;19926034;30236174;19689467;26175787;24998315;23086825;29691960;17320609;19144060;3571587",
"title": "Acute mediastinitis associated with tracheobronchial tuberculosis and aspergillosis: a case report and literature review.",
"title_normalized": "acute mediastinitis associated with tracheobronchial tuberculosis and aspergillosis a case report and literature review"
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{
"abstract": "We describe a 6-year-old female patient who developed carbamazepine-associated toxic epidermal necrolysis. With active wound care, systemic methylprednisolone and intravenous immunoglobulin pulse therapies and multidisciplinary supportive care, the patient improved significantly. This case indicates that improving the management of Stevens-Johnson syndrome/Toxic epidermal necrolysis patients requires attention not only to the process of wound management but also to individual supportive care and active therapeutic intervention. Only through this can standardized care, including muco-cutaneous and visceral wound care, be delivered to provide high-quality care with improved clinical prognosis and quality of life.",
"affiliations": "Department of Dermatology Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China.;Department of Dermatology Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China.;Department of Dermatology Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China.;Department of Dermatology Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China.",
"authors": "Liang|Yuan|Y|;Chu|Yan|Y|;Xu|Zigang|Z|;Ma|Lin|L|",
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"doi": "10.1002/ped4.12040",
"fulltext": "\n==== Front\nPediatr Investig\nPediatr Investig\n10.1002/(ISSN)2574-2272\nPED4\nPediatric Investigation\n2096-3726 2574-2272 John Wiley and Sons Inc. Hoboken \n\n10.1002/ped4.12040\nPED412040\nClinical Experience\nClinical Experience\nSuccessful treatment of a female pediatric patient with carbamazepine‐induced toxic epidermal necrolysis: Active wound care and systemic therapy\nLiang Yuan \n1\n Chu Yan \n1\n Xu Zigang \n1\n Ma Lin \n1\nbch_maleen@aliyun.com \n1 \nDepartment of Dermatology\nBeijing Children's Hospital\nCapital Medical University\nNational Center for Children's Health\nBeijing\nChina\n\n* Correspondence\n\nLin Ma, Department of Dermatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.\n\nEmail: bch_maleen@aliyun.com\n\n16 7 2018 \n6 2018 \n2 2 10.1002/ped4.2018.2.issue-2114 118\n05 2 2018 19 4 2018 © 2018 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric DevelopmentThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nWe describe a 6‐year‐old female patient who developed carbamazepine‐associated toxic epidermal necrolysis. With active wound care, systemic methylprednisolone and intravenous immunoglobulin pulse therapies and multidisciplinary supportive care, the patient improved significantly. This case indicates that improving the management of Stevens‐Johnson syndrome/Toxic epidermal necrolysis patients requires attention not only to the process of wound management but also to individual supportive care and active therapeutic intervention. Only through this can standardized care, including muco‐cutaneous and visceral wound care, be delivered to provide high‐quality care with improved clinical prognosis and quality of life.\n\nDrug reactionWound careToxic epidermal necrolysis source-schema-version-number2.0cover-dateJune 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:01.07.2020\n\n\nLiang \nY \n, \nChu \nY \n, \nXu \nZ \n, \nMa \nL \n. Successful treatment of a female pediatric patient with carbamazepine‐induced toxic epidermal necrolysis: Active wound care and systemic therapy\n. Pediatr Invest . 2018 ;2 :114 ‐118\n. 10.1002/ped4.12040 \n\n\n\n\nFunding source\n\n\nNational Natural Science Foundation of China (Grant no. 81602754); Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding (code: ZYLX201601); Project of Excellent Talents in Beijing City (code: 2013A003034000013).\n==== Body\nMETHODS AND RESULTS\nA 6‐year‐old female was transferred to the dermatology department of Beijing Children's Hospital with a 6‐day history of a progressive rash, fever, malaise, and conjunctivitis. The patient had been healthy until 2 weeks before admission, when carbamazepine was prescribed to treat a headache. Six days before admission, a rash appeared on the patient's neck and trunk, the body temperature rising to 39°C. The rash rapidly progressed, forming extensive confluent dusky macules, patches, and necrosis eruption with blistering, and body temperature increased to 41°C. A diagnosis of drug eruption was made. Carbamazepine treatment was discontinued and methylprednisolone administered intravenously (1.5 mg/kg body weight). After 3 days, the rash spread to involve most of the body, with increased vesicles and bullae and the appearance of oral, vulvar, and ocular lesions. The patient was admitted to the dermatology unit for suspected carbamazepine‐induced toxic epidermal necrolysis (TEN).\n\nOn examination, the patient displayed fever (38.9°C) and coalescing violaceous macules with multiple flaccid vesicles and bullae involving the face, trunk, back, extremities, feet, and hands. Nikolsky's sign (ready removal of the epidermis with slight tangential pressure) was positive, involving approximately 70% of the total body surface, while epidermal detachment was >45%. Erosions with hemorrhagic crusts developed on the lips. Oral, anal, and vulvar ulcerations and bilateral pseudo‐membranous conjunctivitis were present. The physical examination was normal. The patient was clinically diagnosed as having TEN, which was identified from the pathology of a skin biopsy.\n\nOver the following 48 hours, the patient developed increased pain in the mouth with dysphagia, pain on urination, and additional blistering skin lesions, sloughing of the skin and oral mucosa occurred (Figure 1), full‐thickness epidermis peeled off the hands in sheets (Figure 2), and megalgia made the patient agitated. On the third day after hospitalization, the condition continued to deteriorate, the patient displaying high fever, tachypnea, tachycardia, oliguria, and mild hypotension, the extent of epidermal skin detachment increased, involving the trunk, back, arms, and hands, and sloughing of oral and respiratory mucosa worsened. The patient complained of severe pain in the skin, had dyspnea, and became increasingly dysphoric. Later that day, the patient was transferred to the intensive care unit (ICU). On admission to the ICU, body temperature was 40°C, the pulse 211 beats/minute, the respiratory rate 35 breaths/minute, and the blood pressure 146/67 mm Hg. Multiple mucosa erosions, ulcerations, severe hemorrhagic crusting involving oral, nasal, vulvar, and anal mucosa, and pseudo‐membranous conjunctivitis occurred. Breathing was rough and wheezy, while heart sounds were low and muffled. Bowel sounds were absent. The patient had extensive sloughing from the face, trunk, hands, and feet, with a denuded, second‐degree burn appearance, and intact bullae covered much of the skin of the arms and legs. In total, 93% of the epidermis was involved, only the scalp being spared. Because multiple‐organ dysfunction was present, involving the lungs, heart, liver, and gastrointestinal tract, nasal continuous positive airway pressure (NCPAP) treatment was initiated, whereby a double‐cavity central venous catheter was inserted and a normal saline infusion started to maintain fluid and achieve electrolyte repletion. Methylprednisolone (20 mg/kg body weight), midazolam, morphine, azithromycin, vancomycin, cedilanid, and dopamine were administered intravenously. To the intravenous therapy were added 5% albumin solution and fresh frozen plasma. Total parenteral nutrition was initiated.\n\nFigure 1 Epidermal sloughing exposes bare dermis. Coalescing violaceous macules can also be obs erved. There is widespread involvement of the face and upper trunk. Erosions with hemorrhagic crusts on the lips can also be seen.\n\nFigure 2 Extensive necrolysis results in the detachment of sheets of epidermis and exposure of large areas of denuded dermis of one hand.\n\nThe wounds were blistered and produced moderate amounts of clear drainage fluid. Bland petroleum dressings were applied to cover the raw exposed dermis, while the denuded hands were covered with the patient's own detached epidermis in a glove‐like manner. Chlortetracycline eye ointment was applied on the mucosal surfaces of the perianal region and vaginal labia and lips to avoid synechia formation. Advice on ocular care was obtained by consulting the ophthalmology department. Treatment involved daily removal of mucosal strands and adhesions between the lids and between the lids and the globe and the application of topical antimicrobial drops to prevent infection and topical corticosteroids to reduce inflammation and scarring.\n\nOn the fourth hospitalization day, body temperature was normal and the rash did not deteriorate. By day 6, oxygen saturation was maintained at 95% after the NCPAP treatment was terminated. On the eighth hospitalization day, the patient could eat some rice soup and noodles and parental nutrition was stopped. There was strong resolution of the rash and pain medications were slowly discontinued. During the third week, the skin wounds began to heal, followed by gradual healing of ocular, oral, and anogenital mucosal lesions without scarring. The patient was discharged on the twentieth day after hospitalization. Four months after discharge, the patient had almost completely recovered, except for persisting variegated skin pigment changes (Figure 3). The skin of the hands and the fingernails were essentially normal, having recovered under the protection of the patient's own detached epidermis (Figure 4). Laboratory analyses and medications are presented in detail in Tables 1 and 2.\n\nFigure 3 After 4 months, the patient's face had almost completely recovered, except for persisting variegated skin pigment changes.\n\nFigure 4 After 4 months, the skin of the hands and the fingernails were essentially normal.\n\nTable 1 Laboratory analyses of the patient\n\nLaboratory analyses\tD1*\tD2*\t\naD3\t\nbD6\tD7\tD9\tD10\tD12\tD16\t\nSodium (mmol/L)\t\t\t128.0\t130.5\t\t130.0\t\t\tN\t\nAlbumin (g/L)\t\t\t23\t24\t\t29\t\t\tN\t\nAspartate aminotransferase (U/L)\t\t\t671\tN\t\tN\t\t\tN\t\nAlanine aminotransferase (U/L)\t\t\t51\tN\t\tN\t\t\tN\t\nCreatine kinase (U/L)\t\t\t988\tN\t\tN\t\t\tN\t\nCreatine kinase‐MB (U/L)\t\t\t176\tN\t\tN\t\t\tN\t\nBlood glucose (mmol/L)\t\t\t9.21\tN\t\tN\t\t\tN\t\nWhite cell count (×109/L)\t8.0\t7.0\t5.0\t\t15.1\t\t14.7\t10.5\t9.7\t\nHemoglobin (g/L)\t119\t103\t100\t\t\t\t106\t115\t103\t\nPlatelet count (×109/L)\t137\t\t315\t\t\t\t599\t475\t\t\nC‐reactive protein level (mg/L)\t< 8\t\t29\t\t22\t\t\t< 8\t< 8\t\nChest radiograph\t\t\tPatchy infiltrates\t\t\t\tN\t\tN\t\nD1* and D2*: Hospital day 1 and day 2\n\na D3: patient transferred from the department of dermatology to the intensive care unit\n\nb D6: patient transferred from the intensive care unit to the department of dermatology\n\nJohn Wiley & Sons, LtdTable 2 Treatment options of the patient in detail\n\nMedications\tD‐3*\tD1\tD2\t\naD3\tD4\tD5\t\nbD6\tD7\tD8\tD9\tD10\tD11\tD12\tD13\tD14\tD15\tD16\tD17\tD18\tD19\t\nDexamethasone (mg/d)\t\t12.5\t15\t15\t\t\t\t\t\t10\t10\t7.5\t7.5\t5\t5\t4\t4\t3\t2\t1\t\nMethylprednisolone (mg/d)\t40\t\t\t\t560\t560\t560\t270\t60\t\t\t\t\t\t\t\t\t\t\t\t\nIVIG (g/d)\t\t25\t25\t25\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nBlood plasma (ml/d)\t\t\t\t\t300 \t300\t\t200\t\t\t\t\t\t\t\t\t\t\t\t\t\nAlbumin (g/d)\t\t\t\t\t\t\t\t\t10\t10\t\t\t\t\t\t\t\t\t\t\t\nAzithromycin (mg/d)\t\t250\t250\t250\t250\t250\t250\t250\t\t\t\t\t\t\t\t\t\t\t\t\t\nVancomycin (mg/d)\t\t\t\t\t\t\t\t\t500\t500\t500\t500\t500\t500\t500\t\t\t\t\t\t\nMidazolam\t\t\t\t+\t+\t+\t+\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nMorphine\t\t\t\t+\t+\t+\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nCedilanid\t\t\t\t+\t+\t+\t+\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nDopamine\t\t\t\t\t+\t+\t+\t+\t\t\t\t\t\t\t\t\t\t\t\t\t\nD‐3*: 3 days before admission\n\na D3: patient transferred from the department of dermatology to the intensive care unit\n\nb D6: patient transferred from the intensive care unit to the department of dermatology Weight of the patient: 27kg\n\nJohn Wiley & Sons, LtdDISCUSSION\nSJS and TEN are drug‐induced, immune‐mediated blistering disorders, which are characterized by different extents of full‐thickness epidermal necrosis and detachment of the mucosal and skin surfaces. According to the severity and extent of widespread epidermal detachment, SJS/TEN is classified as SJS, SJS/TEN overlap and TEN when involving <10%, 10–30%, and 30% of the body surface area, respectively. An important feature of SJS/TEN is the varying degrees of detachment of the epidermis and wound formation, leading to multiple organ dysfunction and infection. Generally, the more severe the epidermal necrolysis, the greater the mortality risk. Therefore, patients require early transfer to an intensive care or burn unit, where wound care can be optimally managed, fluid and electrolyte losses can be corrected, infection surveillance can be conducted, and multidisciplinary consultation can be performed.1 A multicenter review found that delayed referral of TEN patients to a burn center was associated with a significantly lower survival rate.2\n\n\nSeveral retrospective studies3, 4 noted that a new epidermal layer developed after approximately 12–16 days, which was produced by the residual dermal appendages, provided the exposed dermis was maintained moist and viable. Before epidermal re‐population proceeds, covering of the exfoliated skin to protect and preserve the dermis with an appropriate dressing or skin substitute is pivotal, because there are potential advantages, including accelerating dermal re‐epithelialization, preventing transcutaneous fluid, protein, and heat loss from the wound, establishing a barrier to exogenous microbial colonization, and helping pain control. However, there is a lack of evidence for which wound covering to apply. Experiences from burn centers favor the use of a biological skin substitute, including porcine xenograft and cadaveric allograft,5 or biosynthetic dressings, for example, Biobrane, after aggressive cleansing and irrigation of the wound and debridement of any loose or imminently detached epidermis.6 Harr et al. stressed that wounds should be treated conservatively, without skin debridement, because the epidermis should remain as intact as possible to act as a natural biological dressing, aiding re‐epithelialization of the exposed dermis and avoiding scar formation.7 We propose preserving any loose epidermis and blistered skin carefully to act as biological membranes as well as covering the exfoliated area with non‐adhesive wound dressings, including silver nitrate, silver‐containing synthetic material, and Vaseline gauze with a gauze overlay soaked in povidone iodine solution. Moreover, when surface infection is present, topical antimicrobial agents are necessary, but topical sulfa‐containing medications should be avoided. It is essential that such wounds are managed in a bacterial‐controlled environment that minimizes the risk of sepsis.\n\nCare of the mucosal surface is important to maintain normal functions, prevent infections, and avoid sequelae, including among others synechia, scarring, and dysfunction. Special mention should be made of ophthalmologic care management. Inflammation of the mucosal surfaces of the eye and eyelids may result in chemosis, conjunctivitis, pseudomembrane formation, and corneal and conjunctival epithelial sloughing, which are very painful and prone to desiccation, corneal ulceration, and local infection. It is imperative to consult an ophthalmologist for assistance with eye care in patients with SJS/TEN, to prevent or mitigate acute blinding, corneal and conjunctival scarring, symblepharon, severe dry eyes, and trichiasis.8, 9 Acute management normally includes ocular‐surface lubrication and conjunctival hygiene, for example, two‐hourly application of a lubricant to prevent desiccation, daily saline irrigation, and removal of the conjunctival fornixes with a glass rod to break down mucosal strands, to maintain ocular hygiene and prevent adhesion. Furthermore, the use of topical antimicrobial drops and corticosteroids to avoid infection and reduce inflammation and scarring is recommended.10, 11 An amniotic membrane transplantation should be considered for patients with extensive loss of ocular surface epithelia as an effective means to temporarily protect the corneas.12\n\n\nIn the presented patient, throughout the acute illness, oculotect gel (Hypo Fears Gel), levofloxacin eye drops, and tetracycline cortisone eye ointment was administered topically. The patient's eyes recovered completely without any complications.\n\nOther mucosal management strategies include regular application of emollients and lubricants on the raw mucosal surfaces, including the lips, glans, perianal region, and between the vaginal labia, to keep these mucous membranes separated, of topical corticosteroids to reduce mucosal inflammation, and of topical analgesia and antiseptics to prevent severe pain and infections.5, 13\n\n\nIn the presented patient, chlortetracycline eye ointment was applied on the lips and urogenital area as a lubricant, petrolatum gauze was placed between the vaginal labia, and a urethral catheter was worn during the acute period, and the patient healed without and sequela.\n\nIn addition, management of epithelium‐lined structures related to visceral wounds is essentially supportive, treating infections as they occur, replacing fluid, protein, and blood losses, and supporting failing organ systems, while awaiting re‐epithelialization of these inaccessible surfaces. Special attention should be paid on admission to the evaluation of any involvement of the airway. When a related problem is present, the patient should be promptly transferred to an ICU or burn center, where mechanical ventilation is likely to be applied. When necessary, bronchoscopy should be undertaken to prevent atelectasis and airway obstruction by the removal of sloughed bronchial epithelium.10\n\n\nIn summary, improving the management of SJS/TEN patients requires attention both to the process of the wound management and to individual supportive care and active therapeutic interventions. Only through this can standardized care, including both muco‐cutaneous and visceral wound care, be delivered to provide high‐quality care with improved clinical prognosis and quality of life.\n\nCONFLICT OF INTEREST\nThe authors declare that they have no competing interests.\n==== Refs\nREFERENCES\n1 \n\nBelver \nMT \n, \nMichavila \nA \n, \nBobolea \nI \n, \nFeito \nM \n, \nBellon \nT \n, \nQuirce \nS \n. Severe delayed skin reactions related to drugs in the paediatric age group: A review of the subject by way of three cases (Stevens‐Johnson syndrome, toxic epidermal necrolysis and DRESS)\n. Allergol Immunopathol (Madr) . 2016 ;44 :83 ‐95\n.26089185 \n2 \n\nMahar \nPD \n, \nWasiak \nJ \n, \nHii \nB \n, et al. A systematic review of the management and outcome of toxic epidermal necrolysis treated in burns centres\n. Burns . 2014 ;40 :1245 ‐1254\n.24685065 \n3 \n\nBoorboor \nP \n, \nVogt \nPM \n, \nBechara \nFG \n, et al. Toxic epidermal necrolysis: use of Biobrane or skin coverage reduces pain, improves mobilisation and decreases infection in elderly patients\n. Burns . 2008 ;34 :487 .17919820 \n4 \n\nRogers \nAD \n, \nBlackport \nE \n, \nCartotto \nR \n. The use of Biobrane® for wound coverage in Stevens‐Johnson Syndrome and Toxic Epidermal Necrolysis\n. Burns . 2017 ;43 :1464 ‐1472\n.28526303 \n5 \n\nCartotto \nR \n. Burn Center Care of Patients with Stevens‐Johnson Syndrome and Toxic Epidermal Necrolysis\n. Clin Plast Surg . 2017 ;44 :583 ‐595\n.28576247 \n6 \n\nPalmieri \nTL \n, \nGreenhalgh \nDG \n, \nSaffle \nJR \n, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century\n. J Burn Care Rehabil . 2002 ;23 :87 .11882797 \n7 \n\nHarr \nT \n, \nFrench \nLE \n. Toxic epidermal necrolysis and Stevens‐Johnson syndrome\n. Orphanet J Rare Dis . 2010 ;5 :1 ‐11\n.20074341 \n8 \n\nGueudry \nJ \n, \nRoujeau \nJC \n, \nBinaghi \nM \n, \nSoubrane \nG \n, \nMuraine \nM \n. Risk factors for the development of ocular complications of Stevens‐Johnson syndrome and toxic epidermal necrolysis\n. Arch Dermatol . 2009 ;145 :157 .19221260 \n9 \n\nFu \nY \n, \nGregory \nDG \n, \nSippel \nKC \n, \nBouchard \nCS \n, \nTseng \nSCG \n. The Ophthalmologist's Role in the Management of Acute Stevens‐Johnson Syndrome and Toxic Epidermal Necrolysis\n. Ocul Surf . 2010 ;8 :193 ‐203\n.20964982 \n10 \n\nCreamer \nD \n, \nWalsh \nSA \n, \nDziewulski \nP \n, et al. UK guidelines for the management of Stevens‐Johnson syndrome/toxic epidermal necrolysis in adults 2016\n. J Plast Reconstr Aesthet Surg . 2016 ;69 :e119 .27287213 \n11 \n\nKohanim \nS \n, \nPalioura \nS \n, \nSaeed \nHN \n, et al. Acute and Chronic Ophthalmic Involvement in Stevens‐Johnson Syndrome/ Toxic Epidermal Necrolysis ‐ A Comprehensive Review and Guide to Therapy\n. II. Ophthalmic Disease. Ocul Surf . 2016 ;14 :168 ‐188\n.26882981 \n12 \n\nHsu \nM \n, \nJayaram \nA \n, \nVerner \nR \n, \nLin \nA \n, \nBouchard \nC \n. Indications and outcomes of amniotic membrane transplantation in the management of acute stevens‐johnson syndrome and toxic epidermal necrolysis: a case‐control study\n. Cornea. \n2012 ;31 :1394 .23135531 \n13 \n\nNiemeijer \nIC \n, \nvan Praag \nMC \n, \nVan \nGN \n. Relevance and consequences of erythema multiforme, Stevens‐Johnson syndrome and toxic epidermal necrolysis in gynecology\n. Arch Gynecol Obstet . 2009 ;280 :851 ‐854\n.19277691\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2574-2272",
"issue": "2(2)",
"journal": "Pediatric investigation",
"keywords": "Drug reaction; Toxic epidermal necrolysis; Wound care",
"medline_ta": "Pediatr Investig",
"mesh_terms": null,
"nlm_unique_id": "101731527",
"other_id": null,
"pages": "114-118",
"pmc": null,
"pmid": "32851244",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "26882981;19277691;27287213;28526303;26089185;17919820;11882797;20964982;21162721;28576247;24685065;23135531;19221260",
"title": "Successful treatment of a female pediatric patient with carbamazepine-induced toxic epidermal necrolysis: Active wound care and systemic therapy.",
"title_normalized": "successful treatment of a female pediatric patient with carbamazepine induced toxic epidermal necrolysis active wound care and systemic therapy"
} | [
{
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},
{
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}
],
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},
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"literaturereference": "LIANG Y, CHU Y, XU Z, MA L.. SUCCESSFUL TREATMENT OF A FEMALE PEDIATRIC PATIENT WITH CARBAMAZEPINE?INDUCED TOXIC EPIDERMAL NECROLYSIS: ACTIVE WOUND CARE AND SYSTEMIC THERAPY. PEDIATR. INVEST. 2018?2(2):114?118",
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{
"abstract": "We present a patient in whom a combination of perinuclear antineutrophil cytoplasmic antibody-positive vasculitis, oligoarthritis, tendinitis, and myositis was considered to be associated with isotretinoin use. Discontinuation of the drug resulted in complete clinical and biochemical remission (normalization of perinuclear antineutrophil cytoplasmic antibody titer). Although we were unable to prove causality, no other underlying cause for the patient's course was found. We report this occurrence to bring it to the attention of physicians prescribing isotretinoin.",
"affiliations": "Department of Pediatrics, Queen Paola Children's Hospital, Antwerp, Belgium.;Department of Pediatrics, Queen Paola Children's Hospital, Antwerp, Belgium.;Department of Pathology, University Hospital of Antwerp, Antwerp, Belgium.;Pharmacy, University Hospital of Brussels, Brussels, Belgium.;Department of Pediatrics, Queen Paola Children's Hospital, Antwerp, Belgium.;Department of Pediatrics, Queen Paola Children's Hospital, Antwerp, Belgium.;Department of Pediatrics, Queen Paola Children's Hospital, Antwerp, Belgium.",
"authors": "Mangodt|Thomas C|TC|http://orcid.org/0000-0001-9421-9932;Joos|Rik|R|;Siozopoulou|Vasiliki|V|;Cortoos|Pieter-Jan|PJ|;Baeten|Hans|H|;Docx|Martine|M|;van den Akker|Machiel|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019268:Antibodies, Antineutrophil Cytoplasmic; D003879:Dermatologic Agents; D015474:Isotretinoin",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.13445",
"fulltext": null,
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"issn_linking": "0736-8046",
"issue": "35(3)",
"journal": "Pediatric dermatology",
"keywords": "arthritis; isotretinoin; myositis; p-ANCA; retinoid; tendinitis; vasculitis",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000152:Acne Vulgaris; D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019268:Antibodies, Antineutrophil Cytoplasmic; D001168:Arthritis; D003879:Dermatologic Agents; D003937:Diagnosis, Differential; D006801:Humans; D015474:Isotretinoin; D008279:Magnetic Resonance Imaging; D008297:Male; D009220:Myositis; D012867:Skin; D052256:Tendinopathy; D014657:Vasculitis; D028761:Withholding Treatment",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e173-e177",
"pmc": null,
"pmid": "29644707",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Perinuclear antineutrophil cytoplasmic antibody-positive vasculitis, oligoarthritis, tendinitis, and myositis associated with isotretinoin in a 15-year-old boy: Case report and review of literature.",
"title_normalized": "perinuclear antineutrophil cytoplasmic antibody positive vasculitis oligoarthritis tendinitis and myositis associated with isotretinoin in a 15 year old boy case report and review of literature"
} | [
{
"companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-170950",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
},
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"medicinalproduct": "ISOTRETINOIN."
}
],
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"reaction": [
{
"reactionmeddrapt": "Vasculitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Arthritis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myositis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Tendonitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Antineutrophil cytoplasmic antibody positive",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MANGODT TC, JOOS R, SIOZOPOULOU V, CORTOOS PJ, BAETEN H, DOCX M ET AL. PERINUCLEAR ANTINEUTROPHIL CYTOPLASMIC ANTIBODY?POSITIVE VASCULITIS, OLIGOARTHRITIS, TENDINITIS, AND MYOSITIS ASSOCIATED WITH ISOTRETINOIN IN A 15?YEAR?OLD BOY: CASE REPORT AND REVIEW OF LITERATURE. PEDIATR DERMATOL. 2018?APR 11:EPUB AHEAD OF PRINT",
"literaturereference_normalized": "perinuclear antineutrophil cytoplasmic antibody positive vasculitis oligoarthritis tendinitis and myositis associated with isotretinoin in a 15 year old boy case report and review of literature",
"qualification": "1",
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},
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},
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"transmissiondate": "20181010"
},
{
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"patient": {
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},
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"medicinalproduct": "ISOTRETINOIN."
}
],
"patientagegroup": null,
"patientonsetage": "15",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Myositis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Tendonitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Arthritis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anti-neutrophil cytoplasmic antibody positive vasculitis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
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"abstract": "BACKGROUND\nLithium carbonate is widely used as a first-line therapeutic agent for the depressive and manic phases of bipolar disorder. Although limb tremors and hypothyroidism are well-known side effects of lithium carbonate, other rare adverse reactions can also occur.\n\n\nMETHODS\nA 53-year-old Japanese woman diagnosed with lithium intoxication developed dysgeusia and glossalgia during treatment with lithium carbonate. She also showed symptoms of a swaying gait, finger tremors, and dysarthria. All of these symptoms subsided when her blood lithium concentration was reduced to a level below that which induces intoxication.\n\n\nCONCLUSIONS\nWe present a rare case of lithium carbonate-induced dysgeusia accompanied by glossalgia. Early detection of these symptoms is important in clinical settings because they can be overlooked until patients lose their appetite, which severely impairs their quality of life.",
"affiliations": "Department of Psychiatry, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi, Kyoto, 606-8507, Japan. shanyu@kuhp.kyoto-u.ac.jp.;Department of Psychiatry, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi, Kyoto, 606-8507, Japan.;Department of Psychiatry, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi, Kyoto, 606-8507, Japan.;Department of Psychiatry, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi, Kyoto, 606-8507, Japan.;Department of Psychiatry, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi, Kyoto, 606-8507, Japan.",
"authors": "Hanyu|Shota|S|;Sugita|Naoko|N|;Matsuda|Miyuki|M|;Murai|Toshiya|T|;Fujiwara|Hironobu|H|",
"chemical_list": "D016651:Lithium Carbonate; D008094:Lithium",
"country": "England",
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"doi": "10.1186/s13256-020-02495-6",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2495\n10.1186/s13256-020-02495-6\nCase Report\nLithium intoxication–induced dysgeusia accompanied by glossalgia in a patient receiving lithium carbonate: a case report\nHanyu Shota shanyu@kuhp.kyoto-u.ac.jp Sugita Naoko Matsuda Miyuki Murai Toshiya Fujiwara Hironobu grid.411217.00000 0004 0531 2775Department of Psychiatry, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi, Kyoto, 606-8507 Japan \n10 9 2020 \n10 9 2020 \n2020 \n14 14919 5 2020 12 8 2020 © The Author(s) 2020Open 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.Background\nLithium carbonate is widely used as a first-line therapeutic agent for the depressive and manic phases of bipolar disorder. Although limb tremors and hypothyroidism are well-known side effects of lithium carbonate, other rare adverse reactions can also occur.\n\nCase presentation\nA 53-year-old Japanese woman diagnosed with lithium intoxication developed dysgeusia and glossalgia during treatment with lithium carbonate. She also showed symptoms of a swaying gait, finger tremors, and dysarthria. All of these symptoms subsided when her blood lithium concentration was reduced to a level below that which induces intoxication.\n\nConclusions\nWe present a rare case of lithium carbonate–induced dysgeusia accompanied by glossalgia. Early detection of these symptoms is important in clinical settings because they can be overlooked until patients lose their appetite, which severely impairs their quality of life.\n\nKeywords\nLithium carbonateSide effectDysgeusiaGlossalgiaissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nLithium carbonate (lithium) is a first-line mood stabilizer that reduces the risk of suicide in patients with bipolar disorder. However, attention should be paid to the use of this agent because of its narrow therapeutic concentration range in the blood. Clinicians should monitor serum lithium concentrations as well as endocrine and renal functions [1]. To effectively prevent manic and depressive recurrences of bipolar disorder, lithium should be administered to maintain a blood concentration of 0.60–1.20 mEq/L [2]. Severe side effects develop more often at blood concentrations ≥1.50 mEq/L [3]. Typical side effects include limb tremors, renal dysfunction, and hypothyroidism [1].\n\nHere, we report a case of dysgeusia accompanied by glossalgia as symptoms of lithium intoxication in a patient taking lithium carbonate. This case report highlights the importance of the early detection of these symptoms because they are often unrecognized or overlooked and can cause a loss of appetite that severely impairs the patient’s quality of life. Dysgeusia as a symptom of lithium intoxication is rarely reported. To the best of our knowledge, dysgeusia accompanied by glossalgia has not previously been reported in patients taking lithium carbonate.\n\nCase presentation\nOur patient was a 53-year-old Japanese woman. Her sister had bipolar disorder–like episodes (details unknown). When the patient was a high school student, her parents often commented that she was inferior to her sister in appearance. She became further worried about her looks when her teacher told her that she was not suitable to be a tour conductor, which was what she wanted to be. From the age of 18 to 35, she drank approximately 1400 ml of beer every day. However, from the age of 36, she had tried to abstain from alcohol, although she sometimes drank a lot when she felt stressed. Five years before her admission (year − 5), she became unemployed because she was often absent from her job as a result of her mother’s death. Because this caused her to consider herself worthless, she visited a psychiatrist (Fig. 1). She was prescribed antidepressants, including noradrenergic and specific serotonergic antidepressants (NaSSAs) and selective serotonin reuptake inhibitors (SSRIs), to treat her depression. She had ongoing mild suicidal ideation in a state of depression, but she only tried to kill herself once. Most of the time she just stated, “I am meaningless, so I should die,” but did not put this thought into action. Before her current admission (year 0), she had been hospitalized three times for depression and once for mania (Fig. 1). After being discharged from her third hospitalization, she showed a decreased need for sleep and became wasteful with money. It became difficult for her to control her manic state. Thus, she was again admitted to the hospital and was diagnosed with bipolar disorder. She was started on lithium carbonate, and her manic state improved, and she left the hospital. However, she continued to visit the hospital for lingering depression.\nFig. 1 The patient was hospitalized three times for depression and once for mania\n\n\n\nOne month before her current admission, she had started to experience severe depression, and she subsequently began to lose her appetite as a result of severe dysgeusia and glossalgia. To improve her mental and physical condition, she was admitted to the hospital (day 1). In addition to the aforementioned symptoms, she developed a swaying gait, finger tremors, and dysarthria approximately 1 week before hospitalization. She also vomited and had diarrhea before and after hospitalization. Despite having depression before admission, she was in a manic state upon admission. She stated, “Somehow I am so happy and full of energy.”\n\nBecause her swaying gait, finger tremors, and dysarthria had continued for about 1 week, and because she had been prescribed 800 mg/day lithium carbonate (before the current hospitalization, she had received lithium carbonate for approximately 2 years), we investigated cerebellar infarction and lithium intoxication for her differential diagnosis. Her computed tomographic scan showed no intracranial lesions. Blood examinations revealed a blood lithium concentration of 1.99 mEq/L, which is within the range of intoxication. Results of blood tests were mostly within the normal range, except for mean corpuscular volume 104.4 fl, mean corpuscular hemoglobin 34.7 pg, and alkaline phosphatase 458 U/L (Table 1). The patient’s vital signs upon admission included blood pressure of 109/66 mmHg, pulse rate of 84 beats per minute, and body temperature of 36.9 °C. She sometimes complained of pain in her tongue and a taste disorder. Her tongue was diffusely red, but its shape appeared normal on admission. We asked her about dysgeusia and glossalgia, but presumably because of her confused mental state and physically disordered condition as the side effects of lithium treatment, she just said, “I have a pain in my tongue, and I can’t taste anything.” At that time, she needed urgent medical care for her lithium intoxication; therefore, we did not ask her any further questions about her symptoms for the differential diagnosis.\nTable 1 Laboratory findings on admission\n\nLaboratory test\tValue\t\nWhite blood cells\t4220/μl\t\nRed blood cells\t360 × 104/μl\t\nHemoglobin\t12.5 g/dl\t\nMCV\t104.4 fl\t\nMCH\t34.7 pg\t\nPlatelets\t16.2 × 104/μl\t\nAST\t22 U/L\t\nALT\t28 U/L\t\nLDH\t196 U/L\t\nAlkaline phosphatase\t458 U/L\t\nγ-GTP\t20 U/L\t\nTotal protein\t6.3 g/dl\t\nAlbumin\t4.1 g/dl\t\nTotal bilirubin\t0.5 mg/dl\t\nCreatinine\t0.71 mg/dl\t\neGFR\t66.7 ml/min/1.73 m2\t\nBUN\t15 mg/dl\t\nAmylase\t67 U/L\t\nNa+\t138 mEq/L\t\nK+\t3.7 mEq/L\t\nCl\t109 mEq/L\t\nMg\t1.9 mg/dl\t\nCa2+\t9.1 mg/dl\t\nCRP\t0.1> mg/dl\t\nResults are from a blood test upon admission\n\nAbbreviations: ALT alanine aminotransferase, AST aspartate aminotransferase, BUN blood urea nitrogen, Cl chloride, CRP C-reactive protein, eGFR estimated glomerular filtration rate, LDH lactate dehydrogenase, MCH mean corpuscular hemoglobin, MCV mean corpuscular volume, γ-GTP γ-glutamyl transpeptidase\n\n\n\nTo treat the patient’s dehydration and increase her urinary excretion of lithium [4], we started infusing physiological saline and stopped prescribing lithium carbonate (day 1). Her blood concentration of lithium declined to 0.91 mEq/L on day 3 and to 0.13 mEq/L on day 8 (Fig. 2). In terms of symptoms, her dysgeusia and glossalgia were relieved on day 4, her dysarthria was relieved on day 5, and her swaying gait and finger tremors were relieved on day 7. By day 8, all of her symptoms had disappeared. Because cessation of lithium carbonate treatment could raise the patient’s risk for the recurrence of bipolar disorder, we continued with follow-up observation of her symptoms of this disorder. During the follow-up observation, she underwent rehabilitation, including occupational therapy, so that she could return to her normal life after being discharged from the hospital. From day 14, her depression reappeared, and an initial dose of 200 mg/day of lithium carbonate was prescribed. Once she had recovered from this depression, she left the hospital (day 30). By the time the patient was discharged, the color of her tongue had returned to normal.\nFig. 2 The blood concentration of lithium declined over time. The dotted lines indicate the therapeutic range\n\n\n\nDiscussion\nDiagnosis by exclusion and clinical course is essential for the diagnosis of drug-induced disorders. On the basis of information obtained upon admission, the results of a blood sample, and the observed changes in blood lithium concentration, we retrospectively considered several diseases for our patient’s differential diagnosis.\n\nCauses of glossalgia include (1) aphthous stomatitis, (2) oral candidiasis, (3) herpangina, (4) scarlet fever, (5) Hunter’s glossitis, (6) Plummer-Vinson syndrome, (7) Sjögren syndrome, (8) xerostomia, (9) neuralgia, (10) psychogenic pain, (11) drug-induced pain, and (12) idiopathic pain [5]. The shape of our patient’s tongue looked normal, and she did not have a fever, headache, skin rash, or dry mouth; therefore, (1) aphthous stomatitis, (2) oral candidiasis, (3) herpangina, (4) scarlet fever, (7) Sjögren syndrome, and (8) xerostomia can be excluded. Regarding (5) Hunter’s glossitis, it should be treated with cobalamin for 2–4 weeks or folate for 6 months to supplement a deficiency [6, 7]. After admission, our patient ate only hospital meals and did not receive cobalamin or folate preparations. Moreover, her blood vitamin B12 concentration on day 3 was normal (295 μg/ml). Although her blood folate concentration was not measured, she rapidly recovered from glossalgia after admission; thus, (5) Hunter’s glossitis is not likely to have been the cause. Regarding (6) Plummer-Vinson syndrome, therapy for this syndrome consists of iron agents for 3 months [8, 9]. However, our patient’s blood test results on day 3 were normal (hemoglobin 12.3 g/dl, iron 126 μg/dl), and it is unlikely that her iron deficiency improved during the first 2 days after admission. Thus, Plummer-Vinson syndrome can also be ruled out. Because the patient’s mental condition was constant for the first 4 hospital days, (10) psychogenic pain is also unlikely to have been the cause. Her glossalgia improved in inverse proportion to her blood lithium concentration; therefore, (11) drug-induced pain is the most likely cause of the glossalgia among (9) neuralgia, (11) drug-induced pain, and (12) idiopathic pain.\n\nCauses of dysgeusia include (a) psychogenic disorders, (b) drug-induced disorders, (c) zinc deficiency, (d) having a cold, (e) systemic diseases, (f) iatrogenic disorder (after oral surgery), (g) iron deficiency, (h) trauma, and (i) idiopathic disorders [10]. Our patient did not have a cold, ongoing systemic disease, or a history of oral surgery or injury. Thus, (a) psychogenic disorders, (d) having a cold, (e) systemic diseases, (f) iatrogenic disorder (after oral surgery), (g) iron deficiency, and (h) trauma were probably not the causes of her dysgeusia. In terms of (c) zinc deficiency, this disorder is treated with zinc supplementation for 5–6 months. After admission, our patient ate only hospital meals and did not receive any zinc supplements [11]. Furthermore, her blood zinc concentration on day 3 was normal (85 μg/dl). Therefore, (c) zinc deficiency can be excluded. Among (b) drug-induced disorders and (h) idiopathic disorders, the most likely cause of the dysgeusia is (b) drug-induced disorders, for the same reason as for the symptom of glossalgia.\n\nThese factors therefore suggest that lithium carbonate induced our patient’s dysgeusia and glossalgia.\n\nThere are several causes of lithium intoxication. Renal dysfunction can increase the blood concentration of lithium carbonate because it extends its half-life [12]. However, our patient did not have decreased renal function. Other causes of lithium intoxication include overdose, diuretic drugs, and hypovolemia. Before admission, our patient was regularly prescribed 800 mg/day of lithium carbonate. This was her first experience of lithium intoxication, but she had previously overdosed on an antidepressant; therefore, she might potentially have also overdosed on lithium carbonate [13], although she did not state this clearly. She was not receiving diuretic drugs, but she vomited and had diarrhea. Therefore, she might have been dehydrated both before and upon admission.\n\nAs shown in Fig. 2, our patient’s blood lithium concentration on day 3 was 0.91 mEq/L, but her dysgeusia and glossalgia symptoms were not relieved until day 4. These results suggest that symptoms can be present even if blood lithium concentrations are within the normal therapeutic range (0.60–1.20 mEq/L). We therefore advise clinicians to pay close attention to these symptoms, regardless of blood lithium concentrations during the course of lithium intoxication treatment, because these side effects may recur. If patients cannot tolerate the side effects of lithium, a switch to valproate, quetiapine, or lamotrigine as a second-line therapy is recommended [14–19]. For patients who do not respond to these drugs or cannot tolerate their side effects, aripiprazole, olanzapine, or risperidone are alternatives. We therefore considered a switch to a different medication as a treatment option for this patient [14, 15, 17, 18]. Currently, however, our patient is leading her life without the recurrence of mania, depression, or adverse drug reactions at a lithium blood concentration of 0.4 mEq/L.\n\nLithium is considered to affect two intracellular signaling pathways, inositol monophosphate and glycogen synthasekinase-3, which are related to mental stability and neurological function [20]. However, the mechanisms by which lithium causes dysgeusia and glossalgia are unknown. Therefore, further research is needed.\n\nDysgeusia caused by lithium carbonate treatment is rare. One case report refers to dysgeusia accompanied by dysosmia [21], and other reports mention dysgeusia alone [22–26]. Other case reports on tongue-related side effects of lithium carbonate treatment include geographic tongue, black hairy tongue, and orolingual dyskinesia [27–29]. Therefore, to the best of our knowledge, the present report of lithium-intoxication-induced dysgeusia accompanied by glossalgia has not previously been reported. We believe that these side effects of lithium carbonate occur more frequently than expected. This is partly because patients assume they are unrelated to their medicine or illness and do not mention them to their doctors, and partly because doctors may overlook them or consider them psychogenic. Thus, clinicians should ask patients about the presence of glossalgia and dysgeusia when they prescribe lithium carbonate.\n\nConclusion\nWe present a rare case of lithium carbonate–induced dysgeusia accompanied by glossalgia. This report addresses the importance of its early detection and treatment. Because adverse events rarely occur in the tongue, clinicians often overlook them. In our patient, the discovery of the symptoms was delayed because the patient did not mention them until they became severe and unbearable. This led to a loss of appetite and impaired quality of life. These side effects of lithium carbonate treatment might cause poor medication adherence, which can potentially lead to an exacerbation of the symptoms of bipolar disorder.\n\nThis article is based on a paper first published in Clinical Psychiatry 2020;735:343–7 and is reproduced here with the kind permission of Igaku Shoin.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nSH, MM, and NS attended to the patient. SH wrote the manuscript. HF, NS, and TM gave conceptual advice. All authors read and approved the final manuscript.\n\nFunding\nNo funding was obtained from any agencies.\n\nAvailability of data and materials\nThe datasets analyzed in this case report are available from the corresponding author on request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. McKnight RF Adida M Budge K Stockton S Goodwin GM Geddes JR Lithium toxicity profile: a systematic review and meta-analysis Lancet 2012 379 721 749 10.1016/S0140-6736(11)61516-X 22265699 \n2. 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Grunze H Vieta E Goodwin GM Bowden C Licht RW Möller HJ The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder World J Biol Psychiatry 2013 14 154 219 10.3109/15622975.2013.770551 23480132 \n16. National Institute for Health and Care Excellence (NICE). Bipolar disorder: assessment and management. NICE Clinical Guideline 185. London: NICE [last updated 11 Feb 2020].\n17. Goodwin GM Haddad PM Ferrier IN Aronson JK Barnes T Cipriani A Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology J Psychopharmacol 2016 30 495 553 10.1177/0269881116636545 26979387 \n18. Ostacher MJ Tandon R Suppes T Florida best practice psychotherapeutic medication guidelines for adults with bipolar disorder: a novel, practical, patient-centered guide for clinicians J Clin Psychiatry 2016 77 920 926 10.4088/JCP.15cs09841 26580001 \n19. Malhi GS Gessler D Outhred T The use of lithium for the treatment of bipolar disorder: recommendations from clinical practice guidelines J Affect Disord 2017 217 266 280 10.1016/j.jad.2017.03.052 28437764 \n20. Meltzer H Katzung BG Masters SB Trevor AJ Antipsychotic agents & lithium Basic and clinical pharmacology 2009 11 New York McGraw-Hill Medical 487 \n21. Ilse F Joost H Long lasting impairment of taste and smell as side effect of lithium carbonate in a cluster headache patient Headache 2016 56 1201 1203 10.1111/head.12872 27317012 \n22. Duffield JE Side effects of lithium carbonate Br Med J 1973 1 491 10.1136/bmj.1.5851.491-a \n23. Himmelhoch JM Hanin I Side effects of lithium carbonate [letter] Br Med J 1974 4 233 10.1136/bmj.4.5938.233 \n24. Bressler B An unusual side-effect of lithium Psychosomatics 1980 21 688 689 10.1016/S0033-3182(80)73635-6 7208774 \n25. Rogers GA Flavors altered by lithium Am J Psychiatry 1981 138 261 10.1192/bjp.138.3.261 \n26. Takeshi T Shosuke W Nobuhiko H Takayuki H Strange taste and mild lithium intoxication BMJ Case Rep 2011 2011 bcr0520114267 \n27. Gracious BL Llana M Barton DD Lithium and geographic tongue J Am Acad Child Adolesc Psychiatry 1999 38 1069 1070 10.1097/00004583-199909000-00005 10504802 \n28. Selvakumar N Selvapandian TJ Menon V Rajkumar RP Black hairy tongue (Lingua villosa nigra) in a young male precipitated by lithium Asian J Psychiatr 2016 24 71 72 10.1016/j.ajp.2016.08.021 27931913 \n29. Chen WY Chen AC Tsai SJ Lin JJ Reversible oro-lingual dyskinesia related to lithium intoxication Acta Neurol Taiwanica 2013 22 32 35\n\n",
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"title": "Lithium intoxication-induced dysgeusia accompanied by glossalgia in a patient receiving lithium carbonate: a case report.",
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"abstract": "Diarrhoea lasting longer than 14 days and failing to respond to conventional management is defined as severe and protracted diarrhoea (SD). In this study, we investigated the prevalence, pathogens and prognosis of SD in primary immunodeficiency diseases (PIDs). Among 246 patients with predominantly paediatric-onset PIDs from 2003-2015, 21 [Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG2 (one each)] and five [CVID (four), SCID (one)] without identified mutations had SD before prophylactic treatment. Detectable pathogens included pseudomonas, salmonella (six each), E. coli, cytomegalovirus, coxsackie virus and cryptosporidium (one each), all of whom improved after a mean 17 days of antibiotics and/or IVIG treatment. Seven (7/26; 27.0%) patients died [respiratory failure (four), lymphoma, sepsis and intracranial haemorrhage (one each)]. The patients with WAS, CGD and CD40L and SD had a higher mortality rate than those without. Another five males with mutant XIAP, STAT1, FOXP3 (one each) and STAT3 (two) had undetectable-pathogenic refractory diarrhoea (RD) that persisted >21 days despite aggressive antibiotic/steroid treatment and directly resulted in mortality. For the patients with RD without anti-inflammatory optimization, those with mutant XIAP and FOXP3 died of Crohn's-like colitis and electrolyte exhaustion in awaiting transplantation, while transplantation cured the STAT1 patient.",
"affiliations": "Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. wen2707@hotmail.com.;Division of Gastroenterology, Department of Pediatrics, Chang Gung Children's Hospital, Taoyuan, Taiwan. cgj2841@adm.cgmh.org.tw.;Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.;Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.;Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.;Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan. long@adm.cgmh.org.tw.",
"authors": "Lee|Wen-I|WI|;Chen|Chien-Chang|CC|;Jaing|Tang-Her|TH|;Ou|Liang-Shiou|LS|;Hsueh|Chuen|C|;Huang|Jing-Long|JL|",
"chemical_list": "D015415:Biomarkers",
"country": "England",
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"doi": "10.1038/s41598-017-03967-4",
"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 396710.1038/s41598-017-03967-4ArticleA Nationwide Study of Severe and Protracted Diarrhoea in Patients with Primary Immunodeficiency Diseases Lee Wen-I wen2707@hotmail.com 12Chen Chien-Chang cgj2841@adm.cgmh.org.tw 3Jaing Tang-Her 14Ou Liang-Shiou 2Hsueh Chuen 5Huang Jing-Long long@adm.cgmh.org.tw 121 grid.145695.aPrimary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan 2 grid.145695.aDivision of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan 3 0000 0004 0572 8447grid.413798.0Division of Gastroenterology, Department of Pediatrics, Chang Gung Children’s Hospital, Taoyuan, Taiwan 4 Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan 5 Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan 16 6 2017 16 6 2017 2017 7 366927 10 2016 9 5 2017 © The Author(s) 2017\nOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.Diarrhoea lasting longer than 14 days and failing to respond to conventional management is defined as severe and protracted diarrhoea (SD). In this study, we investigated the prevalence, pathogens and prognosis of SD in primary immunodeficiency diseases (PIDs). Among 246 patients with predominantly paediatric-onset PIDs from 2003–2015, 21 [Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG2 (one each)] and five [CVID (four), SCID (one)] without identified mutations had SD before prophylactic treatment. Detectable pathogens included pseudomonas, salmonella (six each), E. coli, cytomegalovirus, coxsackie virus and cryptosporidium (one each), all of whom improved after a mean 17 days of antibiotics and/or IVIG treatment. Seven (7/26; 27.0%) patients died [respiratory failure (four), lymphoma, sepsis and intracranial haemorrhage (one each)]. The patients with WAS, CGD and CD40L and SD had a higher mortality rate than those without. Another five males with mutant XIAP, STAT1, FOXP3 (one each) and STAT3 (two) had undetectable-pathogenic refractory diarrhoea (RD) that persisted >21 days despite aggressive antibiotic/steroid treatment and directly resulted in mortality. For the patients with RD without anti-inflammatory optimization, those with mutant XIAP and FOXP3 died of Crohn’s-like colitis and electrolyte exhaustion in awaiting transplantation, while transplantation cured the STAT1 patient.\n\nissue-copyright-statement© The Author(s) 2017\n==== Body\nIntroduction\nThe intestinal tract is the largest lymphoid organ in the body and contains lymphocytes, macrophages, and dendritic cells to prevent pathogenic invasion, modulate inflammation1, 2, and produce sufficient antibodies for optimal neutralization, opsonization, and complement activation3, 4. If these cellular and humoral immune responses do not effectively cooperate and mutually balance, unwanted or excess reactions will injure the epithelium, mucosa, submucosa, and connective tissue, consequently leading to persistent diarrhoea despite nothing per os, hydration, antibiotics and immunosuppressant therapy1–3.\n\nSevere and protracted diarrhoea (SD) is generally defined as prolonged diarrhoea lasting for more than 2 weeks, usually emerging within 2 years of life and requiring parenteral nutrition5, although the definition has undergone several revisions to better delineate the duration and clinical course6. Some studies have emphasised that specific aetiologies including infections that persist for longer than expected should be included in the definition.\n\nExcluding congenital enterocyte defects7, 8, SD is often accompanied by “little effect of treatment”, “failure to gain weight”, and/or co-morbidity with “recurrent infections”, all of which are warning signs of primary immunodeficiency diseases (PIDs)9. Increasing evidence suggests that SD can mimic inflammatory bowel disease (IBD) and that it is associated with PIDs patients who have defective IL-12/2310–16 and IL-10 signalling17–21, profound T cell defects22–29, nicotinamide adenine dinucleotide phosphate oxidase anomalies30, 31, anti-apoptosis signalling of X-linked inhibitor of apoptosis (XIAP)32–35, and nuclear factor kappa B transcription (NEMO) signalling36. Research linking SD to monogenetic PIDs has shed light on the pathogenesis, and suggests that hematopoietic stem cell transplantation (HSCT) can be a potential cure, especially if there is profound T and polymorphonuclear cell deficiencies leading to recurrent opportunistic life-threatening infections and serious persistent intestinal inflammation.\n\nWith increased susceptibility to infections and inflammation, PIDs patients can develop the SD phenotype and present with frequent diarrhoea for longer than 14 days despite conventional management1, 3. In this nationwide study from the referral institute of Primary Immunodeficiency Care and Research (PICAR), we investigated the prevalence, pathogens and prognosis of PIDs patients with the SD phenotype.\n\nResults\nEnrolled Patients\nOf the enrolled patients, 26 (2 females) had the SD phenotype, including the Btk gene in six, IL2RG in four, WASP in three, CD40L in three, gp91 in three, gp47 in one, RAG2 in one, and four with CVID and one with SCID without identified genetic defects. The mutations included splicing, deletion, missense and stop mutations, but not insertion mutations (Table 1). Their median age at onset of the SD phenotype was 14 months (range 2–273 months; mean ± S.D. 48.6 ± 65.0 months), with a median duration of diarrhoea of 14 days (range 14–18 days; mean 15.0 ± 1.6 days), median length of total parental nutrition (TPN) of 7 days (range 4–10 days; mean 7.0 ± 2.0 days), and median length of antibiotic treatment of 16.5 days (range 16–20 days; mean 16.9 ± 1.7 days) including ceftriaxone, a combination of ceftazidime and amikacin, and carbapenems and/or meropenem. Neutropenia was noted in four patients (Btk1-2, Btk3, Btk5 and SCID2-IL2RG) with pseudomonas colitis and two (SCID3-IL2RG and CGD4-gp47) with salmonella colitis. These patients also developed bronchiectasis (11), sepsis (7), and significant other events (21) before adequate prophylactic treatment which included sulfamethoxazole/trimethoprim and fluconazole for T cell deficiency, sulfamethoxazole/trimethoprim, itraconazole, and/or interferon-gamma for polymorphonuclear cell deficiency, regular immunoglobulin infusion for B cell deficiency, and ampicillin-sulbactam for bronchiectasis.Table 1 Severe and protracted diarrhoea in the patients with PIDs who responded to antibiotics.\n\nGender\tTested age (months)\tGenetic mutations\tColitis pathogen\tEffective treatment [IgG level mg/dL at episode] (diarrhoea/treatment duration, days)**\tTPN\tAssociated symptoms\t\n(days)\tBronchiectasis\tSepsis\tOther significant events (mortality, cause)\t\n\nPredominantly antibody deficiencies\n\t\nBtk1-1/M\t40\tBtk: Int 14 (−2)A > G; skip exon 14\tundefined\tIVIG [93], CTZ, AMK (15/16)\t7\t+\t+\t\t\nBtk1-2/M\t14\tBtk: Int 14 (−2)A > G; skip exon 14\tPseudomonas\tIVIG [102], CTZ, AMK (14/15)\t7\t\t\t\t\nBtk2/M\t9\tBtk: c.1821C > T; p. Arg 641 Cys\tPseudomonas\tIVIG [92], CTZ, AMK (14/15)\t8\t\t+\tRecurrent cellulitis\t\nBtk3/M\t36\tBtk: c. 1042 T > G; p. Phe304Val\tPseudomonas\tIVIG [107], CTZ, AMK (14/15)\t8\t\t\tRecurrent sinopulmonary infections\t\nBtk4/M\t110\tBtk: c.232 C > T; p. Glu78Stop\tSalmonella\tIVIG [205], CTX, CAR (14/16)\t7\t\t\t\t\nBtk5/M\t26\tBtk: c.1562 A > T; p. Asp 521 Val\tPseudomonas\tIVIG [78], CTZ, AMK (17/19)\t9\t\t+\tPolyarthritis, facial cellulitis\t\nCVID1/M\t273\tUndefined*\tundefined\tIVIG [263], CTX, AMK (18/20)\t10\t+\t\tRecurrent sinopulmonary infections\t\nCVID2/M\t127\tUndefined*\tundefined\tIVIG [169], CTZ, AMK (15/17)\t5\t+\t\tRecurrent sinopulmonary infections, failure to thrive\t\nCVID3/M\t129\tUndefined*\tundefined\tIVIG [205], CTZ, AMK (14/16)\t4\t+\t\tRecurrent sinopulmonary infections, Takayashi arteritis\t\nCVID-4/F\t92\tUndefined*\tSalmonella\tIVIG [187], CTX (15/18)\t5\t\t\tRecurrent sinusitis, otitis media\t\n\nCombined immunodeficiencies\n\t\nSCID1-IL2RG/M\t10\tIL2RG: c. 220 T > G; p. Trp74Gly\t\nE. coli\n\tIVIG [104], CTX (14/17)\t8\t\t+\tPJP, BCG-related infection, stem cell transplantation\t\nSCID2-IL2RG/M\t6\tIL2RG: c. 676 G > T; p. Arg226Cys\tPseudomonas\tIVIG [99], CTZ, AMK (14/16)\t6\t\t\tBCG-related infection, stem cell transplantation\t\nSCID3-IL2RG/M\t3\tIL2RG: c. 865 C > T; Arg289Stop\tSalmonella\tIVIG, CTX (14/15)\t5\t\t\tInterstitial pneumonitis (respiratory failure)\t\nSCID4-IL2RG/M\t3\tIL2RG: c.854 G > A, skip exon 6\tCytomegalovirus\tIVIG [107], CTX, Gancyclovir (20/21)\t12\t\t+\tPneumonitis (respiratory failure)\t\nSCID5/M\t2\tundefined\tundefined\tIVIG [245], CTZ, AMK (15/17)\t7\t+\t\tPneumonitis, pulmonary haemorrhage, (respiratory failure)\t\nSCID6-RAG2/F\t4\tRAG1: Leu474Arg, Arg776Gln\tundefined\tIVIG [542], CTX, AMK (14/16)\t7\t\t\tStem cell transplantation\t\nHIGM1-CD40L/M\t121\tCD40L: Del 347 A\tCryptosporidium\tIVIG [213], CTX, AMK (15/18), nitazoxanide (15/18)^\t10\t+\t\tPJP, Recurrent sinopulmonary infections\t\nHIGM2-CD40L/M\t3\tCD40L: c.526 T > A; p.Tyr 169 Asn\tSalmonella\tIVIG [87], CTX (17/19)\t8\t+\t\t\t\nHIGM3-CD40L/M\t5\tCD40L: c.526 T > A; p.Tyr 169 Asn\t\nE. coli Coxsackievirus B4\tIVIG [112], CTX, AMK (14/15)\t4\t+\t+\tCholecystitis, cholangitis, mortality (lymphoma)\t\n\nCombined immunodeficiencies with associated or syndromic features\n\t\nWAS1/M\t3\tWASP: Del promoter, exon 1 and 2\tundefined\tIVIG [421], CTX, AMK (14/17)\t7\t\t+\tBloody diarrhoea, mortality (Staphy. aureus sepsis)\t\nWAS2/M\t3\tWASP: Del 243–250 nu\tundefined\tIVIG [354], CTX, AMK (14/16)\t5\t\t\tBloody diarrhoea, severe atopic dermatitis, mortality (intracranial haemorrhage)\t\nWAS3/M\t2\tWASP: c. 91 G > A, p. Glu31Lys\tundefined\tIVIG [743], CTX, AMK, MEP (18/20)\t10\t\t\tBloody diarrhoea, stem cell transplantation\t\n\nCongenital phagocyte number, function or both\n\t\nCGD1-gp91/M\t31\tGp91: Del 1693G\tIBD-like\tCTX, AMK, prednisolone (14/17)\t5\t+\t\tAspergillosis, pneumatocele, BCG-related infection\t\nCGD2-gp91/M\t14\tGp91: c.1028 C > A, p.Thr343Lys\tSalmonella\tCTX (14/15)\t5\t\t\tStaphy. aureus lymphadenitis, perianal ulcers, stem cell transplantation\t\nCGD3-gp91/M\t94\tGp91: c.1249 G > T, p. Gly412Val\tSalmonella\tCTX (14/16)\t7\t+\t\tAspergillosis, BCG-related infection, (respiratory failure)\t\nCGD4-gp47/M\t102\tGp47: del 75, 76GT (exon 2)\tPseudomonas\tCTZ, AMK (14/17)\t7\t+\t\tAspergillosis, recurrent oral ulcers\t\nAbbreviations: CAR: carbapenems (100 mg/kg/day, divided q 6 hours); CTX: ceftriaxone (100 mg/kg/day); CTZ: ceftazidime (100 mg/kg/day); AMK: amikacin (15 mg/kg/day); IVIG: intravenous immunoglobulin (0.5–0.8 g/kg/dose); MEP: meropenem (20–30 mg/kg/day, divided q 12 hours); PJP, Pneumocystis jirovecii pneumonia; BCG, Bacillus Calmette-Guerin. “+” means “with” bronchiectasis or/and sepsis\n\n*The eight genes of inducible costimulator (ICOS), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), CD19, B-cell activating factor receptor (BAFFR), CD81, CD20, CD21, Cytotoxic T-lymphocyte–Associated antigen 4 (CTLA-4) and LPS-responsive beige-like anchor (LRBA) were analysed, but all were wild type.\n\n**ceftriaxone (100 mg/kg/day) was given for suspected Salmonella or Shigella colitis, and a combination of ceftazidime (100 mg/kg/day) and amikacin (15 mg/kg/day) for Pseudomonas colitis before the pathogen cultures were available.\n\n^Nitazoxanide (200 mg/day bid) was discontinued when frequent diarrhoea had subsided and the stool culture became negative.\n\n\n\n\nAnother five male patients had a poor response to intravenous immunoglobulin (IVIG) and empiric antibiotics plus steroids over 3 weeks, and were defined as having the refractory diarrhoea (RD) phenotype (Table 2) with blood-stained diarrhoea but without obvious protein-losing enteropathy. Four patients had a peri-anal abscess without fistula formation, and one (patient 4) had a perforated colon and severe pyoderma in the abdominal wall that damaged his rectus muscularis. Peritoneal reconstruction with a 10 × 10 cm skin graft was performed to cover the injured abdominal wall, however he was complicated by an intestinal peritoneal cutaneous fistula (Fig. 1). Anaemia, elevated ESR, and hypoalbuminemia indicated chronic inflammation, consistent with the coloscopic observation (Fig. 2) and the pathological findings (Figs 3 and 4).Table 2 Gastrointestinal and associated clinical features of the patients with PIDs and refractory diarrhoea.\n\nGenetic mutation\tPatient 1 XIAP Int5(+1)G > A\tPatient 2 STAT1 T385M\tPatient 3 FOXP3 M370L\tPatient 4 STAT3 Int10(−2)A > G\tPatient 5 STAT3 G469R\t\n\nGastrointestinal manifestations (“+” means positive findings; “-” means negative findings)\n\t\nGender/Onset/Present age\tM/10 M/2Y8M (died)\tM/1 M/13Y2M\tM/NB/4 M (died)\tM/5Y/14Y6M\tM/15Y2M/19Y3M\t\nFrequency at worst per day\t16\t11\t12\t7\t8\t\nBloody-stain\t+\t+\t+\t+\t+\t\nProtein-losing enteropathy\t−\t−\t−\t−\t−\t\nFailure to thrive\t+\t+\t+\t−\t−\t\nPeri-anal abscess\t+\t+\t+\t−\t+\t\nFistula\t−\t−\t−\t+\t−\t\n\nEndoscopic pathology*\n\t\nOesophagus\tNo definite lesion\tIsolated tiny erosions\tNo definite lesion\tNo definite lesion\tErythematous mucosa\t\nStomach and duodenum\tNo definite lesion\tScattered erosions at antrum\tNo definite lesion\tNo definite lesion\tErythematous mucosa with some erosions at stomach. Ulcer with granulation at duodenal bulb\t\nJejunum and ileum\tMultiple segments of wall thickening and skipped lesion\tNo definite lesion\tNo definite lesion\tPerforation and inflammation\tMild inflammatory process at proximal jejunum\t\nColon\tCobblestone mucosal pattern and multiple pseudo-polyp-like lesions with aphthous ulceration. Much whitish to yellowish exudates coating on oedematous mucosa.\tSome oedematous mucosa\tScattered hyperaemic and oedematous mucosa\tChronic inflammation and perforation\tScattered hyperaemic and oedematous mucosa\t\n\nMedication^ for diarrhoea\n\t\n\tEmpiric antibiotics, IVIG, prophylactics, methylprednisolone, TPN (10 M)\tEmpiric antibiotics, IVIG, prophylactics, methylprednisolone, stem cell transplantation, TPN (2Y11M)\tEmpiric antibiotics, IVIG, prophylactics, methylprednisolone, sirolimus, TPN (3 M)\tEmpiric antibiotics and IVIG, if flare-up, methylprednisolone, TPN (2Y8M)\tEmpiric antibiotics and IVIG if flare-up, methylprednisolone, TPN (2 M)\t\n\nAssociated symptoms\n\t\n(Onset age)\tIncomplete HLH (4 M)\tMRSA pustulosis (1 M)\tJaundice caused by TPN-relayed\tSevere pyoderma and colon perforation\tRecurrent MRSA cellulites and carbuncles (2Y)\t\n\tNorovirus enteritis (10 M)\tBCG-induced lymphadenitis (7 M)\tcholestasis (1 M)\t\t\t\n\tRefractory anaemia and thrombocytopenia (1Y)\tRefractory pneumonia (7 M) Bronchiectasis (10 M)\t\t\t\t\n\tSplenectomy (1Y)\tIntermittent oral candidiasis\t\t\t\t\n\tSepsis by Klebsiella pneumonia, extended spectrum β lactamase (ESBL) E. coli, and Candida (1Y) Pneumo-peritoneum from the perforated colon (1Y)\tHepato-splenomegaly (4 M)\t\t\t\t\n\nSignificant laboratory findings\n\t\nHb mg/dL (>10)\t10.2\t\n9.8\n\t\n9.6\n\t11.1\t13.2\t\nESR /min (<45)\t\n45.0\n\t\n56.1\n\t\n47.2\n\t\n58.2\n\t5.0\t\nAlbumin mg/dL (>3.5)\t\n2.2\n\t3.5\t\n1.7\n\t3.8\t4.1\t\nLiver function\t\n AST (13–40 U/L)\t\n340\n\t\n63\n\t\n53\n\t\n44\n\t13\t\n ALT (<36 U/L)\t\n257\n\t27\t\n45\n\t25\t21\t\n\nImmune assessments\n\t\nNeutrophil (2100–4520/mm3)\t\n1040\n\t4361\t4456\t4095\t4460\t\nAbsolute lymphocytes (2000–6500 /mm3)\t2600\t\n245\n\t3176\t3549\t1934\t\nCD4 (31–56%)\t34.6\t34.2\t44.5\t31.9\t38.7\t\nCD4CD45RA (12–45%)\t19.3\t\n9.1\n\t31.4\t20.1\t25.7\t\nCD8 (12–35%)\t37.2\t\n1.5\n\t35.4\t24.3\t33.2\t\nCD4 memory (**)\t15.2\t24.5\t\n12.2\n\t\n11.4\n\t17.2\t\nCD19 (6–27%)\t20.3\t31.4\t15.2\t26.6\t12.8\t\nCD19 memory (**)\t\n1.0\n\t\n0.7\n\t2.5\t\n0.3\n\t\n1.2\n\t\nNK (3–22%)\t6.1\t5.3\t3.1\t5.8\t9.7\t\nIgM (49–156 mg/dL)\t358\t252\t63\t219\t92\t\nIgG (334–1230 mg/dL)\t527\t1072\t673\t1130\t877\t\nIgA (15–113 mg/dL)\t40\t\n434\n\t39\t63\t136\t\nIgE (<100 IU/ml)\t\n254\n\t16\t\n2920\n\t\n45900\n\t\n4940\n\t\nLymphocyte proliferation (cpm)\t\n PHA 2.5 ug/ml (29228–58457)\t\n284\n\t\n1453\n\t45721\t32156\t24783\t\n PWM 0.1 ug/ml (11395–28487)\t\n280\n\t\n787\n\t21529\t15786\t22146\t\n Candida 2.5 ug/ml (5351–13328)\t\n41\n\t\n53\n\t10142\t8514\t9327\t\n BCG 0.002 ug/ml (1740–4352)\t\n18\n\t\n16\n\t2143\t4023\t3417\t\n Superoxide production (86–99%)\t87.4\t94.5\t94.6\t89.7\t91.3\t\n TNF-α suppression (4.7–21.4%)\t7.5\t5.0\t18.1\t10.9\t8.4\t\nAbbreviations: cpm, counts per minute; M in sex, male; Y and M in tested age, years and months; MRSA, Methicillin-resistant Staphylococcus aureus .\n\n*Oesophageal, gastric, and duodenal lesions were demonstrated by endoscopy; small intestinal lesions were revealed by small bowel series with contrast medium; colonic lesions were demonstrated by colonofiberoscopy.\n\n^Empiric antibiotics refer to ceftriaxone (100 mg/kg/day) for presumed Salmonella or Shigella colitis; ceftazidime (100 mg/kg/day) and amikacin (15 mg/kg/day) for presumed Pseudomonas colitis although not proven in stools and blood cultures. The prophylactics given to patient 1, 2, and 3 were fluconazole (5 mg/kg/day) as anti-fungal treatment and co-trimoxazole (trimethoprim 5 mg/kg/day) as anti-pneumocystis jirovecii pneumonia treatment. Immunosuppressants of prednisolone (1–2 mg/kg/day) and sirolimus (3 mg/m2) were given.\n\n**Note: The percentage of memory CD4 + cells was calculated from CD4 + multiple [CD4 + CD45RO + /CD4 + CD45RA + plus CD4 + CD45RO + ], while the percentage of memory CD19 + cells was from CD19 + multiple [CD19 + CD27 + /CD19 + CD27 + plus CD19 + CD27−].\n\nNormal ranges of the percentage of memory CD4+ cells were 3–26% in infants between 3 months and 3 years of age (from 10 healthy infants) and 18–57% in children over 3 years of age (from 8 healthy children). Normal ranges of the percentage of memory CD19+ cells were 1.4–2.4% in infants between 3 months and 3 years of age (from 11 healthy infants) and 1.4–6.6% in children over 3 years of age (from 9 healthy children). Underlined bold numbers represent values below the normal ranges, while bold numbers represent values above the normal range.\n\n\nFigure 1 The morbidity of refractory severe and protracted diarrhoea (RD) in patient 4 was caused by a cutaneous peritoneal intestinal fistula.\n\n\nFigure 2 Colonofiberoscopy revealed a cobblestone mucosal pattern and multiple pseudo-polyp-like lesions.\n\n\nFigure 3 (A) Small intestine biopsy of patient 1 revealed marked villous atrophy and acute and chronic inflammation (hematoxylin-eosin [H&E] staining, magnification 100X) and (B) granulomatous inflammation (white arrows) composed of aggregates of epithelioid histiocytes in the lamina propria (H&E, 200X). (C,D) Colon biopsy of patient 1 showed ulceration and acute and chronic inflammation, with prominent epithelial apoptosis (white arrows) and intra-epithelial neutrophils (H&E, 400X).\n\n\nFigure 4 An endoscopic biopsy in patient 2 demonstrated (A) moderate lymphocytic infiltrates in the oesophagus (H&E staining, 200X) and (B) paucity of plasma cells in the stomach (H&E, 400X). (C) In patient 3, repeated colonic biopsies disclosed mildly increased lymphocytes and decreased plasma cells without granuloma, ulcer, or cryptitis (H&E, 400X). (D) A gastric biopsy in patient 5 revealed chronic active gastritis and colonization of Helicobacter pylori (H&E, 200X).\n\n\n\n\nImmunologic Studies and Genetic Analysis\nThe characteristics of PIDs patients with the SD phenotype (Table 1) including micro-thrombocytopenia, recurrent sinopulmonary infections, hypogammaglobulinemia, catalase-positive pathogens, opportunistic infections, and lymphopenia were recognized as Wiskott-Aldrich syndrome (WAS), X-linked agammaglobulinemia (XLA), X-linked hyper IgM syndrome (HIGM), common variable immunodeficiency (CVID), chronic granulomatous disease (CGD), severe combined T- and B-cell immunodeficiency (SCID), according to the genetic mutations of the updated PIDs classification37, 38.\n\nThe immunologic evaluation of these five patients with RD (Table 2) showed that one had neutropenia, one had decreased absolute lymphocytes, naïve CD4, and CD8 cells, two had decreased memory CD4 cells, and four had decreased memory CD19 B cells. Quantitative levels of IgE were increased in four patients and the level of IgA was increased in one. Lymphocyte proliferation was decreased in two patients, while four had impaired liver function. Superoxide production from stimulated PMNs and suppression of TNF-α production through IL-10 signalling in LPS-treated PBMCs were within normal range.\n\nOf note, patient 1 also had extreme splenomegaly and recurrent hemophagocytic lymphohistiocytosis with a high EBV viral load32–35. He had a splicing mutation at intron 5 (+1) G > A (Supplementary Fig. 1A), missing exon 5, frameshift at the 354th Val ending at the 379th due to the lack of the RING (Really Interesting New Gene) domain in the XIAP gene (Supplementary Fig. 1B) to inhibit caspase 3 or 7 activity. His mother was a carrier. Patient 2 had a STAT1 mutation impairing the IFN-γ-IL-12/23 circuit, thereby increasing susceptibility to mycobacterial and Candida infections. A [Thr385Met] STAT1 mutation in the DNA-binding domain region also caused an IPEX-like phenotype (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked)39–41. This genetic mutation was finally identified 8 years post-transplantation (Supplementary Fig. 1C). Patient 3 had the IPEX phenotype, which had caused the death of his maternal uncle due to diabetes. His [Met370Leu] FOXP3 mutation changed the fork-head domain and decreased the percentage of Treg cells (CD25 + + CD4+/CD4+, 5.8% vs. 32.6%) (Supplementary Fig. 1D and E). In patients 4 and 5, extremely high IgE levels and recurrent cutaneous infections were the distinct manifestations of hyper IgE syndrome. The STAT3 mutations were found to have IVS 10 (−2) A > G leading to a splicing loss of exon 11 and missense mutation of Gln469Arg in exon 15 (Supplementary Fig. 1F and G, respectively, in the DNA-binding domain region). Both were de novo loss-of-function mutations and their family members did not have the hyper IgE syndrome phenotype.\n\nTreatment Response and Prognosis\nSalmonella and pseudomonas strains were the most common of 17 identified pathogens in the patients with the SD phenotype (in 6 and 6 patients, respectively). Even though cytomegalovirus and cryptosporidium were only isolated in one patient with SCID4-IL2RG and one with HIGM1-CD40L, both had persistent cramping pain and high CRP levels, implying possibly mixed bacterial pathogens in such opportunistic infections. Both patients improved with effective antibiotic treatment plus gancyclovir and nitazoxanide, respectively. Giardia and clostridium difficile toxin A were not detected in any of our patients. In addition to IVIG infusion for those with hypogammaglobulinemia according to age, those with the SD phenotype improved within 3 weeks by effective and empritic antibiotics. However, even though all of the patients with RD without hypogammaglobulinemia received consistent treatment including IVIG and empiric antibiotics plus methylprednisolone over 3 weeks, only a limited effect was achieved. The exception was patient 4 who had a STAT3 mutation, in whom the number of RD flare-ups decreased from 5–6 episodes per year to 1–2 episodes per year after receiving steroids and regular IVIG treatment. During his episodes, the frequency was an average 5–6 times per day lasting for 15–22 days.\n\nSeven of the 26 patients (27.0%) with SD died of respiratory failure (four), and lymphoma, sepsis, and intracranial haemorrhage (one each) rather than directly of severe diarrhoea. Compared to the patients with the same PIDs without the SD phenotype (Table 3 and Supplemental Fig. 2), those with XLA and SCID with the SD phenotype trended to have a lower mortality rate. In contrast, the patients with WAS, CGD and HIGM with the SD phenotype had a relatively higher mortality rate, although none of the differences reached statistical significance except XLA patients.Table 3 The relationship between mortality and the SD phenotype (severe and protracted diarrhoea) in each group of patients or whether directly related to SD or RD (refractory diarrhoea) phenotype.\n\nDiseases\tWith SD phenotype\tWithout SD phenotype\tStatistic test p value\t\nAlive\tDeath\tAlive\tDeath\tKalpan-Meier survival*\t\n(patient number)\t(patient number)\t\nXLA\t6\t0\t4\t2\t\n0.0486\n\t\nSCID\t3\t3\t7\t9\t0.5122\t\nWAS\t1\t2\t15\t4\t0.066\t\nCGD\t3\t1\t15\t2\t0.5623\t\nHIGM\t2\t1\t10\t0\t0.3173\t\nTotal\t15\t7\t51\t17\t0.9230\t\n\nMortality\n\t\nSD phenotype\n\t\t\nRD phenotype\n\t\t\t\n\nNon-related\n\t\nRelated\n\t\nNon-related\n\t\nRelated\n\t\t\n7\t0\t0\t2\t\t\n*Kalpan-Meier survival analysis defined the diagnosis day as the first follow-up day to compare those PIDs patients with and without the SD phenotype. For those without SD, the starting time of K-M analysis was the diagnosis day by characteristic presentations or/and molecular and genetic confirmation. They had no the SD phenotype to date. For those with SD, the starting time of K-M analysis was the diagnosis day by characteristic presentations accompanying SD or/and molecular and genetic confirmation.\n\n\n\n\nIn contrast to the SD group, the higher mortality rate in the RD group (two deaths of five patients; 40%) was directly related to their overwhelming RD phenotype. The parents of patient 1 (with an XIAP mutation) chose a conservative strategy rather than HSCT despite a poor response to aggressive treatment and methylprednisolone. Anti-TNF-α biologics were considered, however the RD phenotype worsened and endemic norovirus enterocolitis prevailed. Unfortunately, he died of severe Crohn’s colitis and accelerated hemophagocytic lymphohistiocytosis. Patient 3 (with a FOXP3 mutation) succumbed from recurrent RD while waiting for a suitable HSCT donor. Patient 2 (with a STAT1 mutation) underwent successful HSCT to terminate recurrent opportunistic and life-threatening infections as well as the RD phenotype. Patient 5 had broader gastrointestinal tract lesions from the stomach to the colon and lost 3 kg after having diarrhoea for 2 months. Concomitant Helicobacter pylori colonization was found in the second endoscopic stomach specimen, and additional amoxicillin and clarithromycin (2 weeks) and omeprazole (12 weeks) treatment attenuated the cramping and frequent diarrhoea.\n\nDiscussion\nThis is the first study to report the prevalence, distribution, pathogens and prognosis of SD from a national PIDs referral centre. Twenty-six patients (10.6%) who had insufficient opsonized and neutralized IgG (Btk, CVID, SCID and HIGM), diminished reactive oxygen species production (CGD), and lazy lymphocytes with cytoskeletal dysfunction (WAS), thus impairing pathogenic eradication developed the SD phenotype before adequate prophylactic therapy and needed an extended duration of antibiotic treatment. Severe bacterial colitis in immune-competent patients often responds to effective antibiotics within 7 days in Taiwan in the previous study42. Of note, pseudomonas colitis was most commonly found in the patients with predominantly antibody deficiencies, of whom one (Btk2) met the diagnostic criteria43 of Shanghai fever including community-acquired diarrhoea with fever, sepsis and pseudomonas cultures from facial ecthyma gangrenosum. His pathogen was not a multi-drug resistant strain.\n\nIn the pathogenesis of the extreme presentation of the RD phenotype, persistent intestinal inflammation seemed to play a greater role than infection, reflecting the poor response to antibiotics. Therefore, alternative biologics or anti-inflammatory immuno-suppressants stronger than steroids should be administered to patients with XIAP, STAT1, FOXP3, or STAT3 mutations. While alimentary enterocytes with these mutations interact with microorganisms for gut homeostasis, the XIAP mutation selectively impairs nucleotide-binding and oligomerization domain 1/2 signalling for chemo-attractant production (IL-6, IL-8, and MCP-1), and does not effectively terminate cognate caspase-related cascades for apoptosis in damaged and/or infected intestinal epithelium32–35. The dominant gain-of-function hypermorphic [Thr385Met] STAT1 mutation prolongs STAT1 phosphorylation to exaggerate IFN-γ, IFN-α, IL-6, and IL-21 cytokine signaling39–41. The FOXP3 mutation in Treg cells attenuates IL-10 and TGF-β production to release unwanted autoantibodies in autoimmune disorders17–21. In addition, we previously showed that the STAT3 mutation diminishes Th17 production44, inhibiting the intestinal tight junction45, 46, epithelial cell proliferation, goblet cell restoration, and mucin production47, 48. Furthermore, a novel suppressive Th17 subset has been shown to cause regulatory Th17 (rTh17) cells to induce mucosal tolerance when Th17 cells are recruited to the intestinal tract49. Taken together, the pathologic mechanisms orchestrated by these mutations break intestinal mucosal tolerance and augment persistent intestinal inflammation, thereby causing the RD phenotype. Successful HSCT is, in practice, rescue therapy to terminate the RD phenotype in patients with XIAP, FOXP3 and STAT1 mutations as well as recurrent infections50.\n\nHelicobacter pylori-infected gastric mucosa can express higher levels of IL-17 via the STAT3 pathway51 and promote intestinal metaplasia and dysplasia to carcinoma in PIDs patients in whom malignant transformation has been reported to be 10 times higher than the general population52. However, the lack of IL-17 secretion in patients with the loss-of-function STAT3 mutation due to defective Th17 cell development does not enhance alimentary malignant transformation to induce the tumour-secreting-endocrine RD phenotype. Whether the Helicobacter pylori infection in our patient 5 with a STAT3 mutation was related to the RD phenotype is unclear, and further large-scale prospective studies are warranted to elucidate this issue.\n\nThere are several limitations to this study. First, some aetiological pathogens and triggering factors of SD were not identified, even though comprehensive PCR and stool cultures were performed to detect viruses, fungi, parasites and bacteria. Clearly delineating between infection and inflammation remains a challenge in PIDs patients with immune disturbances. Hence, both empiric antibiotics and steroids should be recommended to those with the RD phenotype. Second, in three RD patients with FOXP3, XIAP, and STAT1 mutations, successful HSCT reconstructed immunity and therefore resolved the RD phenotype as well as the recurrent infections. However, only one patient with the STAT1 mutation received timely HSCT. The hesitation of the other two parents to undergo HSCT increased the mortality rate despite an early diagnosis and aggressive treatment. Third, the prevalence of IBD in PIDs patients is under-estimated. IBD or IBD-like diarrhoea may emerge at an older age since the life expectancy of PIDs patients has increased due to advanced treatment strategies, thereby increasing the potential to develop inflammation and autoimmune disorders. The limited follow-up duration of our patients with predominantly paediatric-onset PIDs may explain the lower prevalence of IBD or IBD-like diarrhoea.\n\nIn conclusion, the 26 (10.5%) patients in this nationwide cohort of 246 PIDs patients were mostly male and developed the SD phenotype before adequate prophylactic treatment. Most cases were caused by salmonella and pseudomonas infections, and they needed IVIG and an extended period of antibiotic treatment. Five (2.0%) male patients with the RD phenotype had XIAP mutations resulting in defective nucleotide-binding and oligomerization domain 1/2 signalling, the hypermorphic STAT1 mutation causing hyper-cytokine signalling, and profound Treg and Th17 cell defects caused by FOXP3 and STAT3 mutations. Early recognition and timely effective interventions to suppress inflammation are beneficial to decrease the mortality rate of PIDs patients with the RD phenotype.\n\nMethods\nPatients\nFrom 2003 to 2015, 246 index cases with PIDs from 215 families were identified from the PICAR Institute’s registry (Supplemental Table 1)37. Infectious colitis was diagnosed if the clinical manifestations of bloody diarrhoea, tenesmus, severe cramping abdominal pain and a high CRP level (>40 mg/mL) were unequivocal even if no pathogen was isolated after extensive culture and PCR amplification. According to our previous studies on the epidemiologic intestinal pathogens in patients with PIDs37, 53, ceftriaxone (100 mg/kg/day) or meropenem (30 mg/kg/day) was given for suspected Salmonella or Shigella colitis, and a combination of ceftazidime (100 mg/kg/day) and amikacin (15 mg/kg/day) or carbapenem (100 mg/kg/day) for pseudomonas colitis in the presence of neutropenia resembling Shanghai fever was given within the first 24 hours before the pathogen cultures were available43. When the blood cultures were sterile and infectious manifestations of tenesmus, severe cramping abdominal pain, fever, and elevated CRP level subsided, the antibiotics were discontinued.\n\nRegardless of whether empiric or sensitive antibiotics were given for the identified pathogens and IVIG (0.6–0.8 g/kg) for the patients with hypogammaglobulinemia, frequent diarrhoea of more than three episodes of unformed stools within a period of 24 hours for longer than 2 weeks was defined as the SD phenotype. In cases of frequent diarrhoea that failed to respond to antibiotics, one dose of IVIG and steroids (methylprednisolone 2–5 mg/kg/day) for more than 3 weeks was defined as the refractory SD (RD) phenotype in this study. The prognosis of the patients with PIDs suffering from SD and RD were compared using Kalpan-Meier survival (GraphPad software) tests. For those without SD, the starting time of K-M analysis was the diagnosis day by characteristic presentations or/and molecular and genetic confirmation. They had no the SD phenotype to date. For those with SD, the starting time of K-M analysis was the diagnosis day by characteristic presentations accompanying the SD phenotype or/and molecular and genetic confirmation.\n\nThe Chang Gung Human Investigation Committee approved all carried methods and all experimental protocols in this study, and the patients’ parents or guardians’ informed consent were obtained. We confirmed that all methods were performed in accordance with the relevant guidelines and regulations.\n\nImmunologic Functional Assessment and Candidate Gene Approach\nIn addition to immunoglobulin levels and lymphocyte subpopulations (i.e., CD3+, CD4+, CD4 + CD45RA+, CD4 + CD45RO+, CD19+, CD19 + CD27+, and CD19 + CD27−), characteristics and well-syndromes of PIDs accompanying the SD phenotype were identified by experienced physicians, and were consistent with defective lymphocyte proliferation to mitogens and antigens, and phorbol myristate acetate-stimulated polymorphonuclear reactive oxygen species as represented by H2O2 production as previously described54.\n\nTo evaluate IL-10 signalling in the patients with RD and unrecognized molecular defects at that time, purified PBMCs (5 × 106/ml) were stimulated overnight with 50 ng/ml E. coli LPS (Sigma-Aldrich, St. Louis, Mo) alone or with 20 ng/ml recombinant human IL-10 (R&D Systems, Minneapolis, MN). The supernatants were analysed using a commercially available TNF-α ELISA development kit in duplicate using a Tecan Sunrise ELISA micro-plate reader (R&D Systems, Minneapolis, MN). Candidate genetic analysis in the patients with the RD phenotype predisposing to IBD included, at least, IL10, IL10RA, IL10RB, NEMO, FOXP3, XIAP, STAT3 and STAT155, 56. Every two oligonucleotide primers were selected to cover the entire coding region by Sanger sequencing57.\n\nElectronic supplementary material\n\nSupplemental information\n\n \n\n\nElectronic supplementary material\n\n\nSupplementary information accompanies this paper at doi:10.1038/s41598-017-03967-4\n\n\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors thank all of the patients and their families for their kind cooperation and their physicians for the referrals. This study received grants from Chang-Gung Medical Research Progress (Grant CORPG3F0051-53 and CMRPG 4B0051-53), National Science Council (Grants NSC 99-2314-B-182A-096-MY3, NSC 102-2314-B-182A-039-MY3, MOST 104-2663-B-182A-005 and NMRPG3C6071) and Taiwan Foundation for Rare Disorders (TFRD).\n\nAuthor Contributions\nL.W.I., C.C.C. and H.J.L. designed the study and organised the team; L.W.I., H.J.L., and O.L.S. performed the immunologic assessments and genetic analysis; C.C.C., J.T.H. and C.C.C. took care of the patients; and H.C. studied the pathology. All of the authors contributed to this work and approved the submitted version of the manuscript.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Agarwal S Mayer L Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency Clin. Gastroenterol. Hepatol. 2013 11 1050 1063 10.1016/j.cgh.2013.02.024 23501398 \n2. 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Dupuis-Girod S Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients Pediatrics. 2003 111 e622 627 10.1542/peds.111.5.e622 12728121 \n29. Cannioto Z IBD and IBD mimicking enterocolitis in children younger than 2 years of age Eur. J. Pediatr. 2009 168 149 155 10.1007/s00431-008-0721-2 18546019 \n30. Marks DJ Inflammatory bowel disease in CGD reproduces the clinico-pathological features of Crohn’s disease Am. J. Gastroenterol. 2009 104 117 124 10.1038/ajg.2008.72 19098859 \n31. Muise AM NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2 Gut. 2012 61 1028 1035 10.1136/gutjnl-2011-300078 21900546 \n32. Marsh RA XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lympho-histiocytosis and not as X-linked lympho-proliferative disease Blood. 2010 116 1079 1082 10.1182/blood-2010-01-256099 20489057 \n33. Pachlopnik Schmid J Clinical similarities and differences of patients with X-linked lympho-proliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency) Blood. 2011 117 1522 1529 10.1182/blood-2010-07-298372 21119115 \n34. Yang X Clinical and genetic characteristics of XIAP deficiency in Japan J. Clin. Immunol. 2012 32 411 420 10.1007/s10875-011-9638-z 22228567 \n35. Speckmann C X-linked inhibitor of apoptosis (XIAP) deficiency: The spectrum of presenting manifestations beyond hemophagocytic lympho-histiocytosis Clin. Immunol. 2013 149 133 141 10.1016/j.clim.2013.07.004 23973892 \n36. Cheng LE Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome Clin. 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Pediatr. 2013 25 708 714 10.1097/MOP.0000000000000029 24240290 \n41. Sampaio EP Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis J. Allergy Clin. Immunol. 2013 131 1624 1634 10.1016/j.jaci.2013.01.052 23541320 \n42. Chen HM Wang Y Su LH Chiu CH Nontyphoid salmonella infection: microbiology, clinical features, and antimicrobial therapy Pediatr. Neonatol. 2013 54 147 152 10.1016/j.pedneo.2013.01.010 23597525 \n43. Chuang CH Shanghai fever: a distinct Pseudomonas aeruginosa enteric disease Gut. 2014 63 736 743 10.1136/gutjnl-2013-304786 23943780 \n44. Lee WI Clinical, immunological and genetic features in Taiwanese patients with the phenotype of hyper-immunoglobulin E recurrent infection syndromes (HIES) Immunobiology. 2011 216 909 917 10.1016/j.imbio.2011.01.008 21324546 \n45. Kinugasa T Claudins regulate the intestinal barrier in response to immune mediators Gastroenterology. 2000 118 1001 1011 10.1016/S0016-5085(00)70351-9 10833473 \n46. Chen Y Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop J. Biol. Chem. 2003 278 17036 17043 10.1074/jbc.M210429200 12624114 \n47. Brand S IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 over-expression in vitro Am. J. Physiol. Gastrointest. Liver Physiol. 2007 292 G1019 1028 10.1152/ajpgi.00239.2006 17204547 \n48. Sugimoto K IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis J. Clin. Invest. 2008 118 534 544 18172556 \n49. Esplugues E Control of TH17 cells occurs in the small intestine Nature. 2011 475 514 518 10.1038/nature10228 21765430 \n50. Slatter MA Gennery AR Advances in hematopoietic stem cell transplantation for primary immuno-deficiency Expert Rev. Clin. Immunol. 2013 9 991 999 10.1586/1744666X.2013.836061 24128161 \n51. Caruso R IL-23-mediated regulation of IL-17 production in Helicobacter pylori-infected gastric mucosa Eur. J. Immunol. 2008 38 470 478 10.1002/eji.200737635 18200634 \n52. Dhalla F da Silva SP Lucas M Travis S Chapel H Review of gastric cancer risk factors in patients with common variable immunodeficiency disorders, resulting in a proposal for a surveillance programme Clin. Exp. Immunol 2011 165 1 7 10.1111/j.1365-2249.2011.04384.x 21470209 \n53. Lee WI Distribution, infections, treatments and molecular analysis in a large cohort of patients with primary immunodeficiency diseases (PIDs) in Taiwan J. Clin. Immunol. 2006 26 274 283 10.1007/s10875-006-9013-7 16783466 \n54. Lee WI Distribution and clinical aspects of primary immunodeficiencies in a Taiwan pediatric tertiary hospital during a 20-year period J. Clin. Immunol. 2005 25 162 173 10.1007/s10875-005-2822-2 15821893 \n55. Lee WI Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome Blood. 2005 105 1881 1890 10.1182/blood-2003-12-4420 15358621 \n56. Lee WI Clinical aspects and genetic analysis of Taiwanese patients with the phenotype of hyper-immunoglobulin E recurrent infection syndromes (HIES) J. Clin. Immunol. 2011 31 272 280 10.1007/s10875-010-9479-1 21120687 \n57. RAPID: Resource of Primary Immunodeficiency Diseases. http://rapid.rcai.riken.jp/ website.\n\n",
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"abstract": "BACKGROUND\nPseudobulbar affect is a very distressing and underdiagnosed neuropsychiatric disorder that causes contextually inappropriate episodes of laughing and crying and general emotional incontinence. Although many proposed etiologies exist, the most widely accepted theory espouses the disruption of a corticopontine-cerebellar circuit that governs the modulation of emotional response. Pseudobulbar affect is commonly diagnosed secondary to primary neurological disorders such as amyotrophic lateral sclerosis, multiple sclerosis, and traumatic brain injury. Traditional pharmacological treatment of pseudobulbar affect is largely comprised of antidepressant therapy, including tricyclic antidepressants such as amitriptyline and selective serotonin reuptake inhibitors such as fluvoxamine. However, neither of these medication classes has been studied for the treatment of pseudobulbar affect in controlled trials, and their utility remains questionable.\n\n\nMETHODS\nWe describe a case of a 62-year-old Caucasian man with history of traumatic brain injury, ischemic brainstem stroke, and depression who developed intractable pseudobulbar affect. This patient's intensely distressing symptoms were not alleviated by amitriptyline. However, after being placed on fixed-dose 20 mg/10 mg dextromethorphan/quinidine (Nuedexta), our patient experienced complete resolution of his symptoms. He has experienced no deleterious side effects.\n\n\nCONCLUSIONS\nThis case provides anecdotal evidence for the efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect with remarkably swift and complete cessation of symptoms. As a secondary point, it is worth noting that our patient had experienced two devastating neurological traumas, both in anatomical areas that have been implicated in the corticopontine-cerebellar circuit thought to be responsible for pseudobulbar affect. However, only the second trauma, an acute left pontine infarction, produced symptoms of emotional disinhibition. The authors hope that reporting this case will provide both context for physicians managing this condition and hope for patients with this socially and psychiatrically damaging disease.",
"affiliations": "University of Pikeville, Kentucky College of Osteopathic Medicine, The Medical Center, Bowling Green, KY, 42101, USA. fletcheryoung@upike.edu.;University of Pikeville, Kentucky College of Osteopathic Medicine, The Medical Center, Bowling Green, KY, 42101, USA.",
"authors": "Young|Fletcher Graham|FG|http://orcid.org/0000-0002-6466-4020;Nguyen|Diep|D|",
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"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947 BioMed Central London \n\n2525\n10.1186/s13256-020-02525-3\nCase Report\nTreatment of pseudobulbar affect (PBA) in a patient with a history of traumatic brain injury, partial brain resection, and brainstem stroke: a case report\nhttp://orcid.org/0000-0002-6466-4020Young Fletcher Graham fletcheryoung@upike.edu Nguyen Diep diepnguyen@upike.edu grid.447470.40000 0000 8996 0681University of Pikeville, Kentucky College of Osteopathic Medicine, The Medical Center, Bowling Green, KY 42101 USA \n4 12 2020 \n4 12 2020 \n2020 \n14 23520 3 2020 8 9 2020 © The Author(s) 2020Open 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.Background\nPseudobulbar affect is a very distressing and underdiagnosed neuropsychiatric disorder that causes contextually inappropriate episodes of laughing and crying and general emotional incontinence. Although many proposed etiologies exist, the most widely accepted theory espouses the disruption of a corticopontine–cerebellar circuit that governs the modulation of emotional response. Pseudobulbar affect is commonly diagnosed secondary to primary neurological disorders such as amyotrophic lateral sclerosis, multiple sclerosis, and traumatic brain injury. Traditional pharmacological treatment of pseudobulbar affect is largely comprised of antidepressant therapy, including tricyclic antidepressants such as amitriptyline and selective serotonin reuptake inhibitors such as fluvoxamine. However, neither of these medication classes has been studied for the treatment of pseudobulbar affect in controlled trials, and their utility remains questionable.\n\nCase presentation\nWe describe a case of a 62-year-old Caucasian man with history of traumatic brain injury, ischemic brainstem stroke, and depression who developed intractable pseudobulbar affect. This patient’s intensely distressing symptoms were not alleviated by amitriptyline. However, after being placed on fixed-dose 20 mg/10 mg dextromethorphan/quinidine (Nuedexta), our patient experienced complete resolution of his symptoms. He has experienced no deleterious side effects.\n\nConclusions\nThis case provides anecdotal evidence for the efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect with remarkably swift and complete cessation of symptoms. As a secondary point, it is worth noting that our patient had experienced two devastating neurological traumas, both in anatomical areas that have been implicated in the corticopontine–cerebellar circuit thought to be responsible for pseudobulbar affect. However, only the second trauma, an acute left pontine infarction, produced symptoms of emotional disinhibition. The authors hope that reporting this case will provide both context for physicians managing this condition and hope for patients with this socially and psychiatrically damaging disease.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s13256-020-02525-3.\n\nKeywords\nPseudobulbar affectStrokeEmotional incontinenceDextromethorphan/quinidineCase reportissue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nPseudobulbar affect (PBA) is a neuropsychiatric condition defined by pronounced emotional lability and hypersensitivity to emotional or social stimuli. PBA most often presents as involuntary and inappropriate laughing or crying and occurs out of proportion or incongruent to the patient’s subjective emotional state. Although many proposed etiologies exist, PBA is thought to relate to the release of brainstem emotional control centers from regulation by the frontal lobes [1]. Specifically, the most widely accepted theory maintains that the classic signs of emotional dysmetria are caused by the disruption of a distinct corticopontine–cerebellar circuit that governs the modulation of emotional response [2] (Fig. 1).\nFig. 1 Proposed pathophysiology of pseudobulbar affect. a Input from the motor, frontal, and temporal cortices to the brainstem is modulated by input from the cerebellum. Inhibitory input from the somatosensory cortex modulates the motor input. b Reduced inhibitory input (broken red arrows in the cortex) results in disinhibition, giving rise to inappropriate emotional reactions to stimuli. Permission was granted by Miller et al. (©Taylor & Francis [2]) to reuse this figure\n\n\n\nPBA is nearly always produced secondary to neurological trauma such as stroke, brain tumor, or progressive neurodegenerative disease such as amyotrophic lateral sclerosis (ALS) [1]. However, because PBA often involves laughing and crying, the condition is frequently mistaken for a symptom of clinical depression, post-traumatic stress disorder, bipolar disorder, or another purely psychiatric condition. Perhaps because of this symptomatic overlap with other common neuropsychiatric conditions, a set of definitive criteria for the diagnosis of PBA has yet to be agreed on. Currently, interested physicians may rely on the published and widely circulated diagnostic criteria of Poeck or Cummings [3, 4], or they may rely on several standardized grading tools that physicians may use to measure the severity of a patient’s symptoms, such as the Center for Neurologic Study-Lability Scale, which is a validated, self-administered questionnaire focused on patient control of laughing and crying [5].\n\nThe prevalence of PBA in the United States is thought to be greatly underrecognized [6]. A survey of 8876 patients with commonly associated underlying neurological conditions of Alzheimer disease, ALS, multiple sclerosis (MS), Parkinson disease, stroke, and traumatic brain injury revealed a prevalence of roughly 10% in this population, and estimates of the overall prevalence in the United States are between 1.8 million and 7.1 million, depending on the diagnostic criteria applied [6]. Moreover, it has been estimated that less than half of patients with PBA have received an appropriate diagnosis for this condition [6].\n\nFixed-dose 20 mg/10 mg dextromethorphan/quinidine ([DM/Q] Nuedexta; Avanir Pharmaceuticals, Aliso Viejo, CA, USA) is the first and only drug approved for the treatment of PBA. Dextromethorphan is the most well known as a noncompetitive N-methyl-d-aspartate receptor antagonist, but it has a multifaceted pharmacology and has interactions with serotonin transporters, noradrenaline transporters, sigma-1 receptors, and α3β4 nicotinic acetylcholine receptors. However, its specific mechanism of action in the treatment of PBA is currently unknown [7]. Quinidine is a class Ia sodium channel–blocking antiarrhythmic, but it is combined with dextromethorphan because of its secondary ability to competitively inhibit cytochrome P450 2D6, which increases and prolongs the plasma levels of dextromethorphan, increasing bioavailability [7]. The most common adverse reactions to DM/Q are diarrhea, dizziness, and cough [8]. It is recommended that patients be monitored for hypokalemia and hypomagnesemia before and during treatment with DM/Q, particularly those with risk factors for QT prolongation. The combination is a pregnancy category C drug and is also contraindicated in patients with a history of atrioventricular block, thrombocytopenia, hepatitis, bone marrow depression, or lupus-like syndrome [8]. Additionally, although DM/Q is currently approved only to treat PBA, it may soon become a far more commonly prescribed medication. Conditions currently being investigated with dextromethorphan as a stand-alone or add-on treatment in clinical trials include Rett syndrome, rheumatoid arthritis, Gulf War illness, diabetic macular edema, attention-deficit/hyperactivity disorder, agitation in depression, schizophrenia, Alzheimer disease, and episodic migraine [9]. In this case report, we describe the utility and efficacy of DM/Q in a patient with severe PBA and significant neuropsychiatric comorbidities, and we advocate for its application in similar clinical scenarios.\n\nCase presentation\nWe present a case of a 62-year-old Caucasian man with several neurovascular and psychiatric conditions. The patient was first injured in 1980 in a construction worksite accident, wherein he was struck by a falling cinder block and experienced significant cranial trauma that required a right frontotemporal craniotomy and partial brain resection. The resected bone was then replaced with artificial titanium plating. Following this surgery, the patient remained comatose for a period of 6 days, finally awakening on Christmas Day 1980. Follow-up magnetic resonance imaging and computed tomography confirmed the presence of a large, right-sided cystic encephalomalacia with subsequent gliosis subjacent to the resected brain tissue. Following this initial injury, the patient surprisingly made a full recovery, with no permanent neurological deficits. However, he began to experience painful and intractable headaches. Despite the best efforts of his physicians, these headaches soon became debilitating and made it difficult for the patient to hold a steady job. For the next 30 years, he struggled with his injury, eventually becoming homeless. During one visit to the hospital, he was diagnosed with major depressive disorder and subsequently was started on amitriptyline, which the patient has taken ever since. For most of this period, however, the patient had little or no regular healthcare, and his health slowly deteriorated.\n\nIn 2013, the patient, a lifetime smoker, experienced a thromboembolic left pontine infarction. He again recovered, and, interestingly, this event caused a dramatic reduction in the frequency and intensity of the patient’s headaches. However, this time, the patient retained a unilateral right-sided oculomotor nerve palsy and significant speech deficits for years afterward. Several days after this stroke, the patient began to experience episodes of inappropriate laughing and crying and general emotional incontinence. At this time, he was diagnosed with PBA. In addition to his amitriptyline, initial attempts at treatment with several commonly prescribed antidepressants had no effect on the patient’s PBA symptoms. The patient stated that he was not so much bothered by his emotional incontinence in and of itself, but rather by the perception of others in social or everyday public settings. The patient gradually became more socially reserved. Apprehensive of inappropriate and involuntary displays of emotion, the patient started to avoid public settings altogether, such as church and the grocery store. In early 2017, after years of unsuccessful pharmacotherapy, the patient was placed on DM/Q 30 mg by mouth twice daily. At this time, the patient’s vital signs were recorded as follows: blood pressure 116/82 mmHg, weight 296 lb., body mass index 42.47 kg/m2, heart rate 82 beats/minute, respiratory rate 20 breaths/minute, body temperature 97.7 °F, and oxygen saturation 93%. Within 1 week, he experienced total resolution of his symptoms. The patient has experienced no negative side effects. Additionally, he reports that if he forgets or is unable to take this medication for 2–3 days, he begins to experience breakthrough symptoms, which quickly resolve after resuming medication.\n\nThis patient’s quality of life is now much improved. The authors are happy to report that he is recently married and living comfortably, thanks to federal government benefits. Through great personal effort, the patient has recovered near-full speech ability and is no longer apprehensive of social settings.\n\nDiscussion\nAlthough the precise mechanisms of DMQ in ameliorating PBA are not known, modulation of excessive glutamatergic transmission within corticopontine–cerebellar circuits may contribute to its benefits [2]. Before the approval of DM/Q in 2011, PBA and similar syndromes involving emotional incontinence were, and still are, treated off-label with antidepressants, including tricyclic antidepressants such as amitriptyline and selective serotonin reuptake inhibitors such as fluvoxamine [2]. However, experimental evidence in the form of clinical trials supporting the efficacy of these medication classes in treating PBA is lacking [10]. DM/Q, however, has been proved to be very effective. In a randomized, double-blind, controlled 4-week study of 140 patients with PBA and ALS, DM/Q 30/30 mg was proved to be superior to its individual component drugs [11]. A 12-week, double-blind, placebo-controlled study of DM/Q 30/30 mg showed similar efficacy in 150 patients with MS and PBA. A subsequent 12-week study of patients with PBA and ALS or MS showed superiority to placebo for the 20/10- and 30/10-mg doses [12]. In a 12-week randomized, double-blind trial titled STAR, 326 patients with ALS and MS who had clinically significant PBA were treated twice daily with either DM/Q or placebo [13]. Efficacy was maintained over the length of the trial, an open-label extension (30/10 mg dose), with further improvement of mean efficacy scores [13]. In a 12-week noncomparative cohort study of 120 patients, PRISM II, DM/Q 20/10 mg twice daily also improved PBA secondary to traumatic brain injury [14]. Across these studies, DM/Q was generally safe and well tolerated, with no evidence of clinically relevant cardiac or respiratory effects. Adverse side effects have been described as mostly mild or moderate and include nausea, dizziness, headache, weakness, and gastrointestinal complaints [11, 13].\n\nThe success in our patient’s case speaks to the efficacy of DM/Q for the treatment of PBA in acutely affected patients, but it also raises questions regarding the pathophysiological “gate control” model of PBA, which posits the cerebellum as the apparatus responsible for unconscious modulation of emotional expression, scaling it appropriately and producing an emotionally congruent response according to the contextual information transmitted via descending pathways from the sensory cortex through the frontal and temporal cortices [15].Our patient had experienced two devastating neurological traumas, both in anatomical areas that have been implicated in the corticopontine–cerebellar circuit thought to be responsible for PBA. The patient’s first injury, which resulted in the removal of a significant portion of the frontotemporal cortex, should theoretically have interrupted the flow of contextual information to the pons and cerebellum and produced symptoms of emotional disinhibition. However, only the second trauma many years later, an acute left pontine infarction, induced the predicted symptoms of PBA.\n\nWith these data in mind and the success in our patient’s case, the authors encourage managing physicians to consider DM/Q for the treatment of PBA in affected neuropsychiatric patients and to keep in mind the clinical variability of this condition.\n\nConclusions\nAlthough DM/Q has been proved to be both safe and clinically efficacious in controlled studies, it is a relatively new entrant in the field of neuropsychiatric illness. Although the precise therapeutic mechanism is still a subject of study, it is possible that DM/Q will play a much larger role in the treatment of a diverse array of neurological illnesses in the near future. Its network of neurochemical mechanisms is a subject of ongoing research and has been promoted as a possible candidate for medical therapies for depression, pain, seizures, and methotrexate toxicity [9].\n\nThis case provides anecdotal evidence for the efficacy of DM/Q in the treatment of PBA, with a remarkably swift and complete cessation of symptoms in an acutely affected patient. It is the only drug approved for the treatment of PBA, but many physicians are understandably wary of straying from established avenues of pharmacotherapy. The authors hope that reporting this case will provide both context for physicians managing this condition and hope for patients with this socially and psychiatrically damaging disease. In addition, this case underlines the need for a more precise understanding of the pathophysiology of PBA, because the current “gate control” model cannot adequately explain the discrepancy in resultant symptoms between the patient’s two neurological traumas. Further research is required in order to provide a more complete pathological picture of this complex neurological disease.\n\nSupplementary Information\n\nAdditional file 1:\nFigure 2 Structural formula of dextromethorphan. Figure 3 Structural formula of quinidine sulfate. Table 1 Concurrent Medications. Table 2 History.\n\n \n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nFletcher Graham Young and Diep Nguyen contributed equally to this work.\n\nAcknowledgements\nThe authors acknowledge and thank Dr. Sanjay Kaul for his guidance and support, the patient for his consent and insight, and also the staff and educators of the Medical Center of Bowling Green, KY, USA.\n\nAuthors’ contributions\nBoth authors contributed to the efforts of research, writing, and editing that produced this manuscript. Both authors read and approved the final manuscript.\n\nAuthors’ information\nFletcher Young, MBA, OMS-IV, and Diep Nguyen, OMS-IV, and are medical students attending the Kentucky College of Osteopathic Medicine. They are currently engaged in clinical rotations at The Medical Center Hospital in Bowling Green, KY.\n\nFunding\nNo funding agency had a role in the study design, data collection and analysis, decision to publish or the preparation of the manuscript.\n\nAvailability of data and materials\nData sharing is not applicable to this article. No datasets were generated or analyzed for this report.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Rosen HJ Cummings J A real reason for patients with pseudobulbar affect to smile Ann Neurol 2007 61 92 96 10.1002/ana.21056 17212357 \n2. Miller A, Pratt H, Schiffer RB. Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments. Expert Rev Neurother. 2011;11(7):295 1077–88. 10.1586/ern.11.68.\n3. Poeck K Vinken PJ Bruyn GW Pathophysiology of emotional disorders associated with brain damage Handbook of clinical neurology 1969 Amsterdam North Holland 343 367 \n4. Cummings JL Arciniegas DB Brooks BR Defining and diagnosing involuntary emotional expression disorder CNS Spectr 2006 11 S6 1 7 10.1017/S1092852900026614 \n5. Smith RA Berg JE Pope LE Callahan JD Wynn D Thisted RA Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients Mult Scler 2004 10 6 679 685 10.1191/1352458504ms1106oa 15584494 \n6. Work SS Colamonico JA Bradley WG Pseudobulbar affect: an under-recognized and under-treated neurological disorder Adv Ther 2011 28 586 601 10.1007/s12325-011-0031-3 21660634 \n7. Taylor CP Traynelis SF Siffert J Pope LE Matsumoto RR Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (Nuedexta®) clinical use Pharmacol Ther 2016 164 170 182 10.1016/j.pharmthera.2016.04.010 27139517 \n8. Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) oral capsules, prescribing information. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc.; Oct 2010. Revised August 2011. https://www.nuedexta.com/sites/default/files/pdfs/Prescribing_Information.pdf. Accessed 27 May 2020.\n9. Nguyen L Thomas KL Lucke-Wold BP Cavendish JZ Crowe MS Matsumoto RR Dextromethorphan: an update on its utility for neurological and neuropsychiatric disorders Pharmacol Ther 2016 159 1 22 10.1016/j.pharmthera.2016.01.016 26826604 \n10. Hakimi M Maurer CW Pseudobulbar affect in parkinsonian disorders: a review J Mov Disord 2019 12 1 14 21 10.14802/jmd.18051 30732430 \n11. Brooks BR Thisted RA Appel SH Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial Neurology 2004 63 1364 1370 10.1212/01.WNL.0000142042.50528.2F 15505150 \n12. Panitch HS Thisted RA Smith RA Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis Ann Neurol 2006 59 780 787 10.1002/ana.20828 16634036 \n13. Pioro EP Brooks BR Cummings J Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect Ann Neurol 2010 68 693 702 10.1002/ana.22093 20839238 \n14. Hammond FM Sauve W Ledon F Davis C Formella AE Safety, tolerability, and effectiveness of dextromethorphan/quinidine for pseudobulbar affect among study participants with traumatic brain injury: results from the PRISM-II open label study PM R 2018 10 10 993 1003 10.1016/j.pmrj.2018.02.010 29477412 \n15. Haiman G Pratt H Miller A Brain responses to verbal stimuli among multiple sclerosis patients with pseudobulbar affect J Neurol Sci 2008 271 1-2 137 147 10.1016/j.jns.2008.04.017 18504049\n\n",
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"fulltext": "\n==== Front\nHepatol CommunHepatol Commun10.1002/(ISSN)2471-254XHEP4Hepatology Communications2471-254XJohn Wiley and Sons Inc. Hoboken 10.1002/hep4.1416HEP41416CorrespondenceCorrespondenceTargeted Temperature Management as a Cause of Liver Injury CorrespondenceAzhari Hassan M.D.\n1\nSwain Mark G. M.D., M.Sc.\n1\n\n1 \nCalgary Liver Unit, Division of Gastroenterology & Hepatology\nUniversity of Calgary\nCalgary\nAB\nCanada\n07 8 2019 10 2019 3 10 10.1002/hep4.v3.101415 1416 © 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.We describe a case of hepatitis following targeted temperature management (TTM) observed in our practice. Recent published data found association between cases of acute liver failure and exposure to TTM, a relationship that is not well known or established.\n\n\n source-schema-version-number2.0component-idhep41416cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:01.10.2019Potential conflict of interest: Dr. Swain advises Gilead and Intercept. He is on the speakers’ bureau for Abbott.\n==== Body\nTo The Editor:\n\nTargeted temperature management (TTM) is an evidence‐based therapeutic modality that is used frequently after cardiac arrest to enhance neurologically intact survival and lower overall mortality by maintaining a lower body temperature.1 Elevated liver enzymes are a common finding in survivors of cardiac arrest and are often attributed to hypoxic hepatitis, which has been found in up to 13.5% of patients.2\n\n\nIn our practice, we saw a 61‐year‐old man with no known liver disease or alcohol use history who had presented with cardiac arrest. Cardiopulmonary resuscitation was performed followed by percutaneous coronary intervention, and he was subsequently started on TTM protocol at a target body temperature of 32°C to 34°C for 24 hours using an Icy Intravascular Heat Exchange Catheter (ZOLL Circulation, Inc., Chelmsford, MA). He was treated medically with aspirin, ticagrelor, unfractionated heparin, nitroglycerin patch, metoprolol, perindopril, and 2 g of acetaminophen per 24 hours. He had been on no medications prior to presentation.\n\nOn presentation, bloodwork revealed an elevated alanine aminotransferase (ALT) (138 IU/L; normal 1‐60 IU/L) and lactate dehydrogenase (LDH) (316 IU/L; normal 100‐235 IU/L) with normal gamma‐glutamyltransferase (GGT). Immediately after resuscitation, ALT and LDH rose to 655 IU/L and 853 IU/L, respectively, while GGT rose to 113 IU/L. Total bilirubin, international normalized ratio, and alkaline phosphatase remained within normal ranges throughout hospitalization. By day 5 following arrest, ALT had reached a nadir at 263 IU/L before rising to 426 IU/L by day 7 following arrest, while GGT rose to 326 IU/L (Fig. 1). Investigations were unsuccessful in identifying an etiology for those derangements, and they included a chronic liver disease and viral hepatitis workup along with ultrasound Doppler studies.\n\nFigure 1 Trends in liver enzymes following cardiac arrest.\n\nThe patient described had a delayed rise in liver enzymes, suspicious for being induced by TTM. Whereas hypoxic hepatitis usually manifests as an elevation in liver enzymes along with LDH, this patient’s LDH peaked immediately following arrest and proceeded to return to baseline, whereas the ALT and GGT went through another rise. A recent study by Iesu et al. found that acute liver failure (ALF) occurred in 56% of post‐cardiac arrest patients admitted to intensive care unit at a median time of 3 days following arrest.3 Interestingly, TTM was found to have been administered to 94% of patients who eventually developed ALF, versus only to 81% of those who did not develop ALF. Studies are needed to further characterize the incidence and mechanism of elevated liver enzymes after TTM, to direct monitoring and treatment in the future.\n==== Refs\nReferences\n1 \n\nHowes \nD \n, \nGray \nSH \n, \nBrooks \nSC \n, \nBoyd \nJG \n, \nDjogovic \nD \n, \nGolan \nE \n, et al. Canadian Guidelines for the use of targeted temperature management (therapeutic hypothermia) after cardiac arrest: a joint statement from the Canadian Critical Care Society (CCCS), Canadian Neurocritical Care Society (CNCCS), and the Canadian Critical Care Trials Group (CCCTG) . Resuscitation \n2016 ;98 :48 ‐63 .26417702 \n2 \n\nOh \nSH \n, \nKim \nHJ \n, \nPark \nKN \n, \nKim \nSH \n, \nKim \nYM \n, \nYoun \nCS \n, et al. Hypoxic hepatitis in survivors of out‐of‐hospital cardiac arrest . Am J Emerg Med \n2015 ;33 :1166 ‐1170 .26032661 \n3 \n\nIesu \nE \n, \nFranchi \nF \n, \nCavicchi \nFZ \n, \nPozzebon \nS \n, \nFontana \nV \n, \nMendoza \nM \n, et al. Acute liver dysfunction after cardiac arrest . PLoS One \n2018 ;13 :1 ‐13 .\nAuthor names in bold designate shared co‐first authorship.\n\n",
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"journal": "Hepatology communications",
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"title": "Targeted Temperature Management as a Cause of Liver Injury.",
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