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"abstract": "Cancer in transplant recipients represents a therapeutic challenge even when the patient is already under mTOR inhibitors. A 78-year-old man received a deceased donor kidney transplant in 1993. After 6 months, he developed a multifocal cutaneous and nonvisceral Kaposi's Sarcoma while on cyclosporine immunosuppressant therapy. The patient was converted to sirolimus monotherapy in 2001 with subsequent complete recovery within 2 years. In 2007, the patient was diagnosed with an esophageal adenocarcinoma stage IIA. An esophagectomy was performed without requirement of further treatment. He has continued on sirolimus monotherapy ever since, with no other incidents and no recurrences of either tumor. In this report, we describe an interesting case of a second cancer while on immunosuppressive therapy with anticancer activity. Moreover, the present knowledge of the matter is discussed.",
"affiliations": "Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.;Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.;Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Fundació Clínic - IDIBAPS, Barcelona, Spain.;Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Fundació Clínic - IDIBAPS, Barcelona, Spain.;Department of Medicine, Universitat de Barcelona, Barcelona, Spain.;Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.;Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.;Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.;Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.",
"authors": "Canha|Catarina|C|;Ferreira|Raquel|R|;Rovira|Jordi|J|;Moya-Rull|Daniel|D|;Castells|Antoni|A|;Diekmann|Fritz|F|;Oppenheimer|Federico|F|;Campistol|Josep Maria|JM|;Revuelta|Ignacio|I|",
"chemical_list": "D015415:Biomarkers; D007166:Immunosuppressive Agents; D009363:Neoplasm Proteins; D016572:Cyclosporine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D001379:Azathioprine; D011241:Prednisone; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.1111/tri.12600",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "28(10)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "TOR-inhibitors; immunosuppression; immunosuppression clinical; kidney clinical; malignancies and long term compliations; molecular diagnostic; solid tumors",
"medline_ta": "Transpl Int",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D001379:Azathioprine; D015415:Biomarkers; D016572:Cyclosporine; D057915:Drug Substitution; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D009363:Neoplasm Proteins; D016609:Neoplasms, Second Primary; D010766:Phosphorylation; D011183:Postoperative Complications; D011241:Prednisone; D011499:Protein Processing, Post-Translational; D012514:Sarcoma, Kaposi; D015398:Signal Transduction; D020123:Sirolimus; D012878:Skin Neoplasms; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "1240-4",
"pmc": null,
"pmid": "25939687",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A case of esophageal adenocarcinoma on long-term rapamycin monotherapy.",
"title_normalized": "a case of esophageal adenocarcinoma on long term rapamycin monotherapy"
} | [
{
"companynumb": "ES-WATSON-2016-15144",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
"d... |
{
"abstract": "To describe a new association between nonsenile nuclear cataracts and pigmentary glaucoma in patients with controlled intraocular pressure (IOP).\n\n\n\nRetrospective consecutive case series of nonsenile nuclear cataracts seen in patients with pigmentary glaucoma with controlled IOP in a single glaucoma specialist practice. Eight eyes of 7 patients with pigmentary glaucoma and visually significant cataract who underwent cataract removal were reviewed.\n\n\n\nPatients with pigmentary glaucoma developed rapidly progressing, nonsenile nuclear cataracts, with resulting myopic shifts between 4 and 13 D from baseline in <2 years. The patients had controlled IOP and there were no associations between medication use and cataract development.\n\n\n\nA new association between pigmentary glaucoma and nonsenile nuclear cataracts is described. In these patients, the IOP remains controlled and no association is seen between the cataract and medication use. The cataract is rapidly progressive and can cause a myopic shift between 4 and 13 D. Awareness of the purely nuclear cataract and its' clinical presentation can assist the clinician when approaching the patient with pigment dispersion and decreasing vision. To the best of our knowledge, this is a new association and warrants further investigation.",
"affiliations": "*Gavin Herbert Eye Institute †School of Medicine, University of California, Irvine, Irvine, CA.",
"authors": "Mosaed|Sameh|S|;Haider|Asghar|A|;Kim|Deborah|D|;Zhang|Zina|Z|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0000000000000238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "25(7)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000328:Adult; D002386:Cataract; D002387:Cataract Extraction; D017889:Exfoliation Syndrome; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014065:Tonometry, Ocular; D014792:Visual Acuity",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "547-50",
"pmc": null,
"pmid": "25719238",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Association of Pigmentary Glaucoma and Nonsenile Nuclear Cataracts.",
"title_normalized": "association of pigmentary glaucoma and nonsenile nuclear cataracts"
} | [
{
"companynumb": "ALCN2016US005661",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TIMOLOL"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "Accurate and expeditious diagnosis and treatment of pulmonary embolism in cancer patients improves patient outcomes. D-dimer is often used to rule out pulmonary embolism. However, this test is less accurate in cancer patients, and it is unclear whether cancer patients with normal D-dimer levels can present with pulmonary embolism. All consecutive patients who presented to The University of Texas MD Anderson Cancer Center in Houston, Texas, USA, between May 2009 and November 2015 who underwent computed tomography pulmonary angiography and plasma D-dimer level measurement were retrospectively reviewed. Patients with suspected pulmonary embolism and normal D-dimer levels were identified. Among the 8023 cancer patients identified, 1156 (14%) had pulmonary embolism. Only 35 patients with pulmonary embolism (3%) had normal plasma D-dimer levels. Twenty-six of these patients had acute pulmonary embolism and the other nine had subacute or chronic pulmonary embolism. Thirteen of the 26 acute cases were in patients with hematological cancer. Most patients (23/35, 66%) had subsegmental or segmental pulmonary embolism. Only one patient had pulmonary embolism in the main pulmonary arteries. Although it is uncommon (3%), cancer patients with radiologic evidence of pulmonary embolism can present with normal D-dimer levels. Recognizing the possibility of this uncommon occurrence is critical in the decision process for ordering diagnostic tests for evaluation of suspected pulmonary embolism.",
"affiliations": "Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. syeung@mdanderson.org.",
"authors": "Qdaisat|Aiham|A|;Wu|Carol C|CC|;Yeung|Sai-Ching Jim|SJ|",
"chemical_list": "D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-019-01863-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "48(1)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Cancer; D-dimer; Normal; Pulmonary embolism; Thrombosis; Venous thromboembolism",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000072226:Computed Tomography Angiography; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011655:Pulmonary Embolism; D011871:Radiology; D012189:Retrospective Studies",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "174-179",
"pmc": null,
"pmid": "31041652",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "10498557;11522543;11943938;12034410;12814981;16461960;16601844;17319909;17918266;18419743;19008457;24758676;25018062;26414967;30630988;9867786",
"title": "Normal D-dimer levels in cancer patients with radiologic evidence of pulmonary embolism.",
"title_normalized": "normal d dimer levels in cancer patients with radiologic evidence of pulmonary embolism"
} | [
{
"companynumb": "US-CELGENEUS-USA-20190609827",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "POMALIDOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "We report the case of a 39-year-old patient who presented an episode of upper gastrointestinal bleeding due to hemobilia. The imaging tests showed the gallbladder occupied by solid tissue, with a diagnosis of intracholecystic papillary neoplasm after the cholecystectomy. The intracholecystic papillary neoplasm of the gallbladder is a newly established entity and it is considered a subtype of intraductal papillary neoplasm of the bile duct. Its presentation in the form of hemobilia has barely been described in the literature.",
"affiliations": "Digestivo, Hospital Universitario Son Espases, España.;Digestivo, Hospital Universitario Son Espases.;Digestivo, Hospital Universitario Son Espases.;Anatomía Patológica, Hospital Universitario Son Espases.;Digestivo, Hospital Universitario Son Espases, España.",
"authors": "Páez Cumpa|Claudia|C|;Erimeiku Barahona|Alicia|A|;Payeras Capó|Mª Antonia|MA|;Amengual Antich|Isabel|I|;Garrido Durán|Carmen|C|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.17235/reed.2016.4205/2016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-0108",
"issue": "109(1)",
"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": "D000231:Adenocarcinoma, Papillary; D000328:Adult; D001650:Bile Duct Neoplasms; D002763:Cholecystectomy; D004384:Duodenoscopy; D006431:Hemobilia; D006801:Humans; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9007566",
"other_id": null,
"pages": "70-73",
"pmc": null,
"pmid": "28099033",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemobilia due to intracholecystic papillary neoplasm.",
"title_normalized": "hemobilia due to intracholecystic papillary neoplasm"
} | [
{
"companynumb": "ES-UCBSA-2017028950",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOSARTAN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Patients taking tacrolimus have an increased predisposition to hyperuricemia. Although literature has widely established the risk of gout in patients taking cyclosporine, the widespread use of tacrolimus in patients following liver transplantation necessitates further investigation into the potential connection between the drug's use and gout. Moreover, hyperuricemia in the context of liver transplants is associated with increased morbidities and mortalities. We describe a case of gout in a liver transplant patient taking the calcineurin inhibitor tacrolimus.",
"affiliations": "Internal Medicine, Florida Hospital, Orlando, USA.;Internal Medicine, University of Central Florida, Orlando, USA.;Internal Medicine, Presence Saint Francis Hospital, Evanston, USA.;Internal Medicine, Florida Hospital, Orlando, USA.",
"authors": "Afridi|Summia Matin|SM|;Reddy|Srikar|S|;Raja|Ahmad|A|;Jain|Akriti G|AG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.4247",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4247Internal MedicineRheumatologyTransplantationGout Due to Tacrolimus in a Liver Transplant Recipient Muacevic Alexander Adler John R Afridi Summia Matin 1Reddy Srikar 2Raja Ahmad 3Jain Akriti G 1\n1 \nInternal Medicine, Florida Hospital, Orlando, USA \n2 \nInternal Medicine, University of Central Florida, Orlando, USA \n3 \nInternal Medicine, Presence Saint Francis Hospital, Evanston, USA \nSummia Matin Afridi summiamatin@gmail.com13 3 2019 3 2019 11 3 e42477 3 2019 13 3 2019 Copyright © 2019, Afridi et al.2019Afridi et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/18091-gout-due-to-tacrolimus-in-a-liver-transplant-recipientPatients taking tacrolimus have an increased predisposition to hyperuricemia. Although literature has widely established the risk of gout in patients taking cyclosporine, the widespread use of tacrolimus in patients following liver transplantation necessitates further investigation into the potential connection between the drug’s use and gout. Moreover, hyperuricemia in the context of liver transplants is associated with increased morbidities and mortalities. We describe a case of gout in a liver transplant patient taking the calcineurin inhibitor tacrolimus.\n\ngouthyperuricemialiver transplanttacrolimusrheumatologyThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nGout typically manifests earlier in life in men than women and is rare in childhood. Non-modifiable risk factors for gout include age, gender and ethnicity; modifiable risk factors include obesity, diabetes mellitus, chronic kidney disease, and hypertension [1]. Within renal transplant patients, the relationship between gout and cyclosporine is well established [2]. Following renal transplants, there is belief that uric acid secretion can decrease; cyclosporine exacerbates these uric acid levels due to the side effects of hyperuricemia and reduced glomerular filtration rate (GFR). We present a case of newly diagnosed gout in a liver transplant patient taking tacrolimus.\n\nCase presentation\nA 60-year-old gentleman with past medical history of liver transplant five years ago presented to the hospital with acute onset of right-sided knee pain. For his immunosuppressive regimen, he took 2 mg/day of tacrolimus. His complete medication history was reviewed and no significant drug-drug interactions were found. His social history was negative for excessive alcohol use and high-protein diet. His physical examination was significant for right knee warmth, swelling, and erythema with tenderness upon palpation.\n\nLabs indicated normal white blood cell count, normal creatinine at 0.81 mg/dl, tacrolimus at 9.3 ng/ml, uric acid at 6.1 mg/dl, and elevated C-reactive protein at 18.1 mg/L. Synovial fluid analysis showed 27,000 nucleated cells with differential of >90% neutrophils and 1+ monosodium urate crystals (Table 1). Fluid cultures were negative and ruled out septic arthritis. This patient was diagnosed with acute gouty arthritis, and the patient was administered colchicine for three days. His tacrolimus dosage was decreased from 2 mg/day to 1 mg/day. With treatment, the patient’s symptoms resolved, and he was continued on the adjusted dose of tacrolimus with outpatient follow-up.\n\nTable 1 Synovial Fluid Analysis.\nRBC: Red Blood Cell\n\nCharacteristics\tFindings\t\nColor\tYellow\t\nFl Nucleated Cells\t27,000\t\nFl RBCs\t333\t\nNeutrophils\t93\t\nLymphocytes\t0\t\nMonocytes\t7\t\nMicroscopy\tIntra-cellular Monosodium Urate Crystals 1+\t\npH\t7.8\t\nGlucose\t122\t\nDiscussion\nFor tacrolimus, the effect on uric acid levels is not as well established compared to cyclosporine’s effect [3]. Hyperuricemia has been reported in patients taking tacrolimus, but there have been only a few reported cases of gout [4, 5]. The reason for the discrepancy between cyclosporine-induced and tacrolimus-induced gout may be that cyclosporine can promote increased uric acid reabsorption in the proximal tubules and decreased GFR following afferent arteriole vasoconstriction, whereas tacrolimus is only known to reduce the excretion of uric acid [6]. Even though this particular patient possessed risk factors for gout such as male gender, his acute gouty attack may have been precipitated by the use of tacrolimus for his immunosuppressive regimen following his liver transplant. Hyperuricemia can be seen in 14-47% of liver transplant patients, predominantly due to accompanying decreased renal function [7].\n\nIn liver transplant patients, tacrolimus has emerged as the go-to maintenance regimen over cyclosporine due to data indicating increased patient and graft survival and decreased acute rejection [8]. Therapeutic levels of tacrolimus remain controversial. They need to be individually catered to patients and their specific comorbidities and functional status. Current guidelines indicate the following: in the first four to six weeks following a liver transplant, the trough levels of 10-15 ng/ml are recommended and 5-10 ng/ml thereafter to maintain a balance between nephrotoxicity and acute rejection [9]. In the context of our patient (tacrolimus level at 9.3 ng/ml), his tacrolimus levels were on the upper range of target trough levels and may have been significant enough to cause tubular dysfunction. Since tacrolimus undergoes liver metabolism, the elevated tacrolimus levels in a patient with liver transplant combined with noncompliance with outpatient follow-up may have contributed to hyperuricemia and the development of gout.\n\nConclusions\nEvery clinician should be aware of potential side effects of calcineurin inhibitors such as cyclosporine and tacrolimus. Their effects should be monitored during initial hospitalization, and expert opinion should be sought for dose adjustments. Also, the patients should be advised about the importance of regular outpatient follow-up to monitor drug levels and avoid the potential of drug-induced toxicities.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008 Arthritis Rheum Zhu Y Pandya BJ Choi HK 3136 3141 63 2011 21800283 \n2 Cyclosporine-induced hyperuricemia and gout N Engl J Med Lin HY Rocher LL McQuillan MA Schmaltz S Palella TD Fox IH 287 292 321 1989 2664517 \n3 Influence of cyclosporine and tacrolimus on serum uric acid levels in stable kidney transplant recipients Transplant Proc Kanbay M Akcay A Huddam B Usluogullari CA Arat Z Ozdemir FN Haberal M 3119 3120 37 2005 16213325 \n4 Hyperuricemia, gout, and renal function after liver transplantation Transplantation Neal DA Tom BD Gimson AE Gibbs P Alexander GJ 1689 1691 72 2001 https://insights.ovid.com/pubmed?pmid=11726834 11726834 \n5 Gastrointestinal and metabolic problems associated with immunosuppression with either CyA or FK 506 in liver transplantation Transplant Proc Van Thiel DH Iqbal M Jain A Fung J Todo S Starzl TE 37 40 22 1990 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903855/ 1689893 \n6 Drug-induced hyperuricaemia and gout Rheumatology Ben Salem C Slim R Fathallah N Hmouda H 679 688 56 2017 27498351 \n7 Hyperuricemia after orthotopic liver transplantation: divergent associations with progression of renal disease, incident end-stage renal disease, and mortality BMC Nephrol Longenecker J Waheed S Bandak G Murakami CA McMahon BA Gelber AC Atta MG 103 110 18 2017 28347282 \n8 Cyclosporin versus tacrolimus for liver transplanted patients Cochrane Database Syst Rev Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS Gluud LL 5161 4 2006 \n9 Review on immunosuppression in liver transplantation World J Hepatol Moini M Schilsky ML Tichy EM 1355 1368 7 2015 26052381\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(3)",
"journal": "Cureus",
"keywords": "gout; hyperuricemia; liver transplant; rheumatology; tacrolimus",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e4247",
"pmc": null,
"pmid": "31131170",
"pubdate": "2019-03-13",
"publication_types": "D002363:Case Reports",
"references": "11726834;16213325;1689893;17054241;21800283;26052381;2664517;27498351;28347282",
"title": "Gout Due to Tacrolimus in a Liver Transplant Recipient.",
"title_normalized": "gout due to tacrolimus in a liver transplant recipient"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2019SP009914",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "Hepatocellular carcinoma (HCC) in proximity to major hepatic vasculature poses a risk for invasion, which would contraindicate liver transplantation, yet, is difficult to treat with thermal ablation. This study was undertaken to evaluate the feasibility of irreversible electroporation (IRE) as a bridge to transplantation for high-risk tumors. All patients with HCC in proximity to major hepatic vasculature treated with laparoscopic IRE as bridge to transplantation were studied. Patient and tumor characteristics, length of stay, and treatment-related complications were recorded. Tumor response was assessed with CT and explant pathology. Five patients with a median Model for End Stage Liver Disease (MELD) of 13 (7-21) underwent IRE. The median tumor size was 2.7 cm (1.5-3.7 cm). Adjacent structures included the right portal vein, hepatic veins/inferior vena cava (IVC) and left portal vein. Length of stay was one day for all patients. One patient suffered portal vein thrombosis. The transplant occurred at a median of 142 days (47-264) after IRE. Pathologic necrosis ranged from 30 to 100 per cent, without any vascular invasion. Four patients remain alive with no evidence of disease with median follow-up of 403 (227-623) days. The remaining patients died because of transplant-related complications on post IRE day 297. IRE shows promise as a bridge to liver transplant for high risk HCC in a preliminary series, justifying further prospective evaluation.",
"affiliations": null,
"authors": "Cannon|Robert M|RM|;Bolus|David N|DN|;White|Jared A|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-1348",
"issue": "85(1)",
"journal": "The American surgeon",
"keywords": null,
"medline_ta": "Am Surg",
"mesh_terms": "D000368:Aged; D006528:Carcinoma, Hepatocellular; D018274:Electroporation; D005240:Feasibility Studies; D006801:Humans; D007902:Length of Stay; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0370522",
"other_id": null,
"pages": "103-110",
"pmc": null,
"pmid": "30760354",
"pubdate": "2019-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Irreversible Electroporation as a Bridge to Liver Transplantation.",
"title_normalized": "irreversible electroporation as a bridge to liver transplantation"
} | [
{
"companynumb": "US-009507513-2009USA005396",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
"drugadditional":... |
{
"abstract": "The hypervirulent K1 serotype Klebsiella pneumoniae is responsible for a new invasive syndrome, typically associated to hepatic abscesses with extra-hepatic complications. Initially described in Taiwan, it has significantly spread to several Asian countries and more recently to Europe and North America, thus constituting an emerging and global problem. The authors describe a case report of a 64-years-old portuguese caucasian woman without any previous diseases or epidemiological risk factors such as trips or contact with Asian products or population, diagnosed with a pyogenic liver abscess with pleural effusion caused by this hyper-virulent strain. A successful clinical cure was achieved after the etiological identification and treatment with antimicrobial therapy combined with catheter drainage. This is the first identification of hypervirulent Klebsiella pneumonia ST 23 clone in Portugal in the context of an invasive syndrome.",
"affiliations": "Serviço de Doenças Infecciosas. Hospital de Santa Maria. Centro Hospitalar de Lisboa Norte. Lisboa. Portugal.;Serviço de Medicina I. Hospital de Santa Maria. Centro Hospitalar de Lisboa Norte. Lisboa. Portugal.;Unidade Laboratorial Integrada. Departamento de Doenças Infecciosas. Instituto Nacional de Saúde Doutor Ricardo Jorge. Lisboa. Portugal.",
"authors": "Pereira|Aida|A|;Petrucci|Tiago|T|;Simões|Maria João|MJ|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.7705",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": "30(6)",
"journal": "Acta medica portuguesa",
"keywords": "Klebsiella Infections; Klebsiella pneumonia; Liver Abscess; Portugal",
"medline_ta": "Acta Med Port",
"mesh_terms": "D005260:Female; D006801:Humans; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D046290:Liver Abscess, Pyogenic; D008875:Middle Aged; D011174:Portugal",
"nlm_unique_id": "7906803",
"other_id": null,
"pages": "496-499",
"pmc": null,
"pmid": "28898618",
"pubdate": "2017-06-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Klebsiella pneumoniae from K1 and Hypervirulent Clone ST23: First Documented Case in Portugal.",
"title_normalized": "klebsiella pneumoniae from k1 and hypervirulent clone st23 first documented case in portugal"
} | [
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"abstract": "BACKGROUND\nSynchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously.\n\n\nMETHODS\nWe report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free.\n\n\nCONCLUSIONS\nAn early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.",
"affiliations": "Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan. norinori@med.kanazawa-u.ac.jp.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.;Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa, 920-8641, Japan.",
"authors": "Araki|Yoshihiro|Y|https://orcid.org/0000-0001-5783-109X;Hayashi|Katsuhiro|K|https://orcid.org/0000-0001-8665-2154;Yamamoto|Norio|N|http://orcid.org/0000-0002-7250-625X;Takeuchi|Akihiko|A|https://orcid.org/0000-0002-4071-5620;Miwa|Shinji|S|https://orcid.org/0000-0002-5962-8287;Igarashi|Kentaro|K|https://orcid.org/0000-0003-2278-1736;Higuchi|Takashi|T|https://orcid.org/0000-0002-7489-1657;Abe|Kensaku|K|https://orcid.org/0000-0002-7405-9019;Taniguchi|Yuta|Y|https://orcid.org/0000-0002-4322-6566;Yonezawa|Hirotaka|H|https://orcid.org/0000-0003-0713-0396;Morinaga|Sei|S|https://orcid.org/0000-0003-2961-9432;Asano|Yohei|Y|https://orcid.org/0000-0002-8777-6076;Nojima|Takayuki|T|https://orcid.org/0000-0003-1236-4162;Tsuchiya|Hiroyuki|H|https://orcid.org/0000-0003-0730-7921",
"chemical_list": "D000077330:Saline Solution; D004317:Doxorubicin; D007455:Iodine; D009584:Nitrogen; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1186/s12893-020-01018-w",
"fulltext": "\n==== Front\nBMC Surg\nBMC Surg\nBMC Surgery\n1471-2482 BioMed Central London \n\n1018\n10.1186/s12893-020-01018-w\nCase Report\nReconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature\nhttps://orcid.org/0000-0001-5783-109XAraki Yoshihiro y.araki428@gmail.com 1 https://orcid.org/0000-0001-8665-2154Hayashi Katsuhiro khayashi830@gmail.com 1 http://orcid.org/0000-0002-7250-625XYamamoto Norio norinori@med.kanazawa-u.ac.jp 1 https://orcid.org/0000-0002-4071-5620Takeuchi Akihiko a_take@med.kanazawa-u.ac.jp 1 https://orcid.org/0000-0002-5962-8287Miwa Shinji miwapoti@yahoo.co.jp 1 https://orcid.org/0000-0003-2278-1736Igarashi Kentaro kenken99004@yahoo.co.jp 1 https://orcid.org/0000-0002-7489-1657Higuchi Takashi guchi@384.jp 1 https://orcid.org/0000-0002-7405-9019Abe Kensaku abeken.1005@gmail.com 1 https://orcid.org/0000-0002-4322-6566Taniguchi Yuta yutataniguchi0925@yahoo.co.jp 1 https://orcid.org/0000-0003-0713-0396Yonezawa Hirotaka hirotakayonezawa3@gmail.com 1 https://orcid.org/0000-0003-2961-9432Morinaga Sei reddchicke@yahoo.co.jp 1 https://orcid.org/0000-0002-8777-6076Asano Yohei you.you.mounin@gmail.com 1 https://orcid.org/0000-0003-1236-4162Nojima Takayuki nojima@kanazawa-med.ac.jp 12 https://orcid.org/0000-0003-0730-7921Tsuchiya Hiroyuki tsuchi@med.kanazawa-u.ac.jp 1 1 grid.9707.90000 0001 2308 3329Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan \n2 grid.9707.90000 0001 2308 3329Department of Pathology, Kanazawa University, Kanazawa, Japan \n22 1 2021 \n22 1 2021 \n2021 \n21 5619 8 2020 15 12 2020 © The Author(s) 2021Open 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\nSynchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously.\n\nCase presentation\nWe report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free.\n\nConclusions\nAn early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.\n\nKeywords\nSynchronous multicentric osteosarcomaSkull lesionBone scanChemotherapyTotal necrosisFrozen autograftBackgroundissue-copyright-statement© The Author(s) 2021\n==== Body\nSynchronous multicentric osteosarcoma (SMOS) is characterized by simultaneous multicentricity of intraosseous lesion without visceral involvement, such as lung metastasis [1]. SMOS is a rare disease that accounts for approximately 1% of osteosarcomas, and had been reported to have a poor survival because of the difficulty of treating all lesions [2–7]. Domenico et al. reported that the 2-year overall survival of SMOS was approximately 30%, and the 5-year overall survival was < 10% [2]. There have been a few reports regarding the long-term survival of SMOS patients [2, 5, 6, 8]. No standard treatment algorithm has been previously reported because of its rarity, and most cases were treated according to the general guidelines for the management of osteosarcoma.\n\nOsteosarcoma at the skull region is also rare, and acounting for only 6 to 8% of osteosarcomas [3, 9]. The mortality was reported to be about 50% at 5 years [9, 10]. The poor outcome was reported to be due to the difficulty of surgical treatment with a wide excision due to the complicated anatomy of the skull [10–12]. In most cases, synthetics or no reconstruction was selected after the excision of skull lesion. However, complications such as failure of synthetics, or infection, and local relapse of skull osteosarcoma often leads to severe functional disorders due to brain damage, such as extremity paralysis and meningitis, although metastases to the lung and brain are less frequent than extremity osteosarcoma [7, 13, 14].\n\nChemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS also had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically [5, 7, 8]. Aggressive surgery with a clear margin for all lesions of SMOS is also essential for a good oncological outcome [5, 7, 8].Thus, planning of an appropriate strategy for the treatment of SMOS, which combines chemotherapy and surgery, is essential for obtaining a good clinical outcome (Fig. 1).Fig. 1 Our treatment strategy for synchronous multicentric osteosarcoma (SMOS)\n\n\n\nWe herein report an 18-year-old girl with multicentric synchronous osteosarcoma, including a skull lesion, and describe the clinical findings and treatment outcome for chemotherapy, two-stage tumor excision for all lesions. Our study was approved by the ethics committee of Kanazawa University Hospital (Institutional Review Board (IRB) number 2019–61(3094)) in compliance with the guidelines of the 1975 Declaration of Helsinki. Written informed consent was provided by the patient to obtain her case details and any accompanying images published.\n\nCase presentation\nAn 18-year-old woman was referred to our department with a major complaint of a pain and swelling around the left distal femur. The symptom had been increasing for the past 6 months. She consulted a local doctor because her symptoms had not improved over time. Neither trauma nor injury was reported. Her previous history was also unremarkable, and no family history was found. A physical examination revealed swelling around her left distal femur and tenderness upon palpation. Neither ballottement of the left knee joint nor an evident soft tissue mass were observed. Laboratory tests revealed a threefold higher alkali-phosphatase level than the upper limit, but no other abnormal data, including the lactate dehydrogenase level and inflammation reaction, was found. A bone sclerotic lesion with periosteal reaction on the distal femur was found on X-ray (Fig. 2a, b). Computed tomogram (CT) of the left distal femur revealed a sclerotic and lytic lesion causing partial cortical destruction with soft tissue extension to the medial part of the surrounding muscles. No distant metastasis, including to the lung and regional lymph nodes, were observed on chest or abdominal CT. Magnetic resonance imaging (MRI) showed an intraosseous lesion combined with an unclear circumscribed extraosseous mass, which was hypointense on T1-weighted (Fig. 2c) and hyperintense on T2-weighted images. Unevenly contrasted lesion was observed on enhanced MRI (Fig. 2d). An open biopsy for the left distal femoral lesion was performed. Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed (Fig. 2e). A systemic Technetium-99 m scintigraphy (bone scan) (Fig. 3a) revealed other bone lesions of the left occipital bone (Fig. 3b) and right proximal humerus (Fig. 3c), in addition to the left distal femoral lesion (Fig. 3d), although no evident physical findings on either the right proximal humerus or left occipital bone were observed. However, a relatively strong uptake was observed at all three lesions. Thallium scintigram also revealed the strong accumulation of tracers only on the three bone lesions. A close examination by MRI revealed the enhancement of right proximal humeral bone lesion and left occipital bone lesion (Fig. 3e, f), the same as the left distal femoral lesion (Fig. 3g). Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of synchronous multicentric osteosarcoma (SMOS) was made. There is much debate in the previous studies as to whether it represents multiple primary tumors or metastatic disease. However, the case for multiple primary tumors was favored, because there was no obvious route for spread if the lungs were tumor-free, which was thought to rule out hematogenous metastasis. The prognosis of SMOS is generally considered to be poor according to the findings of previous studies [2–7].Fig. 2 Radiological and pathological findings of a bone lesion at the left distal femur. a, b Preoperative roentgenogram on the anteroposterior view (a), and the lateral view (b). c Intraosseous lesion combined with extraosseous lesion on MRI was observed, which was hypointense signal on T1 weighted images, and hyperintense signal on T2 weighted images. d Enhanced MRI revealed unevenly contrasted lesion on axial images. e Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed. White scale bar shows 100 µm\n\nFig. 3 Systemic bone scan and MRI findings before neoadjuvant chemotherapy. a–c Bone scan revealed uptake for the following three location (a); left occipital bone (b), right proximal humerus (c), and left distal femur (d). e The left occipital lesion on axial enhanced MRI, and a white arrow shows the intracortical lesion. f The right proximal humeral lesion on coronal enhanced MRI. g The left distal femoral lesion on coronal enhanced MRI\n\n\n\nShe underwent five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, which was the same as the standard regimen for the treatment of osteosarcoma. The dose of doxorubicin was 60 mg/m2, and that of cisplatin was 120 mg/m2. The chemotherapy was performed every three weeks. After the completion of neoadjuvant chemotherapy, the uptake of all lesions on the bone scan diminished (Fig. 4a–d), and the enhancement of all lesions on MRI decreased (Fig. 4e–g). The accumulation of tracers on thallium scintigram also decreased. The chemotherapy was observed to be highly effective based on the radiological findings. The alkali-phosphatase level dramatically decreased and become normal in laboratory tests.Fig. 4 Systemic bone scan and MRI findings after five courses of neoadjuvant chemotherapy. a The uptake of all lesions on the bone scan was diminished. b Occipital bone lesion. c Right proximal humeral lesion. d Left distal femoral lesion. e The left occipital lesion had slightly shrunk in size on axial enhanced MRI (a white arrow shows the intracortical lesion.). f The enhancement was drastically decreased on coronal MRI of the right proximal humeral lesion. g The size and enhancement was decreased on coronal MRI of the distal femur\n\n\n\nSurgical treatment of wide excision for the primary lesion of the left distal femur and reconstruction with megaprosthesis was planned at 4 months after the diagnosis. The distal femoral lesion was widely excised with extraosseous lesion and biopsy tract, preserving popliteal artery, veins and sciatic nerve (Fig. 5a). The bone was cut at 3 cm proximal from the edge of the bone lesion. A portion of the vastus medialis and intermedius were excised along with the tumor. The iodine-coated tumor prosthesis [15–17] was used for reconstruction (Fig. 5b, c). The pathological findings for the excised specimen revealed total necrosis of the lesion (Fig. 5d), and free surgical margins for both the bone and soft tissue lesions of the left distal femur.Fig. 5 Intraoperative photos, the postoperative roentgenogram, and the histological findings of the retracted specimen. a Wide excision of the left distal femoral lesion was performed. b Reconstruction using iodine-coated tumor prosthesis was performed. c Postoperative roentgenogram. d. Histological findings revealed the total necrosis of tumor cells of the retracted specimen tissue of the distal femur. White scale bar shows 100 µm\n\n\n\nSince physical recovery from the primary surgery and wound healing were observed, adjuvant chemotherapy was resumed at seventeen days postoperatively for the residual lesions of the humerus and occipital bone. The regimen for an adjuvant chemotherapy was the same as a neoadjuvant chemotherapy. A mildly decreased cardiac function was observed on echocardiogram after the completion of the first course of adjuvant chemotherapy, and chemotherapy with another regimen of high-dose methotrexate (10 g/m2) and vincristine (2 mg/body) was performed for the second course of adjuvant chemotherapy. The improvement of cardiac function was confirmed, and the doxorubicin (60 mg/m2) and cisplatin (96 mg/m2, 80% dose of standard regimen) were given again for the third course of adjuvant chemotherapy. A total of eight courses of chemotherapy were completed, including three courses of adjuvant chemotherapy. The total dose of doxorubicin and cisplatin was 420 mg/m2 and 816 mg/m2, respectively. The humeral lesion had almost completely disappeared radiologically, and the occipital lesion was only slightly visible on images. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests.\n\nTumor excision of both the humeral lesion and the occipital lesion, and reconstruction using a frozen autograft, rather than a tumor prosthesis or synthetics, was planned at 6 months after the diagnosis, because a histological analysis demonstrated that chemotherapy showed good efficacy in the treatment of the primary lesion. For the humeral lesion, the tumor location was identified using a fluoroscopy, based on preoperative MRI findings. For the skull lesion, the tumor location was identified with the assistance of a navigation system. At first, tumor excision for the occipital lesion was performed with a margin of at least 2 cm (Fig. 6a), and the excised bone was treated with liquid nitrogen for 20 min (Fig. 6b). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 6c). The autograft was returned to the original position with plate fixation (Fig. 6d). Then, hemicortical excision for the right proximal humeral lesion was performed with a margin of at least 2 cm, preserving axillary nerve, and then the excised bone was treated with liquid nitrogen for 20 min (Fig. 7a). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 7b). The autograft was returned to the original position with screw fixation (Fig. 7c, d).Fig. 6 Surgical treatment for a skull lesion and the postoperative roentgenogram. a Skull lesion was excised with wide margin. b, c The excised bone was treated with liquid nitrogen for twenty minutes (b), and dissolved at room temperature for 15 min, and then was washed with 0.3% iodine saline and distilled water (c). d The frozen bone was returned to the original position and plate fixation was performed. Postoperative roentgenogram was shown\n\nFig. 7 Surgical treatment for a proximal humeral lesion and the postoperative roentgenogram. a, b The retracted hemicortical bone of the proximal humeral lesion was treated with liquid nitrogen (a) and was dissolved at room temperature, and washed by 0.3% iodine saline and distilled water (b). c The frozen autograft was returned to the original position with screw fixation, preserving axillary nerve. d Postoperative roentgenogram was shown\n\n\n\nFurther chemotherapy was not administered after the second surgery because the adverse events due to chemotherapy, such as a myelosuppression and a mildly-decreased cardiac function, were observed. She was discharged from the hospital after the recovery from the surgery was confirmed. She was prudently observed under active surveillance, and underwent close follow-up examinations in an outpatient clinic every 3 or 4 months after discharge.\n\nAt 68 months’ follow-up after the detection of SMOS, a disease-free condition with neither local recurrence nor metastasis was obtained, and bone union for the humerus and skull lesion had also been achieved on images (Fig. 8a–c). The patient’s cardiac function was normal on an echocardiogram, and no other adverse events was observed at the last follow-up. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests. An excellent function for both the upper extremity (30/30 points) and lower extremity (30/30 points) according to the International Society of Limb Salvage (ISOLS) score had been acquired. No neurological deficit was observed.Fig. 8 The postoperative roentgenogram at the latest follow-up. a Bone union at the osteotomy site for proximal humeral lesion, was completely achieved. b Bone union at the osteotomy site for skull lesion, was achieved. c Postoperative complications were not observed after tumor prosthesis reconstruction of the left distal femur\n\n\n\nDiscussion and conclusions\nMulticentric osteosarcoma accounts for only approximately 1% of all osteosarcomas, and is divided into two types: synchronous and metachronous type [2, 3]. Domenico et al. reported that the median survival in patients with metachronous multicentric osteosarcoma (n = 34) was 43 months, while the median survival in those with SMOS (n = 22) was 14 months [2]. A particular poor prognosis was reported for SMOS patients, and there have been few previous report concerning long-term survivors of SMOS [2, 5, 6, 8]. To our knowledge, the survival of SMOS, including cases with skull lesions, tends to be extremely short (4–18 months) [7, 13, 14]. There were three main reasons for the successful outcome of the present case. First, the early correct identification of tumors at all locations could be made using a bone scan. Second, multiple chemotherapeutic agents, including doxorubicin and cisplatin, would contribute to the good response of the tumors, as histological examinations revealed complete necrosis in the excised specimen of the distal femur in our case. Third, surgical treatment for the other lesions could be performed with the reference to the results of neoadjuvant chemotherapy, which showed histological efficacy.\n\nOur treatment strategy for SMOS is basically the same as that for osteosarcoma (Fig. 1). To identify precisely all of the locations of SMOS lesions before treatment is important for observing the treatment course. The good efficacy of chemotherapy is essential for obtaining good outcome. After the completion of neoadjuvant chemotherapy, a radiological assessment is performed to determine the efficacy of chemotherapy. If the course is assumed to have poor efficacy based on radiological assessment, the chemotherapy regimen should be changed. When good efficacy is radiologically confirmed after five or six courses of neoadjuvant chemotherapy, subsequent surgical excision of the primary lesion, with a wide margin, is planned and performed. Then, based on the pathological assessment of the efficacy of neoadjuvant chemotherapy in the excised specimen, an adjuvant chemotherapy regimen is selected. If the neoadjuvant chemotherapy shows good histological efficacy, three or four courses of adjuvant chemotherapy with the same regimen are performed, and an appropriate surgical treatment for the residual lesions is planned, including biological reconstruction, which can retain a normal function and achieve a good cosmetic outcome. If the histological efficacy of neoadjuvant chemotherapy is poor, the regimen should be changed for adjuvant chemotherapy, and surgical treatment with as wide an excision as possible and reconstruction using tumor prosthesis or synthetics, should be planned after several courses of chemotherapy.\n\nWhen the surgical margins for all lesions are histologically clear, the primary treatment is considered to be over, or additional adjuvant chemotherapy may be considered if the patients can afford to undergo these treatments, with careful observation for adverse events. After completion of the primary treatment, the postoperative state will be prudently observed at follow-up in an outpatient clinic, with examinations every three or four months until at least five years at least after surgery.\n\nOsteosarcoma commonly presents with lung metastases, and a standard examination includes chest CT. Additional examinations are not regularly performed except for when a patient presents symptoms, such as pain or swelling. Patients with skull osteosarcoma often present with headache, motor impairment, or cranial nerve palsies, depending on the tumor site [9–12]. However, in our case, no symptoms at the left occipital region or the right proximal humerus were observed, and it was not until a bone scan was performed that multicentric bone lesions were noted. A bone scan can assess the accumulation of tracers, thereby reflecting remodeling of the affected bone, and a systemic bone scan is useful as a regular examination for the early detection of other bone lesions [18], even if no symptoms are observed. Metachronous type multicentric osteosarcoma, or bone metastases of SMOS during the treatment course, might be due to tiny lesions with symptoms mild enough to be overlooked at the first visit. Therefore, the early correct identification of tumors at all locations is important when considering the strategy for SMOS.\n\nChemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically due to the efficacy of chemotherapy, which was assessed according to the Rosen and Huvos classification [5, 7, 8]. One patient received chemotherapy with a regimen of doxorubicin, cisplatin, ifosfamide, and methotrexate, and another received chemotherapy with a regimen of doxorubicin, cisplatin, and methotrexate [5, 7], while yet another patient received chemotherapy with a regimen of methotrexate, ifosfamide, bleomycin, doxorubicin, and cisplatin [8]. The present patient received chemotherapy with a regimen of doxorubicin, cisplatin, methotrexate, and etoposide. The two drugs, namely doxorubicin and cisplatin, have been commonly used for long survivors in previous SMOS patients including our case. Multiple chemotherapeutic agents including the above-mentioned two drugs might contribute to the good outcome observed in SMOS patients, although no definitive conclusions could be made due to the small sample population.\n\nThe histological confirmation of the efficacy of neoadjuvant chemotherapy in the whole section of the distal femoral lesion, especially the bone lesion, was necessary for determining whether the same regimen chemotherapy for the other two lesions should be continued or not. When a frozen autograft is used for reconstruction after wide excision, the efficacy of chemotherapy on excised soft tissue lesion can be evaluated histologically; however, the efficacy is not evaluated in bone lesion. Frozen autograft is available for almost all bone tumors and has been reported to be associated with many advantages, including preservation of the bone stock, retention of the joint function in cases in which the epiphysis is preserved, and the fact that the graft can be a perfect fit for the excised bone defect. However, the indications need to be well considered in each case. In cases involving multiple bone lesions, such as the present case, the selection of an appropriate treatment strategy is essential, and we referred to the results of a histological assessment of the effects of neoadjuvant chemotherapy on the primary bone lesion when considering treatment for residual lesions. In addition, the epiphysis could not be preserved in the present case because the lesion extended to the epiphysis. Thus, a tumor prosthesis was selected for reconstruction after wide excision of the distal femoral primary lesion.\n\nHemicortical excision with a clear margin and reconstruction using a frozen autograft treated with liquid nitrogen is reportedly a reliable technique for retaining a good joint function through minimally resection of the tumor and preservation of as much of the normal tissue around the resected tumor as possible [19–25]. This procedure was applied in our case because the neoadjuvant chemotherapy showed good histological efficacy for the primary lesion. In our case, an excellent right shoulder joint function was restored, and a bone union was achieved, and no recurrence or postoperative complications were observed (Fig. 8a).\n\nComplete excision with a wide margin was associated with an improved survival, and local recurrence after surgery of the skull tumor is the major cause of treatment failure and decreases the survival rate. However, the anatomy of the head is complicated, and complete resection of the skull lesion is often difficult to achieve [10–12]. Synthetic or plate reconstruction after tumor excision is generally performed to protect the brain and fill bone defects, but there are sometimes cosmetic issues, and the complications, such as infection, or motor impairment due to brain damage, cannot be denied. Tumor excision of skull lesions and reconstruction using a frozen autograft treated with liquid nitrogen have been rarely reported [26–28]. However, this cryotherapy treatment and orthotopic transplantation method not only eliminates the tumor cells, but it also provides for bone filling which perfectly matches the same size as the bone defect, while also reducing the incidence rates of complications [19, 20, 26–28]. The good histological efficacy of neoadjuvant chemotherapy for the primary lesion was observed in our case; thus, reconstruction using a frozen autograft treated with liquid nitrogen after tumor excision with a clear margin, was applied. After surgery, a bone union was achieved without postoperative complications or local recurrence (Fig. 8b).\n\nIn conclusion, SMOS including a skull lesion is rare; nevertheless, the early, correct diagnosis, and proper strategy of chemotherapy and surgery for all lesions, are essential for ensuring a good clinical outcome. Reconstruction using a frozen autograft treated with liquid nitrogen was found to be feasible for bone lesions, including a skull lesion, even in a case of multicentric osteosarcoma, when the histological efficacy of neoadjuvant chemotherapy for the primary lesion was good. Our patient achieved an excellent right shoulder function, and a good cosmetic and functional outcome without any complications by reconstruction by following reconstruction using a frozen autograft. In addition, clinically disease-free survival of over five years after the diagnosis can be obtained, although further follow-up with regular close examinations will be required, as the survival associated with this disease is commonly poor.\n\nAbbreviations\nSMOSSynchronous multicentric osteosarcoma\n\nCTComputed tomogram\n\nMRIMagnetic resonance imaging\n\nISOLSInternational society of limb salvage\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank the past and the present other members of our department for their work.\n\nAuthors’ contributions\nT.H., Y.N., H.K., and A.Yos. conceived and designed the study. N.T. performed histological examination of all the specimen. A.Yos. carried out data acquisition. H.T., A.K.,T.Y., Y.H., M.Se., and A.Yoh. provided assistance for data acquisition. T.H., Y.N., H.K., T.A., M.Sh. and I.K. managed the patients for the appropriate treatment and observed them at the follow-up outpatient clinic after treatment completion. T.H., Y.N., H.K., and A.Yos. contributed to the analysis and interpretation of laboratory data and critical appraisal. A.Yos. analyzed all the patient's data and wrote the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\nAll data generated or analyzed during the present study are included in this published article.\n\nEthics approval and consent to participate\nThe study was approved by the Ethical Institutional Review Board of the Kanazawa University Hospital (2019-061 (3094)), and written informed consent was obtained from all study participants.\n\nConsent for publication\nThe written consent for publication of the manuscript, including personal and clinical details, and any identifying images, from the patient and her parents was obtained by the Kanazawa University Hospital.\n\nCompeting interests\nThe authors declare no conflicts of interest in association with the present study.\n==== Refs\nReferences\n1. Silverman G Multiple osteosarcoma Arch Pathol 1936 21 88 95 \n2. Domenico C Doris EW Franco B Multicentric osteosarcoma: clinicopathologic and radiographic study of 56 cases Am J Clin Pathol 2011 136 5 799 807 10.1309/AJCP0V0OATKCNAZP 22031320 \n3. Dialani L Valerie A Ian AC WHO Classification of tumours. Soft tissue and bone tumours 2020 5 Lyon IARC \n4. Cabello RR Sánchez CJ Padilla MA Osteoblastic and fibroblastic multicentric osteosarcoma BMJ Case Rep. 2011 10.1136/bcr.06.2011.4413 22674697 \n5. Bacci G Picci P Ferrari S Synchronous multifocal osteosarcoma: results in twelve patients treated with neoadjuvant chemotherapy and simultaneous resection of all involved bones Ann Oncol 1996 7 8 864 866 10.1093/oxfordjournals.annonc.a010769 8922204 \n6. Longhi A Fabbri N Donati D Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases J Chemother 2001 13 3 324 330 10.1179/joc.2001.13.3.324 11450892 \n7. Jaffe N Pearson P Yasko AW Lin P Herzog C Raymond K Single and multiple metachronous osteosarcoma tumors after therapy Cancer 2003 98 11 2457 2466 10.1002/cncr.11800 14635081 \n8. Aizawa T Okada K Abe E Tsuchida S Shimada Y Itoi E Multicentric osteosarcoma with long-term survival Skeletal Radiol 2004 33 1 41 45 10.1007/s00256-003-0717-y 14628102 \n9. Enrico M Joeky TS Valerie TW Timothy RS Marike LDB Treatment and survival of osteosarcoma and ewing sarcoma of the skull: a SEER database analysis Acta Neurochir (Wien) 2019 161 2 317 325 10.1007/s00701-018-3754-y 30578430 \n10. Salvati M Ciappetta P Raco A Osteosarcomas of the skull. Clinical remarks on 19 cases Cancer 1993 71 2210 2216 10.1002/1097-0142(19930401)71:7<2210::AID-CNCR2820710708>3.0.CO;2-W 8453540 \n11. Wu G Liang Q Liu Y Primary osteosarcoma of frontal bone : a case report and review of literature Medicine (Baltimore) 2017 96 51 e9392 10.1097/MD.0000000000009392 29390546 \n12. Lim S Lee S Rha SY Rho JK Cranofacial osteosarcoma: single institutional experience in Korea Asia Pac J Clin Oncol 2016 12 1 e149 e153 10.1111/ajco.12072 23718845 \n13. Sato H Hayashi N Yamamoto H Synchronous multifocal osteosarcoma involving the skull presenting with intracranial hemorrhage: case report Neurol Med Chir (Tokyo) 2010 50 5 407 409 10.2176/nmc.50.407 20505300 \n14. Cho H Park BJ Park YK Multifocal osteosarcoma of the skull: multiple primary or metastatic? A case report Korean J Pathol 2014 48 2 146 150 10.4132/KoreanJPathol.2014.48.2.146 24868228 \n15. Tsuchiya H Shirai T Nishida H Innovative antimicrobial coating of titanium implants with iodine J Orthop Sci 2012 17 595 604 10.1007/s00776-012-0247-3 22806173 \n16. Shirai T Tsuchiya H Terauchi R A retrospective study of antibacterial iodine-coated implants for postoperative infection Medicine (Baltimore) 2019 98 45 e17932 10.1097/MD.0000000000017932 31702678 \n17. Shirai T Shimizu T Ohtani K Antibacterial iodine-supported titanium implants Acta Biomater 2011 7 1928 1933 10.1016/j.actbio.2010.11.036 21115142 \n18. Gupta MM Bahri NU Parekh HP Watal P Chudasama SL Synchronous multifocal osteogenic sarcoma on multimodality imaging including bone scintigraphy Indian J Nucl Med 2014 29 3 185 188 10.4103/0972-3919.136591 25210291 \n19. Tsuchiya H Wan SL Sakayama K Yamamoto N Nishida H Tomita K Reconstruction using an autograft containing tumour treated by liquid nitrogen J Bone Jt Surg Br 2005 87 2 218 225 10.1302/0301-620X.87B2.15325 \n20. Yamamoto N Hayashi K Tsuchiya H Progress in biological reconstruction and enhanced bone revitalization for bone defects J Orthop Sci 2019 24 3 387 392 10.1016/j.jos.2019.01.015 30797666 \n21. Igarashi K Yamamoto N Shirai T The long-term outcome following the use of frozen autograft treated with liquid nitrogen in the management of bone and soft-tissue sarcomas Bone Jt J. 2014 96 B4 555 561 10.1302/0301-620X.96B4.32629 \n22. Higuchi T Yamamoto N Nishida H Knee joint preservation surgery in osteosarcoma using tumour-bearing bone treated with liquid nitrogen Int Orthop 2017 41 10 2189 2197 10.1007/s00264-017-3499-x 28573513 \n23. Wei MC Po KW Cheng FC Lien HC Chien LL Tain HC High-grade osteosarcoma treated with hemicortical resection and biological reconstruction J Surg Oncol 2012 105 8 825 829 10.1002/jso.23005 22212886 \n24. Higuchi T Yamamoto N Hayashi K Takeuchi A Abe K Taniguchi Y Araki Y Tada K Tsuchiya H Successful joint preservation of distal radius osteosarcoma by en bloc tumor excision and reconstruction using a tumor bearing frozen autograft: a case report BMC Surg 2018 18 1 12 10.1186/s12893-018-0346-y 29490656 \n25. Takeuchi A Yamamoto N Shirai T Nishida H Hayashi K Watanabe K Miwa S Tsuchiya H Successful correction of tibial bone deformity through multiple surgical procedures, liquid nitrogen-pretreated bone tumor autograft, three-dimensional external fixation, and internal fixation in a patient with primary osteosarcoma: a case report BMC Surg. 2015 15 124 10.1186/s12893-015-0112-3 26643043 \n26. Zhu ZC Yang YF Yang X Treatment of cryotherapy and orthotopic transplantation following chondromyxoid fibroma of zygomatic bone: a case report Medicine (Baltimore) 2018 97 31 e11707 10.1097/MD.0000000000011707 30075574 \n27. Kitagawa R Murakami H Kato S En bloc resection and reconstruction using a frozen tumor-bearing bone for metastases of the spine and cranium from retroperitoneal paraganglioma World Neurosurg 2016 90 e1 5 10.1016/j.wneu.2015.09.102 \n28. Fan MC Wang QL Sun P Cryopreservation of autologous cranial bone flaps for cranioplasty: a large sample retrospective study World Neurosurg 2018 109 e853 e859 10.1016/j.wneu.2017.10.112 29107719\n\n",
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"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D064592:Autografts; D001859:Bone Neoplasms; D002945:Cisplatin; D002985:Clinical Protocols; D003131:Combined Modality Therapy; D017679:Cryotherapy; D004317:Doxorubicin; D005260:Female; D005266:Femoral Neoplasms; D006801:Humans; D006811:Humerus; D007455:Iodine; D020360:Neoadjuvant Therapy; D009378:Neoplasms, Multiple Primary; D009584:Nitrogen; D009777:Occipital Bone; D012516:Osteosarcoma; D019651:Reconstructive Surgical Procedures; D000077330:Saline Solution; D012888:Skull Neoplasms; D014182:Transplantation, Autologous",
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"title": "Reconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature.",
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"title": "Isolation of multidrug-resistant Salmonella in Singapore.",
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"abstract": "Chimeric antigen receptor T (CAR-T)-cell therapy is a promising treatment for relapsed/refractory multiple myeloma (RRMM). In our previous report, CD19- and BCMA-targeted CAR-T co-administration was associated with a high response rate. Although cytokine release syndrome (CRS) and neurotoxicity are frequent complications following CAR-T treatment, cerebral infarction is rarely reported as a CAR-T-related complication. We reported a 73-year-old female MM patient who received CD19- and BCMA-targeted CAR-T for refractory disease. Her disease responded to CAR-T therapy, but she developed neurological symptoms following CRS. Cranial CT and MRI demonstrated multiple cerebral infarctions and bilateral anterior cerebral artery (ACA) occlusion. We suggest that cerebral infarction other than CAR-T-related neurotoxicity is the underlying cause of abnormal neuropsychological symptoms, and diagnostic imaging tests should be actively performed to exclude ischemic cerebrovascular events.",
"affiliations": "Department of Hematology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, Jiangsu, China.;Department of Hematology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, Jiangsu, China.;Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.;Department of Hematology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, Jiangsu, China.;Department of Hematology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, Jiangsu, China.;Department of Hematology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, Jiangsu, China.;Department of Rheumatology, Affiliated Hospital of Jiangsu University, Zhenjiang , Jiangsu, China.;Department of Hematology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, Jiangsu, China. feixiaomingujs@126.com.",
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"abstract": "Sympathetic ophthalmia (SO) is a panuveitis that usually occurs after trauma to one eye. We describe two cases of SO occurring after 23-gauge vitrectomy. Case 1 involved a 66-year-old woman who underwent pars plana vitrectomy (PPV) for a rhegmatogenous retinal detachment. Two months later, she presented with decreased visual acuity (VA) and bilateral uveitis. Case 2 involved a 43-year-old woman who underwent a second PPV for recurrent retinal detachment. Two months later, she presented with bilateral panuveitis. Both patients were diagnosed with SO and were treated with methylprednisolone and cyclosporine. The first patient was further treated with a dexamethasone intravitreal implant (Ozurdex®) owing to the side effects of methylprednisolone. The VA and symptoms improved significantly after treatment in both patients. Bilateral granulomatous panuveitis following PPV should alert surgeons to consider SO. Appropriate interventions for SO can produce positive outcomes.",
"affiliations": "Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.;Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.;Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.;Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.;Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.;Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.",
"authors": "Shen|Junhui|J|https://orcid.org/0000-0003-0160-0000;Zhang|Zheng|Z|;Ye|Dian|D|;Wen|Zuohui|Z|;Shu|Xupeng|X|;Chen|Zhiqing|Z|",
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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\n1473-2300\nSAGE Publications Sage UK: London, England\n\n34382463\n10.1177/03000605211032782\n10.1177_03000605211032782\nCase Reports\nSympathetic ophthalmia after vitreoretinal surgery: a report of two cases\nhttps://orcid.org/0000-0003-0160-0000\nShen Junhui 12*\nZhang Zheng 12*\nYe Dian 12\nWen Zuohui 12\nShu Xupeng 12\nChen Zhiqing 12\n1 Eye Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China\n2 Key Laboratory of Ophthalmology of Zhejiang Province, Hangzhou, Zhejiang, China\n* These authors contributed equally to this work.\n\nZhiqing Chen, Eye Center, The Second Affiliated Hospital of the School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang 310009, P.R. China. Email: chenzhiqing@zju.edu.cn\n12 8 2021\n8 2021\n49 8 0300060521103278223 2 2021\n25 6 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nSympathetic ophthalmia (SO) is a panuveitis that usually occurs after trauma to one eye. We describe two cases of SO occurring after 23-gauge vitrectomy. Case 1 involved a 66-year-old woman who underwent pars plana vitrectomy (PPV) for a rhegmatogenous retinal detachment. Two months later, she presented with decreased visual acuity (VA) and bilateral uveitis. Case 2 involved a 43-year-old woman who underwent a second PPV for recurrent retinal detachment. Two months later, she presented with bilateral panuveitis. Both patients were diagnosed with SO and were treated with methylprednisolone and cyclosporine. The first patient was further treated with a dexamethasone intravitreal implant (Ozurdex®) owing to the side effects of methylprednisolone. The VA and symptoms improved significantly after treatment in both patients. Bilateral granulomatous panuveitis following PPV should alert surgeons to consider SO. Appropriate interventions for SO can produce positive outcomes.\n\nSympathetic ophthalmia\n23-gauge vitrectomy\nretinal detachment\nbilateral granulomatous panuveitis\ninflammation\ndexamethasone intravitreal implant\nNatural Science Foundation of Zhejiang Provinc LQ20H120011 National Natural Science Foundation of China https://doi.org/10.13039/501100001809 82000886 typesetterts2\n==== Body\nIntroduction\n\nSympathetic ophthalmia (SO), a bilateral granulomatous panuveitis, is usually caused by a penetrating ocular trauma. The injured eye is called the inciting eye, and the uninjured eye is called the sympathetic eye. Generally, the interval between the penetrating ocular injury and SO ranges from 2 weeks to 2 years; however, the time between the second to the eighth weeks is considered the most dangerous stage. In particular, SO is more likely following injury to the ciliary body or a wound with uveal incarceration or intraocular foreign bodies.1 The incidence of SO following an injury is 0.2% to 0.5%. Recent findings have shown that SO also occurs following ocular surgeries, such as vitreoretinal surgeries, with an incidence of 0.01%.2 Although the SO incidence is low, this condition can lead to bilateral blindness if not treated.3 Herein, we present two cases of SO after vitreoretinal surgery to treat rhegmatogenous retinal detachment (RRD).\n\nCase reports\n\nCase 1\n\nThe first patient was a 66-year-old woman who presented with blurred vision in the right eye. The best-corrected visual acuity (BCVA) was hand motion (HM) in the right eye (OD) and 20/32 in the left eye (OS). Ultra-wide-field scanning laser ophthalmoscopy (SLO) revealed macula-off RD, with a retinal tear at the superior peripheral retina of the right eye (Figure 1a). She was diagnosed as having a right eye cataract and right eye RRD. She also had a history of diabetes mellitus. She underwent cataract extraction, intraocular lens implantation, pars plana vitrectomy (PPV), and gas tamponade in her right eye. After 1 week, her BCVA was 20/100 OD and 20/32 OS. She also underwent SLO and spectral-domain optical coherence tomography (SD-OCT), which revealed that the retina had reattached. Two months later, she presented with a headache, tinnitus, and acute vision loss, and her BCVA was limited to light perception (LP) in both eyes. Slit-lamp examination revealed small keratic precipitates (KP), aqueous flare and cells in the anterior chamber, vitreous opacity, and RD with edema in both eyes. SLO (Figure 1b), SD-OCT (Figure 1c), and B-scan ultrasonography (Figure 1d) revealed vitreous opacity, optic disc edema, exudative RD, and choroidal detachment with edema in both eyes. Increased choroidal thickness was noted with SD-OCT. Fundus fluorescein angiography (FFA) revealed relatively lower fluorescence at the inferior retina and optic disc fluorescein staining in the late phase in both eyes (Figure 1e). She was ultimately diagnosed as having SO according to her clinical characteristics and operation history.\n\nFigure 1. Bilateral ocular imaging findings for a 66-year-old woman with sympathetic ophthalmia after pars plana vitrectomy (PPV) surgery for rhegmatogenous retinal detachment in the right eye. At presentation, the patient’s visual acuity was hand motion and 20/32 for the right and left eyes, respectively. Fundus examination (a) revealed macula-off retinal detachment (RD) with a retinal tear at the superior peripheral retina of the right eye before surgery. Two months after PPV and gas tamponade, the patient was diagnosed with sympathetic ophthalmia, and her best-corrected visual acuity (BCVA) for both eyes was light perception. Fundus examination (b) showed optic disc edema, exudative retinal detachment, and choroidal detachment in both eyes. Spectral-domain optical coherence tomography (c) confirmed the presence of subretinal and intraretinal fluid and a wrinkled choroid in both eyes. B-scan ultrasonography (d) showing vitreous opacity, retinal detachment, and choroidal detachment with edema in both eyes. Fundus fluorescein angiography (FFA) (e) showing blocked fluorescence at the inferior retina, and optic disc fluorescein staining in both eyes.\n\nShe was treated with prednisolone acetate and pranoprofen eye drops and received pulse methylprednisolone therapy (500 mg/day) for 6 days. Subsequently, oral methylprednisolone was started at 48 mg/day (1 mg/kg/day), which was slowly tapered. Changes in blood routine laboratory values, including blood glucose, and liver and renal function were monitored. When oral methylprednisolone was reduced to 24 mg/day, she developed serious side effects, including hyperglycemia and osteoporosis. Slit-lamp examination revealed fewer KP and less anterior chamber inflammation in both eyes (Figure 2a). SLO revealed vitreous opacity, but the retinal and choroidal edema in both eyes had improved compared with earlier examinations (Figure 2b). SD-OCT revealed that the subretinal fluid volume had decreased compared with previous examinations; however, choroidal edema remained in both eyes (Figure 2c). A dexamethasone intravitreal implant (Ozurdex®; Allergan Inc., Irvine, CA, USA) was injected into her right eye, followed by a second injection into her left eye 1 week later. Concurrently, she was given methylprednisolone (12 mg/day). One month after the Ozurdex® treatment, her VA and other symptoms showed marked improvement. Anterior segment and fundus examinations (Figure 2d) showed no inflammatory reactions in either eye, and SD-OCT confirmed complete absorption of the subretinal fluid (Figure 2e). Her BCVA was 20/63 OD and 20/25 OS. She continued to take oral methylprednisolone (4 mg/day) and cyclosporine (100 mg/day), and the doses were slowly tapered.\n\nFigure 2. Bilateral ocular clinical and imaging findings for a 66-year-old woman with postsurgical sympathetic ophthalmia after treatment. One month after pulse methylprednisolone therapy and high-dose oral methylprednisolone, slit-lamp examination (a) showed less KP and anterior chamber inflammation in both eyes. Fundus examination (b) showed that the vitreous opacity, and retinal and choroidal edema in both eyes were improved compared with previous examinations. Spectral-domain optical coherence tomography (c) showed less subretinal fluid in both eyes compared with previous examinations. Three months after Ozurdex® intravitreal injections and methylprednisolone treatment, her BCVA was 20/63 OD and 20/25 OS. Fundus examination (d) and spectral-domain optical coherence tomography (e) showing that the subretinal fluid had completely disappeared in both eyes, and choroidal edema remained in the right eye.\n\nCase 2\n\nThe second patient was a 43-year-old woman who presented with blurred vision in the left eye. She underwent cataract extraction; however, she had previously undergone intraocular lens implantation in both eyes 15 years earlier because of congenital cataracts. The BCVA was 20/25 OD and 20/32 OS. SLO revealed a flap tear and RRD at the upper temporal retina of the left eye (Figure 3a). She was diagnosed as having left eye pseudophakia RRD, and she underwent PPV and silicone oil tamponade in her left eye. The retina was reattached, and her BCVA was 20/25 OD and 10/80 OS. Three months later, she presented with acute vision loss, and her BCVA was 20/25 OD and 20/250 OS. SLO revealed a detached retina from the nasal side, which was diagnosed as recurrent RD in the left eye. She underwent a second PPV with the aid of an iris hook and silicone oil tamponade in her left eye. After 1 week, her BCVA was 20/25 OD and HM OS, and B-scan ultrasonography revealed that the retina was well reattached. She subsequently presented with increased intraocular pressure (IOP), and received laser iridoplasty, mannitol, and IOP-lowering eye drops for the left eye. Her IOP then returned to normal. Two months after the second PPV, she presented with floating shadows in the front of the right eye. Her BCVA was 20/200 OD and HM OS, and IOP was 26.5 mmHg OD and 31 mmHg OS. Slit-lamp examination revealed small KP, and aqueous flare and cells in the anterior chamber in both eyes. SLO revealed a yellowish-white exudate located around the optic disc and macula of both eyes (Figure 3b). SD-OCT revealed vitreous opacity and increased choroidal thickness in both eyes, and she had neurosensory detachment and subretinal fluid collection under the macula of the right eye (Figure 3c). B-scan ultrasonography revealed vitreous opacity with posterior RD in the right eye (Figure 3d). FFA revealed hyperfluorescence of the optic disc followed by dye leakage from the optic disc and multiple pinpoint leakages at the nasal optic disc in the late phase in the right eye. Additionally, there was dye leakage from the optic disc and multiple pinpoint leakages around the optic disc and macula in the late phase in the left eye (Figure 3e). She was diagnosed with choroiditis and SO.\n\nFigure 3. Bilateral ocular imaging findings for a 43-year-old woman with sympathetic ophthalmia after pars plana vitrectomy (PPV) surgery for recurrent rhegmatogenous retinal detachment (RRD) in the left eye. At presentation, the patient’s visual acuity was 20/25 in the right eye (OD) and 20/32 in the left eye (OS). Fundus examination (a) showing a flap tear and RRD at the upper temporal retina in the left eye. Two months after a second PPV and silicone oil tamponade for recurrent RRD, fundus examination (b) showed yellowish-white exudate located around the optic disc and macula in both eyes. Spectral-domain optical coherence tomography (c) confirmed neurosensory detachment and subretinal fluid collection under the macula of the right eye and vitreous opacity in both eyes. B-scan ultrasonography (d) revealed vitreous opacity with posterior retinal detachment in the right eye. Fundus fluorescein angiography (FFA) (e) showed dye leakage from the optic disc and multiple pinpoint leakages at the nasal optic disc in the right eye, and dye leakage from the optic disc and multiple pinpoint leakages around the optic disc or macula in the left eye.\n\nMethazolamide was given to lower the IOP. Simultaneously, she was treated with prednisolone acetate, bromfenac sodium eye drops, and pranoprofen eye drops. Additionally, she received oral methylprednisolone at the following dosages: 48 mg/day for the first week, 44 mg/day for the second week, and 40 mg/day for the third and fourth weeks. During the fifth week, she was treated with methylprednisolone (24 mg/day) and cyclosporine (100 mg/day). Changes in blood routine laboratory values, including blood glucose, and liver and renal function were monitored monthly. Two months after treatment, her BCVA was 20/25 OD and 20/100 OS; however, the IOPs of both eyes remained very high at 30.3 mmHg OD and 38 mmHg OS. Carteolol + brinzolamide + brimonidine tartrate eye drops were prescribed for both eyes to lower the IOP. Slit-lamp examination revealed no inflammatory reactions in the anterior chamber of either eye. Interestingly, we also found dark conjunctival pigmentation around the sclerotomy sites in the left eye, which is a reported preliminary sign of SO (Figure 4a).5 SLO revealed that the yellowish-white exudate in both eyes had decreased compared with previous examinations (Figure 4b), and SD-OCT revealed that the subretinal fluid in both eyes had almost disappeared, and that the cystoid macular edema in the left eye remained (Figure 4c). Two months after treatment, her IOP was 23.3 mmHg OD and 34.5 mmHg OS. The IOP-lowering eye drops were changed to bimatoprost and timolol maleate + brinzolamide + brimonidine tartrate. Three months after treatment, her IOP had returned to normal, and her BCVA was 20/20 OD and 20/100 OS. SLO and SD-OCT confirmed that the subretinal fluid had completely resolved (Figure 4d and e). She continued to take cyclosporine (100 mg/day), which was slowly tapered.\n\nFigure 4. Bilateral ocular clinical and imaging findings for a 43-year-old woman with postsurgical sympathetic ophthalmia after treatment. Two months after high-dose oral methylprednisolone, slit-lamp examination (a) showed no inflammatory reaction in the anterior chamber of both eyes and dark conjunctival pigmentation around the sclerotomy sites in the left eye. Fundus examination (b) revealed less yellowish-white exudates in both eyes compared with previous examination. Spectral-domain optical coherence tomography (c) revealed that the subretinal fluid in both eyes had almost disappeared compared with the previous examination. Three months after treatment, her best-corrected visual acuity (BCVA) was 20/20 in the right eye (OD) and 20/100 in the left eye (OS). Fundus examination (d) and spectral-domain optical coherence tomography (e) confirmed that the subretinal fluid had completely disappeared in both eyes.\n\nThis case report was prepared in accordance with CARE reporting guidelines.4\n\nDiscussion\n\nThe etiology of SO remains unknown, but it is believed to be an autoimmune reaction. An ocular penetrating injury permits contact between intraocular antigens and the extraocular system, which leads to contact between intraocular tissue and the lymphatic system, causing an autoimmune reaction. Sensitized lymphocytes attack the uveal tissue of the other eye with the same antigen, resulting in SO.6 Some SO cases occur following ocular surgeries, such as RD surgery, cataract surgery, trabeculectomy, and penetrating keratoplasty.7 PPV reportedly increases the risk of postsurgical SO because this surgery may cause a break in the blood–retinal barrier, which is deemed responsible for SO.8–10 To the best of our knowledge, ours is the first report of postsurgical SO from China.\n\nWe reported two cases of SO followed by PPV. In Case 1, the patient presented with extraocular symptoms, including headache and tinnitus. These symptoms are rare in SO patients; only 9% of patients with SO experience headaches, and only 3% have tinnitus.11 These symptoms are typical of Vogt–Koyanagi–Harada (VKH) disease; however, patients with VKH do not typically have a history of ocular penetrating injuries or ocular surgeries.12 Postoperative complications, such as ocular hypertension, hypotony, wound leakage, and hyphema, were not observed in our cases. Case 2 was a patient with pseudophakia RRD. Multiple surgical interventions have been reported to increase the risk of postsurgical SO, given that a large number of uveal proteins are released during repeated surgeries.2,13,14 In addition, because the patient’s pupils in Case 1 were unable to dilate sufficiently, an iris hook was used to assist the PPV. She presented with ocular hypertension after the PPV, which can be induced by either inflammation or steroid eye drops. For 23-gauge vitrectomy in our hospital, all sclerotomies are sutured after surgery. In Case 2, dark conjunctival pigmentation around the sclerotomy site was found in the inciting eye and, according to the literature, this is considered a preliminary sign of SO.5 Dark conjunctival pigmentation around sclerotomy sites indicates uveal antigens that are exposed to the lymphatic system and cause an autoimmune reaction. Classical granulomatous uveitis typically presents with mutton-fat KP, but we observed only small KP in both patients. Nevertheless, SO with nongranulomatous inflammation is not uncommon.15 Dalen–Fuchs nodules are semicircular nodules that are mainly composed of epithelioid cells and lymphocytes within the choroid. These nodules are present in one-third of SO patients;16,17 however, we did not observe these nodules in our cases. This may be because our intervention was early and had preceded the development of granulomatous uveitis, or because the follow-up time was insufficient.\n\nPreviously, it was generally believed that patients would have better vision in the sympathetic eye if the inciting eye was enucleated within 2 weeks of SO onset.18 However, this opinion remains controversial.19 Current evidence and experts suggest that corticosteroids and immunomodulators, such as cyclosporine, are very effective in treating SO.20 Prompt treatment can control SO and maintain good vision in the sympathetic eye.21 The first patient (Case 1) was treated with pulse methylprednisolone therapy and oral steroids. It should be noted that this patient was intolerant to high doses of steroids because of serious side effects. The Ozurdex® dexamethasone intravitreal implant has been approved for the treatment of noninfectious uveitis.22 Both of this patient’s eyes received a single intravitreal injection of Ozurdex® to avoid side effects related to systemic steroids. Small doses of oral steroids and systemic immunosuppression were then used on a maintenance basis. The second patient did not receive Ozurdex® owing to the high IOP. Instead, she was treated with oral steroids and systemic immunosuppressive drugs, which were slowly tapered. Indeed, the VA and symptoms in both patients improved significantly; however, long-term follow-up is necessary. With the increasing application of PPV, ophthalmologists should be alert to the possibility of postsurgical SO and provide appropriate treatments.\n\nSupplemental Material\n\nsj-pdf-1-imr-10.1177_03000605211032782 - Supplemental material for Sympathetic ophthalmia after vitreoretinal surgery: a report of two cases\n\nClick here for additional data file.\n\nSupplemental material, sj-pdf-1-imr-10.1177_03000605211032782 for Sympathetic ophthalmia after vitreoretinal surgery: a report of two cases by Junhui Shen, Zheng Zhang, Dian Ye, Zuohui Wen, Xupeng Shu and Zhiqing Chen in Journal of International Medical Research\n\nDeclaration of conflicting interest: The authors declare that there is no conflict of interest.\n\nEthics statement: The study protocol was approved by the ethics committee of the Second Affiliated Hospital, School of Medicine, Zhejiang University (approval number: 2020-749). Written informed consent was obtained from the patient in this study.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Natural Science Foundation of China (No. 82000886) and the Natural Science Foundation of Zhejiang Province (No. LQ20H120011).\n\nORCID iD: Junhui Shen https://orcid.org/0000-0003-0160-0000\n==== Refs\nReferences\n\n1 Williams A Shepler A Chu C , et al . Sympathetic ophthalmia presenting 5 days after penetrating injury. Am J Ophthalmol Case Rep 2020; 19 : 100816.32695926\n2 Tyagi M Agarwal K Reddy Pappuru R , et al . Sympathetic ophthalmia after vitreoretinal surgeries: incidence, clinical presentations and outcomes of a rare disease. Semin Ophthalmol 2019; 34 : 157–162.31055985\n3 Shah D Al-Moujahed A Newcomb C , et al . Exudative retinal detachment in ocular inflammatory diseases: risk and predictive factors. Am J Ophthalmol 2020; 218 : 279–287.32621891\n4 Gagnier JJ Kienle G Altman DG , et al . The CARE guidelines: consensus-based clinical case reporting guideline development. Headache 2013; 53 : 1541–1547.24266334\n5 Cha D Woo S Ahn J , et al . A case of sympathetic ophthalmia presenting with extraocular symptoms and conjunctival pigmentation after repeated 23-gauge vitrectomy. Ocul Immunol Inflamm 2010; 18 : 265–267.20662657\n6 Lee J Shin J Lee J , et al . Recurrent sympathetic ophthalmia with annular choroidal detachment after pembrolizumab treatment: a case report. Ocul Immunol Inflamm 2019: 1–4.\n7 El Khatib B Patel M Hacopian A , et al . Sympathetic ophthalmia two weeks after 23-gauge vitrectomy. J Ophthalmic Inflamm Infect 2020; 10 : 15.32588152\n8 Pollack A McDonald H Ai E , et al . Sympathetic ophthalmia associated with pars plana vitrectomy without antecedent penetrating trauma. Retina 2001; 21 : 146–154.11321141\n9 Kilmartin D Dick A Forrester J. Sympathetic ophthalmia risk following vitrectomy: should we counsel patients? Br J Ophthalmol 2000; 84 : 448–449.10781505\n10 Gass J. Sympathetic ophthalmia following vitrectomy. Am J Ophthalmol 1982; 93 : 552–558.7081353\n11 Castiblanco C Adelman R. Sympathetic ophthalmia. Graefes Arch Clin Exp Ophthalmol 2009; 247 : 289–302.18795315\n12 Yang P Liu S Zhong Z , et al . Comparison of clinical features and visual outcome between sympathetic ophthalmia and Vogt-Koyanagi-Harada disease in Chinese patients. Ophthalmology 2019; 126 : 1297–1305.30959067\n13 Su D Chee S. Sympathetic ophthalmia in Singapore: new trends in an old disease. Graefes Arch Clin Exp Ophthalmol 2006; 244 : 243–247.16028023\n14 Jonas J Holbach L Schönherr U , et al . Sympathetic ophthalmia after three pars plana vitrectomies without prior ocular injury. Retina 2000; 20 : 405–406.10950423\n15 Rahi A Morgan G Levy I , et al . Immunological investigations in post-traumatic granulomatous and non-granulomatous uveitis. Br J Ophthalmol 1978; 62 : 722–728.708674\n16 Behdad B Rahmani S Montahaei T , et al . Enhanced depth imaging OCT (EDI-OCT) findings in acute phase of sympathetic ophthalmia. Int Ophthalmol 2015; 35 : 433–439.25772275\n17 Abdelmaksoud A Terk-Howe Khoo N Sears K , et al . Novel optical coherence tomography findings of a case of sympathetic ophthalmia after 23-guage vitrectomy. Retin Cases Brief Rep 2019.\n18 Lubin J Albert D Weinstein M. Sixty-five years of sympathetic ophthalmia. A clinicopathologic review of 105 cases (1913–1978). Ophthalmology 1980; 87 : 109–121.7383540\n19 Dutta Majumder P Anthony E George A , et al . Postsurgical sympathetic ophthalmia: retrospective analysis of a rare entity. Int Ophthalmol 2018; 38 : 2487–2493.29164454\n20 Abdullah M Chowdhury F Akhanda A , et al . Sympathetic ophthalmitis: a rare case report. Mymensingh Med J 2019; 28 : 461–464.31086167\n21 Tan X Seen S Dutta Majumder P , et al . Analysis of 130 cases of sympathetic ophthalmia - a retrospective multicenter case series. Ocul Immunol Inflamm 2019; 27 : 1259–1266.30207811\n22 Iarossi G Coppè A Catena G , et al . Dexamethasone intravitreal implant (Ozurdex) in paediatric patients with non-infectious intermediate uveitis and related cystoid macular oedema: evaluation of macular morphology and function with six-month follow-up; a deeper role of MfERG? Ocul Immunol Inflamm 2020: 1–7.\n\n",
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"keywords": "23-gauge vitrectomy; Sympathetic ophthalmia; bilateral granulomatous panuveitis; dexamethasone intravitreal implant; inflammation; retinal detachment",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D016572:Cyclosporine; D005260:Female; D006801:Humans; D009879:Ophthalmia, Sympathetic; D012163:Retinal Detachment; D012189:Retrospective Studies; D014821:Vitrectomy; D057586:Vitreoretinal Surgery",
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"title": "Sympathetic ophthalmia after vitreoretinal surgery: a report of two cases.",
"title_normalized": "sympathetic ophthalmia after vitreoretinal surgery a report of two cases"
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"abstract": "Context: Deep vein thrombosis (DVT) is a well-known complication of spinal cord injury (SCI). Low-molecular-weight heparin (LMWH) may be used in SCI patients who develop DVT, but can lead to subcutaneous bleeding. If subcutaneous bleeding occurs, then lymphedema, cellulitis, muscle or tendon tearing, or baker's cyst rupture should be considered in the differential diagnosis.Findings: Herein, we present a 61-year-old female patient who was hospitalized for rehabilitation due to paraplegia, and used LMWH due to DVT development. The patient suddenly developed pain, swelling, and discoloration of the left lower extremity. Although subcutaneous hemorrhage was considered initially, ultrasound and MRI revealed a ruptured Baker's cyst. In addition to supportive therapy, ultrasound-guided aspiration was performed.Conclusion/Clinical Relevance: In this report, we present a case of clinically severe Baker's cyst rupture, which occurred in the lower extremity of a SCI patient using LMWH due to DVT in the same extremity. To our knowledge, no similar cases have been reported.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Canakkale State Hospital, Canakkale, Turkey.;Department of Radiology, Canakkale State Hospital, Canakkale, Turkey.",
"authors": "Mengi|Alper|A|https://orcid.org/0000-0003-0898-764X;Ilhan|Ipek|I|",
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"journal": "The journal of spinal cord medicine",
"keywords": "Low molecular weight heparin; Lower extremity; Popliteal cyst; Venous thrombosis; Calf pain",
"medline_ta": "J Spinal Cord Med",
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"nlm_unique_id": "9504452",
"other_id": null,
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"pubdate": "2020-05-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An unexpected event after deep vein thrombosis in spinal cord injury: Ruptured Baker's cyst.",
"title_normalized": "an unexpected event after deep vein thrombosis in spinal cord injury ruptured baker s cyst"
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"abstract": "Hepatic metastases were reported in up to 70% of colorectal cancer patients, among which multifocal hepatic metastasis represents one of the complications that lead to poor prognosis. The majority of the patients carrying multifocal hepatic metastases required pharmaceutical treatments to reduce the tumor size prior to surgical resection. However, the clinical responses to pharmaceutical agents were difficult to predict due to the heterogeneous nature of the multifocal tumors. Here, we report a case with multifocal hepatic metastases from colorectal cancer that was resistant to the primary chemotherapy and Bevacizumab plus chemotherapy, but responded to the combined therapy of Cetuximab and FOLFOX. Genetic tests had revealed that the tumor was highly metastatic due to the mutations of the WNT signaling pathway, and the metastatic tumors might be sensitive to Cetuximab. Consistent with the molecular characterizations, the metastatic tumors continue to emerge after chemotherapy, and rapidly relapsed in great numbers after liver resection. However, the combined therapy of Cetuximab and FOLFOX guided by the genetic tests significantly reduced the size and number of metastatic tumors. To conclude, deciphering the mutation profiles of multifocal metastatic tumors may guide the determination of treatment tactics, which may benefit the patients with non-resectable advanced carcinoma.",
"affiliations": "Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Intenational Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Oncology, HaploX Biotechnology, Shenzhen, China.;Department of Oncology, HaploX Biotechnology, Shenzhen, China.;Department of Oncology, HaploX Biotechnology, Shenzhen, China.;Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.;Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.",
"authors": "Qiu|Chunhui|C|;Xie|Sidong|S|;Cheng|Na|N|;Lin|Qu|Q|;Shen|Guanzhu|G|;Xiang|Zhanwang|Z|;Huang|Tanxiao|T|;Zhang|Xiaoni|X|;Duan|Jingxian|J|;Wei|Li|L|;Zheng|Zongheng|Z|",
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"doi": "10.3389/fonc.2021.612171",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.612171\nOncology\nCase Report\nCase Report: Cetuximab in Combination With Chemotherapy for the Treatment of Multifocal Hepatic Metastases From Colorectal Cancer Guided by Genetic Tests\nQiu Chunhui 1 †\nXie Sidong 2 †\nCheng Na 3 †\n\nLin Qu 4\nShen Guanzhu 5\nXiang Zhanwang 6\n\nHuang Tanxiao 7\n\nZhang Xiaoni 7\nDuan Jingxian 7 *\n\nWei Li 4 *\nZheng Zongheng 8 *\n\n1 Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China\n2 Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China\n3 Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China\n4 Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China\n5 Department of Radiation Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China\n6 Department of Intenational Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China\n7 Department of Oncology, HaploX Biotechnology, Shenzhen, China\n8 Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China\nEdited by: Erika Ruiz-Garcia, National Institute of Cancerology (INCAN), Mexico\n\nReviewed by: Rui Manuel Reis, Barretos Cancer Hospital, Brazil; Ye Wei, Fudan University, China\n\n*Correspondence: Jingxian Duan, duanjx@haplox.com; Zongheng Zheng, zhengzh@mail.sysu.edu.cn; Li Wei, weili6@mail.sysu.edu.cn\n†These authors have contributed equally to this work\n\nThis article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology\n\n06 4 2021\n2021\n11 61217130 9 2020\n16 3 2021\nCopyright © 2021 Qiu, Xie, Cheng, Lin, Shen, Xiang, Huang, Zhang, Duan, Wei and Zheng\n2021\nQiu, Xie, Cheng, Lin, Shen, Xiang, Huang, Zhang, Duan, Wei and Zheng\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nHepatic metastases were reported in up to 70% of colorectal cancer patients, among which multifocal hepatic metastasis represents one of the complications that lead to poor prognosis. The majority of the patients carrying multifocal hepatic metastases required pharmaceutical treatments to reduce the tumor size prior to surgical resection. However, the clinical responses to pharmaceutical agents were difficult to predict due to the heterogeneous nature of the multifocal tumors. Here, we report a case with multifocal hepatic metastases from colorectal cancer that was resistant to the primary chemotherapy and Bevacizumab plus chemotherapy, but responded to the combined therapy of Cetuximab and FOLFOX. Genetic tests had revealed that the tumor was highly metastatic due to the mutations of the WNT signaling pathway, and the metastatic tumors might be sensitive to Cetuximab. Consistent with the molecular characterizations, the metastatic tumors continue to emerge after chemotherapy, and rapidly relapsed in great numbers after liver resection. However, the combined therapy of Cetuximab and FOLFOX guided by the genetic tests significantly reduced the size and number of metastatic tumors. To conclude, deciphering the mutation profiles of multifocal metastatic tumors may guide the determination of treatment tactics, which may benefit the patients with non-resectable advanced carcinoma.\n\ncolorectal cancer\nhepatic metastases\nmultifocal tumors\nWnt signal pathway\nAPC and TP53 co-mutation\nScience and Technology Planning Project of Guangdong Province10.13039/5011000122452015A020210044, 2014A020209022\n==== Body\nBackground\n\nColorectal cancer (CRC) represents the third most common cancer worldwide, causing over 500,000 deaths each year (1). Metastasis remains the key factor that shortens the survival of CRC patients. The 5-year survival of metastatic CRC was 35%-40% despite the fact that the diagnosis methods, treatment strategy, and best supportive care approaches had tremendously improved in the past decades (2). Liver remains the most common site of CRC metastasis, approximately 50% of the CRC patients developed hepatic metastasis during the course of CRC (3). Hepatic resection was considered to be the standard treatment modality for hepatic metastases from CRC (4); however, only around 25% of the patients carrying hepatic metastases from CRC were eligible for hepatic resections considering the tumor size, location, and accessibility (5, 6). To extend the possibility of hepatic resection, neoadjuvant therapy was encouraged. Neoadjuvant chemotherapy was shown to significantly improve the 5-year survival of metastatic CRC patients to 38.9%-74% (7). The combination of chemotherapy and pharmaceutical agents achieved the objective response rate of 40.6%, converting 19/64 unresectable liver metastases from colorectal cancer to curative intent resection (8). Importantly, the resistance to certain pharmaceutical agents could be postulated based on the mutational states of gene markers.\n\nThe mutational landscape of CRC was fully revealed by whole-genome sequencing studies. Mutations in APC, KRAS, BRCA2, and TP53 were frequently observed in CRC and colorectal adenoma patients (9). In hepatic metastases of CRC, KRAS was reported to be a significantly mutated gene, and the mutation status of KRAS was believed to be the predictor of recurrence-free survival of the patients (10). Patients carrying KRAS mutation had significantly decreased progression-free survival following Cetuximab treatment (11). However, KRAS mutation was detected in around 27% of colorectal liver metastases (12), and not all KRAS wild-type patients would respond to Cetuximab (13). Therefore, it is crucial to investigate the predictive biomarkers for different treatment strategies of colorectal liver metastases. This case stands for a unique representation of rapid growing multifocal hepatic metastases that were resistant to chemotherapy and Bevacizumab plus chemotherapy, and relapsed quickly after liver resection with 18 metastatic tumors. Treatment guided by the mutational profiles of the tumors effectively reduced metastases and tumor growth.\n\nCase Presentation\n\nA 51-year-old male with no family history or chronic disease was admitted to the Third affiliated hospital of Sun Yat-sen University. Baseline examination showed that carcinoembryonic antigen (CEA) was 285.6 ug/L ( Supplementary Figure 1A ), and CA199 was within the normal range on Oct 30th, 2019. Colonoscopy showed a 1.3cm x 1.3cm disc-shaped bulging tumor in the splenic flexure of colon. Pathological examination, CT scan, MR scan, and PET-CT scan showed 1 primary tumor in the splenic flexure of colon ( Figures 1A–C ) and 9 liver metastases ( Figures 1D–F , Supplementary Table 1 and Supplementary Figure 2 ). 3 liver metastatic tumors were identified in the left lobe of the liver, whereas the other 6 tumors were in the right lobe. The mean size of the metastatic tumors was 13 ± 2.055mm, ranging from 4mm-22mm ( Supplementary Table 1 and Supplementary Figure 1B ). Pathological examination showed moderately differentiated adenocarcinoma of the colon ( Figures 1A–C ) and liver metastasis ( Figures 1D–F ). Targeted sequencing showed that the tumors cells were KRAS, NRAS, and BRAF wild type with proficient MMR, and was negative for HER-2.\n\nFigure 1 Histopathological examination of the primary and metastatic tumors. (A) Hematoxylin and eosin (H&E) staining of colonic primary tumor shows glandular differentiation and invasion into the submucosa (×20). (B) High-power view shows the malignant epithelial cells arranging in a glandular or cribriform manner (×400). (C) The lymphovascular invasion of colonic adenocarcinoma is indicated by an arrow (×200). (D) H&E staining shows intrahepatic adenocarcinoma (×100). Immunostaining for CK20 (E), ×50 and CDX2 (F), ×50 confirmed the tumor originated in colon.\n\nFrom the 30th of October to the 31st of December, 2019, 4 courses of mFolfox6 chemotherapy were performed. The dosage and durations were Oxaliplatin 85 mg/m2 IV day 1, Leucovorin 400 mg/m2 IV day 1, 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day x 2 days (total 2400 mg/m2 over 46–48 hours) IV continuous infusion, repeated every 2 weeks. After chemotherapy, the sizes of 7/9 tumors were reduced, the average reduction was 2.778 ± 0.7027 mm ( Figure 2A ). However, the number of the liver metastasis increased, 10 more metastatic tumors emerged in segments II-VIII, and their sizes ranged from 4mm-12mm (5.82 mm on average, Supplementary Table 1 , Supplementary Figures 1B , 2 ). The changes in tumor sizes and numbers after different treatments are shown in Figures 2A–D , and the treatment records are shown in Figure 3 . The CEA dropped to 105 ug/L, whereas CA199 remained normal ( Supplementary Figure 1A ). To further reduce the size and number of the tumors, enhanced treatment was recommended, and the combined treatment of EGFR inhibitor and chemotherapy was applied due to the fact that the patient harbored no RAS alteration according to the mutation profile of the patient.\n\nFigure 2 MRI scans illustrating the changes in liver metastatic tumors over time. (A) MRI scans on the 30th of December 2019 shows multiple liver metastases (red circles). (B) MRI scans on the 7th of March 2020 shows the size of some liver metastases was reduced (blue circles) following the combination treatment. (C) MRI scans on the 16th of April 2020 shows multiple liver metastases (red circles). (D) MRI scans on the 28th of June 2020 shows the sizes and numbers of liver metastasis were significantly reduced following the combined treatment.\n\nFigure 3 Schematic diagram showing treatment record of the patient.\n\nTwo cycles of Cetuximab (500 mg/m2 IV over 2 hours, day 1, every 2 weeks) in combination with FOLFOXIRI (Irinotecan 165 mg/m2 IV day 1, oxaliplatin 85 mg/m2 IV day 1,z Leucovorin 400aa mg/m2 day 1, fluorouracil 1200 mg/m2/day x 2 days, continuous infusion starting on day 1. Repeated every 2 weeks) were administered on January 3 and 17, 2020 respectively. The patient did not return to the hospital for treatment in February due to the COVID-19 epidemic. He returned to our hospital in March 2020, his serum CEA dropped to 38.96 ug/L ( Supplementary Figure 1A ), and the CA199 remained normal. MRI scan on March 7th 2020 showed that 5 out of 18 liver metastatic tumors were reduced by 3 ± 0.55 mm ( Figure 2B , Supplementary Table 1 and Supplementary Figure 2 ), 11 tumors remained unchanged, and two tumors enlarged by 1mm. The average size of the metastatic tumors was 7.278 ± 0.885 mm, ranging from 4mm to 17 mm.\n\nAfter MDT discussion, he received surgery on the 13th of March 2020. The intestinal lesion and all eighteen liver lesions were removed. Postoperative pathology examination reported middle grade adenocarcinoma of the colon with infiltration into the submucosa. Suspected vascular tumor thrombosis was also observed. T1-T7,T8-T10, T12, T13, T15-18 were identified as the metastases from the intestinal adenocarcinoma based on the immunohistochemistry staining results of CK20 and CDX2 ( Figures 1E, F ). T 11 and T14 No spare tissues were left in T11 and T14 for CK20 and CDX2 staining after DNA extraction, the H&E staining before DNA extraction confirmed that they were tumors. No metastatic cancer was found in 8 para-intestinal lymph nodes, 11 central lymph nodes, and 8 intermediate lymph nodes.\n\nWhole-exome sequencing (WES) was performed on the intestinal adenocarcinoma sample collected during the surgery, and targeted sequencing with a panel of 680 cancer-related genes was performed on 13 hepatic tumors (T1-T7, T9-T12, T14, T15) that yielded sufficient amounts of tissues for the tests. The other 5 tumor samples did not reach the required tissue weight or tumor purity for DNA extraction, thus did not yield enough DNA for sequencing. The WES result revealed 18 somatic single-nucleotide variations and 3 insertion/deletion events ( Supplementary Table 2 ). The top 5 genes with high variant allele fractions were LRRC14 (c.979C>T, 15.52%), P2RY10 (c.396del, 10.06%), GALNT2 (c.83G>A, 9.23%), CASS4 (c.719C>T, 9.18%), and PRAMEF1 (c.986A>T, 8.48%). Among the 21 mutation loci, FEM1C (c.983G>A, COSM6663046), UTRN (c.9299C>T, COSM6819331), LRRC14 (c.979C>T, COSM6703564), TP53 (c.733G>T, COSM11081), and ABCA7 (c.4513C>T, COSM2156640) were reported in the COSMIC (catalogue of somatic mutations in cancer) database; whereas the other sites of mutations were not documented in the database. The TMB of the sample was 0.53 Muts/Mb.\n\nThe targeted sequencing results of the hepatic tumors revealed substantial heterogeneity among these metastatic tumors. 13 mutation loci were reported, including FOXP2 c.A455T, IKZF1 c.G1143T, TP53 c.G733T, PLIN2 c.C1295T, EPHA5 c.A2303C, APC c.C847T and c.3927_3931del, SF3B1 c.G3890A, NTRK2 c.C1574G, CACNA1C c.G673A, FANCB c.G901C, VHL c.G430A, and AXIN2 c.17_20dup. Notably, only the mutations in TP53, PLIN2, and AXIN2 were shared by the hepatic metastases and the primary intestinal adenoma. As shown in the phylogenic tree of the tumors ( Figure 4A ), T9 was the metastatic tumor that is most closely related to the primary intestinal adenoma evolutionally, they displayed common mutational sites. T1 developed two more mutation sites FOXP2 and IKF1, which was followed by T2, T4, T5, T7, T12, and T14 who further developed 4 mutations. These tumors were located at the same branch of the phylogenic tree due to the fact that they exhibited the identical mutation profile, suggesting that they may be monoclonal and perhaps emerged at the same stage ( Figure 4B ). T10, T11 and T15 were evolutionally very close to T2, T4, T5, T7, T12, and T14, they further developed one or two mutations respectively. Co-mutation of TP53 and APC occurred in T2, T4 T5, T7, T10, T11, T12, T14, and T15, suggesting that these hepatic metastases may be sensitive to Cetuximab treatment (14). Further analysis showed that these tumor cells were KRAS wild-type and pMMR. The TMB was 3.76 ± 0.86Muts/Mb, indicating that the patient may not respond well to immunotherapy. Notably, the tumors harbored TP53 and APC co-mutation had the mean TMB of 5.43 ± 0.69Muts/Mb, whereas all 4 tumors that did not contain the co-mutation had the TMB below the detection threshold.\n\nFigure 4 The genetic heterogeneity of liver metastatic tumors. (A) A phylogenic tree showing the genomic similarity of the liver metastatic tumors and the primary intestinal adenoma. (B) Heatmap showing the frequencies and types of mutations of all mutated genes detected by targeted sequencing. T1-T15 were hepatic tumors and PB was the peripheral blood sample obtained in July 2020.\n\nThe patient received no treatment after the surgery; however, the tumors relapsed in two months. The MRI review in April showed 18 metastases in the left lobe of the liver (segments II-VI), which possibly were recurrent tumors ( Figure 2C ). The average size of the tumors was 8.778 ± 0.712 mm, ranging from 4mm to 15mm ( Supplementary Table 3 and Supplementary Figure 3 ). The recurrent tumors were found in the liver but not the colon, suggesting that the liver metastasis harbored molecular alterations that facilitate rapid tumor growth. The sequencing results showed that key genes involved in the Wnt signaling had mutated, which favors transcription of epithelial-mesenchymal transition (EMT) supported metastasis. Although Cetuximab plus chemotherapy was not the optimal recommendation for the treatment of liver metastases, we still decided to continue with this plan as the mutation status of liver tumors and former treatment history both suggest that the tumors may respond to Cetuximab plus chemotherapy. The patient received six cycles of Cetuximab (Cetuximab 500 mg/m2 IV over 2 hours, day 1, every 2 weeks) combined with mFOLFOX6 (Oxaliplatin 85 mg/m2 IV day 1z Leucovorin 400 mg/m2 IV day 1aa 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day x 2 days, total 2400 mg/m2 over 46–48 hours, IV continuous infusion, repeated every 2 weeks). After the treatment, 10 out of 18 tumors were eliminated, the rest 8 tumors were significantly reduced in size (10.38 ± 1.133 mm versus 6 ± 0.378 mm, p=0.008 ( Figure 2D ), Supplementary Figure 1B ). Targeted sequencing of the cfDNAs captured from the peripheral blood sample on the 10th of July 2020 showed that the mutational profile of the patient remained unchanged ( Supplementary Table 2 ), confirmed that the newly emerged tumors were recurrent tumors that shared the same mutations with the surgery-removed tumors. Despite the fact that the Cetuximab plus mFOLFOX6 regime gave rise to superior clinical responses as predicted by the genetic test, the patient developed a grade 3 rash after the therapy, which seriously affected the life-quality of the patient. As the result, the patient refused to continue the Cetuximab combination therapy. On August 24, 2020, the regimen was adjusted to Bevacizumab (Bevacizumab 5 mg/kg IV, day 1 Repeat every 2 weeks) combined with FOLFOXIRI (Irinotecan 180 mg/m2 IV over 30–90 minutes, day 1 Leucovorinaa 400 mg/m2 IV infusion to match duration of irinotecan infusion, day 1 5-FU 400 mg/m2 IV bolus day 1, then 1200 mg/m2/day x 2 days; total 2400 mg/m2 over 46–48 hours; continuous infusion repeated every 2 weeks). However, severe side effects in the gastrointestinal tract markedly impaired the life quality of the patient, and the CEA level increased to 494.8 ug/L. The patient chose to stop the treatment and never returned to the hospital after two courses of Bevacizumab plus FOLFOXIRI.\n\nDiscussion\n\nIn this case of multifocal hepatic metastases from intestinal adenoma, we reported a large number of rapid growing hepatic metastases that harbored mutations of APC, AXIN2, TP53, PLIN2, and FOXP2. The sizes and numbers of the tumors were markedly reduced by Cetuximab plus chemotherapy but not chemotherapy alone or Bevacizumab plus chemotherapy. The genomic landscape of colorectal cancers had been reported by multiple studies, APC and CTNNB1 were the hallmark mutations of CRC (15, 16). Mutations of KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 were observed more frequently in right-sided CRC, and alterations in the WNT signaling pathway were identified in approximately 96% of CRCs (15). The genomic landscape of liver cancer showed an overlap of prevalent mutations with CRC. TERT, TP53, and CTNNB1 were the frequently mutated genes observed in HCC patients, structural variations in CDKN2A, CCND1, APC, and TERT were also reported in virus-infected HCC (17). In hepatic metastases from CRC, COX-2 was shown to over-express (18), and KRAS mutation may predict the tumor recurrence patterns in patients who had hepatic resections of CRC metastases (10). Here, we report for the first time that TP53, PLIN2, and AXIN2 were the common mutations shared by the primary intestinal adenoma and multifocal hepatic metastases. The multifocal hepatic metastases displayed genetic heterogeneity which improves the understanding of the evolutionary and chronological relationships of the metastatic tumors.\n\nMutations of APC, CTNNBI or AXIN1 would lead to the accumulation of beta-catenin and interfere with the Wnt signaling pathway in HCC and CRC (19). We observed two mutation sites (in 9/13 tumors) in the exons of the APC gene, and both were loss-of-function mutation. It was shown that the inactivation of APC leads to the activation of Wnt signaling (20). Similarly, we reported the frame-shift mutation of AXIN2 in 11/13 liver metastatic tumors. This mutation results in a truncated form of protein with compromised protein function. It was known that AXIN2 was a negative regulator of the Wnt signaling pathway, hence, the observed mutation of AXIN2 may lead to the abnormal activation of the Wnt signaling pathway (21). Activation of the Wnt signaling pathway was shown to trigger the EMT-related genes including SNAIL1 (22); consequently, it would facilitate cell proliferation and the potency of invasiveness (23). In this case, it is highly likely that the Wnt signaling pathway was up-regulated due to the loss-of function mutations of APC and AXIN2, which increased the invasiveness of the tumors and caused multifocal metastases as well as recurrent metastasis in the liver. When first enrolled in the hospital, the patient developed 9 more hepatic tumors in 3 months, 8/9 of the tumors exhibiting TP53 and APC co-mutation also showed higher TMB level. After the resection, another 18 metastatic tumors emerged in the liver within two months. The rapid emerging of liver metastases may also be the result of the aberrant activation of the Wnt signaling. A population-based study reported that 45.8% liver metastases from colon cancer had 1-3 liver metastatic sites (24), the highly invasive metastases with 18 sites were rare in our clinical observation.\n\nWe also observed the co-mutation of TP53 and APC in 9/13 liver metastatic tumors. Studies had reported that the co-mutation of APC and TP53 was associated with sensitivity to Cetuximab therapy in Ras-normal metastatic CRC patients (14, 25). Indeed, FOLFIX chemotherapy alone caused an increased number of liver metastases, whereas the combined treatment of Cetuximab and chemotherapy significantly reduced the size and number of liver metastatic tumors between April 2020 and June 2020, which proved that the mutation profiles of tumors could guide the determination of clinical treatment strategy. In fact, these fast-growing metastatic tumors with loss-of function mutations of the negative regulator of the Wnt signaling pathway responded only to Cetuximab plus chemotherapy. When chemotherapy was applied alone, the number of metastatic tumors increased. The CEA level of the patient increased drastically when the treatment strategy was switched to Bevacizumab plus chemotherapy, and the sizes and number of the tumors were not reduced. Moreover, the surgery was accompanied by the rapid relapse of hepatic tumors. Despite the fact that surgical resection was considered to be the potentially curative treatment for colorectal liver metastases, our case showed that metastatic tumors with potentially Wnt signaling activating mutations may relapse very soon after the surgery, and Cetuximab plus chemotherapy was the optimal strategy for the treatment of tumors that has high potential to metastasize and multiply. Conducting genetic sequencing to check for Wnt signaling-activating mutations might be a good approach to identify such tumors. Notably, we showed that the tumors harbored loss-of function mutations of the negative regulator of the Wnt signaling pathway, which may lead to the aberrant activation of the pathway. However, we do not have spare samples to conduct immune-staining or functional tests. Whether the Wnt signaling pathway was up-regulated in situ requires additional experiments, and we could confirm the finding if similar samples are acquired in the future.\n\nSystemic chemotherapy was applied as neoadjuvant therapy or adjuvant therapy in the treatment of CRC. First-line chemotherapy plans for metastatic CRC include FOLFOX (fluorouracil, leucovorin, oxaliplatin), FOLFIRI (fluorouracil, leucovorin, irinotecan), XELOX (capecitabine plus oxaliplatin), and FOLFOXFIRI (fluorouracil, leucovorin, oxaliplatin, irinotecan) (26). The combined use of Cetuximab, Bevacizumab, and chemotherapy in metastatic CRC was studied for decades; it was shown that patients carrying KRAS mutation had significantly decreased progression-free survival following Cetuximab treatment (11). A more recent study reported that the addition of Cetuximab to chemotherapy conferred disadvantages of survival in patients with operable disease (27). Collectively, these observations confirmed that the use of Cetuximab should be carefully considered, and should follow the guidance of the genetic test results. Despite the fact that the combined use of Cetuximab and chemotherapy reduced the hepatic metastases in this case, the severe adverse effect forced us to change the treatment plan to Bevacizumab plus chemotherapy, which further caused adverse effect in the gastrointestinal tract.\n\nOne limitation of the case is that we struggle to find an effective treatment strategy with less treatment-related adverse events. The disadvantage of the Cetuximab plus chemotherapy plan is that it was reported to induce skin rash in 16% of the patients, whereas in the control group (Chemotherapy alone) only 1% of patients reported skin irritation (27). Alternatively, Bevacizumab was applied in combination with chemotherapy for the treatment of metastatic CRC, the treatment plan was shown to improve the progression-free survival of the patients, although grade 3 or 4 adverse events were more frequently observed too (28). It was reported that 19.7% patients receiving FOLFIRI plus Bevacizumab and 20.4% patients receiving FOLFOXIRI plus Bevacizumab experienced serious adverse events; 20.5%-50% of the patients reported neutropenia (28). Unfortunately, the patient could not endure the severe side effects caused by the treatments and did not return to the hospital since.\n\nConclusion\n\nNext generation sequencing of the multifocal liver metastases from CRC revealed the genetic heterogeneity of the metastatic tumors. The mutations causing abnormal activation of the Wnt signaling pathway would possibly increase the invasiveness of the tumors and promote metastasis, which leads to rapid recurrence of the metastatic tumors in a short period of time after liver resection. Moreover, such tumors may respond well to Cetuximab plus chemotherapy but not chemotherapy alone or Bevacizumab plus chemotherapy. Treatment strategies should be selected based on the mutational profiles of the metastatic tumors.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nWritten informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this manuscript.\n\nAuthor Contributions\n\nCQ, SX, and NC contributed equally to this work. All authors were involved in the drafting of the manuscript. ZZ and LW designed the clinical treatment for the patient. JD, TH, and XZ performed genetic tests and the data analysis. ZZ, SX, GS, NC, ZX, LW, QL, and CQ performed the clinical treatment for the patients. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis research was funded by the Science and Technology Planning Project of Guangdong Province, China (2015A020210044, 2014A020209022) and Shenzhen science, technology and innovation commission (JSGG20180508152646606).\n\nConflict of Interest\n\nJD, TH, and XZ were employed by the company, HaploX Biotechnology.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.612171/full#supplementary-material\n\nClick here for additional data file.\n\nClick here for additional data file.\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A . 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"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "APC and TP53 co-mutation; Wnt signal pathway; colorectal cancer; hepatic metastases; multifocal tumors",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "612171",
"pmc": null,
"pmid": "33889542",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "10700176;18827815;26989027;25155157;19470929;21176063;31015202;11809809;31804558;23844322;19196673;25918280;29334918;17545615;27064257;32216031;25337750;27221540;30207593;15660506;25257725;26578731;29316426;27043642;19727962;17932254;17956532;32014119",
"title": "Case Report: Cetuximab in Combination With Chemotherapy for the Treatment of Multifocal Hepatic Metastases From Colorectal Cancer Guided by Genetic Tests.",
"title_normalized": "case report cetuximab in combination with chemotherapy for the treatment of multifocal hepatic metastases from colorectal cancer guided by genetic tests"
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"abstract": "We evaluated the efficacy and tolerability of chemotherapy in HIV-infected patients with diffuse large B-cell lymphoma (DLBCL) receiving CHOP ± R (n = 17) or Burkitt lymphoma (BL) receiving CODOX-M/IVAC ± R (n = 15). The study was conducted in Beijing Ditan Hospital from January 2009 to August 2015. The following grade 4 adverse effects were observed in BL and DLBCL patients, respectively: neutropenia (80% versus 47.1%), anaemia (46.7% versus 5.9%), thrombocytopenia (53.3% versus 11.8%), bacterial pneumonia (33.3% versus 5.9%), and sepsis (20% versus 5.9%) (p < 0.05). In the BL group, 10 (66.7%) patients died from treatment-related or tumour-related causes, 5 (33.3%) achieved complete response, 1 achieved partial response (6.7%), and 7 developed progressive disease. The 1-year overall survival and progression-free survival rates were 33.3%. Of the DLBCL patients, 3 (17.6%) died from treatment-related causes, 14 (82.4%) achieved complete response, and 3 had progressive disease. The 1-year overall survival and progression-free survival rates were 82.4%. The strongest risk factor for death was relapse between chemotherapy cycles (adjusted hazard ratio = 47.3; 95%CI, 4.2-528.6, p = 0.002). Initiating antiretroviral therapy before chemotherapy failed to improve overall survival. DLBCL patients demonstrated good responses and survival outcomes, while BL patients could not tolerate chemotherapy due to more severe toxicity, and showed poor responses and survival outcomes.",
"affiliations": "Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.;Beijing Shijitan Hospital, Capital Medical University, Beijing, 100020, China.;Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.;Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.;Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.;Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China. 13911022130@163.com.",
"authors": "Xiao|Jiang|J|;Du|Shuxu|S|;Dai|Guorui|G|;Gao|Guiju|G|;Yang|Di|D|;Zhao|Hongxin|H|",
"chemical_list": "D015415:Biomarkers; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
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"doi": "10.1038/s41598-017-02086-4",
"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 208610.1038/s41598-017-02086-4ArticleEfficacy and tolerability of chemotherapy in Chinese patients with AIDS-related Burkitt lymphoma and diffuse large B-cell lymphoma: An observational study Xiao Jiang 1Du Shuxu 2Dai Guorui 1Gao Guiju 1Yang Di 1Zhao Hongxin 13911022130@163.com 11 0000 0004 0369 153Xgrid.24696.3fClinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015 China 2 0000 0004 0369 153Xgrid.24696.3fBeijing Shijitan Hospital, Capital Medical University, Beijing, 100020 China 15 5 2017 15 5 2017 2017 7 190523 9 2016 5 4 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/.We evaluated the efficacy and tolerability of chemotherapy in HIV-infected patients with diffuse large B-cell lymphoma (DLBCL) receiving CHOP ± R (n = 17) or Burkitt lymphoma (BL) receiving CODOX-M/IVAC ± R (n = 15). The study was conducted in Beijing Ditan Hospital from January 2009 to August 2015. The following grade 4 adverse effects were observed in BL and DLBCL patients, respectively: neutropenia (80% versus 47.1%), anaemia (46.7% versus 5.9%), thrombocytopenia (53.3% versus 11.8%), bacterial pneumonia (33.3% versus 5.9%), and sepsis (20% versus 5.9%) (p < 0.05). In the BL group, 10 (66.7%) patients died from treatment-related or tumour-related causes, 5 (33.3%) achieved complete response, 1 achieved partial response (6.7%), and 7 developed progressive disease. The 1-year overall survival and progression-free survival rates were 33.3%. Of the DLBCL patients, 3 (17.6%) died from treatment-related causes, 14 (82.4%) achieved complete response, and 3 had progressive disease. The 1-year overall survival and progression-free survival rates were 82.4%. The strongest risk factor for death was relapse between chemotherapy cycles (adjusted hazard ratio = 47.3; 95%CI, 4.2–528.6, p = 0.002). Initiating antiretroviral therapy before chemotherapy failed to improve overall survival. DLBCL patients demonstrated good responses and survival outcomes, while BL patients could not tolerate chemotherapy due to more severe toxicity, and showed poor responses and survival outcomes.\n\nissue-copyright-statement© The Author(s) 2017\n==== Body\nIntroduction\nMalignant lymphoma is a rapidly growing, aggressive, AIDS-defining cancer that results in death within several weeks or months if left untreated. Some studies have reported that the prevalence of lymphoma in HIV-infected patients has decreased dramatically with the introduction of antiretroviral therapy1. Despite convenient access to antiretroviral regimens through the National Free Antiretroviral Treatment Program (NFATP) in China2, HIV-related lymphomas—mainly Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL)—continue to lead to morbidity and mortality in Chinese HIV-infected patients due to delayed diagnosis of HIV infection, with lymphoma often being the first indicator of their disease3.\n\nIn the era of combination antiretroviral therapy (cART), CHOP-based regimens have been widely used to treat DLBCL in HIV-infected patients as they have better efficacy than other chemotherapy regimens4. Coutinho et al.5 demonstrated that HIV-infected patients diagnosed with DLBCL in the cART era have an excellent outcome when treated with CHOP-R, with an overall survival rate of 78%. CODOX-M/IVAC, a non-cross-resistant, intensive chemotherapy regimen developed by the American National Cancer Institute, confers high cure rates in HIV-infected patients with BL. With regard to toxicity, Rodrigo et al.6 reported that intensive chemotherapy with CODOX-M/IVAC ± R yielded an acceptable toxicity profile and good survival rates in patients with HIV-associated BL receiving cART. However, Mead et al.7, in the United Kingdom Lymphoma Group LY06 Study, found that toxicity was severe, especially in terms of myelosuppression and mucositis. However, the above conclusions are derived from Euro-American HIV-infected patients with lymphoma; the efficacy and tolerability of these chemotherapy regimens in Chinese HIV-infected patients remains obscure.\n\nBeijing Ditan Hospital is an HIV/AIDS referral hospital in China. It provides care and treatment to HIV/AIDS patients, including those with lymphoma. The objective of this observational study was to evaluate the efficacy and tolerability of chemotherapy in Chinese HIV-infected patients with lymphoma.\n\nMethods\nEthical considerations\nThis retrospective observational cohort study was approved by institutional review board of Beijing Ditan Hospital, the Capital Medical University, and complied with the principles of the Declaration of Helsinki. The clinical and therapeutic data were anonymously used and were abstracted from electronic medical records in Ditan Hospital.\n\nSubjects\nWe included all HIV-infected patients with newly diagnosed DLBCL treated with a CHOP regimen with or without rituximab (CHOP ± R) and newly diagnosed BL treated with a CODOX-M/IVAC regimen with or without rituximab (CODOX-M/IVAC ± R) at the Centers for Infectious Diseases, Beijing Ditan Hospital, the largest referral hospital for HIV/AIDS patients in North China, from January 2009 to August 2015. HIV-infected patients diagnosed with DLBCL or BL who did not receive chemotherapy were excluded. We investigated the efficacy, tolerability, and adverse effects of chemotherapy in these patients.\n\nDiagnosis and risk evaluation\nExperienced pathologists used standard diagnostic criteria to diagnose DLBCL or BL on lymph node and bone marrow histopathological and immunohistochemical examination. The standard diagnostic criteria for BL included identification of C-MYC translocation by fluorescence in situ hybridization or of the t(8;14). Immunohistochemical analysis for BCL-2 and MYC expression was performed on paraffin-fixed tissue sections and BCL-2 and MYC immunostaining was carried out with anti-Bcl-2 antibody (abcam ab32124 1:250) and anti-myc antibody (abcam ab32072 1:200) using the BCL-2 and MYC expression diagnostic kit. The cut-offs for immunohistochemical markers for diagnosis of DLBCL were Bcl2 >70% and myc >40%, based on previous reports8, 9.\n\nWe used Han’s cell-of-origin algorithm10 to define germinal centre B-cell-like (GCB) or non-GCB DLBCL. Epstein-Barr virus (EBV) small ribonucleic acids were detected using in situ hybridization and an EBV in situ hybridization kit (ZSGB-Bio ISH502) with EBV-encoded small nuclear early region oligonucleotides on formalin-fixed paraffin-embedded tissue sections11. EBV-negative lymphoid tissues were treated as negative controls.\n\nThe Ann Arbor staging system was used to determine lymphoma stage. Staging investigations included physical examination; routine haematological and biochemical tests; lymph node mass measurement; bone marrow biopsy; and computerized tomography of the brain, chest, abdomen, and pelvis. Patients were regarded as high-risk based on following features: Ann Arbor stage III or IV; elevated lactate dehydrogenase levels; and tumour bulk >10 cm. Patients not meeting these criteria were regarded as low-risk6, 7.\n\nInfectious complications during chemotherapy due to immunosuppression and severe myelosuppression were diagnosed and managed according to the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents recommended by the United States Centers for Disease Control and Prevention (CDC)12.\n\nTreatment and definitions\nPatients diagnosed with DLBCL received a CHOP ± R regimen13, 14 on a 21-day schedule for a total of 8 cycles, and all patients received intrathecal methotrexate 12.5 mg per cycle for central nervous system prophylaxis. Patients with BL were treated with a CODOX-M/IVAC ± R regimen for 4 cycles and intrathecal prophylaxis was provided to patients at high risk of central nervous system involvement. The Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents of the United States CDC15 recommend cART for all HIV-infected patients to reduce the risk of disease progression; in patients with some conditions, such as AIDS-defining illnesses, more urgent initiation of therapy is favoured. In this study, patients with non-Hodgkin lymphoma, an AIDS-defining illness, were advised to initiate cART as soon as possible after being diagnosed with lymphoma, regardless of CD4 cell count. In this study, all patients were initiated on cART prior to receiving chemotherapy, based on the above-stated criteria. The preferred regimen was tenofovir, lamivudine, plus efavirenz, as recommended by the Chinese National Free HIV Antiretroviral Treatment Handbook\n16. In this study, patients who did not start cART until diagnosis of lymphoma initiated treatment with tenofovir, lamivudine, plus efavirenz, while those who had been receiving cART regimens such as zidovudine, lamivudine, plus nevirapine or efavirenz, were switched to tenofovir, lamivudine, plus efavirenz prior to chemotherapy to reduce the risk of zidovudine-associated myelosuppression and nevirapine-induced liver injury when combined with chemotherapy.\n\nAccording to the Guidelines for Prevention and Treatment of Infectious Complications in HIV-Infected Adults and Adolescents recommended by the United States CDC12, HIV-infected adults and adolescents with a CD4 count <200 cells/µL should receive chemoprophylaxis against pneumocystis pneumonia. Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended prophylactic agent, and 1 double-strength tablet daily is the preferred regimen. Patients with a CD4 count <50 cells/µL should receive chemoprophylaxis against disseminated Mycobacterium avium complex disease; azithromycin 1200 mg once weekly is the preferred prophylactic agent. In this study, because the cART regimen used was tenofovir, lamivudine, plus efavirenz, primary prophylaxis against hepatitis B virus infection was not needed, as tenofovir and lamivudine have antiviral activity against hepatitis B virus15. All study patients received primary prophylaxis against pneumocystis pneumonia and Mycobacterium avium complex. Patients received granulocyte-colony-stimulating factor as primary prevention due to severe bone marrow suppression after receiving chemotherapy.\n\nPatients not on cART when diagnosed with lymphoma received an antiretroviral regimen of tenofovir, lamivudine, plus efavirenz, prior to initiation of chemotherapy. Timely laboratory monitoring of HIV viral load was performed based on the Chinese National Free HIV Antiretroviral Treatment Handbook\n16, and the antiretroviral effect was evaluated in patients receiving chemotherapy.\n\nComplete response to chemotherapy was defined as complete disappearance of disease as determined by all available clinical, biochemical, and radiological evidence. Partial response required at least a 50% decrease in the sum of the product of the greatest diameters. Progressive disease (non-response) required assessable disease progression or the appearance of any new lesion(s) during or at the end of chemotherapy17. Relapse in the interval between chemotherapeutic cycles was defined as disease reduction or even complete disappearance during chemotherapy, but relapse or appearance of primary or new lesions in the interval between chemotherapeutic cycles, based on clinical and radiological evidence.\n\nFor patients who survived until discharge, the date last known alive was obtained from the record of the last follow-up in the database in CDC in China. The major end-points in this study included overall survival, defined as the time from initial diagnosis to death, and progression-free survival (PFS), defined as the time from the first day of treatment to the date at which lymphoma progressed or the date on which the patient died from any cause18.\n\nStatistical analysis\nAll statistical data were analysed using SPSS software, version 19.0 (SPSS Institute, Chicago IL, USA). Continuous variables with a skewed distribution are presented as the median with the minimum and maximum range. Categorical variables are presented as numbers and percentages; chi-square or Fisher’s exact tests were used to compare patient characteristics, as appropriate. Column charts were used to illustrate grade 3–4 adverse effects following chemotherapy in the DLBCL and BL group. The log-rank test was used to compare survival distributions of overall survival and PFS between the DLBCL and BL groups. Cox proportional hazards regression models were used to evaluate the association between the following variables and death among HIV-infected patients with lymphoma receiving chemotherapy: baseline CD4 count, initiation of cART prior to chemotherapy, receiving rituximab during therapy, and relapse in the interval between chemotherapeutic cycles. A significance level of 0.05 was set for all statistical testing.\n\nResults\nPatient characteristics\nFrom January 2009 to August 2015, 17 patients were diagnosed with DLBCL and received chemotherapy with a CHOP ± R regimen, while 15 patients were diagnosed with BL and were treated with a CODOX-M/IVAC ± R regimen. In the DLBCL group, 6 patients (35.3%) were on cART at baseline, 11 (64.7%) initiated cART prior to chemotherapy, and 13 (76.5%) received rituximab in addition to CHOP regimen. In the BL group, 4 patients (26.7%) were on cART at baseline, 11 (73.3%) started cART prior to receiving chemotherapy, and 11 (73.3%) received rituximab during chemotherapy (CODOX-M/IVAC + R). The demographic and clinical features of these patients are detailed in Table 1.Table 1 Clinical characteristics of HIV-infected patients with lymphoma receiving chemotherapy.\n\nCharacteristic\tDLBCL (n = 17)\tBurkitt lymphoma (n = 15)\t\n\nAge (mean ± SD)\n\t42.6 ± 13.3\t39.8 ± 8.5\t\n<50 years (%)\t11 (64.7)\t13 (86.7)\t\n≥50 years (%)\t6 (35.3)\t2 (13.3)\t\n\nMale sex, n\n(%)\n\t16 (94.1)\t15 (100.0)\t\n\nTransmission route, n\n(%)\n\t\nHomosexual sexual\t7 (41.2)\t8 (53.3)\t\nHeterosexual sexual\t8 (47.1)\t7 (46.7)\t\nTransfusion\t2 (11.8)\t0 (0.0)\t\n\nHIV-related characteristics\n\t\nBaseline viral load, copies/mL [median (range)]\t9039 (0–284331)\t39294.5 (0–849556)\t\nBaseline CD4 count, cells/µL [median (range)]\t104 (3–747)\t266.5 (11–415)\t\nCD4 count < 50 cells/µL, n (%)\t4 (23.5)\t1 (6.7)\t\nCD4 count 50–199 cells/µL, n (%)\t5 (29.4)\t6 (40.0)\t\nCD4 count ≥ 200 cells/µL, n (%)\t8 (47.1)\t8 (53.3)\t\nHaving received cART at baseline (%)\t6 (35.3)\t4 (26.7)\t\ncART initiation prior to chemotherapy (%)\t11 (64.7)\t11 (73.3)\t\n\nAnn Arbor stage, n (%)\t\nI\t0 (0.0)\t0 (0.0)\t\nII\t5 (29.4)\t5 (33.3)\t\nIII\t7 (41.2)\t2 (13.3)\t\nIV\t5 (29.4)\t8 (53.4)\t\n\nKarnofsky performance status, n (%)\t\n<40%\t7 (41.2)\t11 (73.3)\t\n40–60%\t6 (35.3)\t3 (20.0)\t\n>70%\t4 (23.5)\t1 (6.7)\t\n\nInternational prognostic index score, n (%)\t\n0\t0 (0.0)\t0 (0.0)\t\n1\t3 (17.6)\t1 (6.7)\t\n2\t8 (47.1)\t5 (33.2)\t\n3\t6 (35.3)\t8 (53.4)\t\n4\t0 (0.0)\t1 (6.7)\t\n\nLDH, U/L [median (range)]\t250.4 (152.1–937.9)\t364.8 (209.1–2664.9)\t\nLDH > upper limit of normal (%)\t10 (58.8)\t14 (93.3)\t\n\nB symptoms, n (%)\t3 (17.6)\t6 (40.0)\t\n\nBulky tumour (>10 cm), n (%)\t5 (29.4)\t9 (60.0)\t\n\nRituximab-containing therapy, n (%)\t13 (76.5)\t11 (73.3)\t\nHIV, human immunodeficiency virus; DLBCL, diffuse large B-cell lymphoma; SD, standard deviation; cART, combination antiretroviral therapy; LDH, lactate dehydrogenase.\n\n\n\n\nPathological features of study participants\nThe pathological diagnosis was determined by 2 separate pathologists in Ditan Hospital using immunohistochemical criteria. The cell of origin in the DLBCL arm was subdivided into GCB (10 cases) and non-GCB (7 cases) subtypes; 23.5% (4 cases) expressed BCL-2. BL was subdivided into EBV-positive (9 cases) and EBV-negative (6 cases) types. Fluorescence in situ hybridization was performed to identify c-MYC translocation in BL.\n\nAdverse events\nThe National Cancer Institute grade 3–4 toxicities observed during chemotherapy are summarised in Fig. 1. The proportion of patients in the BL and DLBCL arms, respectively, who experienced grade 4 adverse events were: neutropenia, 80% versus 47.1%; anaemia, 46.7% versus 5.9%; and thrombocytopenia, 53.3% versus 11.8% (p < 0.05). Patients also experienced grade 3–4 infectious complications, with 33.3% versus 5.9% in BL and DLBCL arms, respectively, developing bacterial pneumonia; 20% versus 5.9% developing sepsis; 6.7% versus 11.8% developing invasive fungal infections; and 6.7% versus 0.0% developing pulmonary tuberculosis. During the entire chemotherapy protocol, 8 BL patients (53.3%) required red blood cell transfusion (mean: 11 units), and 8 BL patients (53.3%) required transfusion of platelets (mean: 2.5 units) due to treatment-related myelosuppression. Only 1 DLBCL patient (5.9%) required red blood cell transfusion (of only 2 units).Figure 1 Grade 3/4 adverse effects in BL patients receiving CODOX-M/IVAC ± R and DLBCL patients receiving CHOP ± R chemotherapy.\n\n\n\n\nA significantly greater proportion of patients in the BL group died of treatment related causes (p < 0.01). In the BL group, 7 (46.6%) patients died of treatment-related causes (septic shock [n = 4], haemorrhage [n = 1], severe arrhythmia [n = 1], and renal failure [n = 1]), while in DLBCL group, only 3 patients (17.6%) died of treatment-related causes (septic shock [n = 2] and renal failure [n = 1]) (Table 2). In terms of duration of chemotherapy, the mean cycle length in the BL group receiving the CODOX-M/IVAC ± R regimen was 28.5 days, significantly longer than the 20.9 days that the DLBCL group received the CHOP ± R regimen (p < 0.001).Table 2 Outcome and causes of death following chemotherapy in HIV-infected patients with lymphoma.\n\nCharacteristic\tDLBCL, n (%) (n = 17)\tBurkitt lymphoma, n (%) (n = 15)\t\n\nComplete response\n\t\n14 (82.4)\n\t\n5 (33.3)\n\t\n\nPartial response\n\t\n0 (0.0)\n\t\n1 (6.7)\n\t\nDeath\t0 (0.0)\t1 (6.7)\t\n Cause of death\t\n Tumour metastasis\t0 (0.0)\t1 (6.7)\t\n\nProgressive Disease\n\t\n3 (17.6)\n\t\n7 (46.6)\n\t\nDeath\t3 (17.6)\t7 (46.6)\t\n Cause of death\t\n Septic shock\t2 (11.8)\t2 (13.3)\t\n Tumour metastasis\t0 (0.0)\t2 (13.3)\t\n Renal failure\t1 (5.8)\t1 (6.7)\t\n Haemorrhage\t0 (0.0)\t1 (6.7)\t\n Severe arrhythmia\t0 (0.0)\t1 (6.7)\t\n\nUnable to evaluate\n\t\n0 (0.0)\n\t\n2 (13.3)\n\t\nDeath\t0 (0.0)\t2 (13.3)\t\n Cause of death\t\n Septic shock\t0 (0.0)\t2 (13.3)\t\nHIV, human immunodeficiency virus; DLBCL: diffuse large B-cell lymphoma.\n\n\n\n\nIn the current observational cohort, patients receiving a CODOX-M/IVAC ± R regimen suffered from severe myelosuppression, with 8 patients (53.3%) requiring substantial volumes of red blood cells transfused and 8 (53.3%) requiring platelet transfusion during chemotherapy. Grade 3–4 infectious complications were the other main group of severe adverse events. Haemorrhage, arrhythmia, and renal failure were also fatal adverse events; these occurred in 3 patients during chemotherapy. The mean chemotherapy cycle length in the BL group receiving a CODOX-M/IVAC ± R regimen was significantly prolonged due to management of the above severe adverse events. Chemotherapy-associated deaths occurred in 7 patients (46.6%). These deaths were from septic shock, haemorrhage, arrhythmia, and renal failure.\n\nPatients with DLBCL receiving CHOP ± R also experienced severe myelosuppression, mainly grade 3–4 neutropenia (76.5%); but only 1 patient required red blood cell transfusion during chemotherapy. Grade 3–4 infectious complications experienced by these patients included bacterial pneumonia, sepsis, and invasive fungal infection. There were 3 chemotherapy-associated deaths in this group (17.6%).\n\nTreatment response and survival outcomes\nThe response to treatment, survival outcomes, and cause of death following chemotherapy in HIV-infected patients with lymphoma are listed in Table 2. Of the 17 patients with DLBCL receiving a CHOP ± R regimen, 14 (82.4%) achieved complete response, while 3 experienced progressive disease resulting in death (2 due to septic shock and 1 due to renal failure). Radiotherapy was initiated in 1 patient with BL who showed a poor response to 4 cycles of CODOX-M/IVAC; however, the response to radiotherapy was also poor. One-year overall survival was 82.4%, and the median overall survival duration was 26.6 months (range, 18.8–35.2 months). The overall mortality rate in this group was 17.6%. The 1-year PFS rate was 82.4%, with a median PFS of 25.8 months (range, 17.8–34.1 months), as shown in Figs 2 and 3.Figure 2 Overall survival curve for BL patients receiving CODOX-M/IVAC ± R and DLBCL patients receiving CHOP ± R chemotherapy.\n\n\nFigure 3 Progression-free survival curve for BL patients receiving CODOX-M/IVAC ± R and DLBCL patients receiving CHOP ± R chemotherapy.\n\n\n\n\nOf the 15 patients with BL receiving CODOX-M/IVAC ± R regimen, 5 (33.3%) achieved complete response, 1 achieved partial response (6.7%) and died within 2 months of completing chemotherapy due to progressive disease, while the other 7 patients experienced progressive disease and died during chemotherapy (septic shock [n = 4], haemorrhage [n = 1], severe arrhythmia [n = 1], and renal failure [n = 1]). Two other patients (13.3%) died of septic shock early during the course of chemotherapy, before treatment response could be evaluated. The overall mortality rate in this group was 66.7%. One-year overall survival was 33.3%, and the median overall survival duration was 13.8 months (range, 8.4–20.3 months). One-year PFS was 33.3%, and median PFS was 11.4 months (range, 5.4–18.5 months), as shown in Figs 2 and 3.\n\nRelapse in the interval between chemotherapy cycles\nOf the 17 patients with DLBCL who received the CHOP ± R regimen, 14 attained complete response while 3 had progressive disease with relapse in the interval between chemotherapy cycles: One relapsed between the first and second cycle, 1 between the fourth and fifth cycle, and 1 between the sixth and seventh cycle. All 3 patients died. Of the 15 patients with BL who received the CODOX-M/IVAC ± R regimen, 7 progressed, with relapse between the first and second cycle resulting in poor prognosis.\n\nIn the multivariate analysis, the strongest risk factor for death among HIV-infected patients with lymphoma receiving chemotherapy was relapse in the interval between chemotherapy cycles (adjusted hazard ratio [AHR], 47.3; 95% CI, 4.2–528.6; p = 0.002). Baseline CD4 count, initiation of cART prior to chemotherapy, and receiving rituximab during therapy were not statistically significantly associated with prognosis.\n\nEvaluation of HIV viral load after completion of chemotherapy\nOf the 32 patients receiving chemotherapy, 22 completed it (including 14 DLBCL patients receiving CHOP ± R and 8 BL patients receiving CODOX-M/IVAC ± R). HIV viral load was suppressed below the limit of detection of commercially available assays after completion of chemotherapy.\n\nDiscussion\nThis retrospective study was the first conducted in the Chinese mainland to evaluate the tolerability, efficacy, and outcome of chemotherapy in Chinese HIV-infected patients with AIDS-related BL and DLBCL. In the era of cART, standard dose chemotherapeutic regimens for DLBCL4 and intensive regimens for BL6 are recommended and have been used with success. In this study, we found that patients with DLBCL receiving standard dose CHOP ± R chemotherapy experienced severe adverse events, but that the regimen yielded good efficacy and survival outcomes. In patients with BL, however, intensive chemotherapy with CODOX-M/IVAC ± R was not feasible; it was poorly tolerated and yielded poor survival rates, being unable to overcome BL in our cohort. An important finding in this study was that relapse in the interval between chemotherapy cycles was the strongest risk factor for death in HIV-infected patients with lymphoma receiving chemotherapy. This was demonstrated for patients with BL and DLBCL, indicating a trend toward poor prognosis during chemotherapy despite the small number of patients. In this study, 11 patients experienced relapse in the interval between chemotherapy cycles; the mechanisms underlying relapse may be an area worthy of further elucidation in Chinese HIV-infected patients with lymphoma.\n\nAlthough the NFATP provides free antiretroviral medications to HIV-infected patients in China, the treatment of complications and co-morbidities, including AIDS-defining diseases such as lymphoma, must be paid for by the patients themselves18. Hence, 7 patients did not receive rituximab due to cost constraints. It has been reported that rituximab (a CD20-directed monoclonal antibody) improves overall survival and combines safely with the standard dose chemotherapeutic regimens, CHOP (for DLBCL)19 and CODOX-M/IVAC (for BL)20 in HIV-infected patients. In contrast, Kaplan et al.21 demonstrated in the AIDS-malignancies consortium trial 010, that rituximab did not improve clinical outcomes in a randomized phase 3 trial of CHOP ± R in patients with HIV-associated non-Hodgkin lymphoma. Wasterlid et al.22 also reported that rituximab was not significantly associated with improved overall survival in HIV-infected patients with BL treated with intensive regimens. In the present study, the multivariate analysis indicated that receiving rituximab during chemotherapy was not statistically significantly associated with prognosis. No adverse reactions, apart from 1 case of hypersensitivity reaction, were observed in the 24 patients who received rituximab, indicating that rituximab can be combined safely with the chemotherapeutic regimens used. However, use of rituximab did not show a trend favouring improvement in overall survival in our cohort.\n\nRecent studies6 demonstrated that antiretroviral regimen can be combined safely with intensive CODOX-M/IVAC or standard dose CHOP chemotherapy. In this study, most patients (22/32 cases) were not receiving cART as they were unaware of their HIV status until lymphoma—the first indicator of their disease—was diagnosed. These patients initiated cART prior to chemotherapy, whereas the other 10 patients were already taking cART when diagnosed with lymphoma. Of 32 the patients receiving chemotherapy, 22 completed it, and none had a detectable HIV viral load after completion of chemotherapy, indicating that the cART regimen used (tenofovir, lamivudine, plus efavirenz) did not interact with the chemotherapeutic regimens, and can combined safely with intensive CODOX-M/IVAC ± R or standard dose CHOP ± R chemotherapy in Chinese HIV-infected patients.\n\nIt is undisputable that long-term concomitant cART improves overall survival in patients with AIDS-related BL or DLBCL receiving chemotherapy. Chiang et al.23 demonstrated that short-term cART did not improve immune function, especially in severely immunosuppressed patients. In this study, 22 patients did not initiate cART until immediately prior to receiving chemotherapy. The multivariate analysis indicated that initiating cART prior to chemotherapy was not statistically significantly associated with prognosis, implying that initiating cART prior to receiving chemotherapy does not improve overall survival in patients with AIDS-related BL or DLBCL.\n\nIn this study, we found that intensive chemotherapy with CODOX-M/IVAC ± R yielded severe toxicity because of lower Karnofsky performance status and lower CD4 cell counts. In Chinese patients with HIV-associated lymphoma, most patients were not diagnosed with HIV infection until lymphoma became the first indicator of their disease. Hence, they presented with late-stage disease (AIDS) and lower CD4 counts, making them prone to infectious complications, resulting in lower Karnofsky performance status and intolerance of chemotherapy-induced toxicities. In this study, the intensive chemotherapeutic regimen, CODOX-M/IVAC ± R, was used to treat BL in HIV-infected patients in China, but these patients had poor clinical response rates, poor survival outcomes, and could not tolerate chemotherapy due to severe toxicity. The AMC 048 study24 indicated that, using modified CODOX-M/IVAC-R regimen, the 1-year overall survival was 72% among patients with a Karnofsky performance status >30. The Northern Italy Leukemia Group adopted the B-NHL 2002 regimen to treat a cohort of 105 consecutive, unselected adult patients with BL and demonstrated on multivariate analysis that patients with an Eastern Cooperative Oncology Group performance status >1 did very poorly25. In this study, Karnofsky performance status was <40% in 11 patients (73.3%) in the BL group, and intensive chemotherapy with CODOX-M/IVAC ± R was associated with severe toxicity and poor survival rates, indicating that patients with poor performance status also do poorly in China, and suggesting that intensive chemotherapy is not recommended for patients with lower Karnofsky performance status scores. Dunleavy et al.26 reported low-intensity treatment consisting of infused etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (EPOCH-R) for patients with untreated BL. Their results indicated that a lower-dose short-course combination with a double dose of rituximab (SC-EPOCH-RR)-based treatment was highly effective in adults with sporadic or immunodeficiency-associated BL. Low-intensity EPOCH-R-based treatment may be a good chemotherapeutic option for HIV-infected patients with BL in China.\n\nIn summary, HIV-infected patients with BL and DLBCL receiving chemotherapy experienced severe myelosuppression and infectious complications due to the overall poor performance status and relatively low CD4 counts. Patients with DLBCL demonstrated good clinical responses and survival outcomes when treated with CHOP ± R, but patients with BL could not tolerate chemotherapy with CODOX-M/IVAC ± R due to more severe toxicity; and their clinical response and survival outcomes were poor due to poor performance status and lower CD4 counts. Intensive chemotherapy with CODOX-M/IVAC ± R is not recommended for patients with BL with lower Karnofsky performance status scores and lower CD4 counts in China. Relapse in the interval between chemotherapeutic cycles was the strongest risk factor for death among patients with lymphoma receiving chemotherapy. Short-term cART prior to chemotherapy failed to improve overall survival, but long-term concomitant cART is important to prevent lymphoma and enable successful chemotherapy to treat lymphoma.\n\nJiang Xiao & Shuxu Du contributed equally to this work.\n\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe acknowledge the work of the HIV health care providers for their diagnosis, nursing and treatment of HIV/AIDS patients in Ditan Hospital. We acknowledge the work of social workers and volunteers in Beijing Red Ribbon who provide counselling, and adherence interventions and help to resolve psychosocial issues for HIV/AIDS patients. Support for this work was provided by: (1) Healthcare Talent Training Program in Beijing Health System (grant 2015-3-105). (2) the National Natural Science Fund The study of T-cell repertoire diversity in AIDS patients based on the restoration of thymic function (grant 81371804). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nAuthor Contributions\nConceived and designed the experiments: Hongxin Zhao; Performed experiment: Jiang Xiao and Shuxu Du. Wrote the manuscript: Jiang Xiao. Analysed the data: Jiang Xiao, Shuxu Du, Guorui Dai, Guiju Gao and Di Yang.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Howlader N Shiels MS Mariotto AB Engels EA Contributions of HIV to non-Hodgkin lymphoma mortality trends in the US Cancer Epidemiol. Biomarkers Prev. 2016 25 1289 1296 10.1158/1055-9965.EPI-16-0273 27418269 \n2. Dou Z Changing baseline characteristics among patients in the China National Free Antiretroviral Treatment Program, 2002–09 Int. J. Epidemiol. 2010 39 Suppl 2 ii56 64 21113038 \n3. Xiao J Spectrums of infectious complications and malignancies in HIV-infected patients in tertiary care hospital, China PLoS One. 2013 8 e75915 10.1371/journal.pone.0075915 24204583 \n4. Ribera JM Long-term follow-up of patients with HIV-related diffuse large B-cell lymphomas treated in a phase II study with rituximab and CHOP Br. J. Haematol. 2012 157 637 639 10.1111/j.1365-2141.2012.09046.x 22313456 \n5. Coutinho R HIV status does not impair the outcome of patients diagnosed with diffuse large B-cell lymphoma treated with R-CHOP in the cART era AIDS 2014 28 689 697 10.1097/QAD.0000000000000133 24418826 \n6. Rodrigo JA HIV-associated Burkitt lymphoma: Good efficacy and tolerance of intensive chemotherapy including CODOX-M/IVAC with or without rituximab in the HAART era Adv. Hematol. 2012 2012 735392 10.1155/2012/735392 22190945 \n7. Mead GM An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 study Ann. Oncol. 2002 8 1264 1274 10.1093/annonc/mdf253 \n8. Hu S MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program Blood 2013 121 4021 4031 10.1182/blood-2012-10-460063 23449635 \n9. Lam LT Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma Blood 2008 111 3701 3713 10.1182/blood-2007-09-111948 18160665 \n10. Hans CP Confırmation of the molecular classifıcation of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray Blood 2004 103 275 282 10.1182/blood-2003-05-1545 14504078 \n11. Asano N Age-related Epstein Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients Blood 2009 113 2629 2636 10.1182/blood-2008-06-164806 19075188 \n12. Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of infectious complications in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm. Rep. 58, 1–207, quiz CE1-4 (2009).\n13. Inano S Impact of high-dose chemotherapy and autologous transplantation as first-line therapy on the survival of high-risk diffuse large B cell lymphoma patients: a single-center study in Japan Int J Hematol. 2014 99 162 168 10.1007/s12185-013-1486-6 24338743 \n14. Hagemeister F Long term results of a phase 2 study of vincristine sulfate liposome injection substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas Br J Haematol. 2013 162 631 638 10.1111/bjh.12446 23802738 \n15. Panel on Antiretroviral Guidelines for Adults and Adolescents (2012) Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.\n16. Zhang, F. editor. National Free HIV Antiretroviral Treatment Handbook. 3rd ed. Beijing, China. (People’s Medical Publishing House, 2012) (Chinese).\n17. Cheson BD Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group J. Clin. Oncol. 1999 17 1244 1253 10.1200/JCO.1999.17.4.1244 10561185 \n18. Xiao J Causes of death among patients infected with HIV at a tertiary care hospital in China: An observational cohort study AIDS Res. Hum. Retroviruses. 2016 32 782 790 10.1089/aid.2015.0271 26971827 \n19. Cabanillas F Front-line immunochemotherapy for aggressive non-Hodgkin using dose-dense rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone plus granulocyte-macrophage colony stimulating factor and pegfilgrastim as support Leuk. Lymphoma 2012 53 1929 1933 10.3109/10428194.2012.679264 22448918 \n20. Barnes JA Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt’s lymphoma: a retrospective analysis Ann. Oncol. 2011 22 1859 1864 10.1093/annonc/mdq677 21339382 \n21. Kaplan LD Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab inpatients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010 Blood 2005 06 1538 1543 10.1182/blood-2005-04-1437 \n22. Wästerlid T Impact of chemotherapy regimen and rituximab in adult Burkitt lymphoma: a retrospective population-based study from the Nordic Lymphoma Group Ann. Oncol. 2013 24 1879 1886 10.1093/annonc/mdt058 23446093 \n23. Chiang HH Admissions to intensive care unit of HIV-infected patients in the era of highly active antiretroviral therapy: etiology and prognostic factors Crit. Care 2011 15 R202 10.1186/cc10419 21871086 \n24. Noy A AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma Blood 2015 126 160 166 10.1182/blood-2015-01-623900 25957391 \n25. Intermesoli T High cure rates in Burkitt lymphoma and leukemia: a Northern Italy Leukemia Group study of the German short intensive rituximab-chemotherapy program Haematologica 2013 98 1718 1725 10.3324/haematol.2013.086827 23753030 \n26. Dunleavy K Low-intensity therapy in adults with Burkitt’s lymphoma N. Engl. J. Med. 2013 369 1915 1925 10.1056/NEJMoa1308392 24224624\n\n",
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"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D002051:Burkitt Lymphoma; D002423:Cause of Death; D002681:China; D003520:Cyclophosphamide; D018450:Disease Progression; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone; D011379:Prognosis; D016896:Treatment Outcome; D014750:Vincristine",
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"title": "Efficacy and tolerability of chemotherapy in Chinese patients with AIDS-related Burkitt lymphoma and diffuse large B-cell lymphoma: An observational study.",
"title_normalized": "efficacy and tolerability of chemotherapy in chinese patients with aids related burkitt lymphoma and diffuse large b cell lymphoma an observational study"
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"abstract": "Anti-N-methyl-d-aspartate receptor (anti-NMDA-R) encephalitis is an autoimmune disorder that was first described by Dr Vitaliani in 2005. In 2007, Dalmau et al. found anti-NMDA-R antibody expressed both in the hippocampus and prefrontal nerve cell membrane, finally proposing the diagnosis of autoimmune anti-NMDA-R encephalitis. Most of the patients are female (91%), with ages ranging from 4 to 76 years. The average age is 23 years, a birth peak age, although anti-NMDA-R encephalitis is rare during pregnancy. The disorder is characterized by prominent psychosis, dyskinesias, seizures, autonomic disturbance, and central hypoventilation. We report a 24-year-old woman hospitalized at 28 gestational weeks with acute-onset psychosis. Over the course of 3 weeks, her mental status worsened until she fell into a coma. Both serum and cerebrospinal fluid anti-NMDA-R antibodies were found to be positive. At cesarean section, a healthy baby boy was born and a wedge-shaped bilateral ovarian resection was performed. Treatment with corticosteroids, intravenous immunoglobulin, and plasmapheresis can lead to improved outcomes for both mother and baby.",
"affiliations": "Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.;West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.;Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.;Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.;Independent Scholar, Washington, DC, USA.;Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, China.",
"authors": "Xiao|Xue|X|;Gui|Shunping|S|;Bai|Peng|P|;Bai|Yi|Y|;Shan|Dan|D|;Hu|Yayi|Y|;Bui-Nguyen|Tri M|TM|;Zhou|Rong|R|",
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"mesh_terms": "D000328:Adult; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D003128:Coma; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D055815:Young Adult",
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"abstract": "High-dose tigecycline therapy is gaining wide acceptance in treating infections caused by multidrug-resistant bacteria. There are no reports of cutaneous hyperpigmentation with the use of high-dose tigecycline. Here we report a case of a woman who developed reversible cutaneous hyperpigmentation within 48 h of receiving high-dose tigecycline.",
"affiliations": "Department of Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.;Pharmaceutical Care Division, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.;Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.;Hepatobiliary and Surgical Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.",
"authors": "Alsemari|Muhannad A|MA|https://orcid.org/0000-0003-3181-4261;Hakeam|Hakeam A|HA|https://orcid.org/0000-0002-6979-0966;Alsalman|Hussain|H|;Amin|Tarek|T|",
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"fulltext": "\n==== Front\nTher Adv Infect Dis\nTher Adv Infect Dis\nTAI\nsptai\nTherapeutic Advances in Infectious Disease\n2049-9361 2049-937X SAGE Publications Sage UK: London, England \n\n10.1177/2049936120952605\n10.1177_2049936120952605\nCase Report\nCutaneous Hyperpigmentation Secondary to High-Dose Tigecycline: A Case Report\nhttps://orcid.org/0000-0003-3181-4261Alsemari Muhannad A. Department of Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia\n https://orcid.org/0000-0002-6979-0966Hakeam Hakeam A. Pharmaceutical Care Division, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia\nCollege of Medicine, Alfaisal University, Riyadh, Saudi Arabia\n Alsalman Hussain Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia\n Amin Tarek Hepatobiliary and Surgical Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia\n malsemari@kfshrc.edu.sa\n26 8 2020 \nJan-Dec 2020 \n7 204993612095260516 5 2020 4 8 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).High-dose tigecycline therapy is gaining wide acceptance in treating infections caused by multidrug-resistant bacteria. There are no reports of cutaneous hyperpigmentation with the use of high-dose tigecycline. Here we report a case of a woman who developed reversible cutaneous hyperpigmentation within 48 h of receiving high-dose tigecycline.\n\nadverse effecthigh dosehyperpigmentationtigecyclinecover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nTigecycline is a broad-spectrum antibiotic derived from minocycline and specifically developed to overcome mechanisms of bacterial resistance.1\nIn vitro, tigecycline exerts antibacterial activity against multidrug-resistant Gram-positive and Gram-negative bacteria, including methicillin-resistant staphylococci, vancomycin-resistant enterococci, and extended-spectrum β-lactamase-producing Enterobacteriaceae. Clinically, tigecycline demonstrated efficacy similar to that of comparator antibiotics in treating various bacterial infections.2 The US Food and Drug Administration (FDA) and the European Medicines Agency have approved tigecycline for the treatment of complicated intra-abdominal infections and skin and soft-tissue infections at a dose of 50 mg every 12 h following a loading dose of 100 mg.2\n\nIn 2010, the US FDA issued a box warning for tigecycline use after a pooled analysis of 13 trials for approved and unapproved indications demonstrated a relative mortality increase of 33%.3 The highest incidence of mortality was observed in patients treated for ventilator-associated pneumonia (VAP).3 Inadequate concentrations of tigecycline in pulmonary alveolar cells were postulated as an explanation for the increased mortality in patients with VAP treated with the standard dose of tigecycline.4 Therefore, tigecycline was reintroduced to clinical practice at higher doses to boost its tissue concentration. A recent meta-analysis has supported this approach by demonstrating lower mortality with the high-dose regimen compared with the conventional dose.5 Tigecycline extensively distributes into soft tissues, with a viable skin tissue concentration 3.9 times its serum level.6 Despite this pharmacokinetic feature of tigecycline, cutaneous side-effects were uncommon, and typically appeared in the form of a rash and pruritus at rates of less than 4%, as reported by phase III trials.3\n\nHere, we report a case of a woman who developed cutaneous hyperpigmentation within 48 h of receiving high-dose tigecycline (100 mg every 12 h).\n\nCase report\nA 59-year-old woman underwent an elective pancreaticoduodenectomy for a duodenal neuroendocrine tumor. A computed tomography scan, performed on day 10 postoperatively, revealed intra-abdominal collections suggestive of a pancreaticojejunal leak. Owing to her positive history of penicillin allergy, described as shortness of breath and generalized skin rash, the patient was started on tigecycline 100 mg as a loading dose followed by 50 mg every 12 h in combination with aztreonam and anidulafungin. On day 36 postoperatively, while on the same antimicrobials, the patient developed severe hypotension mandating surgical exploration for source control. Cultures obtained intraoperatively revealed Stenotrophomonas maltophilia resistant to ceftazidime, levofloxacin, and sulfamethoxazole/trimethoprim, but sensitive to colistin. Fungal cultures were positive for Candida parapsilosis. Antimicrobials were accordingly changed to colistin plus tigecycline, in addition to fluconazole as an antifungal. Two days after changing the antimicrobials, the patient developed an acute kidney injury with a nadir estimated glomerular filtration rate (e-GFR) of 34 ml/min/1.72 m2. The colistin and fluconazole doses were adjusted according to the e-GFR, whereas the tigecycline dose was increased to 100 mg every 12 h. Kidney function improved slowly after 5 days of vigorous hydration with intravenous crystalloid solution and the e-GFR increased to 44 ml/min/1.72 m2. After 48 h of increasing tigecycline dose, the patient developed generalized diffuse cutaneous hyperpigmentation, most notably on the lips, hands, thighs, neck, and anterior trunk (Figure 1(a) and (b)). Physical examination revealed extensive darkening of the skin, with no scales, hair loss, or blisters. The patient reported pruritus over the affected areas of her body. On counseling the patient, she denied using any recent topical formulations and stated that she had never experienced such a skin reaction previously. A tigecycline-induced cutaneous adverse effect was suspected, therefore, the high-dose therapy was reverted to the conventional dose. The skin color and pruritus gradually improved over the subsequent 10 days following tigecycline dose reduction. There were noted areas of desquamation involving both hands, but absent in the remaining affected areas. Medications received concomitantly with the high-dose tigecycline included acetaminophen, omeprazole, octreotide, metoclopramide, amlodipine, enoxaparin, colistin, and fluconazole. None of these medications were stopped in the 7 days following the onset of skin discoloration. A skin punch biopsy was obtained from the right thigh of the patient 20 days after tigecycline dose reduction. It revealed a spongiotic epidermis and a dermal perivascular mononuclear infiltrate and scattered eosinophils. Increased basal keratinocyte pigmentation was observed. No histological features suggestive of ischemia were observed (Figure 2). These findings are histologically consistent with drug-related skin changes. The patient continued the conventional dose of tigecycline for 24 days, with gradual convalescence in skin discoloration (Figure 1(c) and (d)).\n\nFigure 1. (a) and (b) Patient 48 h after receiving high-dose tigecycline, (c) and (d) Patient 10 days after reverting to the conventional dose of tigecycline.\n\nFigure 2. Skin section obtained from a skin punch biopsy from the right thigh of the patient 20 days after tigecycline dose reduction. (Hematoxylin and eosin, (a) original magnification ×100, (b) original magnification ×200.)\n\nDiscussion\nIn this report, we describe the occurrence of a reversible cutaneous hyperpigmentation following the use of high-dose tigecycline therapy. Cutaneous adverse reactions have been reported with minocycline, the parent compound of tigecycline.7,8 Minocycline-induced skin hyperpigmentation occurs in a dose-dependent fashion, at an incidence exceeding 14%.8 Although the mechanism of developing skin hyperpigmentation with minocycline has not been completely delineated, it is postulated to occur secondary to the accumulation of black-colored degradation products of minocycline in body tissues.9 It is unknown if tigecycline metabolism produces similar metabolites to explain the skin discoloration observed in our patient.\n\nVandecasteele et al. described skin hyperpigmentation of the upper trunk and arms in a woman with osteomyelitis treated for 102 days with a conventional dose of tigecycline.10 A skin biopsy revealed melanin-containing macrophages. Although the authors reported the cessation of tigecycline therapy after the appearance of skin hyperpigmentation, no information was given regarding the prognosis of this side effect. To our knowledge, that was the only report of cutaneous hyperpigmentation attributed solely to tigecycline therapy.10\n\nIn comparison, our patient developed cutaneous hyperpigmentation as early as 48 h of high-dose tigecycline therapy. This rapid skin discoloration could be attributed to increased tigecycline levels in the skin secondary to the use of a high dose during an episode of acute kidney injury. Although there is no recommendation for dose adjustment of tigecycline in patients with renal impairment, 15% of the tigecycline dose is known to be excreted unchanged in the urine.3,11 The gradual abatement of skin hyperpigmentation following the reduction in tigecycline dose and the improvement in renal function further support our presumption of a tigecycline-related cutaneous reaction. Other concomitant medications such as omeprazole and colistin have been reported to induce skin discolorations.12,13 However, their continuation during the evident improvement in skin color lessens their likelihood of involvement in the observed hyperpigmentation. An unreported drug–drug interaction developing at high levels of tigecycline could be another explanation of the cutaneous discoloration in our patient. It is unknown whether skin hyperpigmentation is linked to more serious complications of tigecycline therapy; however, their unsightly nature may be a source of patient discomfort.\n\nWith the expanding use of high-dose tigecycline therapy, clinicians need to be vigilant regarding this cutaneous adverse effect that may affect patients’ acceptance of the therapy. An objective causality assessment, using the Naranjo Adverse Reaction Probability Scale, indicated a ‘probable’ relationship between the development of skin hyperpigmentation and the high-dose tigecycline therapy.14\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n\nEthics statement: Written informed consent was obtained from the patient, with documentation in the patient’s chart, to publish this case with the accompanying images.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iDs: Muhannad A. Alsemari \nhttps://orcid.org/0000-0003-3181-4261\n\nHakeam A. Hakeam \nhttps://orcid.org/0000-0002-6979-0966\n==== Refs\nReferences\n1. \nPetersen PJ Jacobus NV Weiss WJ , et al\nIn vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936)\n. Antimicrob Agents Chemother \n1999 ; 43 : 738 –744\n.10103174 \n2. \nStein GE Babinchak T \nTigecycline: an update\n. Diagn Microbiol Infect Dis \n2013 ; 75 : 331 –336\n.23357291 \n3. \nTYGACIL®(tigecycline)[packageinsert] . Philadelphia, PA : Wyeth Pharmaceuticals LLC , https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021821s048lbl.pdf (accessed 7 March 2020 ).\n4. \nRamirez J Dartois N Gandjini H , et al\nRandomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia\n. Antimicrob Agents Chemother \n2013 ; 57 : 1756 –1762\n.23357775 \n5. \nGong J Su D Shang J , et al\nEfficacy and safety of high-dose tigecycline for the treatment of infectious diseases: a meta-analysis\n. Medicine (Baltimore) \n2019 ; 98 : e17091 .31567945 \n6. \nStein GE Smith CL Missavage A , et al\nTigecycline penetration into skin and soft tissue\n. Surg Infect (Larchmt) \n2011 ; 12 : 465 –467\n.22136488 \n7. \nKrause W \nDrug-induced hyperpigmentation: a systematic review\n. J Dtsch Dermatol Ges \n2013 ; 11 : 644 –651\n.23650908 \n8. \nDereure O \nDrug-induced skin pigmentation. Epidemiology, diagnosis and treatment\n. Am J Clin Dermatol \n2001 ; 2 : 253 –262\n.11705252 \n9. \nEisen D Hakim MD \nMinocycline-induced pigmentation. Incidence, prevention and management\n. Drug Saf \n1998 ; 18 : 431 –440\n.9638388 \n10. \nVandecasteele SJ De Ceulaer J Wittouck E \nTigecycline induced hyperpigmentation of the skin\n. Open Forum Infect Dis \n2016 ; 3 : ofw033.\n11. \nKasbekar N \nTigecycline: a new glycylcycline antimicrobial agent\n. Am J Health Syst Pharm \n2006 ; 63 : 1235 –1243\n.16790575 \n12. \nRamirez-Hernandez M Martinez-Escribano JA Martinez-Barba E , et al\nCutaneous hyperpigmentation induced by omeprazole mimicking ashy dermatosis\n. J Eur Acad Dermatol Venereol \n2006 ; 20 : 584 –587\n.16684288 \n13. \nZheng G Cao L Che Z , et al\nPolymyxin B-induced skin hyperpigmentation: a rare case report and literature review\n. BMC Pharmacol Toxicol \n2018 ; 19 : 41 .29973293 \n14. \nNaranjo CA Busto U Sellers EM , et al\nA method for estimating the probability of adverse drug reactions\n. Clin Pharmacol Ther \n1981 ; 30 : 239 –245\n.7249508\n\n",
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"keywords": "adverse effect; high dose; hyperpigmentation; tigecycline",
"medline_ta": "Ther Adv Infect Dis",
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"title": "Cutaneous Hyperpigmentation Secondary to High-Dose Tigecycline: A Case Report.",
"title_normalized": "cutaneous hyperpigmentation secondary to high dose tigecycline a case report"
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"abstract": "Fentanyl has a low molecular weight and is lipophilic making it suitable for transdermal administration. However, multiple factors appear to lead to interindividual variation in absorption via this route. Here we describe an unusual case where a patient was found to have twelve 100 μg/hour fentanyl patches in situ which she was using as background analgesia.",
"affiliations": "Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK deborah.lam@nhs.net.;Palliative Medicine, Manchester University NHS Foundation Trust, Manchester, UK.;Palliative Medicine, Manchester University NHS Foundation Trust, Manchester, UK.;Palliative Medicine, Manchester University NHS Foundation Trust, Manchester, UK.",
"authors": "Lam|Deborah|D|;Kay|Samantha|S|;Pickard|Jennie|J|;Harrison|Sophie|S|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1136/bmjspcare-2018-001652",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-435X",
"issue": "9(4)",
"journal": "BMJ supportive & palliative care",
"keywords": "cachexia; drug administration; pain; pharmacology; transdermal fentanyl",
"medline_ta": "BMJ Support Palliat Care",
"mesh_terms": "D000701:Analgesics, Opioid; D002100:Cachexia; D005260:Female; D005283:Fentanyl; D006738:Hospices; D006801:Humans; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D010146:Pain; D003668:Pressure Ulcer; D012869:Skin Absorption; D057968:Transdermal Patch",
"nlm_unique_id": "101565123",
"other_id": null,
"pages": "363-364",
"pmc": null,
"pmid": "30612090",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unusual case of transdermal fentanyl in cachexia.",
"title_normalized": "unusual case of transdermal fentanyl in cachexia"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1063434",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "1",
... |
{
"abstract": "A 40-year-old woman with HIV (CD4 270, viral load undetectable) from Zambia presented with fevers, urinary tract infection symptoms, sterile pyuria and haematuria. She was found to have genitourinary tuberculosis (TB) via mycobacterial culture of urine and ascites, and treated with rifabutin, isoniazid, pyrazinamide and ethambutol. She later had multiple episodes of asymptomatic transaminitis, triggering changes to both TB and HIV regimens. The patient then presented with diffuse rash, fevers, transaminitis and eosinophilia concerning for drug reaction with eosinophilia and systemic symptoms (DRESS). After initial improvement on discontinuation of likely responsible medications and completion of corticosteroid therapy, the patient returned with acute liver failure. This new episode was felt to be severe organ dysfunction due to DRESS, and she was treated with a prolonged corticosteroid taper and changes to her TB regimen. She has since completed therapy for TB, has improving CD4 counts and is without evidence of liver dysfunction.",
"affiliations": "Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.;Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.;Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.",
"authors": "Czapka|Michael|M|;Shukla|Shuchin|S|;Slosar-Cheah|Magdalena|M|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D017828:Rifabutin; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220440",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "HIV / AIDS; hepatitis other; immunology; tuberculosis; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000904:Antibiotics, Antitubercular; D063926:Drug Hypersensitivity Syndrome; D004359:Drug Therapy, Combination; D004977:Ethambutol; D005260:Female; D006801:Humans; D007538:Isoniazid; D011718:Pyrazinamide; D017828:Rifabutin; D014401:Tuberculosis, Urogenital",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28784884",
"pubdate": "2017-08-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11722498;11964706;15817524;18190954;18836557;1928204;21143513;23114284;23983705;24450829;24798353;26142408;26238129;26891664;27464823;9487410",
"title": "Urine trouble: genitourinary tuberculosis and subsequent DRESS syndrome.",
"title_normalized": "urine trouble genitourinary tuberculosis and subsequent dress syndrome"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201708758",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
... |
{
"abstract": "Histoplasmosis has variable clinical presentation that mimics various benign and malignant lesions. It is more often associated with pulmonary lesions and disseminated form of disease. Herein, we report a rare case of localized laryngeal histoplasmosis in a 62-year-old Indian man who presented with hoarseness of voice and dysphagia. Post-renal transplant, he was on immunosuppressive drugs for last three years. Laryngoscopy revealed an ulceroproliferative growth at base of tongue, which was extending upto the pyriform fossa. Histopathology of laryngeal biopsy revealed numerous intracellular fungal yeast forms of Histoplasma that were subsequently confirmed serologically. The patient was put on oral itraconazole therapy and he responded well to the treatment with complete resolution of the disease. Early diagnosis and management of patient helps in preventing dissemination of the disease.",
"affiliations": "Department of Pathology, Bhopal Memorial Hospital and Research Centre, Raisen Bypass Road, 462038 Bhopal, India. Electronic address: pallavi9028@gmail.com.;Department of Pathology, Bhopal Memorial Hospital and Research Centre, Raisen Bypass Road, 462038 Bhopal, India. Electronic address: hannigulwani@yahoo.com.",
"authors": "Jawale|P M|PM|;Gulwani|H V|HV|",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole",
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2017.06.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "27(4)",
"journal": "Journal de mycologie medicale",
"keywords": "Histoplasmosis; Laryngeal; Post-renal transplant; Primary",
"medline_ta": "J Mycol Med",
"mesh_terms": "D000935:Antifungal Agents; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D016867:Immunocompromised Host; D007194:India; D017964:Itraconazole; D016030:Kidney Transplantation; D007830:Larynx; D008297:Male; D008875:Middle Aged; D014456:Ulcer",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "573-576",
"pmc": null,
"pmid": "28736209",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Histoplasmosis presenting as laryngeal ulcer in a post-renal transplant male: An unusual case from India.",
"title_normalized": "histoplasmosis presenting as laryngeal ulcer in a post renal transplant male an unusual case from india"
} | [
{
"companynumb": "IN-ALKEM LABORATORIES LIMITED-IN-ALKEM-2017-01799",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"druga... |
{
"abstract": "We report a midazolam-related death that occurred during endoscopic retrograde cholangiopancreatography (ERCP). The acute intoxication due to midazolam overdose was confirmed by high-pressure liquid chromatography (HPLC) analysis of the blood samples taken from the patient in the intensive care unit (2.8 microg/ml) and postmortem (2.4 microg/ml). The case strongly emphasizes the necessity of the precautions that should be taken when midazolam is intravenously administered.",
"affiliations": "Department of Forensic Pathology, University of Crete, Iraklion, Greece.",
"authors": "Michalodimitrakis|M|M|;Christodoulou|P|P|;Tsatsakis|A M|AM|;Askoxilakis|I|I|;Stiakakis|I|I|;Mouzas|I|I|",
"chemical_list": "D014151:Anti-Anxiety Agents; D008874:Midazolam",
"country": "United States",
"delete": false,
"doi": "10.1097/00000433-199903000-00022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "20(1)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D014151:Anti-Anxiety Agents; D002760:Cholangiopancreatography, Endoscopic Retrograde; D002851:Chromatography, High Pressure Liquid; D016292:Conscious Sedation; D000075202:Contraindications; D062787:Drug Overdose; D017809:Fatal Outcome; D006801:Humans; D007275:Injections, Intravenous; D007431:Intraoperative Complications; D008297:Male; D008874:Midazolam; D008875:Middle Aged",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "93-7",
"pmc": null,
"pmid": "10208347",
"pubdate": "1999-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Death related to midazolam overdose during endoscopic retrograde cholangiopancreatography.",
"title_normalized": "death related to midazolam overdose during endoscopic retrograde cholangiopancreatography"
} | [
{
"companynumb": "GR-ROCHE-233309",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nHaff disease is a rare syndrome of rhabdomyolysis thought to be caused by a heat-stable toxin associated with the consumption of seafood from fresh or brackish water.\n\n\nMETHODS\nWe present the case of a patient with Haff disease who presented to the emergency department with nausea/vomiting, diarrhea, and myalgias after a seafood buffet. Initially, he was treated with i.v. fluids and antiemetics for presumed gastroenteritis, but his symptoms did not improve. He was found to have elevated aspartate aminotransferase and alanine aminotransferase, normal point-of-care ultrasound, urinalysis with large blood and no red blood cells, and an elevated creatine phosphokinase (CPK). He was admitted to the hospital to receive ongoing fluid resuscitation for rhabdomyolysis presumed to be from fish. Liver enzymes and CPK downtrended, and patient was discharged on hospital day 3. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Undiagnosed Haff disease has important clinical implications, including multi-organ failure and death. Always maintain a high level of suspicion for Haff disease in patients with symptoms suggestive of gastroenteritis, but complicated by minor liver function test elevations and dipstick positivity for heme, without significant numbers of red blood cells per high-power field, in the setting of recent seafood ingestion.",
"affiliations": "Department of Emergency Medicine, SUNY Downstate, Kings County Hospital Center, Brooklyn, New York.;Department of Emergency Medicine, SUNY Downstate, Kings County Hospital Center, Brooklyn, New York.;Department of Emergency Medicine, SUNY Downstate, Kings County Hospital Center, Brooklyn, New York.",
"authors": "Ahmad|Surriya C|SC|;Sim|Christianna|C|;Sinert|Richard|R|",
"chemical_list": "D004798:Enzymes; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2019.08.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "57(6)",
"journal": "The Journal of emergency medicine",
"keywords": "ALT; AST; CK; CPK; Haff disease; LFT; buffalo fish; gastroenteritis; liver enzymes; myalgias; rhabdomyolysis; seafood; urinalysis",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase; D003967:Diarrhea; D004636:Emergency Service, Hospital; D004798:Enzymes; D006801:Humans; D008099:Liver; D008297:Male; D012206:Rhabdomyolysis; D000068357:Saline Waters; D017747:Seafood; D014839:Vomiting",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e181-e183",
"pmc": null,
"pmid": "31767218",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Elevated Liver Enzymes as a Manifestation of Haff Disease.",
"title_normalized": "elevated liver enzymes as a manifestation of haff disease"
} | [
{
"companynumb": "NVSC2019US082139",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALUMINUM HYDROXIDE\\DIMETHICONE\\MAGNESIUM HYDROXIDE"
},
... |
{
"abstract": "BACKGROUND\nGabapentin increasingly is being used to treat chronic pain in addition to seizures, anxiety, and bipolar disorder. Chorea has been reported as a potential side effect of gabapentin.\n\n\nMETHODS\nWe report the case of a patient with chronic low back pain who was treated with a host of modalities, including gabapentin. After she increased her dose of gabapentin, she developed chorea of the upper extremities, neck, and head. With cessation of gabapentin, the bulk of her symptoms resolved within 24 hours, and symptoms completely resolved in the following months.\n\n\nCONCLUSIONS\nChorea is thought to appear when the basal ganglia are deregulated. Gabapentin interferes with gamma-aminobutyric acid, the primary inhibitory neurotransmitter in the motor pathway. Chorea associated with gabapentin has been reported in several case studies, but not at a dose as low as the patient took in this case.",
"affiliations": "Center for Pain Management, Summa Western Reserve Hospital, Cuyahoga Falls, OH.;Department of Psychiatry, Wayne State University, and Detroit Medical Center, Detroit, MI.;Department of Pain Management, Ochsner Clinic Foundation, New Orleans, LA.",
"authors": "Souzdalnitski|Dmitri|D|;Chang|Anita Kumar|AK|;Guirguis|Maged|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-5012",
"issue": "14(2)",
"journal": "The Ochsner journal",
"keywords": "Basal ganglia; chorea; chronic pain; drug-related side effects and adverse reactions; gabapentin; gamma-aminobutyric acid",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "276-8",
"pmc": null,
"pmid": "24940142",
"pubdate": "2014",
"publication_types": "D002363:Case Reports",
"references": "14568805;20875433;8618709;18392431;9236582;15886505;7249508;9686247;17938990;19766954",
"title": "Chorea in a chronic pain patient using gabapentin.",
"title_normalized": "chorea in a chronic pain patient using gabapentin"
} | [
{
"companynumb": "PHHY2014US082349",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAVASTATIN\\PRAVASTATIN SODIUM"
},
"drugadditional": ... |
{
"abstract": "Paraneoplastic neurological syndromes (PNS), such as sensory polyneuropathy, are rare, and serum neuronal antibodies that are used for diagnosing this syndrome are occasionally positive. Similarly, neurological immune-related adverse events due to immune checkpoint inhibitors (ICIs) are also rare. However, their etiologies and the relationship between them remain unclear. We herein report a patient with suspected small cell lung cancer who showed sensory polyneuropathy after treatment with atezolizumab in combination with cytotoxic agents (carboplatin and etoposide) and was doubly positive for serum anti-Hu and anti-SOX-1 antibodies. Treatment with ICI and cytotoxic agents may sometimes lead to the development of PNS.",
"affiliations": "Department of Respiratory Medicine, Kitakyushu General Hospital, Japan.;Department of Respiratory Medicine, Kitakyushu General Hospital, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan.;Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan.",
"authors": "Morimoto|Toshiki|T|;Orihashi|Takeshi|T|;Yamasaki|Kei|K|;Tahara|Masahiro|M|;Kato|Kaori|K|;Yatera|Kazuhiro|K|",
"chemical_list": "D001323:Autoantibodies; D016190:Carboplatin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.5629-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33328400\n10.2169/internalmedicine.5629-20\nCase Report\nParaneoplastic Sensory Polyneuropathy Related to Anti-PD-L1-including Anticancer Treatment in a Patient with Lung Cancer\nMorimoto Toshiki 12\nOrihashi Takeshi 1\nYamasaki Kei 2\nTahara Masahiro 2\nKato Kaori 2\nYatera Kazuhiro 2\n1 Department of Respiratory Medicine, Kitakyushu General Hospital, Japan\n2 Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan\nCorrespondence to Dr. Kei Yamasaki, yamasaki@med.uoeh-u.ac.jp\n\n15 12 2020\n15 5 2021\n60 10 15771581\n17 6 2020\n1 11 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nParaneoplastic neurological syndromes (PNS), such as sensory polyneuropathy, are rare, and serum neuronal antibodies that are used for diagnosing this syndrome are occasionally positive. Similarly, neurological immune-related adverse events due to immune checkpoint inhibitors (ICIs) are also rare. However, their etiologies and the relationship between them remain unclear. We herein report a patient with suspected small cell lung cancer who showed sensory polyneuropathy after treatment with atezolizumab in combination with cytotoxic agents (carboplatin and etoposide) and was doubly positive for serum anti-Hu and anti-SOX-1 antibodies. Treatment with ICI and cytotoxic agents may sometimes lead to the development of PNS.\n\nsmall cell lung cancer\nparaneoplastic neurological syndrome\nimmune checkpoint inhibitors\nanti-neuronal antibodies\nanti-Hu antibody\nsensory polyneuropathy\n==== Body\nIntroduction\n\nParaneoplastic neurological syndromes (PNS) are defined as remote effects of cancer unrelated to direct effects of tumors or metastases and are exceedingly rare, affecting less than 1/10,000 cancer patients (1). Neuronal anti-Hu and anti-SOX-1 antibodies are sometimes detected in patients with PNS in the serum or cerebrospinal fluid, and the clinical signs are different from the main symptoms of cancer.\n\nIn general, neurological symptoms tend to progress subacutely and cause severe physical dysfunction. In about 80% of patients, the onset of neurological symptoms and the detection of antibodies precedes the detection of cancer by months to years; therefore, early antibody detection may be useful for predicting PNS.\n\nImmune checkpoint inhibitors (ICIs) have widely been used in the treatment of multiple types of cancer. The main side effects of ICIs are immunological; thyroid function disorders are common, and organ-related side effects are also prevalent (2). Among these side effects, neurological immune-related adverse events (irAEs) due to ICIs are rare; only 0.93% of patients with ICI treatment experience neurological side effects, such as neuropathy, noninfective meningitis, encephalitis, and neuromuscular disorders (3).\n\nAmong neuronal autoantibodies related to PNS, anti-Hu antibody recognizes the nucleus of all central nervous system neurons and causes limbic encephalitis (LE), subacute cerebellar degeneration, and polyneuropathy. PNS with anti-Hu antibody was commonly seen in 78%, of small-cell lung cancer (SCLC) patients; 73% showed signs and symptoms of multifocal involvement of the nervous system, while 74% had sensory neuronopathy (2). In addition to anti-Hu antibody, anti-SOX-1 antibody recognizes the nuclear protein of glial cells and causes axonal neuropathy, demyelinating neuropathy, sensory and motor disorders (4). Five of 55 (9.1%) anti-SOX-1 antibody-positive patients reportedly had coexisting anti-Hu antibodies in SCLC patients (5).\n\nSensory polyneuropathy has clinically been recognized due to the advent of ICIs (3); however, neurological adverse events (nAEs) of ICIs, such as sensory polyneuropathy, are considered PNS and are still rare in patients with lung cancer. We herein report the first SCLC patient with sensory polyneuropathy who tested positive for anti-neuronal antibodies after initial treatment with anti programmed death-ligand 1 (PD-L1) antibody combined with cytotoxic agents.\n\nCase Report\n\nA 70-year-old current-smoking (80 pack-years) Japanese man with a history of hypertension and nonrecurrent colon cancer was admitted to our hospital. Two months earlier, he had experienced dizziness and been diagnosed with brain stem hemorrhaging due to cavernous malformation (hemangioma). In addition, multiple nodules suspected of being brain metastases had been seen on enhanced magnetic resonance imaging (MRI). He has been treated with concentrated glycerin and fructose at a previous hospital, and his symptoms had completely disappeared.\n\nUpon admission to our hospital, a physical examination revealed the following: height, 171.5 cm; body weight, 74.1 kg; body temperature, 35.9℃; heart rate, 103 bpm; blood pressure, 107/71 mmHg; and oxygen saturation, 95% (room air, at rest); no neurological abnormalities were observed. Laboratory results (Table 1) showed a high titer of pro-gastrin-releasing peptide (pro-GRP; 541.5 pg/mL) and a low titer of carcinoembryonic antigen (CEA; 2.5 ng/mL) and cytokeratin fragment 21-1 (CYFRA21-1; 1.7 ng/mL). Chest radiography and high-resolution computed tomography showed two nodules in the right lower lobe with hilar lymphadenopathies. Sputum samples for a cytological examination were not available. Invasive pathological examinations, including bronchoscopy, could not be carried out because the patient was at a high risk of recurrent intracranial hemorrhaging due to cavernous hemangioma. The serum pro-GRP titer has a sensitivity of 86.4%, specificity of 96.4%, positive predictive value of 96.7%, and negative predictive value of 84.4% for discriminating SCLC from non-SCLC (cut-off 77.8 pg/mL) (6), and a titer of over 329.3 pg/mL pro-GRP also suggests extensive SCLC rather than limited disease (6). The high serum level of pro-GRP (541.5 pg/mL) in this patient was thus considered a marker of SCLC. Consequently, he was clinically diagnosed with stage IV SCLC based on the radiological and serological findings.\n\nTable 1. Laboratory Data on Admission.\n\n<Blood cell counts>\tT-bil\t0.8\tmg/dL\tANA\t(-)\t\t\nWBC\t5,100\t/μL\tAST\t28\tIU/L\tAnti-SS-A\t(-)\t\t\nNeutrophils\t72.2\t%\tALT\t37\tIU/L\tAnti-SS-B\t(-)\t\t\nLymphocytes\t21.1\t%\tLDH\t224\tIU/L\tvit.B1\t41.9\tng/mL\t\nEosinophils\t0.6\t%\tγ-GTP\t49\tIU/L\tvit.B12\t539\tpg/mL\t\nMonocytes\t5.5\t%\tBUN\t11.3\tmg/dL\tCEA\t2.5\tng/mL\t\nBasophils\t0.6\t%\tCre\t0.88\tmg/dL\tCYFRA21-1\t1.7\tng/mL\t\nRBC\t5.36×106\t/μL\tNa\t141\tmEq/L\tPro-GRP\t541.5\tpg/mL\t\nHb\t17.1\tg/dL\tK\t4.1\tmEq/L\t<Cerebrospinal fluid>\t\nHt\t49.1\t%\tCl\t107\tmEq/L\tCell\t1\t/μL\t\nPlatelets\t18.3×104\t/μL\tGlucose\t156\tmg/dL\tMono\t1\t/μL\t\n<Blood chemistry>\tHbA1c\t6.3\t%\tProtein\t146\tmg/dL\t\nTP\t7.9\tg/dL\tCRP\t0.02\tmg/dL\tGlucose\t57\tmg/dL\t\nAlb\t4.6\tg/dL\tRF\t<0.1\tIU/mL\tCytology\tNo malignancy\t\nWBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Ht: hematocrit, TP: total protein, Alb: albumin, T-bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: gamma-glutamyl transferase, BUN: blood urea nitrogen, Cre: creatinine, CRP: c-reactive protein, RF: rheumatoid factor, ANA: anti nuclear antibody, Anti-SS-A: anti Sjögren syndrome-A antibody, Anti-SS-B: anti Sjögren syndrome-B antibody, vit.B1: vitamin B1, vit.B12: vitamin B12, CEA: carcinoembryonic antigen, CYFRA: cytokeratin fragment, Pro-GRP: pro-gastrin-releasing peptide\n\nAs the first-line treatment, combination therapy with carboplatin [area under the concentration-time curve (AUC) 5], etoposide (100 mg/m2), and atezolizumab (1,200 mg) was administered (Figure). Three weeks after the chemotherapy, whole-brain irradiation (3×10 Gy) was performed. Four weeks after chemotherapy, tactile and pain disturbances consistent with L2-3 dermatome, loss of bilateral patellar tendon reflexes, and loss of bilateral Achilles tendon reflexes were revealed. No obvious weakness was observed in the manual muscle strength test, Babinski reflexes were negative, and lower limb Barre's sign was positive. Coordination was poor in the finger-nose-finger test and knee-heel test, and gait was oscillating. Lumbar puncture results (Table 1) showed protein cell dissociation and no malignant cells. Enhanced brain MRI showed no evidence of recurrent brain stem hemorrhaging, and the size of all metastatic brain tumors had decreased. Lumbar spinal contrast-enhanced MRI showed no abnormal contrast enhancement of peripheral nerves, and nerve root compression consistent with the symptoms was observed. Serum anti-Hu and anti-SOX-1 antibody tests were both positive, and tests for onconeural antibodies (including anti-CV2, anti-Yo, anti-Ri, anti-amphiphysin, anti-paraneoplastic antigen MA2, anti-recoverin, anti-titin, anti-ZIC4, anti-GAD65 and anti-Tr) were all negative. Nerve conduction testing revealed that amplitude of sensory nerves was not evoked, and no apparent abnormalities in motor nerves were observed (Table 2).\n\nFigure. Clinical course of the patient. IVIg: intravenous immunoglobulin therapy, Pro-GRP: pro-gastrin-releasing peptide\n\nTable 2. The Nerve Conduction Study.\n\nMCS\tDistal latency\n(msec)\tCMAP amplitude\n(mV)\tMCV\n(m/s)\tSNAP\n(μV)\tSCV\n(m/s)\t\nRt. Median\t3.4\t18.9\t50.9\t18.1\t50.9\t\nRt. Ulnar\t3\t15.4\t46.8\t12.5\t47\t\nRt. Peroneal\t5.4\t13.8\t42\t-\t-\t\nRt. Tibial\t6.1\t18.1\t38.3\t-\t-\t\nRt. Sural\t3.8\t-\t-\tnot evoked\tnot evoked\t\nMCS: motor conduction study, SCS: sensory conduction study, CAMP: compound muscle action potential, SNAP: sensory nerve action potential, MCV: motor conduction velocity, SCV: sensory conduction velocity, Rt: right\n\nBased on the neurological findings and results of the nerve conduction test, the patient was diagnosed with sensory polyneuropathy. After systemic chemotherapy with atezolizumab and radiotherapy to the brain, the chest and brain tumors had shrunk, and the elevated serum level of pro-GRP had drastically decreased from 541.5 to 43.9 pg/mL. The clinical timeline of the onset of neurological symptoms was indicative of chemotherapy, particularly atezolizumab-induced. Intravenous immunoglobulin (IVIg) therapy was administered after the first round of systemic chemotherapy, but his neurological symptoms did not improve.\n\nDiscussion\n\nOur patient with suspected SCLC who experienced an nAE of sensory polyneuropathy tested positive for anti-neuronal antibodies after initial treatment with atezolizumab in combination with carboplatin and etoposide.\n\nAnti-acetylcholine receptor antibodies are generally pathogenic (e.g., in myasthenia gravis), but not all lung cancer patients positive for anti-Hu antibodies show neurological symptoms; indeed, among 196 SCLC patients with anti-Hu antibodies, 31 patients (16%) had no neurological symptoms (7). In relation to the treatment with ICIs and PNS with anti-Hu antibody, nivolumab (anti-PD-1 antibody)-induced sensory neuropathy (8), nivolumab-induced LE (9), sintilimab-induced LE, and enteric neuropathy (10) have been reported.\n\nRegarding the etiology of PNS, the decreased expression of multiple Treg-related genes involved in immune regulation in SCLC patients might cause impaired immune tolerance, tissue damage due to autoimmune mechanisms, and PNS (11). PD-L1-coated beads can induce Tregs in vitro, and PD-L1 increases Foxp3 expression and enhances the immunosuppressive ability of Tregs (12), suggesting that anti-PD-L1 antibody treatment may suppress Treg infiltration into tumors. Hence, the present patient was positive for anti-neuronal antibodies, but the neurological symptoms manifested after chemotherapy, suggesting that the PNS was evoked by an ICI, such as atezolizumab, and cytotoxic agents.\n\nIn the management of PNS, underlying disease treatments, such as anticancer therapy, are prioritized, which may partly improve neurological symptoms; however, only 10-20% of patients achieve improvement in their neurological symptoms (13). For patients in whom neurological symptoms persist, plasma exchange, systemic corticosteroids, immunosuppressants, or IVIg therapy are considered but usually prove to be ineffective (14). Thus far, there have been no available data concerning randomized controlled trials for the treatment of PNS; the available data have only been collected from case series, case reports, or expert opinions (class IV evidence) regarding the effect of immunomodulation (IVIg, steroid treatment, plasma exchange, or chemotherapy) on paraneoplastic neuropathy (15). In our case study, although the patient was treated with a high-dose immunoglobulin, no neurological improvement was noted. In addition, the relationship between the presence of anti-neurological antibodies and the prognosis of neurological symptoms remains controversial (16,17).\n\nSeveral limitations associated with the present study warrant mention. First, even though anticancer treatment was performed, there was no pathological evidence of lung cancer. There might have been other differential diagnoses, such as non-SCLC, carcinoid, large-cell neuroendocrine carcinoma, and infectious diseases. Second, as this patient had already presented with neurological symptoms at a previous hospital due to hemorrhaging of cavernous malformation, the discrimination of neurological symptoms of irAEs should have been carefully deliberated. However, the intracranial hemorrhagic symptoms had completely disappeared following treatment with concentrated glycerin and fructose before systemic chemotherapy, and sensory disturbances due to irAEs appeared four weeks after chemotherapy; the disturbances were consistent with those of PNS (Figure). Therefore, we believe that the etiology of the two neurological symptoms are clearly distinguishable. Third, the patient was treated with atezolizumab in combination with carboplatin and etoposide; therefore, the specific agent causing PNS was clinically unclear. However, both ICIs and cytotoxic agents have been reported to cause PNS, suggesting that combination therapy with ICIs and cytotoxic agents may increase the incidence of PNS.\n\nConclusion\n\nIn conclusion, we herein report an anti-Hu and anti-SOX-1 antibody dual-positive patient with suspected SCLC induced by combination treatment with carboplatin, etoposide, and atezolizumab. This irAE is often intractable, so physicians should be aware of this side effect, especially when treating patients with anti-neuronal antibodies using the combination of an ICI and cytotoxic agents.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Honnorat J , Antoine JC . Paraneoplastic neurological syndromes. Orphanet J Rare Dis 2 : 22, 2007.17480225\n2. Dalmau J , Graus F , Rosenblum MK , Posner JB . Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 71 : 59-72, 1992.1312211\n3. Larkin J , Chmielowski B , Lao CD , et al . Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolumab alone in advanced melanoma, including a case series of encephalitis. Oncologist 22 : 709-718, 2017.28495807\n4. Tschernatsch M , Singh P , Gross O , et al . Anti-SOX1 antibodies in patients with paraneoplastic and non-paraneoplastic neuropathy. J Neuroimmunol 226 : 177-180, 2010.20701982\n5. Stich O , Klages E , Bischler P , et al . SOX1 antibodies in sera from patients with paraneoplastic neurological syndromes. Acta Neurol Scand 125 : 326-331, 2012.21751968\n6. Cavalieri S , Morelli D , Martinetti A , et al . Clinical implications for pro-GRP in small cell lung cancer. A single center experience. Int J Biol Markers 33 : 55-61, 2018.28967066\n7. Graus F , Dalmou J , Rene R , et al . Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 15 : 2866-2872, 1997.9256130\n8. Raibagkar P , Ho D , Gunturu KS , Srinivasan J . Worsening of anti-Hu paraneoplastic neurological syndrome related to anti-PD-1 treatment: case report and review of literature. J Neuroimmunol 341 : 577184, 2020.32058173\n9. Matsuoka H , Kimura H , Koba H , et al . Nivolumab-induced limbic encephalitis with anti-Hu antibody in a patient with advanced pleomorphic carcinoma of the lung. Clin Lung Cancer 19 : e597-e599, 2018.29857970\n10. Kang K , Zheng K , Zhang Y . Paraneoplastic encephalitis and enteric neuropathy associated with anti-Hu antibody in a patient following immune-checkpoint inhibitor therapy. J Immunother 43 : 165-168, 2020.32195750\n11. Tani T , Tanaka K , Idezuka J , Nishizawa M . Regulatory T cells in paraneoplastic neurological syndromes. J Neuroimmunol 196 : 166-169, 2008.18455243\n12. Francisco LM , Salinas VH , Brown KE , et al . PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206 : 3015-3029, 2009.20008522\n13. Grisold W , Drlicek M , Liszka-Setinek U , Wondrusch E . Anti-tumour therapy in paraneoplastic neurological disease. Clin Neurol Neurosurg 97 : 106-111, 1995.7788965\n14. Graus F , Vega F , Delattre JY , et al . Plasmapheresis and antineoplastic treatment in CNS paraneoplastic syndromes with antineuronal autoantibodies. Neurology 42 : 536-540, 1992.1312683\n15. Giometto B , Vitaliani R , Lindeck-Pozza E , Grisold W , Vedeler C . Treatment for paraneoplastic neuropathies. Cochrane Database Syst Rev 12 : Cd007625, 2012.23235647\n16. Vedeler CA , Antoine JC , Giometto B , et al . Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol 13 : 682-690, 2006.16834698\n17. Candler PM , Hart PE , Barnett M , Weil R , Rees JH . A follow up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry 75 : 1411-1415, 2004.15377687\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "60(10)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "anti-Hu antibody; anti-neuronal antibodies; immune checkpoint inhibitors; paraneoplastic neurological syndrome; sensory polyneuropathy; small cell lung cancer",
"medline_ta": "Intern Med",
"mesh_terms": "D001323:Autoantibodies; D016190:Carboplatin; D006801:Humans; D008175:Lung Neoplasms; D020364:Paraneoplastic Polyneuropathy; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1577-1581",
"pmc": null,
"pmid": "33328400",
"pubdate": "2021-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15377687;21751968;18455243;9256130;28495807;20701982;32195750;7788965;28967066;1312211;20008522;16834698;23235647;17480225;29857970;1312683;32058173",
"title": "Paraneoplastic Sensory Polyneuropathy Related to Anti-PD-L1-including Anticancer Treatment in a Patient with Lung Cancer.",
"title_normalized": "paraneoplastic sensory polyneuropathy related to anti pd l1 including anticancer treatment in a patient with lung cancer"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1874531",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "In this case report, we discuss a patient presenting with parkinsonism followed by a non-amnestic dementia with aphasic clinical features, as well as frontal dysexecutive syndrome. There was a family history of dementia with an autopsy diagnosis of \"Pick's disease\" in the proband's father. Neuroimaging of the patient revealed focal and severe temporal lobe and lesser frontoparietal lobe atrophy. At autopsy, there was severe frontotemporal lobar degeneration. Histologic evaluation revealed an absence of tau or transactivation response DNA-binding protein of 43 kDa (TDP) pathology but rather severe Lewy body deposition in the affected cortices. Genetic phenotyping revealed a novel missense mutation (p.E83Q) in exon 4 of the gene encoding α-synuclein (SNCA). This case study presents a patient with a novel SNCA E83Q mutation associated with widespread Lewy body pathology with prominent severe atrophy of the frontotemporal lobes and corresponding cognitive impairment.",
"affiliations": "Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.;Department of Neurology, Indianapolis, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.;Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.",
"authors": "Kapasi|Alifiya|A|https://orcid.org/0000-0003-1911-8482;Brosch|Jared R|JR|;Nudelman|Kelly N|KN|;Agrawal|Sonal|S|;Foroud|Tatiana M|TM|;Schneider|Julie A|JA|",
"chemical_list": "C497604:SNCA protein, human; D051844:alpha-Synuclein",
"country": "Australia",
"delete": false,
"doi": "10.1111/neup.12687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-6544",
"issue": "40(6)",
"journal": "Neuropathology : official journal of the Japanese Society of Neuropathology",
"keywords": "Lewy bodies; case report; dementia; frontotemporal lobar degeneration; parkinsonism",
"medline_ta": "Neuropathology",
"mesh_terms": "D001921:Brain; D005260:Female; D057174:Frontotemporal Lobar Degeneration; D006801:Humans; D020961:Lewy Body Disease; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D051844:alpha-Synuclein",
"nlm_unique_id": "9606526",
"other_id": null,
"pages": "620-626",
"pmc": null,
"pmid": "32786148",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": "23033316;19602639;19795154;26401927;18797258;12641375;20601685;22689647;30371827;24681721;22265587;17251522;28592453;28149325;22635379;30439333;25962793;20587488;26049034;25552646;19303592;20354512;24565469",
"title": "A novel SNCA E83Q mutation in a case of dementia with Lewy bodies and atypical frontotemporal lobar degeneration.",
"title_normalized": "a novel snca e83q mutation in a case of dementia with lewy bodies and atypical frontotemporal lobar degeneration"
} | [
{
"companynumb": "US-009507513-2101USA010353",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Loperamide is an over-the-counter antidiarrheal with μ-opioid agonist activity. Central nervous system opioid effects are not observed after therapeutic oral dosing because of poor bioavailability and minimal central nervous system penetration. However, central nervous system opioid effects do occur after supratherapeutic oral doses. Recently, oral loperamide abuse as an opioid substitute has been increasing among patients attempting to self-treat their opioid addiction. Ventricular dysrhythmias and prolongation of the QRS duration and QTc interval have been reported after oral loperamide abuse. We describe 2 fatalities in the setting of significantly elevated loperamide concentrations.",
"affiliations": "Upstate New York Poison Center, Syracuse, NY. Electronic address: williamdeggleston@gmail.com.;Onondaga County Office of the Medical Examiner, Syracuse, NY.;Department of Emergency Medicine, SUNY Upstate Medical University Hospital, Syracuse, NY.",
"authors": "Eggleston|William|W|;Clark|Kenneth H|KH|;Marraffa|Jeanna M|JM|",
"chemical_list": "D017450:Receptors, Opioid, mu; D008139:Loperamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.annemergmed.2016.03.047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "69(1)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000328:Adult; D001145:Arrhythmias, Cardiac; D017809:Fatal Outcome; D006801:Humans; D008139:Loperamide; D008297:Male; D009293:Opioid-Related Disorders; D017450:Receptors, Opioid, mu; D012648:Self Care; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "83-86",
"pmc": null,
"pmid": "27140747",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Loperamide Abuse Associated With Cardiac Dysrhythmia and Death.",
"title_normalized": "loperamide abuse associated with cardiac dysrhythmia and death"
} | [
{
"companynumb": "PHHY2017US059969",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
},
"drugadditional": null,
"d... |
{
"abstract": "We report a case of capillary leak that developed during treatment of antibody-mediated rejection in a kidney transplant recipient. A 53-year-old female transplant recipient experienced an increase in serum creatinine from 1.1 to 1.8 mg/dL. Antibody-mediated rejection was diagnosed by graft biopsy. She was treated with five plasmapheresis sessions (on alternate days with albumin replacement), five doses of immunoglobulin (5 g/dose at 100 mg/kg), a single dose of rituximab (500 mg), and four doses of bortezomib on days 1, 4, 7, and 10 (1.72 mg/dose at 1.3 mg/m2 body surface area). During treatment, edema, slight diarrhea, pancytopenia, hypoalbuminemia, peripheral neuropathy, and postural hypotension were noted. Despite control of liquids, she presented with edema progressing to an increase of more than 10 kg body weight. Prerenal acute graft dysfunction associated with hypotension was diagnosed on day 12, heart failure or other infectious complications being discounted. On day 13, daily hemodialysis was prescribed, and a stable volume status was reached after five hemodialysis sessions. On day 20, the patient recovered diuresis and the edema and diarrhea abated, but she remained on chronic hemodialysis. After excluding other causes of distributive shock, the diagnosis of capillary leak syndrome was based on the presence of hypotension, generalized edema, and hypoalbuminemia in the absence of significant proteinuria. The concomitant presence of diarrhea, peripheral neuropathy, and pancytopenia, suggest a possible causal role for bortezomib. Awareness by clinicians of capillary leak syndrome associated with bortezomib-based treatment of AMR is paramount, despite its rarity.",
"affiliations": "Nephrology Department, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Calle Vasco de Quiroga 15, Tlalpan, Sección XVI, 14000, Mexico City, Mexico. juancarlosramirezsandoval@yahoo.com.;Nephrology Department, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Calle Vasco de Quiroga 15, Tlalpan, Sección XVI, 14000, Mexico City, Mexico.;Nephrology Department, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Calle Vasco de Quiroga 15, Tlalpan, Sección XVI, 14000, Mexico City, Mexico.",
"authors": "Ramirez-Sandoval|Juan C|JC|;Varela-Jimenez|Ricardo|R|;Morales-Buenrostro|Luis E|LE|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-018-0306-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "7(1)",
"journal": "CEN case reports",
"keywords": "Acute antibody-mediated rejection; Acute kidney injury; Clarkson disease; Graft failure; Proteasome inhibitor; Transplantation",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "110-113",
"pmc": null,
"pmid": "29344912",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "21698837;19414839;19422329;19104417;20150504;24033843;22836132;20643990;7249508;24851019;24708575;20617436;26031595",
"title": "Capillary leak syndrome as a complication of antibody-mediated rejection treatment: a case report.",
"title_normalized": "capillary leak syndrome as a complication of antibody mediated rejection treatment a case report"
} | [
{
"companynumb": "MX-ASTELLAS-2018US006606",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "Busulfan (Bu) is an alkylating agent routinely used for conditioning regimens before allogeneic stem cell transplantation (allo-SCT). Bu shows wide pharmacokinetic (PK) variability among patients. Patients can have a higher systemic exposure (expressed as area under the curve [AUC]) with an increased risk of toxicity or a lower AUC with a higher probability of graft rejection and/or disease relapse. After i.v. administration, an optimal Bu therapeutic window (AUC target of 16,000 to 24,000 μM·minute) has been identified. The use of PK-guided Bu dosing leads to improved overall survival (OS) and progression-free survival (PFS) compared with fixed-dose administration in a variety of hematologic diseases. The aim of this study was to evaluate the outcomes and feasibility of a reduced-toxicity conditioning (RTC) regimen comprising thiotepa, Bu, and fludarabine (TBF) with therapeutic drug monitoring of Bu in patients with hematologic disorders. We report on 41 adult patients with myeloid or lymphoid malignancies who underwent an allo-SCT with a PK-guided Bu-based RTC regimen between January 2019 and October 2020. Patients received a total Bu dose to achieve a target AUC of 16,000 μM·minute in combination with Flu and thiotepa. The median time to absolute neutrophil count recovery and transfusion-independent platelet count recovery was 23 days (range, 15 to 42 days) and 29 days (range, 14 to 97 days), respectively. The cumulative incidence (CI) of nonrelapse mortality was 7% at 100 days and 13% at 1 year. Grade 3 liver toxicity was observed in 6 patients. One patient developed sinusoidal obstruction syndrome at day +27. Grade 3 mucositis occurred in 18 patients. Looking at grade ≥3 infections, the CI was 29% at 30 days, 34% at 60 days, 44% at 100 days, and 56% at 1 year. The 180-day CI of grade II-IV acute graft-versus-host disease (GVHD) was 15%, and the 1-year CI of overall chronic GVHD was 20%. With a median follow-up of alive patients of 14.4 months (range, 3.2 to 24 months), the CI of relapse at 1 year was 6%. The 1-year PFS was 81%, and 1-year OS was 84%. In conclusion, these data support the efficacy of PK-guided Bu dose in the context of a TBF conditioning regimen and the feasibility of therapeutic dosage monitoring of i.v. Bu for patients with hematologic diseases. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.",
"affiliations": "IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.;IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.;Fondazione IRCCS Policlinico San Matteo, Clinical and Experimental Pharmacokinetics Unit(,) Pavia, Italy.;Humanitas University, Department of Biomedical Sciences, Milan, Italy.;IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.;IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.;IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.;IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.;Fondazione IRCCS Policlinico San Matteo, Clinical and Experimental Pharmacokinetics Unit(,) Pavia, Italy.;IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.;IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.;IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy. Electronic address: lcastagna63@gmail.com.",
"authors": "Bramanti|Stefania|S|;De Philippis|Chiara|C|;Bartoli|Antonella|A|;Giordano|Laura|L|;Mariotti|Jacopo|J|;Sarina|Barbara|B|;Mannina|Daniele|D|;Valli|Viviana|V|;De Gregori|Simona|S|;Roperti|Martina|M|;Pieri|Gabriella|G|;Castagna|Luca|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtct.2021.08.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2666-6367",
"issue": "27(11)",
"journal": "Transplantation and cellular therapy",
"keywords": "Allogeneic stem cell transplantation; PK-guided busulfan; Reduced-toxicity conditioning regimen",
"medline_ta": "Transplant Cell Ther",
"mesh_terms": null,
"nlm_unique_id": "101774629",
"other_id": null,
"pages": "912.e1-912.e6",
"pmc": null,
"pmid": "34403790",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Feasibility and Efficacy of a Pharmacokinetics-Guided Busulfan Conditioning Regimen for Allogeneic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Adult Patients with Hematologic Malignancies.",
"title_normalized": "feasibility and efficacy of a pharmacokinetics guided busulfan conditioning regimen for allogeneic stem cell transplantation with post transplantation cyclophosphamide as graft versus host disease prophylaxis in adult patients with hematologic malignancies"
} | [
{
"companynumb": "IT-PFM-2021-09326",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": "4",
"drugad... |
{
"abstract": "Otaplimastat is a neuroprotectant that inhibits matrix metalloprotease pathway, and reduces edema and intracerebral hemorrhage induced by recombinant tissue plasminogen activator (rtPA) in animal stroke models. We aimed to assess the safety and efficacy of otaplimastat in patients receiving rtPA.\n\n\n\nThis was a phase 2, 2-part, multicenter trial in stroke patients (19-80 years old) receiving rtPA. Intravenous otaplimastat was administered <30 minutes after rtPA. Stage 1 was a single-arm, open-label safety study in 11 patients. Otaplimastat 80 mg was administered twice daily for 3 days. Stage 2 was a randomized, double-blind, placebo-controlled study involving 69 patients, assigned (1:1:1) to otaplimastat 40 mg, otaplimastat 80 mg, or a placebo. The primary endpoint was the occurrence of parenchymal hematoma (PH) on day 1. Secondary endpoints included serious adverse events (SAEs), mortality, and modified Rankin scale (mRS) distribution at 90 days (clinicaltrials.gov identifier: NCT02787278).\n\n\n\nNo safety issues were encountered in stage 1. The incidence of PH during stage 2 was comparable: 0 of 22 with the placebo, 0 of 22 with otaplimastat 40 mg, and 1 of 21 with the 80 mg dose. No differences in SAEs (13%, 17%, 14%) or death (8.3%, 4.2%, 4.8%) were observed among the 3 groups. Three adverse events (chills, muscle rigidity, hepatotoxicity) were judged to be related to otaplimastat.\n\n\n\nIntravenous otaplimastat adjunctive therapy in patients receiving rtPA is feasible and generally safe. The functional efficacy of otaplimastat needs to be investigated with further large trials. ANN NEUROL 2020;87:233-245.",
"affiliations": "Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul.;Department of Neurology, Soonchunhyang University School of Medicine, Seoul.;Department of Neurology, Myongji Hospital, Hanyang University College of Medicine, Goyang.;Department of Neurology, Pusan National University Hospital, Busan.;Department of Neurology, Korea University Guro Hospital, Seoul.;Department of Neurology, Inje University Busan Paik Hospital, Busan.;Department of Neurology, Kyung Hee University Hospital, Seoul.;Department of Neurology, Kyungpook National University School of Medicine and Hospital, Daegu.;Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul.;Department of Neuroscience, Korea University College of Medicine, Seoul.;Research Headquarters, Shin Poong Pharmaceutical, Ansan, Korea.;Research Headquarters, Shin Poong Pharmaceutical, Ansan, Korea.;Research Headquarters, Shin Poong Pharmaceutical, Ansan, Korea.",
"authors": "Kim|Jong S|JS|0000-0002-3999-4992;Lee|Kyung Bok|KB|;Park|Jong-Ho|JH|;Sung|Sang Min|SM|;Oh|Kyungmi|K|;Kim|Eung-Gyu|EG|;Chang|Dae-Il|DI|;Hwang|Yang Ha|YH|0000-0002-6665-7481;Lee|Eun-Jae|EJ|;Kim|Won-Ki|WK|;Ju|Chung|C|;Kim|Byung Su|BS|;Ryu|Jei-Man|JM|;|||",
"chemical_list": "D000081:Acetamides; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D052999:Quinazolinones; D010959:Tissue Plasminogen Activator; C552779:otaplimastat",
"country": "United States",
"delete": false,
"doi": "10.1002/ana.25644",
"fulltext": "\n==== Front\nAnn NeurolAnn. Neurol10.1002/(ISSN)1531-8249ANAAnnals of Neurology0364-51341531-8249John Wiley & Sons, Inc. Hoboken, USA 10.1002/ana.25644ANA25644Research ArticleResearch ArticlesSafety and Efficacy of Otaplimastat in Patients with Acute Ischemic Stroke Requiring tPA (SAFE‐TPA): A Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Phase 2 Study Otaplimastat in AISKim et alKim Jong S. MDhttps://orcid.org/0000-0002-3999-4992\n1\njongskim@amc.seoul.kr Lee Kyung Bok MD\n2\nPark Jong‐Ho MD\n3\nSung Sang Min MD\n4\nOh Kyungmi MD\n5\nKim Eung‐Gyu MD\n6\nChang Dae‐il MD\n7\nHwang Yang Ha MDhttps://orcid.org/0000-0002-6665-7481\n8\nLee Eun‐Jae MD\n1\nKim Won‐Ki PhD\n9\nJu Chung PhD\n10\nKim Byung Su MS\n10\nRyu Jei‐Man PhD\n10\non behalf of the SAFE‐TPA Investigators \n1 \nDepartment of Neurology\nAsan Medical Center, University of Ulsan College of Medicine\nSeoul\n\n2 \nDepartment of Neurology\nSoonchunhyang University School of Medicine\nSeoul\n\n3 \nDepartment of Neurology\nMyongji Hospital, Hanyang University College of Medicine\nGoyang\n\n4 \nDepartment of Neurology\nPusan National University Hospital\nBusan\n\n5 \nDepartment of Neurology\nKorea University Guro Hospital\nSeoul\n\n6 \nDepartment of Neurology\nInje University Busan Paik Hospital\nBusan\n\n7 \nDepartment of Neurology\nKyung Hee University Hospital\nSeoul\n\n8 \nDepartment of Neurology\nKyungpook National University School of Medicine and Hospital\nDaegu\n\n9 \nDepartment of Neuroscience\nKorea University College of Medicine\nSeoul\n\n10 \nResearch Headquarters, Shin Poong Pharmaceutical\nAnsan\nKorea\n* \nAddress correspondence to\n\nDr Jong S. Kim, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Songpa‐gu, Seoul 05505, Republic of Korea.\n\nE‐mail: jongskim@amc.seoul.kr\n29 11 2019 2 2020 87 2 10.1002/ana.v87.2233 245 08 4 2019 22 10 2019 10 11 2019 © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological AssociationThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Objective\nOtaplimastat is a neuroprotectant that inhibits matrix metalloprotease pathway, and reduces edema and intracerebral hemorrhage induced by recombinant tissue plasminogen activator (rtPA) in animal stroke models. We aimed to assess the safety and efficacy of otaplimastat in patients receiving rtPA.\n\nMethods\nThis was a phase 2, 2‐part, multicenter trial in stroke patients (19–80 years old) receiving rtPA. Intravenous otaplimastat was administered <30 minutes after rtPA. Stage 1 was a single‐arm, open‐label safety study in 11 patients. Otaplimastat 80 mg was administered twice daily for 3 days. Stage 2 was a randomized, double‐blind, placebo‐controlled study involving 69 patients, assigned (1:1:1) to otaplimastat 40 mg, otaplimastat 80 mg, or a placebo. The primary endpoint was the occurrence of parenchymal hematoma (PH) on day 1. Secondary endpoints included serious adverse events (SAEs), mortality, and modified Rankin scale (mRS) distribution at 90 days (http://clinicaltrials.gov identifier: NCT02787278).\n\nResults\nNo safety issues were encountered in stage 1. The incidence of PH during stage 2 was comparable: 0 of 22 with the placebo, 0 of 22 with otaplimastat 40 mg, and 1 of 21 with the 80 mg dose. No differences in SAEs (13%, 17%, 14%) or death (8.3%, 4.2%, 4.8%) were observed among the 3 groups. Three adverse events (chills, muscle rigidity, hepatotoxicity) were judged to be related to otaplimastat.\n\nInterpretation\nIntravenous otaplimastat adjunctive therapy in patients receiving rtPA is feasible and generally safe. The functional efficacy of otaplimastat needs to be investigated with further large trials. ANN NEUROL 2020;87:233–245\n\nMinistry of Health & Welfare, Republic of Korea (through the Korea Health Industry Development Institute (KHIDI))HI15C2796Korea Health Industry Development Institute 10.13039/501100003710 source-schema-version-number2.0cover-dateFebruary 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:06.02.2020\n==== Body\nRecombinant tissue plasminogen activator (rtPA) is the only therapeutic agent approved for patients with acute ischemic stroke (AIS). However, rtPA therapy increases the risk of intracerebral hemorrhage (ICH) or hemorrhagic transformation (HT) through diverse mechanisms.1, 2, 3, 4 It has been shown that rtPA activates matrix metalloproteases (MMPs)5, 6 and aggravates breakdown of the blood–brain barrier, leading to brain edema and HT.7 Thus, there is a need to develop therapeutic strategies to increase the clinical benefit of rtPA in patients with AIS. For this purpose, adjunctive therapies have been developed, some of which have shown promising preclinical results.8, 9, 10, 11 However, clinical trials using such drugs are uncommon; although minocycline,12 uric acid,13 and 3K3A‐APC14 were found to be safe when administered to stroke patients receiving rtPA, their efficacy still remains to be proven.9, 12, 13, 14 Recently, small studies have shown that fingolimod may enhance the efficacy of rtPA administration in patients with AIS receiving rtPA,15 and improve the clinical outcome in patients with a proximal cerebral arterial occlusion in the 4.5‐ to 6‐hour time window.16\n\n\nOtaplimastat (SP‐8203) is a small molecule with a quinazoline‐2,4‐dione scaffold that improves neurological outcomes through multiple cytoprotective mechanisms in various animal stroke models.17, 18, 19, 20 Notably, in both a standalone treatment and a combined treatment with rtPA, otaplimastat showed significant benefit by reducing infarct volume and edema in embolic stroke models.20 In animal models of stroke, delayed rtPA treatment increased brain ICH, and coadministration of otaplimastat significantly improved neurologic outcome and reduced brain edema and ICH by inhibiting MMP activities through upregulation of tissue inhibitor of metalloproteinase‐1.20\n\n\nIn a phase 1 study, up to 240 mg otaplimastat was well tolerated in 77 healthy volunteers without significant side effects (unpublished data). The purpose of this phase 2a study was to assess the feasibility, safety, and potential efficacy of an intravenous infusion of otaplimastat in patients with AIS treated by rtPA.\n\nSubjects and Methods\n\nStudy Design and Participants\n\nThis was a 2‐stage phase 2 trial. Stage 1 was an open‐label, unblinded, single‐arm study in which patients were given high‐dose otaplimastat (80 mg twice daily for 3 days) to examine its safety. At the completion of stage 1, a go/no‐go decision was made in an interim meeting by the independent Data and Safety Monitoring Board (DSMB), composed of global stroke experts and a nonvoting statistician. Stage 2 was a randomized, double‐blind, placebo‐controlled study to evaluate the safety and efficacy of otaplimastat 40 mg or 80 mg twice daily for 3 days versus a placebo. The protocol was approved by the local institutional review board, and all patients or legal representatives provided written informed consent. This study was conducted at 8 medical centers in South Korea from June 5, 2016 to August 22, 2017. This study was performed in accordance with International Conference on Harmonization and Good Clinical Practice guidelines.\n\n\nPatients\n\nAIS patients (19–80 years) who were to receive intravenous rtPA within 4.5 hours were enrolled. Considering that this was the first study that examined the safety of otaplimastat in stroke patients receiving rtPA, patients with a National Institutes of Health Stroke Scale (NIHSS) score of 4 to 10 who were at the relatively lower risk of ICH were enrolled in stage 1. Once the safety of otaplimastat was confirmed in stage 1, we enrolled any patient with an NIHSS score ≥4 in stage 2 to more appropriately reflect routine clinical practice. Inclusion and exclusion criteria are shown in Table 1 (excerpted). Key exclusion criteria included systemic allergic diseases or drug hypersensitivity, abnormal electrocardiogram (ECG) or hematological findings, and a contraindication for the use of rtPA.\n\nTable 1 Inclusion and Exclusion Criteria for the SAFE‐TPA Trial (Excerpted)\n\nInclusion Criteria\tExclusion Criteria\t\n\n1. Adults aged 19 to 80 years\n\n\n2. Able to receive rtPA within 4.5 hours after the onset of early symptoms of acute ischemic stroke\n\n\n3. Available for brain MRI (DWI, GRE/SWI, FLAIR, MRA) scanning\n\n\n4. Signed informed consent by subject or authorized representative\n\n\n\t\n1. Systemic allergic diseases or hypersensitivity to specific drugs\n\n\n2. Patients have condition as follows at screening:\n\n\n(a) Diagnosis with AMI within the past 6 months\n\n\n(b) Arrhythmia causing clinical symptoms such as dyspnea or palpitation within the past 6 months\n\n\n(c) Abnormal ECG findings in stable condition at ER\n\n\n3. Severe heart failure of NYHA class III or class IV\n\n\n4. Fever (≥38°C) or infection signs that require antibiotic therapy at screening\n\n\n5. Pulmonary diseases (asthma, COPD, active tuberculosis, etc) recently treated >1 month at screening\n\n\n6. Decreased hemoglobin (<10 g/dl), decreased platelet count (<100,000/mm3), or hematocrit of <25% in complete blood count\n\n\n7. Hemodialysis and/or treatments due to nephropathies, acute or chronic renal failure at screening\n\n\n8. Diagnosed cancer within 6 months before the screening time, or any treatment for cancer within the previous 6 months, or recurrent/metastatic cancer\n\n\n9. Pregnancy or breastfeeding\n\n\n10. Participated in other clinical trials of other drugs within the past 3 months\n\n\n11. Cannot participate in the trial according to the judgment of investigators\n\n\n12. Contraindication for the use of rtPA\n\n\n\t\n\nStage 1–specific criteria\n\n\n• NIHSS score of 4–10\n\n\n\t\n\nStage 2–specific criteria\n\n\n• NIHSS score of ≥4\n\n\n\t\nAMI = acute myocardial infarction; COPD = chronic obstructive pulmonary disease; DWI = diffusion‐weighted imaging; ECG = electrocardiogram; ER = emergency room; FLAIR = fluid‐attenuated inversion recovery; GRE/SWI = susceptibility‐weighted images generated from gradient‐echo pulse sequences; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; NIHSS = National Institutes of Health Stroke Scale; NYHA class = New York Heart Association Functional classification for heart failure; rtPA = recombinant tissue plasminogen activator.\n\n\nRandomization and Masking\n\nAll patients received otaplimastat 80 mg during stage 1. Using a computer‐generated allocation sequence, patients were randomly assigned (1:1:1) to placebo, otaplimastat 40 mg, or otaplimastat 80 mg for stage 2. Randomization was stratified by site to guarantee a balanced distribution among the groups and performed by using block randomization with a pregenerated random number list. The patients and investigators were masked to the treatment assignments, with otaplimastat and placebo provided in color‐matched vials (Shin Poong Pharmaceutical, Ansan, Korea). The individual treatment code was stored by the main statistician.\n\n\nProcedures\n\nEligibility for rtPA (Actilyse; Boehringer Ingelheim, Biberach, Germany; 0.9 mg/kg) treatment was assessed in the emergency department based on a brain computed tomography (CT) scan. Otaplimastat or placebo was intravenously administered over 30 minutes no later than 30 minutes after starting the rtPA infusion via a different injection route. Study drugs were given twice daily at intervals of 12 hours (±30 minutes) for a total of 6 times over 3 days. Patients underwent magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) within 6 hours after the start of rtPA therapy, and endovascular thrombectomy (EVT) was performed in patients who had an occluded large artery. Afterward, all patients were admitted to the stroke unit. Antiplatelet agents were not used until 1 day after the rtPA infusion. From day 1 to 5, only prespecified doses of aspirin (100 mg/day), clopidogrel (75 mg/day), or both were allowed to patients at the discretion of the attending physician. Afterward, any antiplatelets or anticoagulants were allowed.\n\nAll brain imaging was performed using a common protocol and processed by a centralized facility (Central Imaging Core Lab, Asan Medical Center, Seoul, Korea). The standardized MRI protocol consisted of diffusion‐weighted imaging (DWI), susceptibility‐weighted images generated from gradient‐echo pulse sequences (GRE/SWI), and fluid‐attenuated inversion recovery (FLAIR). MRA consisted of time‐of‐flight MRA for the intracranial arteries and contrast‐enhanced MRA for the neck vessels. All CT scans and the initial 4 MRI sequences (DWI/GRE/SWI, FLAIR) were performed as noncontrast. All serial imaging data and additional postprocedural CT images in patients who underwent EVT were retrospectively analyzed to differentiate contrast extravasation from ICH. The imaging equipment and protocol at each trial site were validated with a standardized qualification control and assurance monitoring procedures before and during the study. The image analysis was blinded and assessed by 2 experienced neurologists or by a third investigator to reach a consensus when conflicting judgments occurred.\n\nA brain CT was performed in stage 1 to evaluate the occurrence of parenchymal hematoma (PH) at 24 ± 3 hours after the first administration of otaplimastat. Patients were examined daily until day 5 for vital signs, NIHSS score, and treatment‐emergent adverse events classified using MedDRA version 19.0. On day 5, brain MRI, MRA, ECG, and laboratory tests were done, and the modified Rankin scale (mRS) and Barthel Index (BI) were assessed. All assessments were repeated on day 14. The prespecified criteria for the no‐go decision for stage 2 was the occurrence of 3 or more cases with symptomatic ICH (sICH) causing neurological deterioration (≥4‐point increase in the NIHSS score) or death during the first 5 days. In stage 2, patients received otaplimastat 40 mg, otaplimastat 80 mg, or placebo twice daily for 3 days and followed the same assessment procedures until day 5. The follow‐up visits at day 28 and day 90 included the NIHSS, laboratory tests, chest X‐ray, ECG, and adverse events. The follow‐up at 90 days also included the mRS and BI.\n\n\nOutcomes\n\nThe primary endpoint of both stages was the incidence of PH within 24 hours on a brain CT scan based on post‐thrombolytic ICH being regarded as an early event (<24 hours) in the National Institute of Neurological Disorders and Stroke rtPA trial and all fatal sICH occurring within 24 hours.21 The definition of ICH followed European Cooperative Acute Stroke Study I and II criteria: hemorrhagic infarct (HI) 1, small petechiae along the margins of the infarct; HI 2, confluent petechiae within the infarcted area but without space‐occupying effect; PH 1, a clot not exceeding 30% of the infarcted area with some mild space‐occupying effect; and PH 2, dense blood clot(s) exceeding 30% of the infarct volume with significant space‐occupying effect.22, 23 Secondary safety endpoints were the incidence rate of sICH within 5 days (ie, any ICH confirmed by brain imaging, worsening of ≥2 points on the NIHSS, neurological deterioration persisting >24 hours); incidence of major systemic bleeding according to the International Society on Thrombosis and Hemostasis definition24; and incidence of serious adverse events, adverse events, and adverse drug reactions or death by any cause. Monitoring of adverse events and safety lasted for 30 days after the last visit. Secondary efficacy endpoints were neurological changes assessed by the NIHSS and clinical outcome evaluated by the mRS and BI at 90 days.\n\nExploratory endpoints were based on MRI findings on day 5: incidence, size, and number of any ICH by GRE, and the rate of cerebral infarct growth and infarct recurrence by DWI.\n\n\nStatistical Analyses\n\nIn stage 1, a safety assessment of 10 subjects was judged to be appropriate for making a relevant decision in the DSMB and 11 patients were enrolled assuming a 10% dropout rate. In stage 2, for the primary endpoint of the incidence of CT‐identified ICH, sample size was calculated based on the simulation results with binomial random variables for the incidence and probability of ≥90% to securely detect the occurrence of at least >1 ICH or sICH events. Assuming an estimated incidence of ICH events of 12.4% in all stroke patients receiving rtPA (19.8% in high‐risk patients), sICH events of 6.9% in all stroke patients receiving rtPA (11.2% in high‐risk patients),25 and a dropout rate of 10%, 69 patients (23 subjects per group) were needed for the study.\n\nThe safety population was defined as patients who had received any study treatment at least once, including cases of incomplete infusion. The modified intention‐to‐treat (mITT) population included all randomized patients who had primary endpoint results without major inclusion/exclusion criteria violations. All endpoints in stage 1 were evaluated using the safety population. In stage 2, the primary endpoints and the proportional differences between groups were estimated with the 90% 2‐sided exact confidence interval (CI) in the mITT population.\n\nAll secondary safety outcomes and the proportional difference between groups were estimated at each time point with a 2‐sided 90% CI. Secondary efficacy endpoints and exploratory endpoints were evaluated with the Wilcoxon rank‐sum test or Fisher exact test in the mITT population, with Holm–Bonferroni correction for multiplicity. If a patient died before a prespecified visit, missing mRS scores were imputed to the worst possible score (6). The mRS distribution was further analyzed using ordinal logistic regression analysis including adjustment of variables associated with outcomes. Non‐normality and overdispersion that violated the proportional hazard assumption were noted. The effects of treatment in multivariate ordinal logistic regression were assessed after adjusting for the effects of age, sex, baseline NIHSS, tPA treatment time after stroke onset, and the use of endovascular surgery. The categorical group variable of 3 levels was included for analyzing the effect of treatment in the model, and the placebo group was considered as the reference group. We used the van Elteren test to assess temporal changes on the NIHSS score from baseline to day 90, using the cross‐tabulation with 2 rows of each group and the columns of modified ridit scores for NIHSS score changes stratified with time.\n\nThe statistical analysis was conducted using SPSS Statistics version 22.0 (IBM, Armonk, NY) and SAS version 9.4 software (SAS Institute, Cary, NC).\n\nResults\nEighty patients were enrolled between June 5, 2016 and August 22, 2018 from 8 South Korean centers. Eleven patients were included in the safety and mITT populations for stage 1 (Fig 1), and their characteristics are shown in Table 2. In stage 2, 69 patients were randomly assigned to 3 groups: 24 to placebo, 24 to otaplimastat 40 mg, and 21 to otaplimastat 80 mg. The stage 2 mITT population included 22 patients in the placebo group, 22 in the otaplimastat 40 mg group, and 21 in the otaplimastat 80 mg group (see Fig 1). The baseline characteristics for stage 2 were balanced among the 3 treatment groups (see Table 2). The median age was 64 years (range = 33–80) and the median NIHSS score was 9 (range = 4–21) on admission. rtPA was administered at a median time of 1.6 hours (range = 0.5–4.2) after stroke onset, and 19 patients (29%, 19/66) underwent EVT. In stage 1, all patients in the safety population (n = 11) received all 6 doses of the study medication. In stage 2, a similar proportion of patients in each group received all 6 doses of the study medication; 88% (21/24) received the placebo, 88% (21/24) received otaplimastat 40 mg, and 91% (19/21) received otaplimastat 80 mg.\n\nFigure 1 Trial profile. In stage 1, 1 patient was excluded because of low (10 g/dl) hemoglobin (exclusion criterion). In stage 2, 1 patient in the otaplimastat 40 mg group received warfarin (international normalized ratio <1.3, a major exclusion criteria violation) and was excluded. One patient with transient ischemic attack enrolled in stage 2 (the placebo group) was excluded in primary outcome analysis because of missing computed tomography (CT) outcome. Prohibited medication was defined as the use of antiplatelet agents or anticoagulants other than the prespecified dose of aspirin or clopidogrel from days 1 to 5. DSMB = Data and Safety Monitoring Board; IP = Investigational Product.\n\nTable 2 Baseline Characteristics of the Primary Analysis Population for Stages 1 and 2\n\nCharacteristic\tStage 1, Safety Population\tStage 2, Modified Intention‐to‐Treat Population\t\nOtaplimastat 80 mg, n = 11\tPlacebo, n = 22\tOtaplimastat 40 mg, n = 22\tOtaplimastat 80 mg, n = 21\t\nDemographics\t\t\t\t\t\nMedian age, yr [min−max]\t72 [38–79]\t59 [49–77]\t63.5 [35–80]\t66 [33–79]\t\nFemale, n (%)\t5 (45%)\t7 (32%)\t5 (23%)\t9 (43%)\t\nRisk factors, n (%)\t\t\t\t\t\nHypertension\t9 (82%)\t13 (59%)\t15 (68%)\t12 (57%)\t\nDiabetes\t6 (55%)\t6 (28%)\t6 (28%)\t7 (33%)\t\nHyperlipidemia\t1 (9%)\t4 (1%)\t4 (18%)\t6 (29%)\t\nAtrial fibrillation\t0\t3 (14%)\t5 (23%)\t2 (10%)\t\nSmoking, current\t4 (36%)\t8 (37%)\t5 (23%)\t4 (19%)\t\nCoronary artery disease\t2 (18%)\t2 (9%)\t0\t3 (14%)\t\nPrevious history of stroke\t0\t3 (14%)\t5 (23%)\t4 (19%)\t\nTOAST classification\t\t\t\t\t\nLarge artery atherosclerosis\t6 (55%)\t3 (14%)\t6 (27%)\t7 (33%)\t\nCardioembolism\t2 (18%)\t5 (23%)\t10 (45%)\t5 (24%)\t\nSmall vessel occlusion\t0\t8 (36%)\t3 (14%)\t4 (19%)\t\nOther determined etiology\t0\t2 (9%)\t1 (5%)\t0\t\nUndetermined etiology\t3 (27%)\t4 (18%)\t2 (9%)\t5 (24%)\t\nNIHSS, median [min−max]\t7 [4–10]\t8 [4–19]\t11 [4–21]\t9 [4–19]\t\nEndovascular therapy, n (%)\t1 (9%)\t5 (24%)\t7 (32%)\t7 (33%)\t\nTime interval, median [min–max]\t\t\t\t\t\nSymptom onset to intravenous rtPA, h\t2.3 [0.7–4.3]\t1.8 [0.9–4.2]\t1.4 [0.5–4.0]\t1.5 [0.8–3.6]\t\nSymptom onset to study drug infusion, h\t2.7 [1.2–4.6]\t2.0 [1.3–4.7]\t1.7 [0.9–4.0]\t1.8 [0.8–4.1]\t\nNIHSS = National Institutes of Health Stroke Scale; rtPA = recombinant tissue plasminogen activator; TOAST = Trial of Org 10172 in Acute Stroke Treatment.\n\nIn stage 1, there were no cases of PH identified on brain CT at 24 hours. In addition, no subject experienced sICH or major systemic bleeding. Treatment‐emergent adverse events were noted in all 11 patients (100%), including nausea, dysuria, and pyrexia, each occurring in 27% of patients (3/11). Of the 39 adverse events recorded, 74% (29/39) were of mild severity and 26% (10/39) were of moderate severity. No serious adverse events or deaths were encountered. None of the adverse events was considered drug related. Therefore, this study met the DSMB criteria for advancement to stage 2.\n\nIn stage 2, for the primary outcome in the mITT population, PH was absent in the placebo (0/22) and otaplimastat 40 mg groups (0/22). One case of PH was detected in a patient who underwent EVT in the otaplimastat 80 mg group (ie, 1/21, 4.8%, 90% CI = 0.2–20.7), which was not significantly different from the placebo (treatment difference = 4.8%, 90% CI = −20.2 to 29.1). No differences were observed between otaplimastat 40 mg or 80 mg versus placebo in the secondary safety outcomes (Table 3). None of the patients developed sICH or major systemic bleeding in any of the 3 study groups. Treatment‐emergent adverse events occurred in 92% (22/24) of patients receiving placebo, 83% (20/24) taking otaplimastat 40 mg, and 95% (20/21) taking otaplimastat 80 mg (see Table 3). The majority were of mild–moderate severity (Table 4). The incidence of serious adverse events was similar between the treatment groups: 13% (3/24) for placebo (cerebral infarction, acute myocardial infarction, and lung adenocarcinoma), 17% (4/24) for otaplimastat 40 mg (3 cases of cerebral infarction and 1 with stress cardiomyopathy, chills, and muscle rigidity), and 14% (3/21) for the otaplimastat 80 mg group (cerebral infarction, toxic hepatitis, and kidney infection). Of the serious adverse events, chills, muscle rigidity, and toxic hepatitis were considered drug related and eventually resolved. Adverse events led to the withdrawal of 2 subjects in the placebo group (acute myocardial infarction and stroke in evolution) and 2 in the otaplimastat 80 mg group (toxic hepatitis and stroke in evolution). Four patients died, 2 in the placebo group (acute myocardial infarction and stroke in evolution) and 1 in each of the otaplimastat groups (both stroke in evolution). None was considered to be related to the study drug.\n\nTable 3 Stage 2 Secondary Safety Outcomes\n\nOutcome\tPlacebo, n = 24\tOtaplimastat 40 mg, n = 24\tOtaplimastat 80 mg, n = 21\t\nsICH within 5 days, n [90% CI]\t0 [0.0, 11.7]\t0 [0.0, 11.7]\t0 [0.0, 13.3]\t\nTreatment difference, % [90% CI]\t\t0 [NC]\t0 [NC]\t\nMajor systemic bleeding, ISTH, n [90% CI]\t0 [0.0, 11.7]\t0 [0.0, 11.7]\t0 [0.0, 13.3]\t\nTreatment difference, % [90% CI]\t\t0 [NC]\t0 [NC]\t\nTreatment‐emergent adverse events, n (%) [90% CI]\t22 (91.7) [76.0, 98.5]\t20 (83.3) [65.8, 94.1]\t20 (95.2) [79.3, 99.8]\t\nTreatment difference, % [90% CI]\t\t−8.3 [−33.1, 17.3]\t3.6 [−21.0, 28.2]\t\nSerious adverse events, n (%) [90% CI]\t3 (12.5) [3.5, 29.2]\t4 (16.7) [5.9, 34.2]\t3 (14.3) [4.0, 32.9]\t\nTreatment difference, % [90% CI]\t\t4.2 [−21.3, 29.2]\t1.8 [−23.2, 26.5]\t\nAdverse drug reactions, n (%) [90% CI]\t0 [0.0, 11.7]\t2 (8.3) [1.5, 24.0]\t1 (4.8) [0.2, 20.7]\t\nTreatment difference, % [90% CI]\t\t8.3 [−17.3, 33.1]\t4.8 [−20.1, 28.9]\t\nDeaths, n (%) [90% CI]\t2 (8.3) [1.5, 24.0]\t1 (4.2) [0.2, 18.3]\t1 (4.8) [0.2, 20.7]\t\nTreatment difference, % [90% CI]\t\t−4.2 [−29.2, 21.3]\t−3.6 [−28.2, 21.0]\t\nCI = confidence interval; ISTH = International Society on Thrombosis and Hemostasis; NC = not calculated; sICH = symptomatic intracranial hemorrhage.\n\nTable 4 Most Common Treatment‐Emergent Adverse Events (Safety Population)\n\nAdverse Event\tIncidence: Patients, n (%) [events, n]\t\nPlacebo, n = 24\tOtaplimastat 40 mg, n = 24\tOtaplimastat 80 mg, n = 21\t\nAny adverse event\t\t\t\t\nTotal\t22 (92%) [136]\t20 (83%) [115]\t20 (95%) [109]\t\nMild\t108 (79%)\t86 (75%)\t80 (74%)\t\nModerate\t26 (19%)\t25 (22%)\t26 (24%)\t\nSeverea\n\t2 (2%)\t4 (4%)\t3 (3%)\t\nPreferred termb\n\t\t\t\t\nHeadache\t8 (33%) [9]\t6 (25%) [8]\t4 (19%) [4]\t\nPyrexia\t6 (25%) [6]\t4 (17%) [4]\t6 (29%) [6]\t\nProductive cough\t3 (13%) [3]\t4 (17%) [4]\t2 (10%) [2]\t\nCough\t2 (8%) [2]\t4 (17%) [4]\t0\t\nConstipation\t6 (25%) [7]\t3 (13%) [3]\t6 (29%) [9]\t\nHiccups\t2 (8%) [2]\t3 (13%) [3]\t1 (5%) [1]\t\nNausea\t2 (8%) [2]\t3 (13%) [3]\t0\t\nCerebral infarction\t1 (4%) [1]\t3 (13%) [3]\t1 (5%) [1]\t\nDiabetes mellitus\t1 (4%) [1]\t3 (12%) [3]\t3 (14%) [3]\t\nHypokalemia\t0\t3 (13%) [3]\t2 (10%) [2]\t\nUrine output decreased\t1 (4%) [1]\t3 (13%) [3]\t2 (10%) [2]\t\nAtrial fibrillation\t1 (4%) [1]\t3 (13%) [3]\t2 (10%) [2]\t\nDiarrhea\t3 (13%) [3]\t2 (8%) [3]\t1 (5%) [1]\t\nDyspepsia\t5 (21%) [5]\t2 (8%) [2]\t1 (5%) [1]\t\nVomiting\t3 (13%) [3]\t2 (8%) [2]\t1 (5%) [1]\t\nDizziness\t1 (4%) [1]\t2 (8%) [2]\t1 (5%) [1]\t\nInsomnia\t2 (8%) [2]\t2 (8%) [2]\t4 (19%) [5]\t\nStroke in evolution\t1 (4%) [1]\t1 (4%) [1]\t3 (14%) [3]\t\nFatigue\t3 (13%) [3]\t1 (4%) [1]\t1 (5%) [1]\t\nGingival bleeding\t3 (13%) [3]\t0\t3 (14%) [3]\t\nRash\t0\t0\t3 (14%) [3]\t\nDepression\t4 (17%) [4]\t0\t2 (10%) [2]\t\nDysuria\t6 (25%) [6]\t0\t2 (10%) [2]\t\na Severe adverse events occurred in 9 patients: 2 with placebo (stroke in progression, ST segment elevation myocardial infarction), 4 with otaplimastat 40 mg (stress cardiomyopathy, stroke in progression, recurrent cerebral infarction, muscle rigidity), and 3 with otaplimastat 80 mg (stroke in progression, acute kidney failure, and toxic hepatitis).\n\nb Events occurring in ≥10% of patients in any treatment group. The total incidence of infections and infestations including pneumonia and kidney infection was not significantly different among the treatment groups: 17% (4/24) for placebo, 8% (2/24) for otaplimastat 40 mg, and 10% (2/21) for the otaplimastat 80 mg group.\n\nSecondary efficacy outcomes were derived from the mRS, the NIHSS, and the BI to demonstrate feasibility for future efficacy trials. The evaluation of ordinal data showed significantly different distribution of mRS scores with otaplimastat 40 mg versus placebo at 90 days (p = 0.026, Fisher exact test with Holm–Bonferroni multiplicity adjustment) but not with otaplimastat 80 mg (p = 0.502; Fig 2A, Table 5). However, the detection of true trends toward favorable mRS score distribution in 90‐day mRS was limited by the small sample size (adjusted odds ratio = 3.2, 95% CI = 0.9–10.9, p = 0.068). Figure 2B shows temporal changes in the NIHSS scores from baseline over the study period in 3 treatment groups. Although the improvement in the NIHSS scores was more pronounced in the otaplimastat 40 mg group (p = 0.006), the difference was not significant versus placebo at 28 days (p = 0.234) or 90 days (p = 0.414; see Table 5). The BI at 90 days was not significantly different among the 3 groups.\n\nFigure 2 Secondary efficacy outcomes. (A) Distribution of the modified Rankin score (mRS) at 90 days and (B) National Institutes of Health Stroke Scale (NIHSS) score changes from baseline (modified intention‐to‐treat population). mRS distribution at 90 days uses imputed data only for death cases (mRS = 6). Error bars indicate standard deviation values. mRS on day 90: placebo, n = 21; otaplimastat 40 mg, n = 20; 80 mg, n = 20. NIHSS: placebo, n = 22; otaplimastat 40 mg, n = 22; 80 mg, n = 21 on day 0 to day 2. Placebo, n = 20; otaplimastat 40 mg, n = 22; 80 mg, n = 19 on day 3. Placebo, n = 20; otaplimastat 40 mg, n = 20; 80 mg, n = 19 on days 4, 5, and 28. Placebo, n = 19; otaplimastat 40 mg, n = 17; 80 mg, n = 17 on day 90. (C) Fold change of infarct growth was calculated as (individual infarct volume on day 5 − individual infarct volume on day 0)/mean of infarct volumes on day 0. Each point represents an individual patient, with the median (red bar) and interquartile ranges (black bars). Placebo, n = 20; otaplimastat 40 mg, n = 20; 80 mg, n = 19.\n\nTable 5 Stage 2 Clinical Outcomes (mITT Population)\n\n\tPlacebo\tOtaplimastat 40 mg\tOtaplimastat 80 mg\t\nMedian [IQR]\tMedian [IQR]\t\np\n\tOR (95% CI) Adjustedp\n\tMedian [IQR]\t\np\n\tOR (95% CI) Adjusted p\n\t\nEvaluable, na\n\t22\t22\t\t\t21\t\t\t\nmRS\t\t\t\t\t\t\t\t\nmRS at day 0\t4 [3 to 4]\t4 [3 to 4]\t0.833\t\t4 [3 to 4]\t0.192\t\t\nmRS at day 90\t1.0 [1.0 to 1.0]\t0.0 [0.0 to 2.0]\t0.026\tOR 3.2 (0.9 to 10.9)b\np = 0.068b\n\t1.0 [0.0 to 3.0]\t0.502\tOR 2.0 (0.6 to 6.7)b\np = 0.246b\n\t\nNIHSS changes\t\t\t0.006c\n\t\t\t0.940c\n\t\t\nBaseline at day 0\t8.0 [5.0 to 14.0]\t11.0 [5.0 to 15.0]\t>0.999\t\t9.0 [5.0 to 13.0]\t>0.999\t\t\nChanges at day 5\t−4.0 [−8.0 to −1.5]\t−7.0 [−11.0 to −4.5]\t0.387\t\t−4.0 [−9.0 to −2.0]\t0.866\t\t\nChanges at day 28\t−4.0 [−9.0 to −3.0]\t−7.0 [−11.5 to −5.0]\t0.234\t\t−5.5 [−10.0 to −2.0]\t0.922\t\t\nChanges at day 90\t−5.0 [−10.0 to −4.0]\t−8.0 [−11.0 to −5.0]\t0.414\t\t−7.0 [−10.0 to −5.0]\t0.880\t\t\nInfarct growth, mld\n\t\t\t\t\t\t\t\t\nBaseline at day 0\t4.9 [0.5 to 8.1]\t5.9 [0.9 to 24.0]\t0.579\t\t3.2 [0.7 to 15.6]\t0.982\t\t\nGrowth at day 5\t3.2 [0.3 to 7.9]\t1.7 [0.0 to 11.1]\t>0.999\t\t3.0 [0.5 to 9.0]\t0.866\t\t\nFold change in 5 days\t0.7 [0.1 to 1.6]\t0.1 [0.0 to 0.9]\t0.303\t\t0.3 [0.0 to 0.8]\t0.423\t\t\nThe mITT population is defined as the population composed of all subjects who belonged to the safety analysis set, fulfilled major inclusion/exclusion criteria, and had at least 1 post‐treatment assessment with primary endpoint. A total of 4 patients missed primary computed tomography outcome analysis and were excluded: 2 in the placebo group (1 transient ischemic attack, 1 death at day 1), and 2 in the 40 mg otaplimastat group (2 withdrew, 1 each at days 0 and 5). Analysis uses observed data. Probability value was obtained by Mann–Whitney test or Fisher exact test at each time point, with multiplicity adjustment by Holm–Bonferroni correction.\n\na mRS at day 90: placebo, n = 21; otaplimastat 40 mg, n = 20; 80 mg, n = 20. NIHSS: placebo, n = 22; otaplimastat 40 mg, n = 22; 80 mg, n = 21 at day 0. Placebo, n = 20; otaplimastat 40 mg, n = 20; 80 mg, n = 19 at day 5 and day 28. Placebo, n = 19; otaplimastat 40 mg, n = 17; 80 mg, n = 17 at day 90. Infarct growth from day 0 to day 5: placebo, n = 20; otaplimastat 40 mg, n = 20; 80 mg, n = 19.\n\nb Ordinal logistic regression analysis for mRS distribution (mRS = 0–6) at day 90 uses imputed data for death cases. Unadjusted probability values are: p = 0.257 for placebo vs 40 mg and p = 0.674 for placebo vs 80 mg. Adjusted probability values and ORs show the effect of treatment, adjusted for age, sex, baseline NIHSS, tissue plasminogen activator treatment time after stroke onset, and the use of endovascular surgery.\n\nc Changes in NIHSS scores were analyzed with the van Elteren test.\n\nd Measurement of infarct growth by diffusion‐weighted imaging on days 0 and 5 (edema unadjusted). Infarct growth on day 5 = individual infarct volume on day 5 − individual infarct volume on day 0. Fold change of infarct growth = infarct growth on day 5 / mean of infarct volumes on day 0.\n\nCI = confidence interval; IQR = interquartile range; mITT = modified intention‐to‐treat; mRS = modified Rankin scale; NIHSS = National Institutes of Health Stroke Scale; OR = odds ratio.\n\nNo significant differences were observed among treatment groups in the exploratory endpoints based on the MRI outcomes (Tables 5 and 6). Notably, the DWI‐identified median lesion volume growth (minimal, maximal) was 3.2 (−0.3, 57.2) with placebo, 1.7 (−3.3, 26.4) with otaplimastat 40 mg, and 3.0 (0.0, 89.1) with otaplimastat 80 mg (see Table 5). The incidence of any ICH was comparable at 35% (7/20) with placebo, 35% (7/20) with otaplimastat 40 mg (treatment difference = 0%, 90% CI = −27.8 to 27.8), and 37% (7/19) with otaplimastat 80 mg (treatment difference = 1.8%, 90% CI = −25.7 to 27.6), but a trend toward increased hemorrhage volumes and infarction recurrence in the otaplimastat 80 mg group was shown (see Table 6). Among 69 patients, 54 (78%) were treated with antiplatelet agents and 33% (18/54) of patients developed any ICH. The ICH rate was not significantly different between the patients receiving monotherapy and those receiving dual therapy (data not shown).\n\nTable 6 Stage 2 Exploratory Magnetic Resonance Imaging Outcomes (Modified Intention‐to‐Treat Population)\n\n\tPlacebo\tOtaplimastat 40 mg\tOtaplimastat 80 mg\t\nValue\t\np\n\tValue\t\np\n\t\nEvaluable, n\t20\t20\t\t19\t\t\nAny ICH at day 5 on GRE\t\t\t\t\t\t\nPatients, n (%)\t7 (35%)\t7 (35%)\t>0.999\t7 (37%)\t>0.999\t\nHI 1\t5 (25%)\t3 (15%)\t>0.999\t5 (26%)\t>0.999\t\nHI 2\t2 (10%)\t3 (15%)\t>0.999\t1 (5%)\t>0.999\t\nPH 1\t0\t0\tNA\t1 (5%)\t>0.999\t\nPH 2\t0\t1 (5%)\t>0.999\t0\tNA\t\nVolume, ml, median [IQR]\t\t\t\t\t\t\nBaseline at day 0\t0.0 [0.0−0.0]\t0.0 [0.0−0.0]\t>0.999\t0.0 [0.0−0.0]\t>0.999\t\nGrowth at day 5\t0.0 [0.0−0.1]\t0.0 [0.0−0.2]\t>0.999\t0.0 [0.0−1.2]\t>0.999\t\nInfarction recurrence until day 5 on DWI\t\t\t\t\t\t\nPatients n (%)\t0\t1 (5%)\t\t5 (26%)\t\t\nInfarct size, ml, median [IQR]\t0.0 [0.0−0.0]\t0.0 [0.0−0.0]\t>0.999\t0.0 [0.0−0.1]\t0.060\t\nDifference between placebo and each treatment group was tested using the Wilcoxon rank sum test, or by Mann–Whitney test or Fisher exact test, with multiplicity adjustment by Holm–Bonferroni correction.\n\nDWI = diffusion‐weighted imaging; GRE = gradient recalled echo; HI = hemorrhagic infarct; ICH = intracerebral hemorrhage; IQR = interquartile range; NA = not applicable; PH = parenchymal hematoma.\n\nDiscussion\nIn this SAFE‐TPA trial, we found no serious adverse events in the stage 1 study. In stage 2, 1 patient developed PH, and 1 had hepatotoxicity in the otaplimastat 80 mg group. In this case, the aspartate aminotransferase level reached up to 759 IU on day 2 and otaplimastat was discontinued (data not shown). This subject was negative for viral hepatitis markers, and the liver function test results returned to the normal level on day 14. Thus, although this potential hepatotoxicity should be investigated further, coadministration of intravenous otaplimastat is feasible and appears to be generally safe in patients with AIS receiving rtPA treatment.\n\nAlthough rtPA treatment grants better clinical outcome, the risks of ICH and mortality are increased when the treatment is delayed.1, 2, 3, 4 Previous studies have consistently shown that otaplimastat reduces the incidence of ICH in experimental animals with stroke receiving rtPA,15, 16, 17 whereas it did not interfere with the fibrinolytic activity of rtPA (authors’ unpublished data). However, in the current study there were no differences in the incidence of ICH on CT scan on day 1, and on GRE at 5 days between the placebo and otaplimastat groups (see Table 3). The rate of sICH in the present study was low compared with that in previous trials, probably owing to the early thrombolytic therapy (mean tPA treatment delay = 1.78 hours), inclusion of patients with relatively young age (mean = 63 years), less severe strokes (mean baseline NIHSS score = 10), and better thrombolytic recanalization (patient population with nearly complete or complete reperfusion within 5 days with modified Thrombolysis in Cerebral Ischemia [mTICI] 2b–3: >77%).26 Thus, the low occurrence of ICH and the small sample size preclude any conclusion regarding the potential benefit of otaplimastat in preventing ICH in patients with AIS receiving rtPA.\n\nFor efficacy outcome, we found that the distribution of the mRS scores was significantly different between the placebo and the otaplimastat 40 mg groups (see Table 5, Fig 2A; p = 0.026), associated with the greater proportion of the patients with good outcome (mRS ≤ 2) in the otaplimastat 40 mg group. The magnitude of the clinical benefit of rtPA treatment itself in our study was larger than that in the recent meta‐analysis with 9 rtPA phase 3 trials (patients with mRS = 0–1 at day 90: 76% vs 31%).3 This very favorable clinical outcome may, at least in part, be attributed to the rapid administration of rtPA (mean = 1.78 hours; see Table 2) after stroke onset in our study, compared with previous rtPA trials (mean = 4.00 hours).3 Considering that the main theoretical neuroprotective mechanism of otaplimastat is to reduce brain edema and ICH after rtPA therapy, especially in delayed therapy,20, 21 the benefit of otaplimastat may have been underappreciated in our patient population.\n\nThe 7‐day NIHSS score27 or early decrease in NIHSS score15, 16, 28 has been used as a marker for clinical efficacy in recent exploratory trials in acute stroke. Notably, the NIHSS score tended to decrease more markedly in the otaplimastat 40 mg than that in the placebo group during the acute phase of stroke, although the difference was not statistically significant at each time point (see Table 5, Fig 2B). In addition, the growth of MRI‐identified infarct volume was the lowest in the otaplimastat 40 mg group (see Table 5, Fig 2C). These findings collectively suggest that otaplimastat may exert a beneficial effect during the early phase of stroke in patients receiving rtPA therapy, although further clarification in a larger trial remains necessary.\n\nRecent clinical trials of neuroprotectant as an adjunctive therapy have evaluated several potential clinically effective mechanisms29, 30: reduction of ICH,14, 15, 16 improvement of recanalization and collateral flow,16 and/or suppression of infarct growth.16 Otaplimastat did not significantly decrease the incidence or volume of ICH (see Tables 3 and 6), although this possibility is not entirely excluded, considering the small sample size and early thrombolysis, as discussed earlier. Considering that patients receiving otaplimastat 40 mg had the lowest rate (53% vs 74% placebo) of full recanalization (mTICI score = 3), it is unlikely that this agent improves recanalization. Nevertheless, patients in the otaplimastat 40 mg group exhibited the trend of quickly diminishing neurological deficits. This observation appears to be in line with pleiotropic neuroprotective mechanisms preclinically elucidated that include reduction of inflammatory cell migration, blood–brain barrier stabilization, and enhanced expression of antioxidant enzymes (ie, MnSOD) in the ischemic brain.18, 19\n\n\nNotably, in patients receiving otaplimastat 80 mg, there was no significant beneficial effect on the mRS distribution. There was no increase in serious adverse effects in this group compared with the otaplimastat 40 mg or placebo groups, except for the one case of hepatotoxicity. Although the otaplimastat 80 mg group had more patients with ICH and recurrent infarction, the clinical outcomes in theses population was not worse than those in other groups with similar initial stroke severity (data not shown). It remains uncertain why the encouraging findings with otaplimastat 40 mg were not mirrored with otaplimastat 80 mg. It was reported that a particular dosage, timing, and duration of MMP inhibition impact the reduction of lesion sizes after ICH, and blood–brain barrier permeability or neurovascular remodeling in the poststroke period.31, 32, 33, 34, 35 For example, an early brief MMP inhibition confers a neuroprotective effect, whereas a prolonged inhibition dysregulates delayed neuroinflammatory responses and hampers recovery.33 Treatment with the MMP inhibitor ilomastat once, but not twice, following focal stroke rescued visual plasticity,34 suggesting the importance of carefully defining dosing regimen to ensure the spatiotemporal inhibition of targeted MMPs and resulting clinical efficacy.\n\nThere are limitations in this study. As discussed above, the small number of enrolled patients does not allow us to make a powerful conclusion, especially for the efficacy endpoints. However, the main purpose of this phase 2 study was to examine the feasibility and safety of otaplimastat adjuvant therapy rather than confirming its efficacy. In addition, because we did not administer otaplimastat in patients who did not receive rtPA, it remains unknown whether this agent is feasible and potentially beneficial in patients who are not treated with rtPA. Especially, along with recent positive clinical trials,36, 37, 38 EVT has been increasingly used. Further studies are needed to examine the feasibility, safely, and efficacy of otaplimastat in patients undergoing EVT without intravenous rtPA.\n\nDespite the limitations, we provided evidence that administering otaplimastat to patients with AIS receiving rtPA is feasible and generally safe. There was also an intriguing signal that otaplimastat 40 mg may improve neurological outcomes in these patients. Further clinical studies on otaplimastat or other potentially useful adjunctive therapies for rtPA may help identify novel ways to improve the clinical outcomes of patients with AIS receiving rtPA.39\n\n\nAuthor Contributions\nJ.S.K. formulated the conception and design of this study; J.S.K., K.B.L., J.‐H.P, S.M.S, K.O., E.‐G.K., D.C., Y.‐H.H., and E.‐J.L. contributed to data acquisition; all authors contributed to the analysis and interpretation of the data, and made critical revision and approved for the final version of the manuscript; J.S.K., E.‐J.L., C.J., and B.S.K. contributed to drafting the text and preparing the figures.\n\nPotential Conflicts of Interest\nNothing to report.\n\nAcknowledgment\nThis study was supported by a grant from the Korea Health Technology R&D project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2796).\n\nWe thank the DSMB members, Drs L. B. Goldstein, P. Amarenco, U. Dirnagl, S. Arbe‐Barnes, and Y. J. Lee for their support of the DSMB; K. W. Kim, S. C. Chung, and the Central Imaging Core Lab members at Asan Medical Center, Seoul, Korea for imaging setup and analysis; J. B. Fiebach for independent review of CT/MRI; K.‐S. Yang and J. S. Lee for statistical support for the study; and N. Richardson for editorial support.\n==== Refs\nReferences\n1 \nNational Institute of Neurological Disorders and Stroke rt‐PA Stroke Study Group \n. Tissue plasminogen activator for acute ischemic stroke . N Engl J Med \n1995 ;333 :1581 −1587 .7477192 \n2 \n\nHacke \nW \n, \nKaste \nM \n, \nBluhmki \nE \n, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke . N Engl J Med \n2008 ;359 :1317 −1329 .18815396 \n3 \n\nEmberson \nJ \n, \nLees \nKR \n, \nLyden \nP \n, et al. 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Thromb Haemost \n2014 ;112 :363 −378 .24671655 \n7 \n\nJickling \nGC \n, \nLiu \nD \n, \nStamova \nB \n, et al. Hemorrhagic transformation after ischemic stroke in animals and humans . J Cereb Blood Flow Metab \n2014 ;34 :185 −199 .24281743 \n8 \n\nChamorro \nA \n, \nDirnagl \nU \n, \nUrra \nX \n, \nPlanas \nAM \n. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation . Lancet Neurol \n2016 ;15 :869 −881 .27180033 \n9 \n\nPena \nID \n, \nBorlongan \nC \n, \nShen \nG \n, \nDavis \nW \n. Strategies to extend thrombolytic time window for ischemic stroke treatment: an unmet clinical need . J Stroke \n2017 ;19 :50 −60 .28178410 \n10 \n\nKanazawa \nM \n, \nTakahashi \nT \n, \nNishizawa \nM \n, \nShimohata \nT \n. Therapeutic strategies to attenuate hemorrhagic transformation after tissue plasminogen activator treatment for acute ischemic stroke . J Atheroscler Thromb \n2017 ;24 :240 −253 .27980241 \n11 \n\nChamorro \nA. \n\nNeuroprotectants in the era of reperfusion therapy . J Stroke \n2018 ;20 :197 −207 .29886725 \n12 \n\nMalhotra \nK \n, \nChang \nJJ \n, \nKhunger \nA \n, et al. Minocycline for acute stroke treatment: a systematic review and meta‐analysis of randomized clinical trials . J Neurol \n2018 ;265 :1871 −1879 .29948247 \n13 \n\nChamorro \nA \n, \nAmaro \nS \n, \nCastellanos \nM \n, et al. Safety and efficacy of uric acid in patients with acute stroke (URICO‐ICTUS): a randomised, double‐blind phase 2b/3 trial . Lancet Neurol \n2014 ;13 :453 −460 .24703208 \n14 \n\nLyden \nP \n, \nPryor \nKE \n, \nCoffey \nCS \n, et al. Final results of the RHAPSODY trial: a multi‐center, phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3K3A‐APC, a recombinant variant of human activated protein C, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke . Ann Neurol \n2019 ;85 :125 −136 .30450637 \n15 \n\nZhu \nZ \n, \nFu \nY \n, \nTian \nD \n, et al. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial . Circulation \n2015 ;132 :1104 −1112 .26202811 \n16 \n\nTian \nDC \n, \nShi \nK \n, \nZhu \nZ \n, et al. Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow . Ann Neurol \n2018 ;84 :717 −728 .30295338 \n17 \n\nNoh \nSJ \n, \nLee \nJM \n, \nLee \nKS \n, et al. SP‐8203 shows neuroprotective effects and improves cognitive impairment in ischemic brain injury through NMDA receptor . Pharmacol Biochem Behav \n2011 ;100 :73 −80 .21835192 \n18 \n\nNoh \nSJ \n, \nLee \nSH \n, \nShin \nKY \n, et al. SP‐8203 reduces oxidative stress via SOD activity and behavioral deficit in cerebral ischemia . Pharmacol Biochem Behav \n2011 ;98 :150 −154 .21172384 \n19 \n\nKim \nW‐K \n, \nJu \nC \n, \nJalin \nAMAA \n, et al. Therapeutic efficacy and pharmacological mechanisms of SP‐8203 for treatment of cerebral ischemia . Stroke \n2015 ;46 :ATP239 (Abstract).\n20 \n\nJu \nC \n, \nAnthony Jalin \nA \n, \nSong \nHY \n, et al. Extension of therapeutic time window of tissue plasminogen activator with SP‐8203 combination therapy in rat embolic stroke models . Eur Stroke J \n2016 ;1 :581 (Abstract).\n21 \nNational Institute of Neurological Disorders and Stroke rt‐PA Stroke Study Group \n. Intracerebral hemorrhage after intravenous t‐PA therapy for ischemic stroke . Stroke \n1997 ;28 :2109 −2118 .9368550 \n22 \n\nHacke \nW \n, \nKaste \nM \n, \nFieschi \nC \n, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS) . JAMA \n1995 ;274 :1017 −1025 .7563451 \n23 \n\nHacke \nW \n, \nKaste \nM \n, \nFieschi \nC \n, et al. Randomised double‐blind placebo‐controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European‐Australasian Acute Stroke Study Investigators . Lancet \n1998 ;352 :1245 −1251 .9788453 \n24 \n\nSchulman \nS \n, \nKearon \nC \n, Subcommittee on Control of Anticoagulation of the Scientific Standardization Committee of the International Society on Thrombosis and Haemostasis \n. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients . J Thromb Haemost \n2005 ;3 :692 −694 .15842354 \n25 \n\nSaposnik \nG \n, \nFang \nJ \n, \nKapral \nMK \n, et al. The iScore predicts effectiveness of thrombolytic therapy for acute ischemic stroke . Stroke \n2012 ;43 :1315 −1322 .22308252 \n26 \n\nTanne \nD \n, \nKasner \nSE \n, \nDemchuk \nAM \n, et al. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the Multicenter rt‐PA Stroke Survey . Circulation \n2002 ;105 :1679 –1685 .11940547 \n27 \n\nKerr \nDM \n, \nFulton \nRL \n, \nLees \nKR \n, et al. Seven‐day NIHSS is a sensitive outcome measure for exploratory clinical trials in acute stroke: evidence from the Virtual International Stroke Trials Archive . Stroke \n2012 ;43 :1401 −1403 .22308254 \n28 \n\nBroderick \nJP \n, \nLu \nM \n, \nKothari \nR \n, et al. Finding the most powerful measures of the effectiveness of tissue plasminogen activator in the NINDS tPA Stroke Trial . Stroke \n2000 ;31 :2335 −2341 .11022060 \n29 \n\nKim \nJS \n. tPA helpers in the treatment of acute ischemic stroke: are they ready for clinical use? \nJ Stroke \n2019 ;21 :160 −174 .31161761 \n30 \n\nMizuma \nA \n, \nYou \nJS \n, \nYenari \nMA \n. Targeting reperfusion injury in the age of mechanical thrombectomy . Stroke \n2018 ;49 :1796 −1802 .29760275 \n31 \n\nLo \nEH \n. A new penumbra: transitioning from injury into repair after stroke . Nat Med \n2008 ;14 :497 −500 .18463660 \n32 \n\nChang \nJJ \n, \nEmanuel \nBA \n, \nMack \nWJ \n, et al. Matrix metalloproteinase‐9: dual role and temporal profile in intracerebral hemorrhage . J Stroke Cerebrovasc Dis \n2014 ;23 :2498 −2505 .25306400 \n33 \n\nZhao \nBQ \n, \nWang \nS \n, \nKim \nHY \n, et al. Role of matrix metalloproteinases in delayed cortical responses after stroke . Nat Med \n2006 ;12 :441 −445 .16565723 \n34 \n\nPielecka‐Fortuna \nJ \n, \nKalogeraki \nE \n, \nFortuna \nMG \n, et al. Optimal level activity of matrix metalloproteinases is critical for adult visual plasticity in the healthy and stroke‐affected brain . Elife \n2015 ;26 :e11290.\n35 \n\nBencsik \nP \n, \nPálóczi \nJ \n, \nKocsis \nGF \n, et al. Moderate inhibition of myocardial matrix metalloproteinase‐2 by ilomastat is cardioprotective . Pharmacol Res \n2014 ;80 :36 −42 .24380772 \n36 \n\nGoyal \nM \n, \nMenon \nBK \n, \nvan Zwam \nWH \n, et al. Endovascular thrombectomy after large‐vessel ischaemic stroke: a meta‐analysis of individual patient data from five randomised trials . Lancet \n2016 ;387 :1723 −1731 .26898852 \n37 \n\nNogueira \nRG \n, \nJadhav \nAP \n, \nHaussen \nDC \n, et al; DAWN Trial Investigators \n. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct . N Engl J Med \n2018 ;378 :11 −21 .29129157 \n38 \n\nAlbers \nGW \n, \nMarks \nMP \n, \nKemp \nS \n, et al; DEFUSE 3 Investigators \n. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging . N Engl J Med \n2018 ;378 :708 −718 .29364767 \n39 \n\nHenninger \nN \n, \nFisher \nM \n. Extending the time window for endovascular and pharmacological reperfusion . Trans Stroke Res \n2016 ;7 :284 −293 .\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0364-5134",
"issue": "87(2)",
"journal": "Annals of neurology",
"keywords": null,
"medline_ta": "Ann Neurol",
"mesh_terms": "D000081:Acetamides; D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D004311:Double-Blind Method; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents; D052999:Quinazolinones; D020521:Stroke; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7707449",
"other_id": null,
"pages": "233-245",
"pmc": null,
"pmid": "31721277",
"pubdate": "2020-02",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "29948247;7563451;29364767;22308252;11022060;30450637;26609811;11940547;16565723;24380772;31161761;27180033;28178410;26898852;15842354;24703208;15459442;29886725;29766770;25106063;22308254;9368550;26739964;25306400;27980241;21172384;26202811;7477192;29129157;30295338;29760275;24671655;24281743;9788453;18463660;21835192;18815396",
"title": "Safety and Efficacy of Otaplimastat in Patients with Acute Ischemic Stroke Requiring tPA (SAFE-TPA): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study.",
"title_normalized": "safety and efficacy of otaplimastat in patients with acute ischemic stroke requiring tpa safe tpa a multicenter randomized double blind placebo controlled phase 2 study"
} | [
{
"companynumb": "KR-ROCHE-2484349",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Patient-controlled epidural analgesia (PCEA) is an excellent choice of analgesia technique in labor; however, patient selection for such treatment is important. A 14 year old healthy parturient receiving PCEA had a very high block due to patient noncompliance.",
"affiliations": "Department of Anesthesiology, University of Texas Medical School at Houston, 6431 Fannin St., MSB 5.020, TX 77030, USA.;Department of Anesthesiology, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS 39216, USA. Electronic address: mpanni@umc.edu.",
"authors": "Guzman-Reyes|Sara|S|;Panni|Moeen K|MK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jclinane.2013.01.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "25(5)",
"journal": "Journal of clinical anesthesia",
"keywords": "Adolescence; Analgesia: patient-controlled; Anesthesia: obstetrical; Labor analgesia; Patient-controlled epidural analgesia",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000293:Adolescent; D015360:Analgesia, Epidural; D016362:Analgesia, Obstetrical; D016058:Analgesia, Patient-Controlled; D005260:Female; D006801:Humans; D007743:Labor, Obstetric; D055118:Medication Adherence; D018579:Patient Selection; D011247:Pregnancy",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "407-408",
"pmc": null,
"pmid": "23965187",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Importance of patient selection for patient-controlled epidural analgesia (PCEA), as even low-concentration solutions may lead to a very high block.",
"title_normalized": "importance of patient selection for patient controlled epidural analgesia pcea as even low concentration solutions may lead to a very high block"
} | [
{
"companynumb": "US-JNJFOC-20131013761",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL CITRATE"
},
"drugadditional": null,
... |
{
"abstract": "A life-threatening cardiopulmonary resuscitation (CPR)-related injury can cause recurrent arrest after return of circulation. Such injuries are difficult to identify during resuscitation, and their contribution to failed resuscitation can be missed given the limitations of conventional CPR. Extracorporeal cardiopulmonary resuscitation (ECPR), increasingly being considered for selected patients with potentially reversible etiology of arrest, may identify previously occult CPR-related injuries by restoring arterial pressure and flow. Herein, we describe two cases of severe CPR-related injuries contributing to recurrent arrest. Each case had ECPR implemented within 60 minutes of the start of CPR. After the presumed cardiac etiology had been addressed with percutaneous coronary intervention, life-threatening cardiovascular injuries with recurrent arrest were noted, and resuscitative thoracotomy was performed under ECPR. One patient survived to hospital discharge. ECPR may provide an opportunity to identify and correct severe resuscitation-related injuries causing recurrent arrest. Chest compression depth >6 cm, especially in older women, may contribute to these injuries.",
"affiliations": "*Emergency Medicine,Subdivision of Cardiovascular Medicine,College of Medicine,Korea University,Seoul,South Korea.;*Emergency Medicine,Subdivision of Cardiovascular Medicine,College of Medicine,Korea University,Seoul,South Korea.;*Emergency Medicine,Subdivision of Cardiovascular Medicine,College of Medicine,Korea University,Seoul,South Korea.;*Emergency Medicine,Subdivision of Cardiovascular Medicine,College of Medicine,Korea University,Seoul,South Korea.;†Thoracic and Cardiovascular Surgery,Subdivision of Cardiovascular Medicine,College of Medicine,Korea University,Seoul,South Korea.;‡Internal Medicine,Subdivision of Cardiovascular Medicine,College of Medicine,Korea University,Seoul,South Korea.;*Emergency Medicine,Subdivision of Cardiovascular Medicine,College of Medicine,Korea University,Seoul,South Korea.",
"authors": "Han|Kap Su|KS|;Lee|Sung Woo|SW|;Park|Kwang Hoon|KH|;Park|Jong Su|JS|;Jung|Jae Seung|JS|;Yu|Cheol Woong|CW|;Kim|Su Jin|SJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1017/cem.2016.389",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1481-8035",
"issue": "19(5)",
"journal": "CJEM",
"keywords": "cardiac injury; cardiopulmonary resuscitation; chest compression; chest injury; extracorporeal cardiopulmonary resuscitation",
"medline_ta": "CJEM",
"mesh_terms": "D000368:Aged; D016887:Cardiopulmonary Resuscitation; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D016757:Death, Sudden, Cardiac; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D005500:Follow-Up Studies; D006323:Heart Arrest; D006341:Heart Rupture; D006801:Humans; D008875:Middle Aged; D013902:Radiography, Thoracic; D018570:Risk Assessment; D012494:Sampling Studies; D016896:Treatment Outcome",
"nlm_unique_id": "100893237",
"other_id": null,
"pages": "404-409",
"pmc": null,
"pmid": "27819221",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Concealed resuscitation-related injuries as reversible cause of recurrent arrest following extracorporeal cardiopulmonary resuscitation.",
"title_normalized": "concealed resuscitation related injuries as reversible cause of recurrent arrest following extracorporeal cardiopulmonary resuscitation"
} | [
{
"companynumb": "KR-BAYER-2017-226123",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Adverse drug reactions that result in patient death warrant special consideration to determine if the outcome was preventable. We report the results of an investigation into the cause of death of a 63 year old male who was thought to have phenytoin-induced toxic epidermal necrolysis (TEN). Most dermatological reactions from drugs are minor and resolve without sequelae once the drug is discontinued. In some cases, reactions are severe and can be life threatening. The patient arrived at the emergency department with extensive exfolative dermatitis. The differential diagnosis included phenytoin-induced TEN, scalded skin syndrome, and phenytoin hypersensitivity. After he was admitted his clinical status deteriorated and he died 13 days after admission. Autopsy findings were significant for necrotizing dermatitis, necrotizing pneumonia, multiple herpetic ulcerations, multisystem organ failure and blood cultures grew Staphylococcus aureus (TSS toxin positive). Findings that indicate a cause of death other than a drug-induced dermatological reaction are presented as well as an overview of the patients' medical history. The differential diagnosis of drug induced skin lesions are also discussed.",
"affiliations": "Department of Emergency Medicine and Clinical Toxicology, UTMG, Memphis 38163, USA.",
"authors": "Blaho|K|K|;Merigian|K|K|;Winbery|S|S|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/1353-1131(95)90005-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1353-1131",
"issue": "2(4)",
"journal": "Journal of clinical forensic medicine",
"keywords": null,
"medline_ta": "J Clin Forensic Med",
"mesh_terms": null,
"nlm_unique_id": "9434927",
"other_id": null,
"pages": "205-11",
"pmc": null,
"pmid": "15335635",
"pubdate": "1995-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Determining the true cause of death in a dermatological disaster.",
"title_normalized": "determining the true cause of death in a dermatological disaster"
} | [
{
"companynumb": "US-PFIZER INC-2019489988",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PHENOBARBITAL"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of cerebral phaeohyphomycosis, a fungal brain infection due to a dark (dematiaceous) fungi in a 6-year-old French Guyanese boy. The child presented fever and drowsiness due to several paraventricular brain abscesses. Neurological surgeries were performed to reduce intracranial hypertension and to obtain abscess biopsies. Mycological cultures of intraoperative samples led to the diagnosis of cerebral phaeohyphomycosis due to Cladophialophora bantiana. The patient neurological status deteriorated and remained critical after several weeks of combination antifungal therapy with voriconazole 8mg/kg/day, liposomal amphotericin B 10mg/kg/day and flucytosine 200mg/kg/day. A complete surgical resection was not possible because of multiple small abscesses. A multidisciplinary ethical staff decided on home medical care with palliative ventriculoperitoneal shunt, nasogastric feeding and analgesics. One year later, the patient's neurological condition had improved and cerebral lesions had regressed, while he had not received any antifungal treatment but only traditional medicines. Cerebral phaeohyphomycosis are rare diseases affecting immunocompromised but also apparently non-immunocompromised patients, as in this case. A complete surgical resection is not always possible and mortality rates are high in spite of treatments with a combination of antifungals. The diagnosis may be difficult because of these dematiaceous fungi's slowly growing and their potential pathogenicity for laboratory staff.",
"affiliations": "Laboratoire de parasitologie-mycologie, hôpital Pierre-Zobda-Quitman, CHU de la Martinique, BP 632, 97261 Fort-de-France cedex, Martinique. Electronic address: charline.miossec@chu-martinique.fr.;Laboratoire de parasitologie-mycologie, hôpital Pierre-Zobda-Quitman, CHU de la Martinique, BP 632, 97261 Fort-de-France cedex, Martinique.;Service de réanimation pédiatrique, hôpital Pierre-Zobda-Quitman, CHU de la Martinique, BP 632, 97261 Fort-de-France cedex, Martinique.;Service de réanimation pédiatrique, hôpital Pierre-Zobda-Quitman, CHU de la Martinique, BP 632, 97261 Fort-de-France cedex, Martinique.;Service de pédiatrie, hôpital Pierre-Zobda-Quitman, CHU de la Martinique, BP 632, 97261 Fort-de-France cedex, Martinique.;Service des maladies infectieuses et tropicales, hôpital Pierre-Zobda-Quitman, CHU de la Martinique, BP 632, 97261 Fort-de-France cedex, Martinique.;Service de neurochirurgie, hôpital Pierre-Zobda-Quitman, CHU de la Martinique, BP 632, 97261 Fort-de-France cedex, Martinique.;Laboratoire de parasitologie-mycologie, hôpital Pierre-Zobda-Quitman, CHU de la Martinique, BP 632, 97261 Fort-de-France cedex, Martinique.",
"authors": "Miossec|C|C|;Jacob|S|S|;Peipoch|L|L|;Brard|M|M|;Jolivet|E|E|;Hochedez|P|P|;Hamlat|A|A|;Desbois|N|N|",
"chemical_list": "D000935:Antifungal Agents",
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2019.100918",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "30(1)",
"journal": "Journal de mycologie medicale",
"keywords": "Cerebral abscess; Cerebral phaeohyphomycomycosis; Cladophialophora bantiana; Dematiaceous fungi",
"medline_ta": "J Mycol Med",
"mesh_terms": "D000935:Antifungal Agents; D001203:Ascomycota; D001922:Brain Abscess; D020314:Central Nervous System Fungal Infections; D060425:Cerebral Phaeohyphomycosis; D002648:Child; D003131:Combined Modality Therapy; D004750:Enteral Nutrition; D005616:French Guiana; D006801:Humans; D007121:Immunocompetence; D007441:Intubation, Gastrointestinal; D008297:Male; D019635:Neurosurgical Procedures; D017287:Ventriculoperitoneal Shunt",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "100918",
"pmc": null,
"pmid": "31926829",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebral phaeohyphomycosis due to Cladophialophora bantiana in a French Guianese child.",
"title_normalized": "cerebral phaeohyphomycosis due to cladophialophora bantiana in a french guianese child"
} | [
{
"companynumb": "FR-009507513-2005FRA009230",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B\\CHOLESTEROL"
},
"drugadditio... |
{
"abstract": "ICPIs were effective for primary and metastatic foci of lung adenocarcinoma, but their repeated use provoked a late relapse of IgM nephropathy and lethal lesions in pancreas and lung. ICPIs should be used carefully in cases of immune-related disease.",
"affiliations": "Department of General Medicine (junior resident) Shimada Municipal Hospital Shimada Japan.;Department of Diagnostic Pathology Shimada Municipal Hospital Shimada Japan.;Department of Nephrology Shimada Municipal Hospital Shimada Japan.;Department of Diagnostic Pathology Shimada Municipal Hospital Shimada Japan.",
"authors": "Odani|Kentaro|K|;Tachibana|Mitsuhiro|M|https://orcid.org/0000-0002-1041-0391;Nogaki|Fumiaki|F|;Tsutsumi|Yutaka|Y|https://orcid.org/0000-0002-4136-9678",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3903",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.3903\nCCR33903\nCase Report\nCase Reports\nLate relapse of IgM nephropathy‐associated nephrotic syndrome after repeated administration of immune checkpoint inhibitor against pulmonary adenocarcinoma\nODANI et al.\nOdani Kentaro 1 2 5\nTachibana Mitsuhiro https://orcid.org/0000-0002-1041-0391\n2\nNogaki Fumiaki 3\nTsutsumi Yutaka https://orcid.org/0000-0002-4136-9678\n2 4 pathos223@kind.ocn.ne.jp\n\n1 Department of General Medicine (junior resident) Shimada Municipal Hospital Shimada Japan\n2 Department of Diagnostic Pathology Shimada Municipal Hospital Shimada Japan\n3 Department of Nephrology Shimada Municipal Hospital Shimada Japan\n4 Diagnostic Pathology Clinic Nagoya Japan\n5 Department of Diagnostic Pathology Kyoto University Hospital Kyoto Japan\n* Correspondence\nYutaka Tsutsumi, Diagnostic Pathology Clinic, Pathos Tsutsumi, 3003 Arimatsu, Midori‐ku, Nagoya, Aichi 458‐0924, Japan.\nEmail: pathos223@kind.ocn.ne.jp\n\n02 3 2021\n4 2021\n9 4 10.1002/ccr3.v9.4 19171924\n07 1 2021\n04 11 2020\n24 1 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nICPIs were effective for primary and metastatic foci of lung adenocarcinoma, but their repeated use provoked a late relapse of IgM nephropathy and lethal lesions in pancreas and lung. ICPIs should be used carefully in cases of immune‐related disease.\n\nICPIs were effective for primary and metastatic foci of lung adenocarcinoma, but their repeated use provoked a late relapse of IgM nephropathy and lethal lesions in pancreas and lung. ICPIs should be used carefully in cases of immune‐related disease.\n\nacute pancreatitis\nIgM nephropathy\nimmune checkpoint inhibitor\nimmune‐related adverse events\ninterstitial pneumonia\npulmonary adenocarcinoma\nsource-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:27.04.2021\nOdani K , Tachibana M , Nogaki F , Tsutsumi Y . Late relapse of IgM nephropathy‐associated nephrotic syndrome after repeated administration of immune checkpoint inhibitor against pulmonary adenocarcinoma. Clin Case Rep. 2021;9 :1917–1924. 10.1002/ccr3.3903\n==== Body\n1 INTRODUCTION\n\nA man in his 60s suffering nephrotic syndrome with IgM nephropathy seven years earlier received immune checkpoint inhibitors (ICPIs) for metastasizing pulmonary adenocarcinoma four years later. Sixty‐two weeks after 21 ICPI injections, adenocarcinoma vanished but nephrotic syndrome relapsed. As late‐onset immune‐related adverse events, acute pancreatitis followed and usual interstitial pneumonia exacerbated.\n\nImmune checkpoint inhibitors (ICPIs) have increasingly attracted medical oncologists’ attention as the target malignant diseases of ICPIs have been expanded considerably. ICPIs activate T‐lymphocytes to attack tumor cells, but these activated T‐lymphocytes may also injure normal cells. Immune activation by ICPIs provokes immunoglobulin production and excessive release of a variety of cytokines, including interleukin‐17, 1 which may result in immune‐related adverse events (irAEs).\n\nIn most clinical trials of ICPIs, patients with immune‐related disorders were excluded from study. In fact, package leaflets of ICPIs seldom describe the disadvantage for patients with pre‐existing immune‐related disorders. The frequency of irAEs caused by ICPIs may increase particularly in patients with a poorly controlled immune‐related disorder or in those who manifest organ injury. 2 Reportedly, ICPIs provoked the relapse of the primary disease in 75% of patients with immune‐related disorder. 3\n\nIgM nephropathy manifesting as nephrotic syndrome was first described in 1978. 4 Immunofluorescence study has revealed deposition of IgM in the mesangial matrix, and ultrastructurally, the deposit shows low electron density. IgM nephropathy‐related nephrotic syndrome often affects adults and is commonly steroid resistant. 5 The distinction between minimal change nephrotic syndrome and focal segmental glomerulosclerosis has long been debated. 6 , 7 At present, the disease entity of IgM nephropathy remains to be established.\n\nWe report herein an autopsy case of a Japanese adult man presenting with late relapse of IgM nephropathy‐associated nephrotic syndrome after repeated administration of an ICPI, pembrolizumab (Keytruda®), against pulmonary adenocarcinoma with systemic metastasis. During the late clinical course, irAEs occurred in the pancreas and lung. The mechanisms of irAEs, particularly those of late‐onset irAEs, are discussed from the viewpoint of pathology.\n\n2 CASE PRESENTATION\n\nA schematic representation of the complex clinical course of the present patient is displayed in Figure 1. The date of hospitalization for relapsed IgM nephropathy was regarded as day X.\n\nFIGURE 1 Schematic presentation of the clinical course of the male patient aged in his 60s\n\nA Japanese man in his 60s had a history of right pyothorax, lung aspergillosis, and emphysema eight years earlier after he stopped smoking 30 cigarettes per day over the previous 40 years. One year later, he suffered deep venous thrombosis in both legs, and warfarin was administered.\n\nSoon, peripheral edema worsened, and a diagnosis of nephrotic syndrome was made on the basis of urinary protein of 12 g/day, serum protein of 4.3 g/dL, and serum cholesterol of 330 mg/dL. Renal biopsy revealed IgM nephropathy with minimal mesangial cell growth and evident mesangial deposition of IgM. Electron microscopy revealed foot process effacement and mild increase of mesangial matrix with focal immune deposits having low electron density (Figure 2). Prednisolone therapy was started at 50 mg/d. Although the disease was steroid‐resistant, the steroid was gradually tapered to avoid exacerbation of pulmonary aspergillosis. Low‐density lipoprotein adsorption treatment was performed seven times, and proteinuria was improved as indicated by a urinary protein‐creatinine (Cr) ratio of 0.2 g/gCr. Two years after the onset of nephrotic syndrome, steroid therapy was completed with the patient in delayed remission.\n\nFIGURE 2 Microscopic appearance of renal biopsy specimen (A, periodic acid‐Schiff reaction, B, immunofluorescence study for IgM, C, D, electron micrographs, bars: 2 μm [C] and 1 μm [D]). The glomeruli resemble those of minimal change glomerulopathy with minimal increase of mesangial cells and matrix. Immunofluorescence study illustrates mesangial IgM deposition, and fine structural study shows foot process effacement and deposition of substances with low electron density in the mesangial matrix along the basement membrane (arrows)\n\nFour years later, a 21‐mm adenocarcinoma of the lung developed in the peripheral part of the right upper lobe. Transbronchial lung biopsy disclosed the histological type as well‐differentiated papillary adenocarcinoma. Positron emission tomography‐computed tomography showed multiple metastases in both upper and lower lobes of the right lung, the hilar, mediastinal and supraclavicular lymph nodes, ribs, and pelvic and femoral bones (cT2aN3M1b). Molecular studies showed wild‐type epidermal growth factor receptor gene and negative anaplastic lymphoma‐kinase expression. The tumor proportion score of programmed cell death ligand‐1 was more than 95%. Pembrolizumab injection (200 mg) was started in week X‐63 and was continued every three weeks (for a total of 21 injections) until week X‐2, at which time the shadow images of the primary and metastatic tumor disappeared.\n\nIn week X‐1 (62 weeks after the initiation of the ICPI), peripheral edema reappeared, and on day X‐2, the urinary protein‐creatinine ratio had increased to 16 g/gCr. On day X, the patient was hospitalized with a diagnosis of relapsed nephrotic syndrome. Pembrolizumab was discontinued, and methylprednisolone 250 mg was administered for three days, followed by prednisolone 40 mg/day, with warfarin added to prevent thrombosis. Urinary proteinuria was unchanged, so a challenge with cyclosporine 100 mg/day was initiated on day X + 10. On day X + 15, the patient complained of abdominal pain, and computed tomography revealed a 9‐cm‐sized mesenteric hematoma. The patient's prothrombin time‐international normalized ratio was 3.17 (standard value: 1.5‐3.0). Prothrombin complex concentrate was administered, and the warfarin and cyclosporine were discontinued. The abdominal symptoms were gradually relieved, and on day X + 25, prednisolone was reduced to 30 mg/day and cyclosporine 50 mg was restarted together with the administration of sulfamethoxazole/trimethoprim (ST) compound. On day X + 30, thrombocytopenia (5.2 × 104/mL) forced discontinuation of the cyclosporine and ST compound, after which the thrombocyte count soon recovered. On day X + 40, abdominal pain recurred, and an imaging study indicated enlargement of the mesenteric hematoma, which had become cystic and was 12 cm in size. On day X + 58, acute pancreatitis was diagnosed based on elevated serum levels of amylase at 538 U/L, AST at 406 U/L,ALT at 595 U/L, and swelling of the pancreas as revealed by computed tomography. The pancreatitis was controlled by diet fasting. After resumption of his diet on day X + 67, exacerbation of the pancreatitis recurred on day X + 74. His serum amylase level reached 1,600 U/L, and the mesenteric cystic lesion had shrunk to 6 cm in size.\n\nFever occurred on day X + 93, the mesenteric cyst had enlarged, and a chest shadow suggestive of interstitial pneumonia appeared. Infection of the mesenteric cyst was suspected, and a drainage tube was inserted. Because of the high level of amylase in the cyst fluid, a diagnosis of pancreatitis‐associated pseudocyst was made. On day X + 102, complications of peripheral edema, pleural effusion, and hypoxemia developed. Despite the injection of furosemide, hypoxia progressed, and the patient died of respiratory failure on day X + 108.\n\nFigure 3 shows the profile of changing renal functions during the patient's long clinical course. Two types of renal function indicators, estimated glomerular filtration rate (eGFR) and urine protein g/g creatinine ratio (UP g/gCr), were chosen for the presentation. The initial prednisolone administration resulted in sustained suppression of proteinuria with moderate renal function impairment (eGFR around 30‐40) until day X.\n\nFIGURE 3 Profiles of changing renal functions throughout the patient's long clinical course. Two renal function indicators, eGFR (mL/min/1.73 m2), and urine protein‐creatinine ratio (g/gCr), are plotted. The key events are indicated by arrows\n\n3 AUTOPSY FINDINGS\n\nAutopsy was performed one hour after death. The final autopsy diagnoses are summarized in Table 1.\n\nTABLE 1 Final Autopsy Diagnosis (male aged 60s)\n\n1. Lung cancer (right upper lobe, well‐differentiated adenocarcinoma, 9 mm in size)\t\na) S/P: administration of pembrolizumab (Keytruda®), 21 times\t\nb) Metastasis: not identified (but with history of lung, nodal, and bone metastases)\t\n2. IgM nephropathy (minimal change glomerulopathy with mesangial deposition of IgM)\n\n\t\na) Nephrotic syndrome (kidney weight: left 125 g, right 85 g)\n\n\t\nb) Pleural effusion (left 1,800 mL, right 500 mL)\n\n\t\nc) Edema in the lower extremities\n\n\t\n3. Acute pancreatitis\n\n\t\na) Hemorrhagic cyst of the mesentery (7 cm in size)\n\n\t\nb) Hemorrhagic cyst on the rectovesicular fossa\n\n\t\nc) Fat necrosis in peripancreatic tissue\n\n\t\nd) Mild pancreatic fibrosis\n\n\t\n4. Usual interstitial pneumonia with acute exacerbation\n\n\t\na) Honeycomb lung (lung weight: left 280 g, right 465 g)\n\n\t\nb) Hyaline membrane formation (diffuse alveolar damage)\n\n\t\n5. Old pulmonary tuberculosis\n\n\t\na) Pleural fibrous adhesion, right\n\n\t\nb) Encapsulated caseous focus, right middle lobe\n\n\t\nJohn Wiley & Sons, Ltd\n\nThe kidneys were mildly atrophic and weighed 125 g (left) and 85 g (right). Microscopically, there were small subcapsular clusters of sclerotic glomeruli, but the remaining glomeruli scarcely showed mesangial cell growth or matrix increase. Interstitial fibrosis was mildly noted. After prolonged protease‐1 digestion of formalin‐fixed, paraffin‐embedded sections, 8 , 9 mesangial deposition of IgM was shown, whereas, deposition of IgA and IgG was negative. These features were diagnostic of the relapse of IgM nephropathy (Figure 4).\n\nFIGURE 4 Microscopic features of autopsy kidney (left: periodic acid‐Schiff reaction, right: IgM immunostaining after prolonged protease‐1 digestion). Mesangial cell growth or increase of mesangial matrix is scarcely noted. Immunostaining after prolonged protease‐1 digestion of formalin‐fixed, paraffin‐embedded sections shows mesangial deposition of IgM\n\nAn encapsulated, 7‐cm‐sized hemorrhagic mesenteric cyst with a drainage tube inserted was located just adjacent to the uncinate process of the pancreas head. Hemosiderin deposition was evident in the cyst wall. Encapsulated foci of fat necrosis were scattered in the peripancreatic fat tissue, and interlobular pancreatic septa were mildly fibrotic. Acute hemorrhagic necrosis of the pancreatic parenchyma was not observed. The mesenteric cyst was regarded as a pancreatitis‐associated lesion (pseudocyst). The pancreatic morphology is shown in Figure 5. A hemorrhagic cystic lesion was also distributed on the rectovesical peritoneal fossa (Douglas’ fossa).\n\nFIGURE 5 Gross appearance of mesenteric pseudocyst (a) and fat necrosis of peripancreatic tissue (b: overall appearance and c: cut surface) and microscopic features of the pancreas (d: HE staining). Old and hemorrhagic cyst of the mesentery, measuring 7 cm, is located adjacent to the uncinate part of the pancreas head. Fat necrosis is observed around the pancreas, and the cut surface displays encapsulated foci of fat necrosis. Mild interstitial fibrosis is discerned microscopically\n\nA 9‐mm‐sized, white‐colored subpleural lung nodule was noted in the anterior part of the right upper lobe. Microscopically, well‐differentiated adenocarcinoma of papillary type was predominant, but focally with a component of poorly differentiated adenocarcinoma. Neither necrotic change nor lymphocytic infiltration was observed. The cancer cells were immunoreactive for thyroid transcription factor‐1, napsin A, and cytokeratin 7, but negative for cytokeratin 5/6 (Figure 6). Metastatic deposits were not confirmed in other organs and tissues.\n\nFIGURE 6 Pulmonary adenocarcinoma in fibrotic lung parenchyma (a: gross appearance of right upper lobe, b: HE staining, c: thyroid transcription factor‐1 immunostaining). The 9‐mm white nodule is located just beneath the pleura. The surrounding lung tissue is fibrotic and honeycombed, focally resembling emphysema. Microscopically, well‐differentiated papillary adenocarcinoma shows neither necrosis nor lymphocytic infiltration. The nuclei of the cancer cells are diffusely immunoreactive for thyroid transcription factor‐1\n\nGross examination of the non‐neoplastic lung revealed subpleural honeycombing and multifocal parenchymal infiltrative change bilaterally (Figure 7). The lungs weighed 280 g (left) and 465 g (right). Microscopically, the pre‐existing alveolar structures were often distorted and surrounded by interstitial fibrosis, and were associated with features of diffuse alveolar damage with hyaline membrane formation (Figure 8). These features were consistent with acute exacerbation of usual interstitial pneumonia. The right pleura showed severe fibrous adhesion in association with a small encapsulated caseous nodule in the collapsed right middle lobe. The pleural lesion was thus regarded as old tuberculosis (see Figure 7). The patient had a history of pulmonary aspergillosis, but Aspergillus infection was not identified.\n\nFIGURE 7 Gross appearance of usual interstitial pneumonia (pulmonary fibrosis) with acute exacerbation (a: left upper lobe, b: right upper and middle lobes). Focal subpleural honeycombing and infiltrative change in the lung parenchyma are noted. The right pleura shows diffuse fibrous adhesion, and an encapsulated caseous focus is noted beneath the pleura of the collapsed middle lobe (arrow)\n\nFIGURE 8 Microscopic features of usual interstitial pneumonia (pulmonary fibrosis) with acute exacerbation (HE staining, a: honeycomb lung, b: hyaline membrane formation). Interstitial fibrosis with disappearance of normal alveolar structures is observed. Hyaline membrane formation is noted at the site of acute exacerbation\n\n4 DISCUSSION\n\nThe disease entity of IgM nephropathy is controversial. IgM nephropathy may be a variant of minimal change nephrotic syndrome or focal segmental glomerulosclerosis, but it occurs commonly in adults and is often steroid‐resistant. 5 , 6 , 7 The present patient underwent two years of steroid administration before achieving delayed remission, and a late relapse of nephrotic syndrome occurred after repeated use of an ICPI. Mesangial IgM deposition was proven by prolonged protease digestion of the formalin‐fixed, paraffin‐embedded autopsy kidney. Antibody molecules can bind cryptic antigens after the rigorous protease digestion step, because formalin‐mediated cross‐linkage between protein networks in the tissue is significantly loosened, as has been reported previously. 8 , 9\n\nAdministration of ICPIs may provoke irAEs in a variety of organs and tissues. Early detection of irAEs and discontinuance of ICPIs are required in clinical practice. 10 Renal irAEs are infrequent at around 4%: glomerulonephritis is especially rare, but interstitial nephritis is relatively common. 11 The period from the initiation of ICPI therapies to acute renal injury ranges from 21 to 245 days (median 91 days), whereas that from its cessation to acute renal injury ranges from 7 to 63 days (median 21 days). 12 In the present case, IgM nephropathy relapsed 63 weeks after the initiation of ICPIs, as indicated in Figure 3. Such a late‐occurring irAE is quite unusual.\n\nICPIs stimulate T‐lymphocytes to battle cancer cells. It is thus reasonable to suppose that the immune activation by ICPIs provoked the relapse of IgM nephropathy, although the detailed mechanism remains unclear. In patients with immune‐related disorder, 75% were accompanied by relapse/exacerbation of the disease after administration of ICPIs but with little evidence for inducing novel‐type irAEs. 3 In cases of malignant melanoma complicated by immune‐related disorders, the anti‐tumor effect of ICPIs was much more beneficial than the risk of relapse/exacerbation of the immune‐related disorders. 13 In patients with nonsmall cell lung cancer complicated by immune‐related disorders, 55% exhibited exacerbation of the disorders, but 74% of the irAEs were regarded as being controllable at grades 1‐2. 14 Immunosuppressants including steroid administered to control the immune‐related disorder did not influence the anti‐tumor effect of ICPIs. 15\n\nThe irAEs tended to occur when the volume of ICPI therapy was increased, 16 and they happened within 12 weeks after the initiation of the therapy. 2 In the present case, after the late relapse of IgM nephropathy, mesenteric hematoma (hemorrhagic pseudocyst) occurred on day X + 15 and exacerbated on days X + 40 and X + 93, and the diagnosis of acute pancreatitis was made on day X + 58. The complication of acute exacerbation of pulmonary fibrosis developed on day X + 93, two weeks prior to the patient's death. Acute pancreatitis was histopathologically proven at autopsy by the presence of hemorrhagic pseudocysts in the mesentery and Douglas’ fossa, multifocal fat necrosis, and mild interstitial fibrosis of the pancreas. In the lung, diffuse alveolar damage with hyaline membrane formation was recognized among honeycombing pulmonary fibrosis of usual interstitial pneumonia type.\n\nWhether the pancreatic and pulmonary complications in the present case were immune‐related could not be definitely confirmed, but the possibility of ICPI‐associated irAEs was strongly suspected. Acute pancreatitis is a rare complication of ICPI‐associated irAEs. In a previous study, increases in the serum levels of amylase and lipase were recorded in only two of 119 cases evaluated, but no associated symptomatic pancreatic lesions were present. 17 Acute fibrinous and organizing pneumonia and diffuse alveolar damage are listed as ICPI‐related irAEs of the lung, and they are often lethal. 18 , 19 In fact, ICPI‐related lung lesions were encountered more often in patients with nonsmall cell lung carcinoma than in those who suffered from other types of malignancy. 20 , 21 The association of the background IgM nephropathy is supposed to be an important factor for the pulmonary irAEs, and further study and the accumulation of similar cases are needed for clarifying their pathophysiology and pathogenesis.\n\nThe remote effects of ICPIs are debatable, and the recognition or definition of irAEs may be difficult. However, the present case indicates that clinicians should be aware of the possibility of late complications of ICPI administration.\n\n5 CONCLUSION\n\nAdministration of ICPIs to cancer patients with immune‐related disorders has not yet been thoroughly investigated. In the present case, an ICPI was adequately effective against primary and metastatic foci of adenocarcinoma of the lung. However, repeated use of the ICPI provoked a late relapse of IgM nephropathy along with late, intractable, and lethal complications in the pancreas and lung. Accumulation of similar cases will be necessary to determine the appropriate use of ICPIs in patients with immune‐related disorders.\n\nCONFLICT OF INTEREST\n\nThe authors do not have any conflicts of interest to declare in relation to the present report. There were no sources of funding for reporting the present case.\n\nAUTHOR CONTRIBUTIONS\n\nWe declare that all the authors made a substantial contribution to the concept of the case report or interpretation of data and approved the version to be submitted. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.\n\nSTATEMENT OF ETHICS\n\nThe patient was unmarried, so his intimate co‐worker provided written informed consent for the publication of this case report. The study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.\n\nACKNOWLEDGMENTS\n\nThe authors cordially thank Prof. of English Tina Hiroko Tajima at St. Marianna University School of Medicine, Kawasaki, Japan, kindly refined the English grammar of our manuscript. Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe datasets generated and/or analyzed during the current report are available from the corresponding author on reasonable request.\n==== Refs\nREFERENCES\n\n1 Harbour SN , Maynard CL , Zindl CL , Schoeb TR , Weaver CT . Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A. 2015;112 :7061‐7066.26038559\n2 Kanz BA , Pollack MH , Johnpulle R , et al. Safety and efficacy of anti‐PD‐1 in patients with baseline cardiac, renal, or hepatic dysfunction. J ImmunoTher Cancer. 2016;4 :60.27777770\n3 Abdel‐Wahab N , Shah M , Lopez‐Olivo MA , Suarez‐Almazor ME . Use of immune checkpoint inhibitors in the treatment of patients with cancer and preexisting autoimmune disease: A systematic review. Ann Intern Med. 2018;168 :121‐130.29297009\n4 Cohen AH , Border WA , Glassock RJ . Nephrotic syndrome with glomerular mesangial IgM deposits. Lab Invest. 1978;38 :610‐619.347169\n5 Mubarak M . IgM nephropathy; time to act. J Nephropathol. 2014;3 :22‐25.24644539\n6 Brugano R , del Sordo R , Covarelli C , Gnappi E , Pasquali S . IgM nephropathy: is it closer to minimal change disease or to focal segmental glomerulosclerosis? J Nephrol. 2016;29 :479‐486.26842624\n7 Connor TM , Aiello V , Griffith M , et al. The natural history of immunoglobulin M nephropathy in adults. Nephrol Dial Transplant. 2017;32 :823‐829.27190379\n8 Messias NC , Walker PD , Larsen CP . Paraffin immunofluorescence in the renal pathology laboratory: more than a salvage technique. Modern Pathol. 2015;28 :854‐860.\n9 Odani K , Itoh A , Yanagida S , et al. Paraneoplastic pemphigus involving the respiratory and gastrointestinal mucosae. Case Rep Pathol. 2020;2020 :7350759.32685228\n10 Murakami N , Motwani S , Riella LV . Renal complications of immune checkpoint blockade. Curr Prob Cancer. 2017;41 :100‐110.\n11 Jung K , Zeng X , Bilusic M . Nivolumab‐associated acute glomerulonephritis: a case report and literature review. BMC Nephrol. 2016;17 :188.27876011\n12 Cortazar FB , Marrone KA , Troxell ML , et al. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016;90 :638‐647.27282937\n13 Puri A , Homsi J . The safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis. Melanoma Res. 2017;27 :519‐523.28817445\n14 Leonardi GC , Gainor JF , Altan M , et al. Safety of programmed death‐1 pathway inhibitors among patients with non‐small‐cell lung cancer and preexisting autoimmune disorders. J Clin Oncol. 2018;36 :1905‐1912.29746230\n15 Horvat TZ , Adel NG , Dang TO , et al. Immune‐related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33 :3193‐3198.26282644\n16 Murakami N , Borges TJ , Yamashita M , Riella LV . Severe acute interstitial nephritis after combination immune checkpoint inhibitor therapy for metastatic melanoma. Clin Kidney J. 2016;9 :411‐417.27274826\n17 Friedman CF , Clark V , Raikhel AV , et al. Thinking critically about classifying adverse events: incidence of pancreatitis in patients treated with nivolumab + ipilimumab. J Natl Cancer Ins. 2017;109 (4 ):djw260.\n18 Larsen BT , Chae JM , Dixit AS , Hartman TE , Peikert T , Roden AC . Clinical and histopathologic features of immune checkpoint inhibitor‐related pneumonitis. Am J Surg Pathol. 2019;43 :1331‐1340.31162288\n19 Ma K , Lu Y , Jiang S , Tang J , Li X , Zhang Y . The relative risk and incidence of immune checkpoint inhibitors related pneumonitis in patients with advanced cancer: a meta‐analysis. Front Pharmacol. 2018;9 :1430.30618738\n20 Cupp J , Culakova E , Poniewierski MS , Dale DC , Lyman GH , Crawford J . Analysis of factors associated with in‐hospital mortality in lung cancer chemotherapy patients with neutropenia. Clin Lung Cancer. 2018;19 :e163‐e169.29233611\n21 Byrne EH , Fisher DE . Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer. 2017;123 :2143‐2153.28543699\n\n",
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"keywords": "IgM nephropathy; acute pancreatitis; immune checkpoint inhibitor; immune‐related adverse events; interstitial pneumonia; pulmonary adenocarcinoma",
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"title": "Late relapse of IgM nephropathy-associated nephrotic syndrome after repeated administration of immune checkpoint inhibitor against pulmonary adenocarcinoma.",
"title_normalized": "late relapse of igm nephropathy associated nephrotic syndrome after repeated administration of immune checkpoint inhibitor against pulmonary adenocarcinoma"
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"abstract": "Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus-2. Patients with hematologic malignancies have been shown to have higher risk of mortality due to COVID-19 than reported in the general adult population. Reports on acute lymphoblastic leukemia and COVID in children are scarce. We present a case of an 11-year-old male patient undergoing treatment for B-cell acute lymphoblastic leukemia with an atypical course of COVID-19. The patient received a positive result of the syndrome coronavirus-2 polymerase chain reaction test performed due to epidemiologic reasons. The chemotherapy was continued since the patient had no clinical signs of COVID-19. The disease started with intensive gastrointestinal bleeding, followed by severe respiratory tract infection over 2 weeks later.",
"affiliations": "Department of Pediatric Hematology and Oncology, Medical University of Gdańsk, Gdańsk, Poland.",
"authors": "Wojciechowska|Małgorzata|M|;Renke|Joanna|J|;Irga-Jaworska|Ninela|N|",
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"pubdate": "2021-06-16",
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"title": "COVID-19-related Gastrointestinal Bleeding in a Pediatric Patient With ALL.",
"title_normalized": "covid 19 related gastrointestinal bleeding in a pediatric patient with all"
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"abstract": "Betalactam (BL) antibiotics are the most common cause of drug hypersensitivity. Amoxicillin (AX), which is often prescribed alongside clavulanic acid (Clav), is the most common elicitor. The aim of this study was to determine whether AX and Clav-responsive T-cells are detectable in patients with immediate hypersensitivity to AX-Clav, to assess whether these T-cells display the same specificity as that detected in skin and provocation testing, and to explore T-cell activation pathways.\n\n\n\nDrug-specific T-cell clones were generated from immediate hypersensitive patients´ blood by serial dilution and repetitive mitogen stimulation. Antigen specificity was assessed by measurement of proliferation and cytokine release. CD4+ /CD8+ phenotype and chemokine receptor expression were analyzed by flow cytometry.\n\n\n\n110 AX-specific and 96 Clav-specific T-cell clones were generated from seven patients with positive skin test to either AX or Clav. Proliferation of AX- and Clav-specific clones was dose-dependent, and no cross-reactivity was observed. AX- and Clav-specific clones required antigen-presenting cells to proliferate, and drugs were presented to CD4+ and CD8+ T-cells by MHC class-II and I, respectively. A higher secretion of IL-13 and IL-5 was detected in presence of the culprit drug compared with the alternative drug. Clones expressed CD69, CCR4, CXCR3, and CCR10.\n\n\n\nOur study details the antigen specificity and phenotype of T-cell clones generated from patients with AX-Clav-induced immediate hypersensitivity diagnosed by positive skin test. AX- and Clav-specific clones were generated from patients irrespective of whether AX or Clav was the culprit, although differences in cytokine secretion were observed.",
"affiliations": "Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.;Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.;Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.",
"authors": "Ariza|Adriana|A|0000-0003-1524-9602;Fernández-Santamaría|Rubén|R|0000-0002-0255-4280;Meng|Xiaoli|X|;Salas|María|M|0000-0002-0583-9492;Ogese|Monday O|MO|;Tailor|Arun|A|;Bogas|Gádor|G|;Torres|María José|MJ|0000-0001-5228-471X;Naisbitt|Dean J|DJ|",
"chemical_list": "D019818:Clavulanic Acid; D000658:Amoxicillin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/all.14298",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-4538",
"issue": "75(10)",
"journal": "Allergy",
"keywords": "T-cell; amoxicillin; clavulanic acid; immediate hypersensitivity; phenotype",
"medline_ta": "Allergy",
"mesh_terms": "D000658:Amoxicillin; D018414:CD8-Positive T-Lymphocytes; D019818:Clavulanic Acid; D002999:Clone Cells; D004342:Drug Hypersensitivity; D006801:Humans; D006969:Hypersensitivity, Immediate",
"nlm_unique_id": "7804028",
"other_id": null,
"pages": "2562-2573",
"pmc": null,
"pmid": "32246774",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Characterization of amoxicillin and clavulanic acid specific T-cell clones from patients with immediate drug hypersensitivity.",
"title_normalized": "characterization of amoxicillin and clavulanic acid specific t cell clones from patients with immediate drug hypersensitivity"
} | [
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"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
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"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nPituitary carcinoma is extremely rare and carries a very poor prognosis. In most cases, apparently indolent tumors become malignant; however, there are no satisfactory biomarkers for predicting tumor behavior. Thus, scientific advances in the search for new biological markers, diagnostic methods, and therapies are needed to improve the prognosis of these patients.\n\n\nMETHODS\nWe report the case of a woman with initial diagnosis of nonfunctioning pituitary adenoma which evolved to carcinoma after 4 years. Diagnosis was confirmed after biopsy of metastatic pulmonary nodules, in which neoplastic cells were immunohistochemically positive for chromogranin, synaptotophysin, prolactin, and growth hormone. Investigation with conventional somatostatin receptor scintigraphy, positron emission tomography-computed tomography (PET-CT) with Ga-68 DOTATATE and F-18 fluorodeoxyglucose (FDG) are showed. During temozolomide therapy, our patient had severe pancytopenia resulting in death from generalized infection despite 10 days of intensive care.\n\n\nCONCLUSIONS\nThe present case of an aggressive pituitary carcinoma rising from a typical adenoma illustrates the importance of developing new prognostic biomarkers in these cases. In addition to demonstrating a serious side effect with the use of temozolomide, our case report suggests that the combined use of Ga-68 DOTATATE and F-18 FDG PET-CT scan may scale somatostatin receptors vs. tumor aggressiveness, therefore, helping to better choose the therapy for aggressive pituitary tumors.",
"affiliations": "Endocrinology Division, Department of Clinical Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.;Oncology Division, Department of Clinical Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.;Department of Radiology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.;Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.;Department of Neurology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.;Endocrinology Division, Department of Clinical Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.;Division of Nuclear Medicine, Department of Radiology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil.",
"authors": "Garmes|Heraldo Mendes|HM|;Carvalheira|José Barreto Campello|JBC|;Reis|Fabiano|F|;Queiroz|Luciano de Souza|LS|;Fabbro|Mateus Dal|MD|;Souza|Vanessa de Fatima Porto|VFP|;Santos|Allan de Oliviera|AO|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/sni.sni_498_16",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-8-16210.4103/sni.sni_498_16Neuro-Oncology: Case ReportPituitary carcinoma: A case report and discussion of potential value of combined use of Ga-68 DOTATATE and F-18 FDG PET/CT scan to better choose therapy Garmes Heraldo Mendes *heraldmg@uol.com.brCarvalheira José Barreto Campello 1barreto@fcm.unicamp.brReis Fabiano 2fabianoreis@gmail.comQueiroz Luciano de Souza 3gradanat@yahoo.com.brFabbro Mateus Dal 4mateus.dalfabbro@gmail.comSouza Vanessa de Fatima Porto nessaporto@hotmail.comSantos Allan de Oliviera 5ados@terra.com.brEndocrinology Division, Department of Clinical Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil1 Oncology Division, Department of Clinical Medicine, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil2 Department of Radiology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil3 Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil4 Department of Neurology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil5 Division of Nuclear Medicine, Department of Radiology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil* Corresponding author\n2017 01 8 2017 8 16231 12 2016 19 2 2017 Copyright: © 2017 Surgical Neurology International2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nPituitary carcinoma is extremely rare and carries a very poor prognosis. In most cases, apparently indolent tumors become malignant; however, there are no satisfactory biomarkers for predicting tumor behavior. Thus, scientific advances in the search for new biological markers, diagnostic methods, and therapies are needed to improve the prognosis of these patients.\n\nCase Description:\nWe report the case of a woman with initial diagnosis of nonfunctioning pituitary adenoma which evolved to carcinoma after 4 years. Diagnosis was confirmed after biopsy of metastatic pulmonary nodules, in which neoplastic cells were immunohistochemically positive for chromogranin, synaptotophysin, prolactin, and growth hormone. Investigation with conventional somatostatin receptor scintigraphy, positron emission tomography-computed tomography (PET-CT) with Ga-68 DOTATATE and F-18 fluorodeoxyglucose (FDG) are showed. During temozolomide therapy, our patient had severe pancytopenia resulting in death from generalized infection despite 10 days of intensive care.\n\nConclusion:\nThe present case of an aggressive pituitary carcinoma rising from a typical adenoma illustrates the importance of developing new prognostic biomarkers in these cases. In addition to demonstrating a serious side effect with the use of temozolomide, our case report suggests that the combined use of Ga-68 DOTATATE and F-18 FDG PET-CT scan may scale somatostatin receptors vs. tumor aggressiveness, therefore, helping to better choose the therapy for aggressive pituitary tumors.\n\nGa-68 DOTATATE PET/CTpituitary carcinomatemozolomide\n==== Body\nINTRODUCTION\nPituitary carcinoma accounts for only 0.1% of all pituitary tumors, representing less than 200 cases in the English language literature. This entity is defined by a primary sellar tumor associated with noncontiguous intracranial lesions or metastasis to distant sites.[619] Pituitary carcinoma is almost invariably first diagnosed in adults as a benign tumor, which after a time becomes aggressive. This period of latency ranges from 4 months to 18 years.[14] The World Health Organization (WHO) proposes the utilization of Ki-67 index, elevated nuclear P53 expression, and mitotic figures to indicate tumor aggressiveness.[3] However, these markers have not been able to define at an early stage which adenoma will change its natural course to become a carcinoma.[3] So far, there are no satisfactory biomarkers for predicting tumor behavior.[16] The prognosis of pituitary carcinoma is very poor. Most of the cases described in the current literature show rapid evolution after confirmation of metastasis, despite use of aggressive treatments available.[18]\n\nIn this report, the authors describe the case of a young woman with primary diagnosis of a nonfunctioning pituitary adenoma, which evolved into carcinoma after 4 years of follow-up.\n\nAlthough several studies have demonstrated security with the use of temozolomide concurrent with radiation therapy,[18] our patient presented with severe collateral damage and eventual death due to irreversible pancytopenia and infection despite 10 days of intensive care.\n\nThe investigation with conventional somatostatin receptor scintigraphy, positron emission tomography-computed tomography (PET-CT) with Ga-68 DOTATATE and F-18 fluorodeoxyglucose (FDG), treatment, and fatal outcome of this aggressive pituitary carcinoma are discussed.\n\nCASE REPORT\nA 32-year-old Caucasian woman was referred to the endocrinology department with 18-month history of right temporal headache, which was accompanied by visual acuity reduction as well as amenorrhea and galactorrhea. She also reported fatigue, weakness, nausea, and sporadic vomiting. Visual field evaluation demonstrated left eye amaurosis and temporal hemianopsia and lower nasal quadrantanopsia in the right eye. Hormonal evaluation was compatible with panhypopituitarism, and the patient was started on cortisol and T4 replacement therapy.\n\nMagnetic resonance imaging (MRI) showed a 4.0 cm diameter solid lobulated lesion with sellar and suprasellar components, predominantly isointense on T1 and hypointense on T2-weighted images and extension to both the cavernous sinuses and optic chiasm. Given that the lesion was associated with optic tract compression, a transesfenoidal surgery for nonfunctioning pituitary macroadenoma was performed. The pathological evaluation revealed pituitary adenoma. Immunohistochemistry demonstrated that Ki-67 was positive in 3% of the cells and supporting the diagnosis of a canonical pituitary adenoma. In addition, p53 staining was positive in rare cells.\n\nAlthough the headache persisted, the patient visual acuity significantly improved, as demonstrated by a striking improvement in visual field examination. The patient was started on cabergoline 0.5 mg 6 cps/week and remained free of progression for 4 years, when in a follow-up chest CT multiple pulmonary nodules with soft tissue density in both lung fields were detected, measuring 0.5–1.2 cm [Figure 1]. In accordance with the hypothesis of lung metastasis.\n\nFigure 1 Multiple pulmonary nodules. Lesions indicated by arrows were confirmed in adjoining planes in the original CT scan to rule out that they might represent vessels\n\nF-18 FDG images showed a markedly increased uptake in the pituitary (SUV 33) as well as in multiple lung nodules (SUV 11.1), pancreas (SUV 6), liver lesions (SUV 10.4) and right kidney nodule (SUV 8.5). Lung biopsy via bronchoscopy confirmed a moderately differentiated neuroendocrine tumor immunohistochemically positive for chromogranin, synaptophysin, prolactin, and growth hormone. Ki-67 was positive in approximately 10% of the cells [Figure 2]. Despite a normal chromogranin dosage and of whole body scintigraphy after Tc-99m HYNIC-octreotide injection showing no abnormal uptake in sellar region, the 3D PET/CT Ga-68 DOTATATE images showed moderate uptake in large pituitary lesion (SUV 4.4) and very mild uptake in some of the lung lesions; however, no increased tracer uptake was detected in the liver, pancreas, and right kidney lesions [Figures 3–5].\n\nFigure 2 (a) Scanned slide of lung biopsy obtained via bronchoscopy, stained with hematoxylin and eosin: Multiple well-defined rounded, strongly basophilic lesions in the lung parenchyma. (b) Cytoplasmic positivity for chromogranin in part of neoplastic cells indicates neurosecretory character\n\nFigure 3 Left: 3D PET/CT Ga-68 DOTATATE showing moderate uptake in large pituitary lesion (SUV = 4.4). Right: Scintigraphy after Tc-99 HYNIC-octreotide showing no abnormal uptake in sellar region. The mild radiotracer uptake in the nasopharynx may be considered nonspecific\n\nFigure 4 3D images after F-18 FDG injection show physiologic brain uptake and markedly increased uptake in the pituitary and in multiple lung and liver lesions (left). Ga-68 DOTATATE show less impressive sellar uptake and very mild uptake in lung lesions (right)\n\nFigure 5 CT, PET, PET/CT and 3D-PET transaxial images. Superior row: F-18 FDG images show intense tracer uptake in the pituitary lesion (SUV33, black arrow). Inferior row: Ga-68 DOTATATE images show much less uptake with peripheral enhancement in the lesion (SUV4.4)\n\nGiven the presence of a pancreatic lump, the diagnosis of a primary pancreatic neuroendocrine tumor was considered, however, the turcica sella MRI showed significantly increased tumor size and signs of chiasm and right optic nerve compression [Figure 6]; the patient was submitted to a transcranial neurosurgery, but only partial removal of the tumor was possible because of hardened consistency.\n\nFigure 6 MRI after enlargement of the lesion: Solid lobulated lesion with hyperintense components on T1 without gadolinium (hemorrhage) (a) and on T2-weighted (b). Heterogeneous enhancement on T1-weighted after gadolinium (c) with extension to both cavernous sinuses and right temporal lobe\n\nTumor tissue of this second sample showed small neoplastic epithelial cells either cubic or polygonal, with slight to moderate nuclear pleomorphism, dense chromatin, and scant pink cytoplasm. The cells were arranged in dense blocks amid fibrous tissue, with extensive necrotic areas, which also showed phagocytosed hemossiderin granules and hematoidin crystals. Mitosis were rare. The diagnosis of pituitary adenocarcinoma was based on the previous lung biopsy which disclosed a metastatic neuroendocrine tumor. The extensive necrotic areas in the pituitary tumor also supported the diagnosis of malignancy [Figure 7]. However, Ki-67 was positive only in approximately 4% and p53 in 3% of these cells.\n\nFigure 7 HE (a) Pituitary tumor at first Surgery: Regular small cells in solid arrangement. Absence of mitosis or necrosis. (b) Second surgery: Nuclear atypia and hyperchromasia are more pronounced. (c) Extensive areas of coagulation necrosis, not observed in the original sample\n\nAfter the diagnosis of pituitary carcinoma and based on PET-CT images obtained with F-18 FDG and Ga-68 DOTATATE, the oncology team indicated concomitant radiochemotherapy. The planned radiotherapy was a total of 5400 cGy (180 cGy × 30 days) plus temozolomide 75 mg/m2/day during the period of radiotherapy. However, on the 19th day of the treatment, the patient returned reporting of fatigue, sore throat, dry cough, and ecchymoses. Blood examination revealed pancytopenia, and despite intensive treatment, the patient died after 10 days due to generalized infection. A postmortem examination was not performed.\n\nDISCUSSION\nBecause only 25% of the nonfunctioning macroadenomas increase in size significantly during follow-up[29] after the first surgery, we opted for clinical follow-up for this patient. Moreover, it is known that the extent of tumor removal has no impact at mortality in these patients.[10] During 4 years, the tumor remained stable and did not induce significant clinical changes despite continuous headache.\n\nSome pituitary tumors that will become carcinoma demonstrate their aggressive behavior early, recur quickly after surgical debulking, and progress rapidly to carcinoma; on the other hand, certain tumors progress to carcinoma after many years of follow-up.[14] Interestingly, despite persistent biochemical markers elevation in the absence of sellar tumor residual, pituitary carcinoma can go unnoticed for many years in a patient who later had cervical adenopathy proven to be GH-immunopositive neuroendocrine tumor on biopsy.[13]\n\nEven without significant growth of the tumor, the disease evolved with the emergence of metastases, showing the need for early markers of evolution in these cases. Histopathological diagnosis in the first surgery was pituitary adenoma, and there were no histological and imunohistochemical features of aggressiveness. Although some studies have shown a strong relationship between Ki-67 index and tumor aggressiveness (mean of 11.9 ± 3.4 for carcinomas to 1.4 ± 0.15 for adenomas),[317] other studies have not proven such a significant association.[15] Some authors have suggested that Ki-67 index appear to increase in conjunction with tumor transformation, however, in our case, even after the tumor growth and diagnosis of carcinoma was confirmed, Ki-67 and p53 continued to be hypoexpressed in tumor tissue.[4] Interestingly, in our case pituitary Ki-67 never increased despite a 10% Ki-67 staining was detected in lung nodule, suggesting that the precursor adenoma presented a clonal dedifferentiation associated with early metastasis.\n\nThe presence of metastasis of a neuroendocrine tumor may indicate pituitary carcinoma, however, the presence of a pancreatic lump in our patient left a doubt regarding the possibility of a neuroendocrine tumor of the pancreas, hindering and delaying the diagnosis of pituitary carcinoma.\n\nWhole body scintigraphy after Tc-99m HYNIC-octreotide injection was less sensitive to detect lesions with increased somatostatin receptors expression than three-dimensional PET-CT Ga-68 DOTATATE images in our patient, it can be verified that the former is more sensitive to detect somatostatin receptors expression. This greater sensitivity has already been described for neuroendocrine tumors;[12] however, the literature does not show a comparison between these two exams in pituitary carcinomas. Although no SPECT/CT images where available for direct comparison, these images show that higher affinity of Ga-68 DOTATATE for the somatostatin receptors made it possible to easily detect the lesion even when only the functional image (PET) is shown.\n\nIn our patient, the concomitant evaluation of PET-CT scan using F-18 FDG and Ga-68 DOTATATE showed an uptake almost eight times more intense with F-18 FDG. This different uptake is probably related with the high aggressiveness of the lesion. Carrying out these two examinations has the potential to define the aggressiveness of the tumor and thus help to indicate which is the better therapy, e.g., molecular-targeted therapy using somatostatin analogs and peptide receptor radionuclide therapy targeting somatostatin receptors or chemotherapy. A recent study showed that in a patient with a PET-CT scan showing multiple foci of increased Ga-68 DOTATATE uptake in pituitary and posterior fossa lesions, the tumor remained stable over 4 years after Lu-177 DOTATATE therapy.[11] In accordance with the need to individualize the therapy for these patients, Lu-177 DOTATATE therapy showed distinct results in three patients.[7]\n\nIn contrast to a recently published study that showed high uptake of Ga-68 DOTATATE in a patient with pituitary carcinoma that the authors proposed Lu-177 DOTATATE therapy, the rational to use temozolomide in our patient was a lower uptake with Ga-68 DOTATATE associated with high F-18 FDG uptake compatible with tumoral aggressiveness.[20]\n\nThe prognosis for the patient of pituitary carcinoma is very poor. Most of the cases described in the current literature show rapid evolution after confirmation of metastasis, despite using aggressive treatments available.[18] Although several studies have demonstrated that the use of temozolomide concurrent or not with radiation therapy is safe,[158] our patient had severe pancytopenia secondary to the use of temozolomide resulting in death from generalized infection despite 10 days of intensive care.\n\nIn conclusion, the present case of an aggressive pituitary carcinoma arising from a typical adenoma show how a benign disease can transform into a devastating one. Thus, the development of new prognostic biomarkers should be an imperative task to better control aggressive pituitary tumors. In addition to demonstrating a serious side effect with the use of temozolomide, our case report suggests that the combined use of Ga-68 DOTATATE and F-18 FDG PET/CT scan may scale somatostatin receptors vs. tumor aggressiveness, therefore helping to better choose the therapy for pituitary carcinoma.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nhttp://surgicalneurologyint.com/Pituitary-carcinoma:-A-case-report-and-discussion-of-potential-value-of-combined-use-of-Ga-68-DOTATATE-and-F-18-FDG-PET/CT-scan-to-better-choose-therapy/\n==== Refs\nREFERENCES\n1 Gilbert MR Wang M Aldape KD Stupp R Hegi ME Jaeckle KA Dose-dense temozolomide for newly diagnosed glioblastoma: A randomized phase III clinical trial J Clin Oncol 2013 31 4085 91 24101040 \n2 Karamouzis I Berardelli R Prencipe N Berton A Bona C Stura G Retrospective observational analysis of non-irradiated non-functioning pituitaryadenomas J Endocrinol Invest 2015 38 1191 7 26215449 \n3 Kovacs K The 2004 WHO classification of pituitary tumors: Comments Acta Neuropathol 2006 111 62 3 16315073 \n4 Lim S Shahinian H Maya MM Yong W Heaney AP Temozolomide: A novel treatment for pituitary carcinoma Lancet Oncol 2006 7 518 20 16750503 \n5 Losa M Bogazzi F Cannavo S Ceccato F Curtò L De Marinis L Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas J Neurooncol 2016 126 519 25 26614517 \n6 Love AP Hinton DR Krieger MD Weiss MH Invasive pituitary adenomas: Significance of proliferation parameters Pituitary 1999 2 117 22 11081161 \n7 Maclean J Aldridge M Bomanji J Short S Fersht N Peptide receptor radionuclide therapy for aggressive atypical pituitary adenoma/carcinoma: Variable clinical response in preliminary evaluation Pituitary 2014 17 530 8 24323313 \n8 Mao Y Yao Y Zhang LW Lu YC Chen ZP Zhang JM Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients? A Multi-center, Randomized, Parallel, Open-label, Phase II Clinical Trial Chin Med J 2015 128 2751 8 26481741 \n9 Molitch ME Pituitary tumours: Pituitary incidentalomas Best Pract Res 2009 23 667 75 \n10 Ntali G Capatina C Fazal-Sanderson V Byrne JV Cudlip S Grossman A Mortality in patients with non-functioning pituitary adenoma is increased: Systematic analysis of 546 cases with long follow-up Eur J Endocrinol 2016 174 137 45 26546611 \n11 Novruzov F Aliyev JA Jaunmuktane Z Bomanji JB Kayani I The use of (68) Ga DOTATATE PET/CT for diagnostic assessment and monitoring of (177) Lu DOTATATE therapy in pituitary carcinoma Clin Nucl Med 2015 40 47 9 25275413 \n12 Oh S Prasad V Lee DS Baum RP Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT Int J Mol Imaging 2011 2011 524130 22121482 \n13 Ragel BT Couldwell WT Pituitary carcinoma: A review of the literature Neurosurg Focus 2004 16 E7 \n14 Roncaroli F Scheithauer BW Horvath E Erickson D Tam CK Lloyd RV Silent subtype 3 carcinoma of the pituitary: A case report Neuropathol Appl Neurobiol 2010 36 90 4 19811617 \n15 Salehi F Agur A Scheithauer BW Kovacs K Lloyd RV Cusimano M Ki-67 in pituitary neoplasms: A review—Part I Neurosurgery 2009 65 429 37 19687686 \n16 Sav A Rotondo F Syro LV Di Ieva A Cusimano MD Kovacs K Invasive, atypical and aggressive pituitary adenomas and carcinomas Endocrinol Metab Clin North Am 2015 44 99 104 25732646 \n17 Scheithauer BW Kovacs KT Laws ER Jr Randall RV Pathology of invasive pituitary tumors with special reference to functional classification J Neurosurg 1986 65 733 44 3095506 \n18 Song Y Qi S Peng Y Long H Liu H Non-functioning pituitary carcinoma: Report of two cases and review of literature Nan Fang Yi Ke Da Xue Xue Bao 2012 32 539 43 22543138 \n19 Thapar K Kovacs K Scheithauer BW Stefaneanu L Horvath Pernicone PJ Proliferative activity and pituitary adenomas and carcinomas among invasiveness: An analysis using the MIB-1 antibody Neurosurgery 1996 38 99 106 8747957 \n20 Xiao J Zhu Z Zhong D Ma W Wang R Improvement in diagnosis of metastatic pituitary carcinoma by 68Ga DOTATATE PET/CT Clin Nucl Med 2015 40 129 31\n\n",
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"issn_linking": "2152-7806",
"issue": "8()",
"journal": "Surgical neurology international",
"keywords": "Ga-68 DOTATATE PET/CT; pituitary carcinoma; temozolomide",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "162",
"pmc": null,
"pmid": "28840066",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
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"title": "Pituitary carcinoma: A case report and discussion of potential value of combined use of Ga-68 DOTATATE and F-18 FDG PET/CT scan to better choose therapy.",
"title_normalized": "pituitary carcinoma a case report and discussion of potential value of combined use of ga 68 dotatate and f 18 fdg pet ct scan to better choose therapy"
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"abstract": "BACKGROUND\nHepatic dysfunction (HD) is a common finding in critically ill patients. The underlying pathophysiological process is one of either cholestasis or hypoxic liver injury (HLI). Using serum bilirubin, our study aimed to determine the incidence of HD in a critically ill trauma population, identify risk factors and analyse the impact on outcomes.\n\n\nMETHODS\nA retrospective observational study was performed on all patients admitted to the Level 1 Trauma Unit ICU at Inkosi Albert Luthuli Central Hospital in Durban, South Africa (IALCH) from 01/01/2012 until 31/12/2012. HD was defined as a total bilirubin greater than 34.2μmol/l (2mg/dL). Additional demographic, physiological, biochemical, and pharmaceutical risk factors for hepatic dysfunction were identified and recorded.\n\n\nRESULTS\nTwo hundred and twenty five patients were included in the study of whom 48 (21.3%) developed HD. An increased duration of ventilation (median 15days [inter-quartile range 6-19] vs 6days [IQR 3-11] p<0.001), prolonged length of stay (median 19days [IQR 8.5-31] vs 7days [IQR 3-13] p<0.001), and higher mortality rate (31.3% vs. 14.7% p=0.01) were all significantly associated with HD. Shock on admission was twice as common in patients developing HD (p<0.001). The only drugs associated with HD were piperacillin-tazobactam (p<0.001) and enalapril (p=0.04). On multivariable analysis however, HD was not associated with mortality.\n\n\nCONCLUSIONS\nHD was common in our study population, and was associated with other organ dysfunction, increased mortality and length of stay.",
"affiliations": "Department of Surgery, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa.;Department of Anaesthetics and Critical Care, Perioperative Research Group, University of KwaZulu-Natal, South Africa. Electronic address: drdavidskinner@gmail.com.;Department of Surgery, Inkosi Albert Luthuli Central Hospital and University of KwaZulu-Natal, South Africa.;University of KwaZulu-Natal Trauma Surgery Training Unit, Deputy Director: IALCH Trauma Service and Trauma ICU, KwaZulu-Natal Department of Health, South Africa.;Department of Surgery, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa.",
"authors": "Saloojee|A|A|;Skinner|D L|DL|;Loots|E|E|;Hardcastle|T C|TC|;Muckart|D J J|DJ|",
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"doi": "10.1016/j.injury.2016.08.017",
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"issue": "48(1)",
"journal": "Injury",
"keywords": "Hepatic dysfunction; Trauma critical care",
"medline_ta": "Injury",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001663:Bilirubin; D056486:Chemical and Drug Induced Liver Injury; D002780:Cholestasis, Intrahepatic; D016638:Critical Illness; D005260:Female; D017052:Hospital Mortality; D006760:Hospitalization; D006801:Humans; D000860:Hypoxia; D007902:Length of Stay; D008099:Liver; D008297:Male; D012189:Retrospective Studies; D013019:South Africa; D055815:Young Adult",
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"pmid": "27599394",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Hepatic dysfunction: A common occurrence in severely injured patients.",
"title_normalized": "hepatic dysfunction a common occurrence in severely injured patients"
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{
"companynumb": "ZA-JNJFOC-20170316200",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
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"activesubstancename": "HALOPERIDOL"
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{
"abstract": "The immune checkpoint inhibitors (ICPi) revolutionize the cancer therapeutics, though not being devoid of toxicity. The immune-related primary adrenal insufficiency (PAI) is a rare, yet potentially life-threatening, adverse event, posing diagnostic and therapeutic challenges. We report the first case of reversible PAI related to nivolumab (programmed cell-death 1 protein inhibitor) in a 42-year-old male with metastatic rectal adenocarcinoma. PAI manifested as profound fatigue, disorientation, hypotension, hyperpigmentation of palmar creases, and hyponatremia without hyperkalemia 16 weeks after initiation of nivolumab. Due to impending adrenal crisis, intravenous stress doses of hydrocortisone and hydration with normal saline were initiated. When the state of patient was stabilized, PAI was confirmed through 250 μg Synacthen test 24 h after temporary cessation of hydrocortisone. Hydrocortisone was fixed at maintenance dose, while mineralocorticoid substitution was not required. PAI was ascribed to nivolumab based on history, physical examination, and laboratory work-up with emphasis on positivity of anti-21-hydroxylase antibodies and exclusion of other causes of PAI by normal imaging of adrenal glands on computed tomography (CT). Reevaluation of adrenal function during follow up demonstrated complete recovery. A review of literature concerning the immune-related PAI indicated that the complete recovery of adrenal function, the normal CT imaging, and the positivity of anti-21-hydroxylase antibodies observed in our patient are exceptional findings of immune-related PAI. Finally, heightened suspicion of immune-related PAI in case of hyponatremia without hyperkalemia and constant vigilance for diagnosis of rare, but real, reversibility of immune-related PAI are of paramount importance.",
"affiliations": "Department of Pharmacology, Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, 75 Mikras Asias, Str., 115 27 Athens, Greece. Electronic address: mdeligiorgi@yahoo.com.;Department of Pharmacology, Clinical Pharmacology Unit, National and Kapodistrian University of Athens, Faculty of Medicine, 75 Mikras Asias, Str., 115 27 Athens, Greece. Electronic address: dtrafal@med.uoa.gr.",
"authors": "Deligiorgi|Maria V|MV|;Trafalis|Dimitrios T|DT|",
"chemical_list": "D001323:Autoantibodies; D000082082:Immune Checkpoint Inhibitors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; D013255:Steroid 21-Hydroxylase",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.intimp.2020.107050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1567-5769",
"issue": "89(Pt B)",
"journal": "International immunopharmacology",
"keywords": "Adrenal function recovery; Anti-21-hydroxylase antibodies; Hyponatremia; Immunotoxicity; Nivolumab; Primary adrenal insufficiency",
"medline_ta": "Int Immunopharmacol",
"mesh_terms": "D000224:Addison Disease; D000230:Adenocarcinoma; D000328:Adult; D001323:Autoantibodies; D006801:Humans; D007010:Hyponatremia; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor; D012004:Rectal Neoplasms; D012074:Remission Induction; D012307:Risk Factors; D013255:Steroid 21-Hydroxylase; D016896:Treatment Outcome",
"nlm_unique_id": "100965259",
"other_id": null,
"pages": "107050",
"pmc": null,
"pmid": "33069924",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Reversible primary adrenal insufficiency related to anti-programmed cell-death 1 protein active immunotherapy: Insight into an unforeseen outcome of a rare immune-related adverse event.",
"title_normalized": "reversible primary adrenal insufficiency related to anti programmed cell death 1 protein active immunotherapy insight into an unforeseen outcome of a rare immune related adverse event"
} | [
{
"companynumb": "GR-AMGEN-GRCSP2020197485",
"fulfillexpeditecriteria": "2",
"occurcountry": "GR",
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"activesubstancename": "CAPECITABINE"
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"abstract": "OBJECTIVE\nCardiovascular complications, including myocarditis, are observed in coronavirus disease 2019 (COVID-19). Major cardiac involvement is a potentially lethal feature in severe cases. We sought to describe the underlying pathophysiological mechanism in COVID-19 lethal cardiogenic shock.\n\n\nRESULTS\nWe report on a 48-year-old male COVID-19 patient with cardiogenic shock; despite extracorporeal life support, dialysis, and massive pharmacological support, this rescue therapy was not successful. Severe acute respiratory syndrome coronavirus 2 RNA was detected at autopsy in the lungs and myocardium. Histopathological examination revealed diffuse alveolar damage, proliferation of type II pneumocytes, lymphocytes in the lung interstitium, and pulmonary microemboli. Moreover, patchy muscular, sometimes perivascular, interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in the cardiac tissue. The lymphocytes 'interlocked' the myocytes, resulting in myocyte degeneration and necrosis. Predominantly, T-cell lymphocytes with a CD4:CD8 ratio of 1.7 infiltrated the interstitial myocardium, reflecting true myocarditis. The myocardial tissue was examined for markers of ferroptosis, an iron-catalysed form of regulated cell death that occurs through excessive peroxidation of polyunsaturated fatty acids. Immunohistochemical staining with E06, a monoclonal antibody binding to oxidized phosphatidylcholine (reflecting lipid peroxidation during ferroptosis), was positive in morphologically degenerating and necrotic cardiomyocytes adjacent to the infiltrate of lymphocytes, near arteries, in the epicardium and myocardium. A similar ferroptosis signature was present in the myocardium of a COVID-19 subject without myocarditis. In a case of sudden death due to viral myocarditis of unknown aetiology, however, immunohistochemical staining with E06 was negative. The renal proximal tubuli stained positively for E06 and also hydroxynonenal (4-HNE), a reactive breakdown product of the lipid peroxides that execute ferroptosis. In the case of myocarditis of other aetiology, the renal tissue displayed no positivity for E06 or 4-HNE.\n\n\nCONCLUSIONS\nThe findings in this case are unique as this is the first report on accumulated oxidized phospholipids (or their breakdown products) in myocardial and renal tissue in COVID-19. This highlights ferroptosis, proposed to detrimentally contribute to some forms of ischaemia-reperfusion injury, as a detrimental factor in COVID-19 cardiac damage and multiple organ failure.",
"affiliations": "Department of Forensic Medicine, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Forensic Medicine, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Anesthesia and Critical Care Medicine, General Hospital Sint Dimpna, Geel, Belgium.;VIB Center for Inflammation Research, Ghent, Belgium.;VIB Center for Inflammation Research, Ghent, Belgium.;Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium.;Department of Anesthesia and Critical Care Medicine, General Hospital Sint Dimpna, Geel, Belgium.;Department of Pathology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Microbiology, Central Laboratory, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Microbiology, Central Laboratory, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.;Department of Intensive Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, Edegem, B-2650, Belgium.;VIB Center for Inflammation Research, Ghent, Belgium.;Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium.",
"authors": "Jacobs|Werner|W|;Lammens|Martin|M|;Kerckhofs|Annelies|A|;Voets|Evy|E|;Van San|Emily|E|;Van Coillie|Samya|S|;Peleman|Cédric|C|;Mergeay|Matthias|M|;Sirimsi|Sabriya|S|;Matheeussen|Veerle|V|;Jansens|Hilde|H|;Baar|Ingrid|I|;Vanden Berghe|Tom|T|;Jorens|Philippe G|PG|https://orcid.org/0000-0002-5434-957X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ehf2.12958",
"fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822\nJohn Wiley and Sons Inc. Hoboken\n\n32959998\n10.1002/ehf2.12958\nEHF212958\nESCHF-20-00594\nOriginal Research Article\nOriginal Research Articles\nFatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID‐19): autopsy reveals a ferroptosis signature\nFatal lymphocytic cardiac damage in COVID‐19\nW. Jacobs et al.\nJacobs Werner 1 2\nLammens Martin 3\nKerckhofs Annelies 1\nVoets Evy 4\nVan San Emily 5 6\nVan Coillie Samya 5 6\nPeleman Cédric 7 8\nMergeay Matthias 4\nSirimsi Sabriya 3\nMatheeussen Veerle 9\nJansens Hilde 9\nBaar Ingrid 10\nVanden Berghe Tom 5 6 7 11\nJorens Philippe G. https://orcid.org/0000-0002-5434-957X\n7 8 10 philippe.jorens@uza.be\n\n1 Department of Forensic Medicine Antwerp University Hospital, University of Antwerp Edegem Belgium\n2 Military Hospital Queen Astrid, Crisis Unit, Belgian Defense Brussels Belgium\n3 Department of Pathology Antwerp University Hospital, University of Antwerp Edegem Belgium\n4 Department of Anesthesia and Critical Care Medicine General Hospital Sint Dimpna Geel Belgium\n5 VIB Center for Inflammation Research Ghent Belgium\n6 Department of Biomedical Molecular Biology Ghent University Ghent Belgium\n7 Infla‐Med Research Consortium of Excellence University of Antwerp Antwerp Belgium\n8 Department of Medicine and Health Sciences, Laboratory of Experimental Medicine and Pediatrics (LEMP) University of Antwerp Antwerp Belgium\n9 Department of Microbiology, Central Laboratory Antwerp University Hospital, University of Antwerp Edegem Belgium\n10 Department of Intensive Care Medicine Antwerp University Hospital, University of Antwerp Wilrijkstraat 10 Edegem B‐2650 Belgium\n11 Department of Biomedical Sciences University of Antwerp Antwerp Belgium\n* Correspondence to: Philippe G. Jorens, Department of Intensive Care Medicine, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, B‐2650 Edegem, Belgium. Tel: +32 3 821 36 39; +32 477 36 21 84. Email: philippe.jorens@uza.be\n\n22 9 2020\n12 2020\n7 6 10.1002/ehf2.v7.6 37723781\n08 7 2020\n30 7 2020\n© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nAims\n\nCardiovascular complications, including myocarditis, are observed in coronavirus disease 2019 (COVID‐19). Major cardiac involvement is a potentially lethal feature in severe cases. We sought to describe the underlying pathophysiological mechanism in COVID‐19 lethal cardiogenic shock.\n\nMethods and results\n\nWe report on a 48‐year‐old male COVID‐19 patient with cardiogenic shock; despite extracorporeal life support, dialysis, and massive pharmacological support, this rescue therapy was not successful. Severe acute respiratory syndrome coronavirus 2 RNA was detected at autopsy in the lungs and myocardium. Histopathological examination revealed diffuse alveolar damage, proliferation of type II pneumocytes, lymphocytes in the lung interstitium, and pulmonary microemboli. Moreover, patchy muscular, sometimes perivascular, interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in the cardiac tissue. The lymphocytes ‘interlocked’ the myocytes, resulting in myocyte degeneration and necrosis. Predominantly, T‐cell lymphocytes with a CD4:CD8 ratio of 1.7 infiltrated the interstitial myocardium, reflecting true myocarditis. The myocardial tissue was examined for markers of ferroptosis, an iron‐catalysed form of regulated cell death that occurs through excessive peroxidation of polyunsaturated fatty acids. Immunohistochemical staining with E06, a monoclonal antibody binding to oxidized phosphatidylcholine (reflecting lipid peroxidation during ferroptosis), was positive in morphologically degenerating and necrotic cardiomyocytes adjacent to the infiltrate of lymphocytes, near arteries, in the epicardium and myocardium. A similar ferroptosis signature was present in the myocardium of a COVID‐19 subject without myocarditis. In a case of sudden death due to viral myocarditis of unknown aetiology, however, immunohistochemical staining with E06 was negative. The renal proximal tubuli stained positively for E06 and also hydroxynonenal (4‐HNE), a reactive breakdown product of the lipid peroxides that execute ferroptosis. In the case of myocarditis of other aetiology, the renal tissue displayed no positivity for E06 or 4‐HNE.\n\nConclusions\n\nThe findings in this case are unique as this is the first report on accumulated oxidized phospholipids (or their breakdown products) in myocardial and renal tissue in COVID‐19. This highlights ferroptosis, proposed to detrimentally contribute to some forms of ischaemia–reperfusion injury, as a detrimental factor in COVID‐19 cardiac damage and multiple organ failure.\n\nLymphocytic myocarditis\nSARS‐CoV‐2‐infection\nCOVID‐19\nAutopsy\nRenal failure\nFerroptosis\nsource-schema-version-number2.0\ncover-dateDecember 2020\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:22.12.2020\nJacobs, W. , Lammens, M. , Kerckhofs, A. , Voets, E. , Van San, E. , Van Coillie, S. , Peleman, C. , Mergeay, M. , Sirimsi, S. , Matheeussen, V. , Jansens, H. , Baar, I. , Vanden Berghe, T. , and Jorens, P. G. (2020) Fatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID‐19): autopsy reveals a ferroptosis signature. ESC Heart Failure, 7 : 3772–3781. 10.1002/ehf2.12958.\n\nWerner Jacobs and Martin Lammens share first authorship.\n\nTom Vanden Berghe and Philippe G. Jorens share senior authorship\n==== Body\nIntroduction\n\nThe ongoing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic is responsible for a great many cases of respiratory syndrome coronavirus disease 2019 (COVID‐19), which is characterized by respiratory distress with radiological and clinical features resembling full‐blown acute respiratory distress syndrome (ARDS). 1 Recently, attention has been drawn to the cardiac complications of this disease. Amongst hospitalized COVID‐19 patients, some form of cardiac injury is seen in up to 27,8 %, 2 as evidenced by a rise in cardiac troponin I (TnI) serum levels. 2 Major cardiac involvement is a potentially lethal feature in severe COVID‐19.\n\nFulminant myocarditis, an acute rapidly progressive form of myocardial failure caused by infectious and non‐infectious agents and in systemic diseases, is characterized and accompanied by marked inflammation and has a poor in‐hospital outcome. 3 The diagnosis of fulminant myocarditis is based on clinical suspicion and can be confirmed by endomyocardial biopsy. In view of the marked inflammation seen in COVID‐19 patients and the apparently very poor prognosis of cardiac failure in young patients, myocarditis rather than ischaemic cardiogenic shock has been proposed as the underlying mechanism in some cases of COVID‐19 related cardiac injury; nevertheless, there is little published data about the underlying pathologic mechanisms that might cause this type of cardiac failure to occur in COVID‐19 patients.\n\nCase report\n\nOn 21 March 2020, a 48‐year‐old man presented at a regional hospital with a 7‐day history of fever, diarrhoea, cough, dysosmia, and dyspnoea. His medical history was uneventful apart from hypertension, for which he took an angiotensin II receptor blocker daily. Initially, oxygen saturation was 87% without oxygen, and his body temperature was 38.6°C; the electrocardiogram revealed no abnormalities. Rapidly progressive shortness of breath and hypoxaemia necessitated intubation within hours, as well as prone ventilation to achieve sufficient oxygenation, which at that time resulted in a decline in the amount of oxygen needed (Fi02 of 55%). Polymerase chain reaction on both the nasopharyngeal aspirate and a throat swab was positive for SARS‐CoV‐2 RNA. Other viruses (cytomegalovirus, herpes simplex virus, adenovirus, and parainfluenza virus) were also tested for but turned out negative. A chest computed tomography showed typical pneumonia, as seen in COVID‐19 infection (Figure 1 A ). Hydroxychloroquine and azithromycin were administered. Rapidly progressive acute kidney injury with anuria necessitated continuous venovenous hemofiltration. Lung protective ventilation in an airway pressure release ventilation mode was applied. In the afternoon of Day 12 of its illness, 5 days after hospital admission (26 March), there was a rapidly progressive lactic acidosis and shock, necessitating vasopressors and inotropics (noradrenaline, adrenaline, and dobutamine). Laboratory tests showed an increase of the troponin I level from 12.1 on admission to 14 932 ng/L (normal value < 45 ng/L) (Table 1 ). Echocardiography showed a hyperdynamic ventricular function, although under massive support of inotropic agents and vasopressors. No significant valvular pathology was seen. Pulmonary pressures could not be measured (in absence of a tricuspid insufficiency). An interventricular septum dimension of 12 mm and posterior wall dimension of 11 mm were noted. The left ventricular end diastolic diameter was 48 mm. There was no pericardial effusion. His lymphocyte count had been low at admission (300 μL−1) and remained low during the whole hospitalization (Table 1 ). Broad‐spectrum antibiotics were added to cover sepsis, and hydrocortisone 100 mg t.i.d. was administered in view of the massive shock. Electrocardiography findings showed marked QRS widening and a positive deflection at the end of the T wave in the absence of hypokalaemia (Figure 1 B ). Given the suspicion of myocarditis and the deep shock, venoarterial extracorporeal membrane oxygenation was installed on the scene by the extracorporeal membrane oxygenation team of the Antwerp University Hospital; the patient was then transported by this team to the intensive care unit of this tertiary referral hospital. At this time, the patient's ferritin levels were massively elevated: the initial level of 1200 μg/L rose up to 32 401 μg/L (normal value < 322 μg/L) and was accompanied by severe hypertriglyceridaemia (481 mg/dL, normal < 120 mg/dL). The serum interleukin 6 level was 281 pg/mL (normal < 7 pg/mL). The N terminal pro brain natriuretic peptide level as a marker of cardiac failure was 9223 pg/mL (normal < 125 pg/mL). Culture of endotracheal aspirate and blood cultures in both hospitals did not reveal any accompanying bacterial infection. Despite the extracorporeal life support, dialysis, and massive pharmacological support, this rescue therapy was not successful: there was an absence of any pulsatility in the arterial waveform, and the patient died due to refractory shock on 27 March 2020.\n\nFIGURE 1 (A) Chest CT. The coronal image shows multiple patchy ground‐glass opacifications in all lung fields (right more than left) (Illness Day 7, Hospital Day 1). (B) Electrocardiogram on Day 5 after admission showing a widened QRS in the absence of hypokalaemia (Illness Day 11, Hospital Day 5).\n\nTABLE 1 Evolution of laboratory results\n\n\t21.03.20\t22.03.20\t23.03.20\t24.03.20\t25.03.20\t26.03.20\t27.03.20\tNormal values\t\nWBC (×103/μL)\t10.6\t12.5\t25.6\t19.4\t11.0\t12.4\t14.6\t3.9–10.6\t\nLymphocytes (×103/μL)\t0.30\t0.26\t0.26\t0.35\tMD\t0.45\t0.77\t1.00–4.80\t\nD‐dimers (μg/L)\t611\tMD\tMD\tMD\tMD\tMD\tMD\t0–549\t\nTroponin I (ng/L)\t12.1\t12.2\t143.2\t97.7\t59.2\t108.4\t14 932\t0.0–34.2\t\nCRP (mg/L)\t247.1\t340.9\t462\t547.7\t472.5\t441.9\t318\t<5.0\t\nFerritin (μg/L)\t1200\tMD\tMD\tMD\tMD\tMD\t32 401\t<322\t\nINR\tMD\tMD\t1.06\t1.04\t1.05\t1.15\t1.15\t0.9–1.2\t\nCRP, C‐reactive protein; INR, international normalized ratio; MD, missing values; WBC, white blood cells.\n\nAs there is a dearth of published pathology data on the underlying physiopathology of organ failure and death in COVID‐19 are similarly lacking, a clinical autopsy was performed after receiving permission from the patient's family.\n\nExternal examination showed an overweight adult male patient. Citrine‐coloured pleural fluid was present in both thoracic cavities. The lungs (left 1498 g, right 1635 g) were purplish, edematous, with a mottled aspect (Figure 2 A ). The pericardial sac was filled with yellow citrine‐coloured fluid. The heart was hypertrophic (605 g) with widened right and left ventricles and thickened ventricle walls (left 15 mm, septum 14 mm, and right 6 mm). On the outer wall of the left ventricle and the endocardium, some petechiae were noticed (Figure 2 B ). The coronaries were perfectly passable without atherosclerosis. The cut surface did not show macroscopic particularities. Ascites fluid was present in the abdominal cavity. The kidneys showed signs of acute kidney injury. The spleen (358 g) showed multiple infarctions without thromboemboli.\n\nFIGURE 2 Macroscopy at autopsy. (A) The lungs were purplish, edematous, and had a mottled aspect. (B) View on the left ventricle with some petechiae in the endocardium.\n\nMicroscopically, diffuse alveolar damage with intra‐alveolar and interstitial oedema and denudation of the alveolar epithelium with hyaline membrane formation was observed in both lungs, indicating ARDS. Re‐epithelialization with proliferation of type II pneumocytes was also found in several zones (Figure 3 ). Multinucleated cells were also identified (Supporting Information, Figure S1 ). The epithelial cells showed striking reactive cytonuclear changes with polymorphic nuclei and prominent nucleoli. No obvious intranuclear or intracytoplasmic viral inclusions were identified. Interstitially, there were diffuse inflammatory infiltrates, dominated by lymphocytes. Only mild neutrophilic inflammation was present. We also report on multiple peripheral pulmonary arterial microemboli in both lungs (Figure 3 , insert), which might reflect the procoagulant profile as well as microangiopathy seen in COVID‐19 patients making them prone to thromboembolic complications in large as well as small alveolar capillary vessels. 4\n\nFIGURE 3 Lung tissue with diffuse alveolar damage, with hyaline formation (arrow), marked type 2 pneumocyte hyperplasia (asterisk) with prominent nucleoli and multinucleation and interstitial mononuclear inflammatory infiltrates (predominantly with lymphocytes) (original magnification ×100). Insert: microembolus.\n\nHistopathological examination showed hypertrophic cardiac tissue with patchy muscular, sometimes perivascular, and slightly diffuse interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes (Figure 4 ). No thrombotic events were observed in the microcirculation of the heart. In the patchy areas, the lymphocytes ‘interlocked’ the myocytes, resulting in myocyte degeneration and necrosis (piecemeal necrosis). Intermingled with lymphocytes, only a very few individual polymorphous neutrophils were found in the affected areas. Signs of inflammation were present in both the epicardium and the myocardium. By immunohistochemistry, the lymphocytes were positive with CD3, CD4, CD8, and a small number of CD20. In the largest inflammatory infiltrate, 92% of the lymphocytes were CD3 + T lymphocytes, and 8% were CD20 + B lymphocytes. The CD4:CD8 ratio was 1.7. These findings indicate a predominant T‐cell phenotype of the cardiac inflammatory infiltrate. Intermingled, there was limited number of CD68‐positive macrophages. CD138 showed a few plasma cells. As no interstitial fibrosis disarray of the muscle fibres was seen, true preexisting cardiomyopathy could be excluded.\n\nFIGURE 4 Histochemical and immunohistochemical examination of a heart tissue sample (several sections of the heart performed: septum n = 2, anterior wall n = 2, posterior wall n = 2, right ventricle n = 1). Lymphocytes infiltrating the cardiomyocytes (A–C), resulting in myocyte degeneration and necrosis (D). Most of the lymphocytes are CD3‐positive (B) and CD4‐positive (C) T‐cells. The CD4‐positive cells progressively infiltrate the cardiomyocytes (C) demonstrated by the progressive disappearance of the desmin‐positive myofibrils (brown in panel D) and are accompanied with only a few CD68‐positive macrophages (E). Staining: HE (A), CD3 (B), CD4 (C), desmin (D), and CD68 (E). Original magnification: ×50 (A, B) and ×200 (C, D).\n\nThe spleen showed a disturbed architecture with multiple recently infarcted zones without thromboemboli. In the kidneys, a striking amount of intratubular oxalate crystals was found. There was also a slight presence of interstitial inflammation in the kidneys and signs of acute tubular necrosis. Furthermore, organ damage in the liver was observed in the context of shock.\n\nMolecular detection of SARS‐CoV‐2 in the samples (heart and lung biopsy, endotracheal and nasopharyngeal aspirate) was done by targeting the SARS‐CoV‐2 envelope (E)‐gene according to a World Health Organization recommended protocol. 5 The cycle threshold (Ct) value for the E‐gene and corresponding viral load (log10 RNA copies/mL) were 28.94/5.6 (nasopharyngeal aspirate), 31.22/4.9 (endotracheal aspirate), 23.44/7.4 (lung biopsy), 35.90/3.5 (pericardial swab), and 31.53/4.9 (heart biopsy). Additional confirmatory testing was performed on the heart biopsy by targeting the SARS‐CoV‐2 nucleocapside (N) gene according to the Centers for Disease Control and Prevention protocol (N1 and N3). 6 The Ct values for the N‐gene in the heart biopsy were 31.74 (N1) and 31.64 (N3).\n\nFerroptosis signature\n\nWe examined the patient's myocardial tissue for markers of ferroptosis, an iron‐catalysed form of regulated cell death that occurs through excessive peroxidation of polyunsaturated fatty acids and is also proposed to detrimentally contribute to some forms of ischaemia–reperfusion injury, stroke, and degenerative diseases. 7 Immunohistochemical staining with E06 (Figure 5 A ), a monoclonal antibody binding to oxidized phosphatidylcholine (reflecting lipid peroxidation during ferroptosis), was positive in morphologically degenerating and necrotic cardiomyocytes adjacent to the infiltrate of lymphocytes. 8 , 9 E06 positivity was also found near arteries, in the epicardium and myocardium. Note a gradient‐like staining, reflecting a wave of synchronized necrosis, as has been reported to occur for ferroptosis. 10 This specific myocardial immunodetection of abundant lipid peroxides with E06 antibody was replicated several times on independent staining procedures. Of note, in a case of sudden death due to viral myocarditis of unknown aetiology, immunohistochemical staining with E06 was negative (Figure 5 B ). The hypertrophic myocardium of a deceased COVID‐19 patient with severe ARDS, but without cardiac failure/myocarditis, showed only small foci of E06 positivity throughout the ventricular wall (Figure 5 C ). The myocardium, also obtained at autopsy, of a COVID‐19 subject without myocarditis (after sudden death due to trauma) did not show this prominent signature for E06 (Figure 5 D ).\n\nFIGURE 5 Immunohistochemical examination of heart tissue for a ferroptosis marker. E06 immunoreactivity (protocol adapted from Haider et al. 9 ) was detected in the area of severe SARS‐CoV‐2 myocarditis, near arteries and throughout the myocardium in a gradient‐like manner (A). In a case of a 16‐year‐old man who suddenly died of non‐COVID‐19 myocarditis due to other aetiology, no signal was detected on staining with E06 (B). The myocardium of a 33‐year‐old male COVID‐19 patient that succumbed to severe acute respiratory distress syndrome and multiple organ failure, but without myocarditis, showed foci of E06 positivity in all areas of the ventricular wall and perivascular regions (C). The myocardium of another control subject without myocarditis, a 48‐year‐old man who was hospitalized after trauma, showed only some E06 positivity in perivascular connective tissue (D). Control stains using only secondary antibodies are available in the Supporting Information.\n\nIn order to elucidate the role of ferroptosis during multiple organ dysfunction syndrome (MODS) 11 including cardiac and renal failure in this patient, immunohistochemical staining was performed on renal tissue using E06 and anti‐4‐hydroxynonenal (HNE) antibody. 4‐HNE is a highly reactive breakdown product of the lipid peroxides that execute ferroptosis. 11 Renal tissue of the COVID‐19 patient with lymphocytic myocarditis stained positively for both E06 and 4‐HNE in the cortical region. More precisely, these ferroptosis markers are detected in the proximal tubuli (Figures 6 A and 6 C ). In the case of sudden death due to myocarditis of other aetiology, the morphologically normal renal tissue displayed no positivity for E06 or 4‐HNE (Figures 6 B and 6 D , respectively). Attempts to stain lung tissue failed due to high background staining from multiple lung haemorrhages.\n\nFIGURE 6 Immunohistochemical examination of renal tissue for potential ferroptosis markers. Renal tissue from the COVID‐19 patient with myocarditis and multiple organ dysfunction syndrome showed morphological signs of acute tubular necrosis, intratubular oxalate crystals, as well as E06 positivity in proximal tubuli (A). The latter also stained positively for the presence of 4‐HNE, one of the breakdown product of lipid peroxides (protocol adapted from Feng et al. 11 ) (C). By comparison, in the case of sudden death due to myocarditis of other aetiology, immunohistochemical staining with E06 (B) and anti‐4‐HNE antibody (D) in the renal tissue showed no presence of these ferroptosis markers (non‐specific staining in the corticomedullary junction is also present on control stains). Control stains using only secondary antibodies are enclosed in the Supporting Information.\n\nDiscussion\n\nAt the time of writing, there are few published autopsy findings in COVID‐19 patients, where damage mostly of the lungs is reported but not of the heart tissue. 12 , 13 , 14 It was described that a few mononuclear cells had infiltrated the interstitium of the heart. 14 , 15 Viral particles and low‐grade interstitial inflammation with vacuolated CD68‐positive macrophages were observed in the endomyocardial biopsy of patients with COVID‐19 related cardiogenic shock. 15 , 16 , 17 Recently, (low loads of) SARS‐COV‐2 genomes have been detected in the endomyocardial biopsies of 5 out of 104 patients with suspected myocarditis or unexplained heart failure. 18 In one patient, histological analysis revealed an active myocarditis with vessels involved in the inflammation process and accompanying necrosis of myocytes; in the four others, predominantly, T‐cells (as stained by a CD3 antibody) were found. 18\n\nWe provide the first in‐depth histopathological description of a histology‐proven fatal case of SARS‐CoV‐2 viral myocarditis in a COVID‐19 patient with cardiogenic shock together with overt respiratory failure. The findings fulfil the histological, immunohistochemical, and microbiological criteria for definite lymphocytic, myocarditis of viral origin: interstitial, principally CD3‐positive, T‐lymphocytic infiltration associated with myocyte damage. 19 The COVID‐19 causality is supported by reverse transcriptase polymerase chain reaction amplification of the viral genome in myocardial tissue. Moreover, lymphocytes are hardly found in the myocardium of patients dying of septic shock, therefore supporting that the cardiac damage seen in this patient is most probably due to lymphocytic myocarditis; in the case of full‐blown septic myocarditis, polynuclear granulocytes would be present. The diagnosis in several previous case reports on fulminant myocarditis due to COVID‐19 has been based on clinical signs only. 20 , 21\n\nOur data give a unique insight into the physiopathogenesis of COVID‐19 related cardiac failure and MODS. The immunohistochemical marker (presence of oxidized phosphatidylcholine) for ferroptosis was positive in myocardial tissue from this COVID‐19 related lymphocytic myocarditis and of a case of fatal COVID‐19 without myocarditis. Indeed, this COVID‐19 patient with lymphocytic myocarditis presented also with refractory shock and multiple organ dysfunction necessitating renal replacement therapy. Microscopically, the renal tissue too displayed signs of acute tubular necrosis, intratubular oxalate crystals, and abundant presence of oxidized phosphatidylcholine and also 4‐HNE in the proximal tubules.\n\nFerroptosis has been conceptualized in 2012 as a novel type of regulated cell death. 22 This form of regulated necrotic cell death is mediated by iron‐catalysed lipid peroxides that compromise the plasma membrane integrity. The abundance of lipid peroxides in myocardium and renal cortex of the COVID‐19 patient with lymphocytic myocarditis might also be related to ischaemia and ischaemia–reperfusion injury in these organs as seen in MODS. 7 , 10 Indeed, such insults cause an increased production of radical oxygen species by, for example, the mitochondrial respiratory chain that could subsequently attack polyunsaturated fatty acids, leading to lipid peroxides that execute ferroptosis. In preclinical models, ferroptosis has been implicated in ischaemia–reperfusion injury of the myocardium, kidney, liver, intestine, and brain. 10 Based on our data, it is tempting to suggest that ferroptosis is a detrimental factor in organ injury during shock and MODS and COVID‐19 lymphocytic myocardial infiltration. The cardiac damage observed in the heart might therefore be multifactorial, related to direct invasion of the virus, acid–base imbalance due to kidney injury, hypoxaemia due to respiratory failure as well as ischaemia–reperfusion related ferroptosis due to the severe cardiogenic shock.\n\nSevere acute respiratory syndrome coronavirus 2 was detected in the heart of 35% of those that died from SARS, 23 with the authors concluding that coronaviruses such as SARS‐CoV are able to infect and invade the myocardium. At that time, myocardial inflammation caused by SARS‐CoV was believed to be predominantly mediated by macrophages, 23 while we additionally show a prominent role for T‐lymphocytes in COVID‐19. In SARS‐infected human cases, marked production of oxidized phospholipids in the inflammatory exudates lining the injured air spaces, pneumocytes, and alveolar macrophages had already been shown, 24 as we show here too in the myocardium and renal tissue as part of the ferroptosis process.\n\nIn this patient, as in many other COVID‐19 patients with or without myocarditis, extreme hyperferritinemia accompanied by a cytokine ‘storm’ was seen. 25 Likewise, the patient's myocardial tissue showed an increased signal for ferritin especially in the epicardial region (data not shown). Ferritin is known to be a pro‐inflammatory mediator inducing expression of pro‐inflammatory molecules 26 ; the high ferritin levels observed in these uncommon clinical conditions (sepsis, myocarditis, etc.) are therefore not just the product of the inflammation but rather may contribute to the development of a cytokine storm therefore considered a form of ‘hyperferritinemic syndrome’. 27 Our group (and others) has shown that exuberant ferroptosis produces high amounts of ferrous iron that could exceed the buffering capacity of ferritin. 28 The unbuffered, free ferrous iron catalyses radical oxygen species via Fenton reactions and hence lipid peroxides. Along with the cytokine storm and inflammation, this iron dysbiosis might thus also contribute to the hyperferritinemia observed in severe COVID‐19 patients. It has been noted that iron dysbiosis, including an increase in plasma ferrous iron and ferritin, also associates with death in critically ill patients with severe acute kidney injury. 29\n\nIn view of the absence of any superimposed infection, fulminant myocarditis was retained as the most plausible diagnosis. More studies are needed to estimate the incidence of SARS‐CoV‐2 viral myocarditis, although a definite diagnosis on clinical—rather than pathological—data will remain difficult. In an era of high‐tech medicine, the autopsy still plays an important role in unravelling the pathophysiology of emerging infectious diseases. In anticipation of the development of effective antiviral therapy, the attenuation of the cytokine storm (e.g. with interleukin 6 receptor blockers) is currently being studied; it remains to be determined if ferroptosis inhibition alone might also be helpful in the treatment of SARS‐CoV‐2 organ failure, including viral myocarditis. Highly potent ferroptosis inhibitors might be promising leads for clinical validation. 30\n\nConflict of interest\n\nThe findings and conclusions in this report are those of the authors. The authors have nothing to disclose.\n\nFunding\n\nVanden Berghe lab at VIB‐UGent Center for Inflammatin Research is supported by Excellence of Science (EOS 30826052 MODEL‐IDI), Research Foundation Flanders (FWO G0B7118N), VLIR‐UOS (grant number: TEAM2018‐SEL018), Charcot Foundation, Stichting Tegen Kanker (FAFC/2018/1250), Ghent University, and VIB. Vanden Berghe lab at the University of Antwerp is part of a consortium of excellence focusing on inflammation (INFLA‐MED), is supported by FWO Kom op tegen Kanker (G049720N), IOF, TOP‐BOF (32254) and FWO (G0C0119N) and has frequent partnerships with international pharma.\n\nAuthor contributions\n\nW.J., M.L., T.V.B., and P.G.J. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. W.J., M.L., A.K., E.V., C.P., T.V.B., and P.G.J. worked on the study concept and design. W.J., M.L., A.K., E.V., E.V.S., S.V.C., C.P., M.M., S.S., V.M., H.J., I.B., T.V.B., and P.G.J. acquired, analysed, or interpreted the data. W.J., M.L., A.K., C.P., T.V.B., and P.G.J. drafted the manuscript. W.J., M.L., A.K., E.V., E.V.S., S.V.C., S.S., V.M., H.J., T.V.B., and P.G.J. provided administrative, technical, or material support. M.L., T.V.B., and P.G.J. supervised the study. All authors contributed to the critical revision of the manuscript for important intellectual content.\n\nBiobank\n\nAll samples were stored in the ‘Biobank Antwerpen’ BE 71030031000; Biobank Antwerpen, BBMR‐ERIC, Belgian Virtual Tumourbank funded by the National Cancer Plan; No. Access: (BB20039), Last: (04, 15, 2020) [BIORESOURCE].\n\nSupporting information\n\nFigure S1. Detail of lung microscopy: multinuclear cells. (HE, original. magnification. 200x).\n\nFigure S2. negative controls of immunohistochemical staining for the ferroptosis marker E06 in myocardium.\n\nControl stains using only secondary antibodies showed no significant signal in the COVID‐19 related myocarditis case (Panel A), nor in patients with sudden death due myocarditis of other etiology (Panel B) or the COVID‐19 patient without myocarditis (Panel C). Likewise, no significant signal was detected in the myocardium of a control subject without myocarditis or COVID‐19 after staining with only the secondary antibody (Panel D).\n\nFigure S3. negative controls of immunohistochemical staining for the ferroptosis markers EO6 and 4‐HNE in renal tissue.\n\nStaining with only the secondary antibodies from the staining protocols of E06 (Panel A) and anti‐4HNE antibody (Panel C) showed a limited signal at the corticomedullary region. In the renal tissue of a case of sudden death due to myocarditis of other etiology a nonspecific signal was detected in the corticomedullary region after staining with these secondary antibodies (Panel B and D).\n\nClick here for additional data file.\n\nAcknowledgements\n\nThe secretarial assistance of Hilde Fleurackers is greatly acknowledged. Professor A. Dendooven (Gent, Antwerpen) is thanked for comment on the revised manuscript. We thank the nurses and clinical staff from the general hospital Sint‐Dimpna, Geel, Belgium, and the Antwerp University Hospital, Edegem, Belgium, who have been providing care for the patient.\n==== Refs\nReferences\n\n1 Zhu N , Zhang D , Wang W , Zhu N , Zhang D , Wang W , Li X , Yang B , Song J , Zhao X , Huang B , Shi W , Lu R , Niu P . A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382 : 727–733.31978945\n2 Guo T , Fan Y , Chen M , Wu X , Zhang L , He T , Wang H , Wan J , Wang X , Lu Z . Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID‐19). JAMA Cardiol 2020; 5 : 811.32219356\n3 Veronese G , Ammirati E , Cipriani M , Frigerio M . Fulminant myocarditis: characteristics, treatment, and outcomes. Anatol J Cardiol 2018; 19 : 279–286.29537977\n4 Ackermann M , Verleden SE , Kuehnel M , Haverich A , Welte T , Laenger F , Vanstapel A , Werlein C , Stark H , Tzankov A , Li WW , Li VW , Mentzer SJ , Jonigk D . Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID‐19. N Engl J Med 2020; 383 : 120–128.32437596\n5 Corman VM , Landt O , Kaiser M , Molenkamp R , Meijer A , Chu DKW , Bleicker T , Brünink S , Schneider J , Schmidt ML , Mulders DGJC , Haagmans BL , van der Veer B , van den Brink S , Wijsman L , Goderski G , Romette JL , Ellis J , Zambon M , Peiris M , Goossens H , Reusken C , Koopmans MPG , Drosten C . Detection of 2019 novel coronavirus (2019‐nCoV) by real‐time RT‐PCR. Euro Surveill 2020; 25 : 2000045.\n6 2019‐Novel Coronavirus (2019‐nCoV) Real‐time rRt‐PCR Panel Primers and Probes. 2020. https://www.fda.gov/media/134922/download\n7 Bayir H , Anthonymuthu TS , Tyurina YY , Patel SJ , Amoscato AA , Lamade AM , Yang Q , Vladimirov GK , Philpott CC , Kagan VE . Achieving life through death: redox biology of lipid peroxidation in ferroptosis. Cell Chem Biol 2020; 27 : 387–408.32275865\n8 Horkko S , Bird DA , Miller E , Itabe H , Leitinger N , Subbanagounder G , Berliner JA , Friedman P , Dennis EA , Curtiss LK , Palinski W . Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid‐protein adducts inhibit macrophage uptake of oxidized low‐density lipoproteins. J Clin Invest 1999; 103 : 117–128.9884341\n9 Haider L , Fischer MT , Frischer JM , Bauer J , Hoftberger R , Botond G , Esterbauer H , Binder CJ , Witztum JL , Lassmann H . Oxidative damage in multiple sclerosis lesions. Brain 2011; 134 : 1914–1924.21653539\n10 Linkermann A , Skouta R , Himmerkus N , Mulay SR , Dewitz C , de Zen F , Prokai A , Zuchtriegel G , Krombach F , Welz PS , Weinlich R , vanden Berghe T , Vandenabeele P , Pasparakis M , Bleich M , Weinberg JM , Reichel CA , Bräsen JH , Kunzendorf U , Anders HJ , Stockwell BR , Green DR , Krautwald S . Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A 2014; 111 : 16836–16841.25385600\n11 Feng H , Schorpp K , Jin L , Yozwiak CE , Hoffstrom BG , Decker AM , Rajbhandari P , Stokes ME , Bender HG , Csuka JM , Upadhyayula PS . Transferrin receptor is a specific ferroptosis marker. Cell Rep 2020; 30 : 3411, e7–3423.32160546\n12 Barton LM , Duval EJ , Stroberg E , Ghosh S , Mukhopadhyay S . COVID‐19 autopsies, Oklahoma, USA. Am J Clin Pathol 2020; 153 : 725–733.32275742\n13 Tian S , Xiong Y , Liu H , Niu L , Guo J , Liao M , Xiao SY . Pathological study of the 2019 novel coronavirus disease (COVID‐19) through postmortem core biopsies. Mod Pathol 2020; 33 : 1007–1014.32291399\n14 Xu Z , Shi L , Wang Y , Zhang J , Huang L , Zhang C , Liu S , Zhao P , Liu H , Zhu L , Tai Y , Bai C , Gao T , Song J , Xia P , Dong J , Zhao J , Wang FS . Pathological findings of COVID‐19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8 : 420–422.32085846\n15 Sala S , Peretto G , Gramegna M , Palmisano A , Villatore A , Vignale D , de Cobelli F , Tresoldi M , Cappelletti AM , Basso C , Godino C , Esposito A . Acute myocarditis presenting as a reverse Tako‐Tsubo syndrome in a patient with SARS‐CoV‐2 respiratory infection. Eur Heart J 2020; 41 : 1861–1862.32267502\n16 Inciardi RM , Lupi L , Zaccone G , Italia L , Raffo M , Tomasoni D , Cani DS , Cerini M , Farina D , Gavazzi E , Maroldi R . Cardiac involvement in a patient with coronavirus disease 2019 (COVID‐19). JAMA Cardiol 2020; 5 : 819–824.32219357\n17 Tavazzi G , Pellegrini C , Maurelli M , Belliato M , Sciutti F , Bottazzi A , Sepe PA , Resasco T , Camporotondo R , Bruno R , Baldanti F , Paolucci S , Pelenghi S , Iotti GA , Mojoli F , Arbustini E . Myocardial localization of coronavirus in COVID‐19 cardiogenic shock. Eur J Heart Fail 2020; 22 : 911–915.32275347\n18 Escher F , Pietsch H , Aleshcheva G , Bock T , Baumeier C , Elsaesser A , Wenzel P , Hamm C , Westenfeld R , Schultheiss M , Gross U. Detection of viral SARS‐COV‐2 genomes and histopathological changes in endomyocardial biopsies. ESC Heart Failure 2020 10.1002/ehf2.12805\n19 Caforio AL , Pankuweit S , Arbustini E , Basso C , Gimeno‐Blanes J , Felix SB , Fu M , Heliö T , Heymans S , Jahns R , Klingel K . Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34 : 2636–2648d.23824828\n20 Hu H , Ma F , Wei X , Fang Y . Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. Eur Heart J 2020 10.1093/eurheartj/ehaa190\n21 Zeng JH , Liu YX , Yuan J , Wang FX , Wu WB , Li JX , Wang LF , Gao H , Wang Y , Dong CF , Li YJ , Xie XJ , Feng C , Liu L . First case of COVID‐19 complicated with fulminant myocarditis: a case report and insights. Infection 2020.\n22 Dixon SJ , Lemberg KM , Lamprecht MR , Skouta R , Zaitsev EM , Gleason CE , Patel DN , Bauer AJ , Cantley AM , Yang WS , Morrison B III , Stockwell BR . Ferroptosis: an iron‐dependent form of nonapoptotic cell death. Cell 2012; 149 : 1060–1072.22632970\n23 Oudit GY , Kassiri Z , Jiang C , Liu PP , Poutanen SM , Penninger JM , Butany J . SARS‐coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest 2009; 39 : 618–625.19453650\n24 Imai Y , Kuba K , Neely GG , Yaghubian‐Malhami R , Perkmann T , van Loo G , Ermolaeva M , Veldhuizen R , Leung YHC , Wang H , Liu H , Sun Y , Pasparakis M , Kopf M , Mech C , Bavari S , Peiris JSM , Slutsky AS , Akira S , Hultqvist M , Holmdahl R , Nicholls J , Jiang C , Binder CJ , Penninger JM . Identification of oxidative stress and Toll‐like receptor 4 signaling as a key pathway of acute lung injury. Cell 2008; 133 : 235–249.18423196\n25 Chen G , Wu D , Guo W , Cao Y , Huang D , Wang H , Wang T , Zhang X , Chen H , Yu H , Zhang X , Zhang M , Wu S , Song J , Chen T , Han M , Li S , Luo X , Zhao J , Ning Q . Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130 : 2620–2629.32217835\n26 Torti FM , Torti SV . Regulation of ferritin genes and protein. Blood 2002; 99 : 3505–3516.11986201\n27 Rosário C , Zandman‐Goddard G , Meyron‐Holtz EG , D'Cruz DP , Shoenfeld Y . The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med 2013; 11 : 185.23968282\n28 Hassannia B , Wiernicki B , Ingold I , Qu F , van Herck S , Tyurina YY , Bayır H , Abhari BA , Angeli JPF , Choi SM , Meul E , Heyninck K , Declerck K , Chirumamilla CS , Lahtela‐Kakkonen M , van Camp G , Krysko DV , Ekert PG , Fulda S , de Geest BG , Conrad M , Kagan VE , vanden Berghe W , Vandenabeele P , vanden Berghe T . Nano‐targeted induction of dual ferroptotic mechanisms eradicates high‐risk neuroblastoma. J Clin Invest 2018; 128 : 3341–3355.29939160\n29 Wenzel SE , Tyurina YY , Zhao J , St. Croix CM , Dar HH , Mao G , Tyurin VA , Anthonymuthu TS , Kapralov AA , Amoscato AA , Mikulska‐Ruminska K , Shrivastava IH , Kenny EM , Yang Q , Rosenbaum JC , Sparvero LJ , Emlet DR , Wen X , Minami Y , Qu F , Watkins SC , Holman TR , VanDemark AP , Kellum JA , Bahar I , Bayır H , Kagan VE . PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 2017; 171 : 628, e26–641.29053969\n30 Devisscher L , Van Coillie S , Hofmans S , Van Rompaey D , Goossens K , Meul E , Maes L , De Winter H , Van Der Veken P , Vandenabeele P , Berghe TV . Discovery of novel, drug‐like ferroptosis inhibitors with in vivo efficacy. J Med Chem 2018; 61 : 10126–10140.30354101\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2055-5822",
"issue": null,
"journal": "ESC heart failure",
"keywords": "Autopsy; COVID-19; Ferroptosis; Lymphocytic myocarditis; Renal failure; SARS-CoV-2-infection",
"medline_ta": "ESC Heart Fail",
"mesh_terms": null,
"nlm_unique_id": "101669191",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32959998",
"pubdate": "2020-09-22",
"publication_types": "D016428:Journal Article",
"references": "21653539;32085846;32219356;32437596;11986201;32275865;23968282;32529795;9884341;19453650;32267502;32959998;32275347;32160546;29537977;32277408;32219357;32217835;32275742;32176300;18423196;25385600;31992387;31978945;30354101;29053969;29939160;32291399;23824828;22632970",
"title": "Fatal lymphocytic cardiac damage in coronavirus disease 2019 (COVID-19): autopsy reveals a ferroptosis signature.",
"title_normalized": "fatal lymphocytic cardiac damage in coronavirus disease 2019 covid 19 autopsy reveals a ferroptosis signature"
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"abstract": "Objective Despite many women suffering from psychosis in their childbearing years, limited data exist about the use of atypical antipsychotic agents in pregnancy. Atypical antipsychotic agents are often used to treat bipolar disorder, instead of lithium or valproate because of the known teratogenicity of those agents. As well, atypical antipsychotics are often prescribed in anxiety disorders and depression. This study sought to describe pregnancy outcomes for women prescribed atypical antipsychotics during pregnancy. Methods This retrospective review included all cases treated by Auckland Maternal Mental Health services in which atypical antipsychotic agents were utilized during pregnancy over three years. Results Over the three years, 45 pregnant women were prescribed atypical antipsychotic agents, most commonly quetiapine or olanzapine. Two-fifths (40%) were diagnosed with bipolar disorder and almost one-third (31%) with a psychotic disorder. Two-thirds (64%) were prescribed multiple psychotropic medications during their pregnancy. Instrumental delivery rates were elevated at 38%. A minority (13%) of the women developed gestational diabetes mellitus. Although 7% of infants were born premature, all were born after 35 weeks. Two major malformations were noted, similar to baseline community rates. Conclusions This naturalistic study adds to the limited literature about treatment with atypical antipsychotic agents in pregnancy, though not adequately powered to detect small differences in malformations or obstetrical outcomes. It also highlights the myriad of indications for which pregnant women are prescribed atypical antipsychotics, and the multiple other risk factors seen in this population.",
"affiliations": "1 The University of Auckland, Auckland, New Zealand.;2 Auckland District Health Board, Auckland, New Zealand.;2 Auckland District Health Board, Auckland, New Zealand.;1 The University of Auckland, Auckland, New Zealand.",
"authors": "Hatters Friedman|Susan|S|;Moller-Olsen|Charmian|C|;Prakash|Chandni|C|;North|Abigail|A|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1177/0091217417696739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2174",
"issue": "51(6)",
"journal": "International journal of psychiatry in medicine",
"keywords": "atypical antipsychotic; bipolar; pregnancy; schizophrenia",
"medline_ta": "Int J Psychiatry Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001714:Bipolar Disorder; D005260:Female; D006801:Humans; D008427:Maternal Health Services; D008605:Mental Health Services; D000077152:Olanzapine; D011247:Pregnancy; D011248:Pregnancy Complications; D011618:Psychotic Disorders; D000069348:Quetiapine Fumarate; D012189:Retrospective Studies; D055815:Young Adult",
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"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Atypical antipsychotic use and outcomes in an urban maternal mental health service.",
"title_normalized": "atypical antipsychotic use and outcomes in an urban maternal mental health service"
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"abstract": "Efficacy and safety profiles of biologics have been established for moderate to severe psoriasis. However, inefficacy or adverse events sometimes require changing the treatment to other biologics. Here, we examine the effectiveness of this strategy. We retrospectively investigated cases requiring switching biologics. We enrolled 275 psoriatic patients treated with biologics between January 2010 and December 2014 in our hospital. Of these, 51 required a switch to another biologic. First-line therapies were infliximab (IFX, n = 26), adalimumab (ADA, n = 18) and ustekinumab (UST, n = 7), and second-line therapies were IFX (n = 5), ADA (n = 21) and UST (n = 25). Reasons for switching were inefficacy (n = 38), adverse events (n = 11) and others (n = 2). The details were primary failure (n = 15), secondary failure (n = 23) and infusion reactions (n = 8). In 49 patients who switched biologics due to inefficacy and adverse events, the mean Psoriasis Area and Severity Index (PASI) score at week 16 was 4.3 for first-line therapies and 2.9 for second-line therapies (P < 0.05). Switching to a second biologic therapy to address the first's inefficacy or adverse events often results in significant improvement in moderate to severe psoriasis.",
"affiliations": "Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.;Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Honda|Hiromi|H|http://orcid.org/0000-0002-4435-8536;Umezawa|Yoshinori|Y|;Kikuchi|Sota|S|;Yanaba|Koichi|K|http://orcid.org/0000-0002-3890-2830;Fukuchi|Osamu|O|;Ito|Toshihiro|T|;Nobeyama|Yoshimasa|Y|http://orcid.org/0000-0002-0125-8930;Asahina|Akihiko|A|http://orcid.org/0000-0001-6127-3182;Nakagawa|Hidemi|H|",
"chemical_list": "D001688:Biological Products; D003879:Dermatologic Agents; D000069285:Infliximab; D000069549:Ustekinumab; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.13860",
"fulltext": null,
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"issn_linking": "0385-2407",
"issue": "44(9)",
"journal": "The Journal of dermatology",
"keywords": "adverse events; biologics; inefficacy; psoriasis; switching",
"medline_ta": "J Dermatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D001688:Biological Products; D003879:Dermatologic Agents; D057915:Drug Substitution; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D017211:Treatment Failure; D016896:Treatment Outcome; D000069549:Ustekinumab",
"nlm_unique_id": "7600545",
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"pages": "1015-1019",
"pmc": null,
"pmid": "28488283",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Switching of biologics in psoriasis: Reasons and results.",
"title_normalized": "switching of biologics in psoriasis reasons and results"
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... |
{
"abstract": "BACKGROUND\nOral tyrosine kinase inhibitors (TKIs) are becoming increasingly common in oncology practice due to ease of administration and patient preference. This class of medications is relatively unknown to emergency physicians.\n\n\nMETHODS\nHere we present a case of electrical storm (ES) thought to be associated with ibrutinib, a TKI. The ES was unabated despite antidysrhythmic therapy and electrical cardioversion, and was treated with supportive care, which eventually included the use of extracorporeal membrane oxygenation. This patient had no risk factors or apparent causes of recurrent ventricular tachycardia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ES has not previously been described with ibrutinib, but may be associated with off-target effects of the drug.",
"affiliations": "Emergency Medicine, University of Michigan, Ann Arbor, Michigan.;Pharmacy Department, Henry Ford Health System, Detroit, Michigan.;Emergency Medicine, University of Michigan, Ann Arbor, Michigan.;Emergency Medicine, University of Michigan, Ann Arbor, Michigan.",
"authors": "Beyer|Alexander|A|;Ganti|Beejal|B|;Majkrzak|Allen|A|;Theyyunni|Nik|N|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D008012:Lidocaine; D008274:Magnesium; D000225:Adenine; D007545:Isoproterenol; D000638:Amiodarone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2016.10.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "52(4)",
"journal": "The Journal of emergency medicine",
"keywords": "dysrhythmia; electrical storm; ibrutinib; torsades des pointes; tyrosine kinase inhibitor; ventricular storm",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000225:Adenine; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D004554:Electric Countershock; D004562:Electrocardiography; D004594:Electrophysiology; D004636:Emergency Service, Hospital; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D007362:Intensive Care Units; D007423:Intra-Aortic Balloon Pumping; D007545:Isoproterenol; D008012:Lidocaine; D008274:Magnesium; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D012121:Respiration, Artificial; D013575:Syncope; D017180:Tachycardia, Ventricular; D016171:Torsades de Pointes; D008258:Waldenstrom Macroglobulinemia; D000078329:Workforce",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "e123-e127",
"pmc": null,
"pmid": "28007361",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Perfect Storm: Tyrosine Kinase Inhibitor-Associated Polymorphic Ventricular Tachycardia.",
"title_normalized": "a perfect storm tyrosine kinase inhibitor associated polymorphic ventricular tachycardia"
} | [
{
"companynumb": "US-JNJFOC-20170405917",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": null,
"... |
{
"abstract": "Relapsing polychondritis (RP) rarely affected the central nervous system (CNS). If the CNS is involved, it can result in psychiatric manifestations. Patients with RP always respond well to glucocorticoids and immunosuppressants. If the therapies fail, biologics can be given, such as tocilizumab, which is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Until now, there have been no randomized clinical trials to test the safety and efficacy of biologics, no reports of RP with psychiatric disorders as initial symptoms, and no reports of tocilizumab used for psychiatric symptoms due to RP. Here, we report a 60-year-old woman with mania, logomania, hallucinations, cognitive disorder, persecutory delusion, and violent tendency as chief complaints. The application of dexamethasone worsened her psychiatric symptoms. After the first infusion of tocilizumab, she achieved complete remission within one week. During the follow-up period, she sustained serological and psychiatric remission. Our case illustrates the safety and efficacy of tocilizumab for psychiatric symptoms of RP.",
"affiliations": "Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshedong Road, Erqi District, Zhengzhou, Henan, China.;Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshedong Road, Erqi District, Zhengzhou, Henan, China. shengyun19690505@163.com.;Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshedong Road, Erqi District, Zhengzhou, Henan, China.;Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshedong Road, Erqi District, Zhengzhou, Henan, China.",
"authors": "Liu|Lijun|L|;Liu|Shengyun|S|;Guan|Wenjuan|W|;Zhang|Lei|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; C502936:tocilizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-016-3509-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "36(8)",
"journal": "Rheumatology international",
"keywords": "Glucocorticoid; Psychiatric symptoms; Relapsing polychondritis; Tocilizumab",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D001714:Bipolar Disorder; D003072:Cognition Disorders; D005260:Female; D006212:Hallucinations; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D011081:Polychondritis, Relapsing; D016896:Treatment Outcome",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "1185-9",
"pmc": null,
"pmid": "27260262",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24347992;1977371;24854377;21958172;23280172;9002018;26903267;23887438;775252;12077711;22298790;24831688;17113965;24074969;20215048;19106169;11815680;12563363",
"title": "Efficacy of tocilizumab for psychiatric symptoms associated with relapsing polychondritis: the first case report and review of the literature.",
"title_normalized": "efficacy of tocilizumab for psychiatric symptoms associated with relapsing polychondritis the first case report and review of the literature"
} | [
{
"companynumb": "CN-BAUSCH-BL-2016-018483",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "1",
... |
{
"abstract": "Pregnancy after lung transplantation has been described, but pregnancy after living donor lobar lung transplantation (LDLT) has not been reported. The aim of this study was to evaluate outcomes after pregnancy with LDLT and discuss current recommendations regarding pregnancy and lung transplantation. A total of four LDLT patients and five pregnancies were identified, all from our institution. No patient has developed worsening pulmonary function or acute or chronic rejection. The complications of pulmonary hypertension and rejection may be overestimated in this population, and recommendations for preventive sterilization at transplantation or abortion at the time of conception are likely unwarranted and unnecessary.",
"affiliations": null,
"authors": "Greene|Christina L|CL|;Barr|Mark L|ML|;Schenkel|Felicia A|FA|;Worrell|Stephanie G|SG|;Starnes|Vaughn A|VA|;McFadden|P Michael|PM|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000000363",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "98(7)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000328:Adult; D003550:Cystic Fibrosis; D005260:Female; D006085:Graft Survival; D006801:Humans; D006976:Hypertension, Pulmonary; D007166:Immunosuppressive Agents; D019520:Living Donors; D008168:Lung; D016040:Lung Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "692-4",
"pmc": null,
"pmid": "25121476",
"pubdate": "2014-10-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes after pregnancy in living lobar lung transplantation.",
"title_normalized": "outcomes after pregnancy in living lobar lung transplantation"
} | [
{
"companynumb": "PHHY2014US134728",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Glycogen storage disease type 1a (GSD 1a) is a metabolic disorder caused by deficiency of an enzyme required for glycogen breakdown, causing hypoglycaemia and lactic acidosis. Metabolic derangements cause disease manifestations affecting the kidneys, liver and platelet function. Physiological changes in pregnancy worsen fasting intolerance and increase reliance on exogenous glucose to avoid lactic acidosis. Fetal macrosomia and declining respiratory function result in high rates of caesarean sections. We report the multidisciplinary team (MDT) management of a 25-year-old woman with GSD 1a in an unplanned pregnancy. Existing percutaneous endoscopic gastrostomy tube feeding, alongside high-calorie drinks and intravenous dextrose during labour, managed the risks of hypoglycaemia and lactic acidosis. Metabolic parameters were regularly monitored and fortnightly growth scans were assessed for macrosomia. Allopurinol was continued throughout the pregnancy to reduce the risk of hyperuricaemia. MDT management optimised maternal and fetal care throughout pregnancy and labour, resulting in a successful vaginal delivery.",
"affiliations": "Tameside Hospital NHS Foundation Trust, Ashton-under-Lyne, UK alice.jones@tgh.nhs.uk.;Manchester University NHS Foundation Trust, Manchester, UK.;Salford Royal NHS Foundation Trust, Salford, Greater Manchester, UK.;Inherited Metabolic Diseases, Salford Royal NHS Foundation Trust, Salford, Greater Manchester, UK.",
"authors": "Jones|Alice May|AM|;Tower|Clare|C|;Green|Diane|D|;Stepien|Karolina M|KM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-241161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "gynaecology and fertility; materno-fetal medicine; metabolic disorders; obstetrics; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D005260:Female; D005953:Glycogen Storage Disease Type I; D006801:Humans; D007003:Hypoglycemia; D007743:Labor, Obstetric; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34380672",
"pubdate": "2021-08-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multidisciplinary management of pregnancy and labour in a patient with glycogen storage disease type 1a.",
"title_normalized": "multidisciplinary management of pregnancy and labour in a patient with glycogen storage disease type 1a"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-324531",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"dru... |
{
"abstract": "The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon-free direct-acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance.\n\n\n\nHere, we aimed at evaluating the effects of direct-acting antiviral therapy-induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct-acting antiviral-mediated hepatitis C clearance in cirrhosis patients was investigated.\n\n\n\nEmploying multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct-acting antiviral treatment.\n\n\n\nElevated pretherapy concentrations of specific soluble immune mediators including MCP-3, GDNF, CDCP1, IL-17C, IL-17A, signalling lymphocytic activation family 1, CCL11, FGF-5, LIF-R, interleukin 10 (IL-10), IL-10RA, IL-15RA, beta NGF, CCL28, CCL25 and NT-3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF-5 and IL-15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma-free patients experienced significant ameliorations.\n\n\n\nThese results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct-acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct-acting antiviral therapies would be superior to the risk of developing carcinoma.",
"affiliations": "Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.",
"authors": "Owusu Sekyere|Solomon|S|;Port|Kerstin|K|0000-0001-8338-3227;Deterding|Katja|K|;Cornberg|Markus|M|;Wedemeyer|Heiner|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050640620976991",
"fulltext": "\n==== Front\nUnited European Gastroenterol J\nUnited European Gastroenterol J\n10.1002/(ISSN)2050-6414\nUEG2\nUnited European Gastroenterology Journal\n2050-6406\n2050-6414\nJohn Wiley and Sons Inc. Hoboken\n\n33349201\n10.1177/2050640620976991\nUEG212046\nOriginal Article\nHepatobiliary\nInflammatory patterns in plasma associate with hepatocellular carcinoma development in cured hepatitis C cirrhotic patients\nOwusu Sekyere Solomon 1 2\nPort Kerstin https://orcid.org/0000-0001-8338-3227\n1\nDeterding Katja 1 3\nCornberg Markus 1 4\nWedemeyer Heiner 1 3 4 5 Wedemeyer.Heiner@mh-hannover.de\n\n1 Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany\n2 Paul‐Ehrlich‐Institut Federal Institute for Vaccines and Biomedicines Langen Germany\n3 Department of Gastroenterology and Hepatology Essen University Hospital Essen Germany\n4 German Center for Infection Research (DZIF) Partner‐site Hannover‐Braunschweig Braunschweig Germany\n5 Integrated Research and Treatment Centre Transplantation (IFB‐Tx) Hannover Medical School Hannover Germany\n* Correspondence\nHeiner Wedemeyer, Department of Gastroenterology, Hepatology and Endocrinology OE6810, Carl‐Neuberg‐Str. 1, 30625 Hannover, Germany.\nEmail: Wedemeyer.Heiner@mh-hannover.de\n\n18 2 2021\n5 2021\n9 4 10.1002/ueg2.v9.4 486496\n30 6 2020\n31 10 2020\n© 2020 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ 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.\n\nAbstract\n\nIntroduction\n\nThe risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon‐free direct‐acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance.\n\nObjective\n\nHere, we aimed at evaluating the effects of direct‐acting antiviral therapy‐induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct‐acting antiviral‐mediated hepatitis C clearance in cirrhosis patients was investigated.\n\nMethods\n\nEmploying multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct‐acting antiviral treatment.\n\nResults\n\nElevated pretherapy concentrations of specific soluble immune mediators including MCP‐3, GDNF, CDCP1, IL‐17C, IL‐17A, signalling lymphocytic activation family 1, CCL11, FGF‐5, LIF‐R, interleukin 10 (IL‐10), IL‐10RA, IL‐15RA, beta NGF, CCL28, CCL25 and NT‐3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF‐5 and IL‐15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma‐free patients experienced significant ameliorations.\n\nConclusions\n\nThese results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct‐acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct‐acting antiviral therapies would be superior to the risk of developing carcinoma.\n\nKey Summary\n\nEstablished knowledge on this subject\n\nCurrent interferon (IFN)‐free direct‐acting antivirals (DAAs) are effective at eliminating hepatitis C virus (HCV), but risks of residual liver disease and development of hepatocellular carcinoma persists.\n\nThe hepatic inflammation that occurs during chronic hepatitis C causes systemic changes in blood soluble immune mediators (SIMs) that impact carcinogenetic processes involved in the growth, invasion and metastasis of hepatocellular carcinoma (HCC).\n\nDAA‐induced HCV cure does not lead to a complete immunological restitution of the altered soluble inflammatory compartment in chronic hepatitis C.\n\nSignificant and/or new findings of this study\n\nAn elevated pre‐therapy plasma profile of an extended repertoire of SIMs in cirrhosis was associated with HCC development post‐DAA therapy.\n\nSuccessful DAA therapy did not alter the baseline elevated plasma SIM profile of cirrhosis patients that developed post‐therapy HCC contrary to its effect in those that remained HCC‐free.\n\nchemokines\ncytokines\ndirect‐acting antivirals\nhepatitis C\nhepatitis C virus cirrhosis\nhepatocellular carcinoma\ninterferon‐free therapy\nsoluble immune mediators\nCenter for Research Grants SFB900 ‘Chronic Infections: Microbial Persistence and its Control’ SFB 738 of the German Research Foundation (DFG) source-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:06.07.2021\n==== Body\n1 INTRODUCTION\n\nHepatocellular carcinoma (HCC) still emerges in some patients despite clearance of hepatitis C virus (HCV) upon successful antiviral therapy. This has been shown not only for interferon (IFN)‐based therapies 1 but also for therapies using IFN‐free direct‐acting antiviral (DAA) regimens. 2 Several studies have demonstrated that HCV cure by IFN‐free DAA therapy does not seem to alter the short‐term risk of HCC emergence, as it tends to remain still high, particularly in patients with established liver cirrhosis. 3 , 4 , 5 , 6 There have been further concerns as to whether the risk of HCC recurrence may even be increased following IFN‐free HCV therapy with DAAs. 7 A need thus exists to evaluate whether, and to what extent, HCC development is impacted by hepatic immune events in cirrhosis patients who receive IFN‐free DAA therapy.\n\nPreliminary reports provided an indication of a possible association between serum levels of distinct cytokines and the development of HCC. 8 , 9 Specifically, HCV clearance by IFN‐free DAA therapy was reported to coincide with the induction of a rapid reduction in inflammation but increase in key HCC angiogenesis drivers such as the vascular endothelial growth factor (VEGF); an immune balance modification that may affect the anti‐tumour surveillance machinery. 9\n\nFurther, a potential pretreatment modification of a repertoire of soluble immune mediators in the serum of patients who eventually developed de novo HCC upon DAA therapy compared to controls was reported. 8 This gave an early indication that a skewed balance of mediators within the inflammatory milieu existent before DAA therapy may contribute to the post‐DAA therapy emergence of HCC. The basis for this observation could perhaps be grounded in findings from a previous report that implicated specific soluble immune mediators (SIMs) as being involved in carcinogenetic processes that impact growth, invasion and metastasis of HCC; the cancer which occurs almost exclusively in inflamed livers. 10 Further to this, we recently showed that SIM‐mediated immune surveillance of HCC may be important for HCC development. 11 Based on this background, we here aimed to address specific SIM‐phenotype associations that impact the odds of HCC development and the related changes that ensue upon IFN‐free therapy‐mediated HCV clearance in cirrhosis patients.\n\n2 MATERIALS AND METHODS\n\n2.1 Patient population\n\nIn this study, we enrolled a total of 31 patients with baseline HCV‐related liver cirrhosis who had undergone IFN‐free hepatitis C therapy with DAAs at the liver outpatient clinic of Hannover Medical School (MHH). The criteria of cirrhosis diagnosis were based on liver histology (F5 and F6 according to ISHAK [modified Knodell score]), transient elastography (>14.5 kPa), and definite morphological signs in ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) as detailed previously. 3 All patients had no coexistent chronic inflammatory disease(s) or any known cancers other than HCC. Of these patients, 15 were those who had developed posttreatment HCC at some point during treatment or within a 24‐weeks follow‐up period (herein referred to as Cirrh‐to‐HCC). Control groups including 16 age‐matched patients who remained HCC‐free upon therapy (herein referred to as Cirrh‐to‐NoHCC) and 10 healthy individuals were also recruited. All patients were HCC‐free by ultrasound, CT or MRI technology before therapy start. In furtherance, an HCC emergence surveillance schedule was routinely done upon therapy initiation for all patients during antiviral therapy and during a 6‐month follow‐up period. This surveillance schedule involved ultrasound imaging routinely performed at 3‐month intervals during antiviral therapy and 6 months after therapy. This surveillance schedule is borne out of routine clinical practice at our centre. The Cirrh‐to‐HCC patients included four recurrences and 11 de novo cases. Overall, no analysed clinical parameter statistically differentiated the two stratified cohorts of HCC or HCC‐free from each other. While the Cirrh‐to‐HCC patients had a median albumin, platelets, bilirubin, aspartate aminotransferase, alanine aminotransferase and fibroscan of 32 g/L, 102 tsd/il, 16 imol/l, 99 U/L, 59 U/L, 27.40 kPa, respectively, the Cirrh‐to‐NoHCC had these measures at 32 g/L, 90 tsd/il, 18 imol/L, 75 U/L, 87 U/L, 21.50 kPa, respectively.\n\nCharacteristics of patient cohorts and a description of the different DAA regimens for treatment according to international guidelines (HCV guidelines, European Association for the Study of the Liver, American Association for the Study of Liver Diseases) have been detailed in Table 1.\n\nTABLE 1 Individual patient characteristics\n\nPatient\tSex\tAge\tHCV gen.\tBaseline MELD score\tChild\tDAA regimen\tTreatment outcome\tHCC status\tTime from initial HCC diagnosis to DAA therapy start (months)\tHCC treatment prior DAA therapy\tTime to HCC after DAA therapy (months)\tCharacteristics of current HCC\tHCC treatment after DAA\t\nHCC 1\tM\t80\t1b\t9\tA6\tSOF/LDV\tSVR\tRecurrence\t23\tRFA, PEI\t1\t1 Nodule, 30 mm, BCLC A2\tAtypical liver resection\t\nHCC 2\tM\t65\t1a\t9\tA6\tSOF/LDV/RBV\tSVR\tDe novo\tn/a\tn/a\t1.5\t1 Nodule, 23 mm, BCLC A2\tRFA\t\nHCC 3\tF\t47\t1b\t7\tB7\tSOF/SIM\tSVR\tDe novo\tn/a\tn/a\t2\t1 Nodule, 24.6 mm, BCLC A4\tLiver segment resection\t\nHCC 4\tM\t63\t1a\t10\tA5\tSOF/RBV\tSVR\tDe novo\tn/a\tn/a\t3\t1 Nodule, 26.3 mm, BCLC A3\tMicrowave ablation\t\nHCC 5\tM\t61\t3a\t14\tB7\tSOF/RBV\tRelapse\tDe novo\tn/a\tn/a\t4\t1 nodule, 24 mm, BCLC A3\tTACE, RFA\t\nHCC 6\tM\t77\t1b\t10\tB7\tAbb3D/RBV\tSVR\tRecurrence\t23\tRFA\t10\t1 Nodule, 6.7 mm, BCLC A2\tRFA\t\nHCC 7\tF\t51\t1a\t8\tA5\tSOF/RBV\tRelapse\tRecurrence\t4\tRFA, TACE\t12\t4+ Nodules, >30 mm, BCLC B\tTACE, RFA 4 months later\t\nHCC 8\tM\t50\t3a\t20\tC12\tSOF/RBV\tRelapse\tDe novo\tn/a\tn/a\t22\t2 Nodules, 12.2 mm, BCLC A4\tRFA\t\nHCC 9\tF\t54\t1a\t11\tB8\tSOF/LDV/RBV\tSVR\tDe novo\tn/a\tn/a\t9\t1 Nodule, 42 mm, BCLC A2\tTACE\t\nHCC 10\tM\t62\t1b\t7\tA6\tSOF/LDV\tSVR\tDe novo\tn/a\tn/a\t0.5\t1 Nodule, 28 mm, BCLC Al\tAtypical liver resection\t\nHCC 11\tM\t51\t1a\t8\tA6\tSOF/RBV\tSVR\tDe novo\tn/a\tn/a\t23\t1 Nodule, 87 mm, BCLC C\tNone\t\nHCC 12\tF\t74\t1b\t8\tA5\tSOF/DAC\tSVR\tDe novo\tn/a\tMWA\tn/a\t1 Nodule, 15 mm, BCLC 0\tPEI\t\nHCC 13\tM\t71\t1a\t8\tA6\tSOF/LDV\tSVR\tRecurrence\t8\tTACE\tn/a\tMultilocular, BCLC B\tTACE\t\nHCC 14\tM\t61\t1b\t7\tA5\tAbb3D/RBV\tPartial‐ response\tDe novo\tn/a\tn/a\t4\t1 Nodule, 12 mm, BCLC 0\tAtypical liver resection\t\nHCC 15\tM\t46\t3a\t15\tB8\tSOF/RBV\tRelapse\tDe novo\tn/a\tn/a\t24\t2 Nodules, max. 20 mm, BCLC A4\tTACE\t\nControl Cirrh‐to‐NoHCC Patients\t\t\t\t\t\t\t\t\t\t\t\t\t\t\nCirrh 1\tM\t59\tlb\t13\tB9\tSOF/SIM\tSVR\t\t\t\t\t\t\t\nCirrh 2\tM\t68\tlb\t11\tA5\tSOF/RBV\tSVR\t\t\t\t\t\t\t\nCirrh 3\tF\t68\t1b\t7\tA5\tSOF/RBV\tSVR\t\t\t\t\t\t\t\nCirrh 4\tM\t48\t1a\t9\tA5\tSOF/SIM\tSVR\t\t\t\t\t\t\t\nCirrh 5\tF\t53\t1b\t11\tA6\tSOF/SIM\tSVR\t\t\t\t\t\t\t\nCirrh 6\tM\t53\t3a\t12\tA5\tSOF/RBV\tSVR\t\t\t\t\t\t\t\nCirrh 7\tM\t59\t1a\t11\tA6\tHAR + RBV\tSVR\t\t\t\t\t\t\t\nCirrh 8\tM\t54\t1b\t9\tA5\tSOF/DAC\tSVR\t\t\t\t\t\t\t\nCirrh 9\tF\t46\t3a\t10\tA6\tSOF/RBV\tSVR\t\t\t\t\t\t\t\nCirrh 10\tF\t61\t1b\t9\tB7\tSOF/RBV\tSVR\t\t\t\t\t\t\t\nCirrh 11\tF\t64\t1b\t10\tA6\tAbb3D/RBV\tSVR\t\t\t\t\t\t\t\nCirrh 12\tF\t63\t1b\t8\tB7\tAbb3D/RBV\tSVR\t\t\t\t\t\t\t\nCirrh 13\tM\t63\t1b\t7\tA5\tHAR + RBV\tSVR\t\t\t\t\t\t\t\nCirrh 14\tM\t42\t1b\t8\tA5\tHAR + RBV\tSVR\t\t\t\t\t\t\t\nCirrh 15\tM\t41\t1a\t8\tA6\tHAR\tSVR\t\t\t\t\t\t\t\nCirrh 16\tF\t56\t3\t‐\tB\tSOF/RBV/plFN\tSVR\t\t\t\t\t\t\t\nAbbreviations: BCLC, Barcelona clinic liver cancer; Cirrh‐to‐NoHCC, cirrhosis not developing HCC; DAA, direct‐acting antiviral; DAC, daclatasvir; gen., genotype; HAR, harvoni; HCC, hepatocellular carcinoma; LDV, ledipasvir; MELD, Model for End‐stage Liver disease; MWA, microwave ablation; n/a, not applicable; PEI, percutaneous ethanol injection; RBV, ribavirin; RFA, radiofrequency ablation; SIM, simeprevir; SOF, sofosbuvir; SVR, sustained virologie response; TACE, transcatheter arterial chemoembolization.\n\n2.2 Measurement of plasma SIM concentrations\n\nWe performed multianalyte plasma SIM profiling employing a multiplex technology (Olink's Proseek Multiplex Inflammation), which simultaneously measured the expression of 91 multiple biomarker proteins (Table S1), based on a proximity extension assay. The precision, reproducibility and scalability of this SIM measurement technology have been previously described. 12 , 13 , 14 Plasma SIM concentrations of patients were analysed at baseline, and longitudinally at the end of therapy and follow‐up of therapy as detailed in the Supporting Information Material. The precise time‐points at which plasma were sampled and used for SIM assessments is detailed in Table S2. Based on a standardised limit of detection, a total of 17 proteins that had a missing data frequency of more than 45% were excluded from the analysis.\n\n2.3 Statistical analyses\n\nData were analysed using the GraphPad Prism software (GraphPad Software) or Microsoft Excel (for spider graphs). Quantitative analyses were done using the Student' t test or the Mann–Whitney test according to the distribution of data. For multiple comparisons, one‐way analysis of variance with a posttest correction was used. Multiple t tests were controlled using the false‐discovery rate (FDR) correction approach, with a desired FDR (Q) of 10%. In general, p < 0.05 were considered to be statistically significant. The statistical test used for each analysis is detailed in the respective figure legends.\n\n3 RESULTS\n\n3.1 Pretherapy‐elevated plasma SIM profiles characterised cirrhosis patients that developed HCC upon DAA therapy\n\nCircumventing the low throughput of conventional methods, we here applied the innovative Proseek multiplex technology to profile multiple SIMs (n = 91) in the plasma of cirrhosis patients who either developed HCC (Cirrh‐to‐HCC) or remained HCC‐free (Cirrh‐to‐ NoHCC) following HCV treatment with current IFN‐free DAAs. Upon a comparison of SIM concentrations at baseline, we observed a similar pattern of expression between Cirrh‐to‐HCC and Cirrh‐to‐NoHCC patients relative to normal values. Thus, compared to healthy individuals, SIMs that were upregulated, downregulated or remained unaltered occurred in a similar manner between the two cohorts (Figure 1a). Generally, most (i.e., over 50%) of the SIMs analysed here displayed superior mean plasma concentrations at this time‐point in the patients with baseline cirrhosis irrespective of their HCC status following treatment. Interestingly however, we identified a set of 16 SIMs including MCP‐3, GDNF, CDCP1, interleukin (IL) 17C (IL‐17C), IL‐17A, signalling lymphocytic activation family 1 (SLAMF1), CCL11, fibroblast growth factor‐5 (FGF‐5), LIF‐R, IL10, IL‐10RA, IL‐15RA, beta NGF, CCL28, CCL25 and NT‐3 that were present at significantly higher concentrations in the Cirrh‐to‐HCC patients after correcting for multiple comparisons.\n\nFIGURE 1 Plasma concentrations of soluble immune mediators (SIMs) at baseline. (a) Comparative pretherapy SIM concentrations of cirrhosis developing hepatocellular carcinoma (Cirrh‐to‐HCC) and cirrhosis not developing hepatocellular carcinoma (Cirrh‐to‐NoHCC) patients relative to healthy controls. Significant variables are indicated in red. (b) Representative graphs of individual SIMs with increased concentrations at baseline in Cirrh‐to‐HCC patients with statistical p ≥ 0.005. (c) Individual SIMs that displayed significantly lower concentrations at baseline in the Cirrh‐to‐HCC compared to Cirrh‐to‐NoHCC cohort\n\n(Figure 1a,b). In addition, FGF‐23, FGF‐19, MMP‐10 and Flt3L displayed a trend of superior pretherapy plasma concentration in the Cirrh‐to‐HCC cohort. We further discovered IL‐12B (an upregulated SIM) and the stem cell factor (scF) (a downregulated SIM) as the only two SIMs that were rather significantly lower in the Cirrh‐to‐HCC compared to the Cirrh‐to‐NoHCC cohort (Figure 1c).\n\nFurther calculating the area under the receiver operating characteristic curves (AUROCs), three of the 16 elevated SIMs showed values above 0.80 (Figure 2a). We further evaluated the potential correlation between baseline plasma SIM levels and the emergence of recurrence and de novo HCC upon DAA treatment initiation. Overall, nine of the 16 SIMs (i.e., GDNF, IL‐17A, IL‐15RA, SLAMF1, CCL11, IL10‐RA, LIF‐R, IL10, CCL28) that showed elevated concentrations in the Cirrh‐to‐HCC patients together with other SIMs such as CCL4 and the delta and Notch‐like epidermal growth factor‐related receptor were particularly present at higher concentrations at baseline in the patients that developed de novo HCC (Figure 2b). Here too, the three SIMs that displayed an AUROC above 0.8 were GDNF (0.9156), IL‐10RA (0.8071) and IL‐15RA (0.8121) (data not shown). Notably, while SIMs such as CCL25, CDCP1 and IL‐17C were significantly higher in both recurrence and de novo HCC (Figure 2c), the plasma concentrations of IL‐17C and the FGF‐5 and FGF‐23 were particularly higher in recurrence HCC with FGF‐5 in particular having an AUROC of 9333 (Figure 2d).\n\nFIGURE 2 Association between baseline plasma soluble immune mediator (SIM) levels and the emergence of posttherapy hepatocellular carcinoma (HCC). (a) Area under the receiver operating characteristic curve (AUROC) of markers of HCC development with values of >0.800 as compared to non‐HCC control group. (b) Baseline plasma SIMs with concentrations higher exclusively in de novo HCC. (c) Plasma SIMs at baseline that showed concentrations significantly higher in both recurrence and de novo HCC alike. (d) Baseline SIM concentrations higher exclusively in recurrence HCC\n\n3.2 Successful DAA therapy did not alter the baseline plasma SIM profiles in cirrhosis patients that developed posttherapy HCC\n\nTo further assess the possible existence of a differential regulation of distinct SIMs during IFN‐free treatment of hepatitis C in relation to HCC emergence, we studied the plasma SIM kinetics in the two Cirrh‐to‐HCC and Cirrh‐to‐NoHCC patient cohorts (Figure 3). Plasma were longitudinally sampled at baseline (therapy start), end‐of‐therapy and follow‐up (i.e., at least 12 weeks postsustained virologic response [SVR]) and the concentrations of the described SIMs measured. Patient Cirrh‐16 who had received IFN‐based therapy was exclude from the analysis. Patients Cirrh‐15, HCC‐1, HCC‐9 and HCC‐14 for whom no plasma samples were available at end‐of‐therapy and/or follow‐up were also excluded from the analysis. We observed that while the HCC‐free control cohort experienced significant therapy‐mediated SIM reductions of some n = 38 SIMs at end‐of‐therapy and/or follow‐up (Figure 3b), those in the eventual HCC developers remained fairly stable with only 16 SIMs experiencing relatively partial but significant reductions (Figure 3a,b). But for GDNF which dipped at end‐of‐therapy and even restored at follow‐up, the SIMs that showed comparatively elevated pretreatment concentrations in the Cirrh‐to‐HCC patients remained stable all through the treatment period as well as follow‐up (Figure 3a). In both cohorts, SCF, FGF‐21 and FGF‐23 showed significant increments upon therapy. Aside from the relatively reduced reductions in the plasma SIM concentrations of the Cirrh‐to‐HCC patients following DAA therapy, there were a considerable number of other SIMs (CCL25, TGF‐alpha, CCL23, CST5, IL15RA, beta‐NGF and FGF‐5) that rather trended upwards compared to their counterparts in the Cirrh‐to‐NoHCC patients.\n\nFIGURE 3 Effect of interferon (IFN)‐free direct‐acting antiviral (DAA) therapy on plasma soluble immune mediator (SIM) levels. Fold changes in plasma SIM concentrations of the cirrhosis patient cohorts that upon DAA therapy either developed HCC (Cirrh‐to‐HCC) or remained without any HCC (Cirrh‐to‐NoHCC) were calculated at end‐of‐therapy (EOT) and follow‐up (FU) time‐points in reference to baseline values. (a) Plasma SIM kinetics of Cirrh‐to‐HCC patients from therapy start (TS) through EOT to FU. (b) Plasma SIM kinetics of Cirrh‐to‐NoHCC patients from TS through EOT to FU. A one‐way analysis of variance with the recommended Geisser–Greenhouse correction was used for statistical evaluations. Significant variables are indicated in red\n\nThe few SIMs that appeared normalised in the Cirrh‐to‐HCC cohort seemed to emanate from the de novo rather than the recurrence HCC subgroup (data not shown). These results highlight an overall nonperturbation of the soluble immune compartment in patients who developed HCC contrary to those who remained HCC‐free upon DAA treatment.\n\n4 DISCUSSION\n\nIn this plasma screening of a large repertoire of SIMs relative to HCC emergence upon IFN‐free therapy for hepatitis C, we showed that a spectrum of pretreatment SIM expressions were highly elevated in patients who later developed HCC and distinguished them from those who did not. Furthermore, pretreatment SIM levels could differentiate de novo from recurrence of HCC emergence. Finally, we demonstrated for the first time that alteration in the inflammatory patterns during IFN‐free HCV therapy differ in significant proportions between Cirrh‐to‐HCC and Cirrh‐to‐ NoHCC patients.\n\nChronic unresolved inflammation is known to promote and exacerbate malignancies. A clear example is HCC, which has over 90% of its cases arising in the context of liver injury and inflammation. Our study here suggests a pre‐existing hyperactivated profile in Cirrh‐to‐HCC patients as evidenced by elevated baseline concentrations of a myriad of SIMs. To the best of our knowledge, these findings show for the first time that elevated pretherapy SIM concentrations (such as those of GDNF, FGF‐5 and IL‐15RA) could serve as independent predictive biomarkers for HCC emergence, and distinguish Cirrh‐to‐HCC from Cirrh‐to‐ NoHCC patients regardless of de novo or recurrence classification. A prior example suggestive of an association between pretherapy serum SIM levels and the emergence of de novo HCC upon DAA treatment in patients with HCV infection has recently been shown. 15 Our data here drawn from Olink's innovative multiplex technology fairly confirms this observation, although with a different set of SIMs aside eotaxin (CCL11). This study thus extends the spectrum of SIMs whose baseline concentrations and possible networks could be linked with HCC emergence in cirrhosis patients receiving DAA therapy for hepatitis C. Whether the activated immune system is a cause or consequence of therapy‐related HCC emergence is an intriguing concern. The results from our data here however seem to suggest the latter as the more plausible option. The elevated pretreatment SIM profile existent before the induction of any therapy‐mediated immune changes could indicate a systemic response of already ongoing immune surveillance against early malignant lesions. This systemic inflammation could in turn lead to tumour‐specific CD8+ T‐cell functional exhaustion, or inhibition as exemplified by the increased pretherapy anti‐inflammatory cytokine IL‐ 10. IL‐10 is a critical immune regulatory molecule, which can deregulate cytokine production and T‐cell proliferation and has a modulatory effect on hepatic fibrinogenesis. 16 , 17 In the midst of the pretherapy hyper‐immune profile which characterised the Cirrh‐to‐HCC patients, the concomitant elevated levels of IL‐10 and its receptor IL10RA at baseline was not surprising. In this setting, IL‐10 levels may play a role in tuning the prevailing proinflammatory SIM ensemble whiles its engagement with elevated IL10RA may directly inhibit CD8+ T‐cell function as shown before 18 and tilts the existing HCC antitumour T‐cell surveillance establishment out of balance. Together with the notable reduction in the immuno‐stimulatory cytokine IL‐12B, this may culminate in the reduced functionality of HCC‐specific immune‐surveilling T cells, which may favour HCC progression, as we demonstrated recently. 11 This assertion lends credence from evidence suggesting that tumour cells have the capacity to secrete distinct SIMs to foster their growth and metastasis as well as subverting hosts' immune anti‐tumour reactions. 19 , 20\n\nAside from IL‐10, the SLAM molecules are known for their roles in regulating immune responses, pathophysiology of neoplasm transformations and entry pathways of certain viruses. 21 Recently, SLAM molecules have come to the fore for their potential in diagnosis and therapy of various cancers. The SLAMF1 in particular is the prototype member of the SLAM family of molecules that initiates signal transduction networks in many immune cells including T and B cells, dendritic cells, monocytesmacrophages, natural killer cells and natural killer T cells that constitutively express them, thus modulating their activation and differentiation. 22 , 23 , 24 In patients with colon cancer, for example, upregulation or silencing of SLAMF1 expressed in lymphocytes was reported to be accompanied by increased or reduced lymphocytic cytotoxic activity, respectively. 25 In our Cirrh‐to‐HCC patient cohort, the elevated SLAMF1 profile existent before DAA therapy initiation was an interesting observation in this regard. On the one hand, it fits very well into our assertion that the elevated SIM profile (as exemplified by SLAMF1) and characteristic systemic inflammation, may be a response to occult HCC in the liver. However, the characteristically higher SLAMF1 level in the patients who developed de novo relative to recurrence HCC and the observation that SLAMF1 levels stayed unaltered upon DAA therapy widen the dimension of plausible conclusions, and warrants further investigation.\n\nFurthermore, assessing the potential immune correlates of IFN‐free therapy‐mediated HCV clearance with emergence of HCC by analysing longitudinal SIM kinetics, we confirmed our earlier report that innate SIM immunity may not necessarily normalise but experience strong reduction in the levels of specific SIMs in the cirrhosis control cohort that did not develop HCC. 26 Previous studies had reported a similar decline in the mean levels of the SIMs IP‐10, MCP‐1, MIP‐1ß, IL‐18 19 and also of CCL‐2, CCL‐3, CCL‐4, CXCL‐8, CXCL‐10, IL‐1b, IL‐15, IFN‐y, IL‐4, IL‐10, TGF‐b, FGFb and PAI‐1 20 following IFN‐free antiviral therapy in patients with chronic hepatitis C.\n\nStrikingly, however, no significant changes of such magnitude were observed in the cirrhosis patients who were treated with DAAs and eventually developed HCC. This relatively sustained release of specific SIMs in these patients indicates independent activation of the immune system of the HCV infection in such a setting. It further entrenches the assertion that the systemic inflammation may be a response to occult HCC in the liver as we earlier opined. On another score, it may be indicative of the mechanistic involvement of distinct SIMs in the emergence of HCC. This is of interest given the proven dysregulatory activity pretherapy SIMs such as MCP‐3, GDNF, SLAMF1, CCL11, CCL25, beta NGF and NT‐3 may have on the mitogen‐activated protein kinase pathway. Further studies are thus required to address the paradox of whether the unaltered SIM expression is a cause or consequence of HCC development upon DAA therapy of hepatitis C.\n\nOn several scores, our findings in this study confirm and extend previous reports, especially by Debes et al. 8 and Villani et al. 9 However, one notable exception deserves a mention. The kinetics of plasma VEGF levels which were reported to be elevated until end‐of‐therapy before it normalised at SVR12 in chronic hepatitis C patients receiving IFN‐free DAA therapy could not be confirmed. In our observation, VEGFA levels significantly declined in the cirrhosis patients that remained HCC‐free posttherapy at both end‐of‐therapy and follow‐up contrary to the unaltered levels in the patients who eventually developed HCC posttherapy, suggesting an association between VEGFA levels and HCC growth. On the contrary, other growth factors such as FGF‐21, FGF‐23 and SCF significantly increased in both cohorts in coincidence with HCV clearance whilst TGF‐alpha, FGF‐5, beta‐ NGF and other mediators such as IL‐15RA, CCL25, CCL23 and CST5 all trended upwards exclusively in the Cirr‐to‐HCC cohort. The differences in observations could stem from the difference in sample size, peculiar cohort characteristics and the contributory role of the other members of the VEGF family that were nondiscriminatorily measured in Villani et al. 9 compared to our assay which measured only VEGFA.\n\nOur study has obvious strengths and limitations. The major strengths include the (a) prospective collection of samples, (b) large panel of SIMs analysed, (c) unbiased approach of SIM profiling and (d) homogeneous treatment cohort and follow‐up for screening. Notwithstanding, the number of HCC cases which still remains small and the accompanying small fractions of recurrence and de novo cases are the notable limitations. As a next step in this project, we aim to conduct a large prospective dedicated study, which will address the shortcomings of these findings and thus provide a better insight into the pretherapy HCC immuno‐surveillance establishment and the changes it experiences following DAA‐induced HCV cure.\n\nIn summary, we discovered that the pretreatment activation profile of the soluble immune compartment as measured by highly elevated SIM patterns correlates with posttherapy HCC development. We further demonstrate how the elevated SIM establishment existent before DAA therapy stays unperturbed upon DAA therapy in patients who develop posttherapy HCC contrary to those who remain HCC‐free. These findings provide an important basis for a potential build‐on to unravel cases where the benefit of DAA therapies would be unequivocally superior to the risk of developing HCC. Attainment of this feat would potentially contribute to improving the management of HCC and the quality of life of patients with chronic hepatitis C.\n\nCONFLICT OF INTERESTS\n\nSolomon O. Sekyere and Kerstin Port have no conflicts of interest to declare. Katja Deterding has received lecture fees from Gilead, AbbVie and Merck. Markus Cornberg has received lecture fees from AbbVie, Bristol‐Myers Squibb, Boehringer Ingelheim Pharma, Gilead, Janssen‐Cilag, MSD Sharp & Dohme/Merck, Roche Diagnostic, Roche Pharma and Siemens; advisory board fees from AbbVie, Bristol Myers Squibb, Boehringer Ingelheim Pharma, Gilead, Roche Diagnostic and Roche Pharma; and data safety board fees from Janssen‐Cilag. Heiner Wedemeyer has received grants from AbbVie, Gilead, Roche, Roche Diagnostics, Abbott, Myr and Eiger, and consulting fees or honoraria from AbbVie, Abbott, BMS, Boehringer Ingelheim, Eiger, Gilead, Janssen, Novartis, MSD/Merck, Roche, Roche Diagnostics and Transgene. In addition, Heiner Wedemeyer has received money for board memberships from AbbVie, Abbott, BMS, Boehringer, Eiger, Gilead, Myr, Novartis and Roche; honoraria for consultancy or speaking from Eiger, Janssen, Siemens, Abbott, AbbVie, Biolex, BMS, Boehringer Ingelheim, ITS, JJ/Janssen‐Cilag, Medgenics, Merck/Schering‐Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV; and for lectures, including service on speakers' bureaus, from the Falk Foundation and OmnisMed.\n\nETHICS APPROVAL\n\nThe study protocol was approved in year 2014 by the ethics committee of Hannover Medical School (Study numbers: 2148‐2014 and 2604‐2014) and conducted as per the Helsinki declaration. All patients who participated in this study gave their written informed consent. All patients who participated in this study gave their written informed consent.\n\nSupporting information\n\nSupplementary Material 1\n\nClick here for additional data file.\n\nSupplementary Material 2\n\nClick here for additional data file.\n\nSupplementary Material 3\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nThe authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by the Center for Research Grants SFB900 ‘Chronic Infections: Microbial Persistence and its Control’ and SFB 738 of the German Research Foundation (DFG). The authors wish to thank all of the participants who volunteered in this project. They are also very grateful to all the physicians and study nurses at the liver outpatient clinic of Hannover Medical School. Finally, the authors appreciate the work of Olink Proteomics, Uppsala, Sweden in their innovative Proseek methodology for the plasma soluble immune mediator measurements and for their data validation service. The authors of this study contributed as follows: conceptualisation—Solomon O. Sekyere and Heiner Wedemeyer; methodology—Solomon O. Sekyere and Heiner Wedemeyer; Olink Proteomics, Uppsala, Sweden; software—Solomon O. Sekyere; Kerstin Port; validation—Solomon O. Sekyere, Heiner Wedemeyer; Olink Proteomics; formal analysis—Solomon O. Sekyere, Heiner Wedemeyer; investigation—Solomon O. Sekyere; resources—Heiner Wedemeyer, Markus Cornberg, Katja Deterding; data curation—Solomon O. Sekyere, Kerstin Port; writing (original draft preparation)—Solomon O. Sekyer; writing (review and editing)—Solomon O. Sekyere, Kerstin Port, Katja Deterding and Heiner Wedemeyer; visualisation—Solomon O. Sekyere and Heiner Wedemeyer; supervision—Heiner Wedemeyer; funding acquisition—Heiner Wedemeyer. The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was supported by the Center for Research Grants SFB900 ‘Chronic Infections: Microbial Persistence and its Control’ and SFB 738 of the German Research Foundation (DFG).\n==== Refs\nREFERENCES\n\n1 van der Meer AJ , Wedemeyer H , Feld JJ , et al. Is there sufficient evidence to recommend antiviral therapy in hepatitis C? J Hepatol. 2014;60 :191–6.23973931\n2 Colombo M , Boccaccio V . HCV therapy and risk of liver cancer recurrence: who to treat? Nat Rev Gastroenterol Hepatol. 2018;15 :392–3.29752455\n3 Ioannou GN , Green PK , Berry K . HCV eradication induced by direct‐acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol. 2017;68 :25–32.\n4 Kanwal F , Kramer J , Asch SM , et al. Risk of hepatocellular cancer in HCV patients treated with direct‐acting antiviral agents. 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Gastroenterology. 2017;154 :515–7.e3.29102620\n9 Villani R , Facciorusso A , Bellanti F , et al. DAAs rapidly reduce inflammation but increase serum VEGF level: a rationale for tumor risk during anti‐HCV treatment. PLoS One. 2016;11 .e0167934 27997563\n10 Capone F , Costantini S , Guerriero E , et al. Serum cytokine levels in patients with hepatocellular carcinoma. Eur Cytokine Netw. 2010;21 :99–104.20478763\n11 Owusu Sekyere S , Schlevogt B , Mettke F , et al. HCC immune surveillance and antiviral therapy of hepatitis C virus infection. Liver Cancer. 2019;8 :41–65.30815394\n12 Assarsson E , Lundberg M , Holmquist G , et al. Homogenous 96‐plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One. 2014;9 .e95192 24755770\n13 Lundberg M , Eriksson A , Tran B , et al. Homogeneous antibody‐based proximity extension assays provide sensitive and specific detection of low‐abundant proteins in human blood. Nucleic Acids Res. 2011;39 :e102.21646338\n14 Thorsen SB , Lundberg M , Villablanca A , et al. Detection of serological biomarkers by proximity extension assay for detection of colorectal neoplasias in symptomatic individuals. J Transl Med. 2013;11 :253.24107468\n15 Debes JD , de Knegt RJ , Boonstra A . The path to cancer and back: immune modulation during hepatitis C virus infection, progression to fibrosis and cancer, and unexpected roles of new antivirals. Transplantation. 2017;101 :910–5.28045877\n16 Couper KN , Blount DG , Riley EM . IL‐10: the master regulator of immunity to infection. J Immunol. 2008;180 :5771–7.18424693\n17 de Souza‐Cruz S , Victoria MB , Tarrago AM , et al. Liver and blood cytokine microenvironment in HCV patients is associated to liver fibrosis score: a proinflammatory cyto‐kine ensemble orchestrated by TNF and tuned by IL‐10. BMC Microbiol. 2016;16 :3.26742960\n18 Smith LK , Boukhaled GM , Condotta SA , et al. Interleukin‐10 directly inhibits CD8(+) T cell function by enhancing N‐glycan branching to decrease antigen sensitivity. Immunity. 2018;48 :299–312.e5.29396160\n19 Carlin AF , Aristizabal P , Song Q , et al. Temporal dynamics of inflammatory cytokines/chemokines during sofosbuvir and ribavirin therapy for genotype 2 and 3 hepatitis C infection. Hepatology. 2015;62 :1047–58.26147061\n20 Saraiva GN , do Rosario NF , Medeiros T , et al. Restoring inflammatory mediator balance after sofosbuvir‐induced viral clearance in patients with chronic hepatitis C. Mediat Inflamm. 2018;2018 :8578051.\n21 Fouquet G , Marcq I , Debuysscher V , et al. Signaling lymphocytic activation molecules Slam and cancers: Friends or foes? Oncotarget. 2018;9 :16248–62.29662641\n22 van Driel BJ , Liao G , Engel P , et al. Responses to microbial challenges by SLAMF receptors. Front Immunol. 2016;7 :4.26834746\n23 Wu N , Veillette A . SLAM family receptors in normal immunity and immune pathologies. 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"issn_linking": "2050-6406",
"issue": "9(4)",
"journal": "United European gastroenterology journal",
"keywords": "chemokines; cytokines; direct-acting antivirals; hepatitis C; hepatitis C virus cirrhosis; hepatocellular carcinoma; interferon-free therapy; soluble immune mediators",
"medline_ta": "United European Gastroenterol J",
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"nlm_unique_id": "101606807",
"other_id": null,
"pages": "486-496",
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"pmid": "33349201",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26834746;24755770;26682762;24107468;20478763;28887168;30815394;29752455;26147061;29662641;29977152;27683821;29729453;23973931;28045877;17692919;27997563;18424693;28642197;26742960;21646338;29102620;29396160;27084592;29035002;29205405",
"title": "Inflammatory patterns in plasma associate with hepatocellular carcinoma development in cured hepatitis C cirrhotic patients.",
"title_normalized": "inflammatory patterns in plasma associate with hepatocellular carcinoma development in cured hepatitis c cirrhotic patients"
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"abstract": "OBJECTIVE\nImmune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors.\n\n\nMETHODS\nDetailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed.\n\n\nRESULTS\nObjective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold.\n\n\nCONCLUSIONS\nOur case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients.",
"affiliations": "Institute of Pathology, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. daniela.hirsch@umm.de.;Institute of Pathology, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.;Department of Medicine III, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.;Department of Medicine III, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.;Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany.;Department of Surgery, University Medical Center Rostock, Rostock, Germany.;Institute of Pathology, Caritas-Hospital Bad Mergentheim, Bad Mergentheim, Germany.;Institute of Applied Pathology, Speyer, Germany.;Department of Medicine III, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.;Department of Medicine III, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. deniz.gencer@umm.de.",
"authors": "Hirsch|Daniela|D|http://orcid.org/0000-0001-8883-922X;Gaiser|Timo|T|;Merx|Kirsten|K|;Weingaertner|Simone|S|;Forster|Michael|M|;Hendricks|Alexander|A|;Woenckhaus|Matthias|M|;Schubert|Thomas|T|;Hofheinz|Ralf-Dieter|RD|;Gencer|Deniz|D|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D045643:DNA Repair Enzymes",
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"doi": "10.1007/s00432-020-03335-2",
"fulltext": "\n==== Front\nJ Cancer Res Clin Oncol\nJ Cancer Res Clin Oncol\nJournal of Cancer Research and Clinical Oncology\n0171-5216 1432-1335 Springer Berlin Heidelberg Berlin/Heidelberg \n\n32776177\n3335\n10.1007/s00432-020-03335-2\nOriginal Article – Clinical Oncology\nClinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system\nhttp://orcid.org/0000-0001-8883-922XHirsch Daniela daniela.hirsch@umm.de 1 Gaiser Timo 1 Merx Kirsten 2 Weingaertner Simone 2 Forster Michael 3 Hendricks Alexander 4 Woenckhaus Matthias 5 Schubert Thomas 6 Hofheinz Ralf-Dieter 2 Gencer Deniz deniz.gencer@umm.de 2 1 grid.411778.c0000 0001 2162 1728Institute of Pathology, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany \n2 grid.411778.c0000 0001 2162 1728Department of Medicine III, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany \n3 grid.9764.c0000 0001 2153 9986Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany \n4 Department of Surgery, University Medical Center Rostock, Rostock, Germany \n5 Institute of Pathology, Caritas-Hospital Bad Mergentheim, Bad Mergentheim, Germany \n6 Institute of Applied Pathology, Speyer, Germany \n9 8 2020 \n9 8 2020 \n2021 \n147 1 263 273\n3 5 2020 22 7 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/.Purpose\nImmune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors.\n\nMethods\nDetailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed.\n\nResults\nObjective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold.\n\nConclusion\nOur case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s00432-020-03335-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nImmunotherapyMicrosatellite instabilityColorectal cancerTumor mutation burdenPembrolizumabNivolumabMedizinische Fakultät Mannheim, Universität Heidelberg (DE)issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\nIn 2017, the U.S. Food and Drug Administration (FDA) granted approval to the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab for patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors that have progressed following prior treatment and who have no alternative treatment options as well as for patients with MSI-H/dMMR metastatic colorectal cancer (mCRC) after failure of fluoropyrimidine, oxaliplatin, and irinotecan. This approval was recognized as a breakthrough given the fact that this was FDA’s first tumor site-agnostic approval.\n\nSeveral uncontrolled studies including patients with MSI tumors originating from different sites (albeit mainly from the colon and rectum) reported a high rate of in part heavily pretreated patients deriving a clinical benefit of treatment with pembrolizumab or nivolumab ± ipilimumab in terms of long-lasting disease stabilization and tumor remissions (Le et al. 2017; Overman et al. 2017, 2018). More recently, results from 45 patients with MSI-H/dMMR mCRC treated 1st line with nivolumab plus low-dose ipilimumab were reported (Lenz et al. 2019). After a median follow-up of 13.8 months, response rate and disease control rate were 60% and 84%, respectively, and 12-month progression-free survival and overall survival rates were 77% and 83%, respectively.\n\nMoreover, the use of checkpoint inhibitors administered only twice during the waiting period for curative surgery in early stage colon cancer led to complete pathological remissions in four of seven patients with MSI-H colon cancer, while none of eight patients with a microsatellite stable tumor exhibited signs of major pathohistological remission (Chalabi et al. 2018).\n\nMSI-H tumors are characterized by an increased tumor mutation burden (TMB), exhibit increased expression of neoantigens and display higher numbers of tumor-infiltrating lymphocytes (Willis et al. 2020). Susceptibility to treatment with checkpoint inhibitors is consequently increased (Nebot-Bral et al. 2019). However, the presence of MSI-H/dMMR features does not guarantee benefit from checkpoint inhibitor treatment and deeper understanding of the landscape of tumor mutations and their potential predictive potential is mandatory, especially when checkpoint inhibitors are being used in earlier treatment lines with potential alternative treatment options. For instance, loss-of-function mutations in genes relevant for antigen presentation or immune response such as JAK1, JAK2, B2M and STK11 have been identified as mediators of resistance to PD-1 inhibition despite overall high TMB (Shin et al. 2017; Skoulidis et al. 2018; Zaretsky et al. 2016).\n\nHerein, we report on six patients with MSI-H/dMMR metastatic gastrointestinal (GI) cancers undergoing treatment with checkpoint inhibitors and along with their tumor mutational profile.\n\nMaterials and methods\nPatients and eligibility criteria\nWe report on our first six consecutive patients for whom treatment with checkpoint inhibitors was initiated between June 2016 and August 2017. Patients suffered from progressive MSI-H/dMMR metastatic cancer of the digestive system (four patients with colon carcinoma, one patient with duodenal carcinoma, one patient with cholangiocarcinoma). All patients had received at least one prior therapy and had evidence of progressive disease prior to checkpoint inhibition. All patients were naïve to anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies. Molecular analysis by targeted next generation sequencing (127 gene panel, 0.8 Mb) was performed post-hoc. Treatment-naïve tumor tissue of the primary tumor (patients P1 to P4 and P6) or a metastatic lesion (P5) was used for molecular testing. The study procedure was approved by the Medical Ethics Commission II of Heidelberg University (Medical Faculty Mannheim; 2020-807R) including a waiver for informed consent.\n\nTreatment\nPatients received either pembrolizumab (2 mg/kg every 3 weeks, maximum dose 200 mg) or nivolumab (3 mg/kg every 2 weeks). Treatment was generally continued until unacceptable toxicity, or disease progression. Serum biomarkers (CEA, CA19-9, CA72-4) were measured on an individual basis but generally at baseline and if elevated at baseline further monitored along with radiographic assessments. Radiographic assessments were performed every two to four months depending on patient performance and disease dynamics.\n\nTumor sample collection for molecular analysis\nFormalin-fixed paraffin-embedded (FFPE) tumor tissues were collected from the archives of the Institutes of Pathology in Mannheim, Bad Mergentheim and Speyer (all Germany). Histology was reviewed by two pathologists (DH, TG) and tumor areas containing at least 40% tumor cells were marked for molecular testing. Treatment-naïve tumor tissue (primary tumor for patients P1–P4 and P6, metastatic lesion for patient P5) was used for molecular testing.\n\nDNA isolation\nDNA extraction of FFPE tumor and respective normal tissues was done as published previously (Hirsch et al. 2012). DNA concentration was measured by fluorometric quantitation (Qubit 3.0 Fluorometer, Life Technologies, Thermo Fisher Scientific, Carlsbad, CA, USA) using the Qubit dsDNA HS (High Sensitivity) Assay Kit (Life Technologies).\n\nAnalysis of mismatch repair/microsatellite status\nMismatch repair/microsatellite status of tumors was determined by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) as described previously (Hirsch et al. 2018). Briefly, IHC was performed using the following primary antibodies: MLH1 (1:25; clone ES05, cat # M3640, Dako, Agilent Pathology Solutions, Agilent, Santa Clara, CA, USA), MSH2 (ready-to-use; clone FE11, cat # IR085, Dako), MSH6 (ready-to-use; clone EP49, cat # IR086, Dako), and PMS2 (1:50; clone EP51, cat # M3647, Dako). Detection was done using the EnVision Detection System, Peroxidase/DAB, Rabbit/Mouse (cat # K5007, Dako). IHC stainings were validated by internal and/or external positive controls as well as negative control specimens. IHC stainings were evaluated by two pathologists (DH, TG). Microsatellite PCR of tumor and corresponding normal DNA was done using a panel of five mononucleotide markers (BAT25, BAT26, NR-21, NR-24, and MONO-27; cf. MSI Analysis System, Promega), and a panel of two mononucleotide (BAT25 and BAT26) and three dinucleotide markers [D5S346, D2S123, and D17S250; so-called Bethesda panel; (Boland et al. 1998)]. Tumors were classified as MSI-H when two or more markers of either the Bethesda panel or the Promega panel showed an allelic size variation (i.e., a band shift compared with corresponding normal DNA).\n\nTargeted next generation sequencing\nTargeted next generation sequencing (NGS) was done using the xGen Pan-Cancer Panel (v1.5; Integrated DNA Technologies, Coralville, IA, USA), spanning 0.8 Mb of the human genome and targeting 127 significantly mutated genes implicated across 12 tumor tissues (Kandoth et al. 2013). We determined the sequences of the tumors and matched normal (non-tumor) DNA for our six patients (matched normal DNA was not available for P5). Library preparation on FFPE isolated DNA was done using the Nextera DNA Exome library preparation kit (Illumina, San Diego, CA, USA) with 50 ng according to the manufacturer’s protocol, except for 14 instead of 10 PCR cycles. The resulting paired-end libraries were pooled using 100 ng of each library. The library pool was used for targeted capture with the xGen Pan-Cancer panel according to the manufacturer’s protocol except for 12 instead of 10 PCR cycles. An aliquot of 1.4 pM was sequenced on a NextSeq500 system (Illumina) using the 150 cycle mid-output kit (2 × 76 bps). Alignment was done using BWA mem 0.7.12-r1039 (Li and Durbin 2009) to hg19. The mean read depth for the targeted regions (mean coverage) was 1061X. We minimized calling FFPE artifacts by applying a minimal variant allele frequency (VAF) threshold of 10% (Melendez et al. 2018). Details on the bioinformatic analysis and variant calling are provided in the Supplementary Information.\n\nCalculation of tumor mutation burden (TMB)\nTMB was calculated as the number of somatic coding mutations per megabase (Mb), including non-synonymous (missense) mutations, synonymous mutations, nonsense (stop) mutations, and/or frameshift mutations present above 10% VAF after filtering. Non-coding alterations and mutations predicted to be germline were not counted. We compared our data to the TMB thresholds suggested by Fabrizio et al. (Fabrizio et al. 2018) (≥ 11.7 mutations per Mb, synonymous and non-synonymous mutations) and Schrock et al. (Schrock et al. 2019) (proposed cut-off 37.4 mutations per Mb with a range of 37–41 mutations per Mb, synonymous and non-synonymous mutations), which both are based on the F1CDx Foundation medicine assay (324 genes, 1.11 Mb) and a VAF of 5% or greater (Frampton et al. 2013). Furthermore, influence of keeping or removing COSMIC listed variants on TMB estimation was evaluated. To assess the impact of VAF on TMB, we tested different cut-offs of 5%, 7.5%, 10%, 15%, and 20%, respectively. Impact of germline filtering was compared between (1) only computational germline filtering, (2) filtering against the matched normal sample, (3) filtering against the panel of other, non-matched normal samples (n = 4), and (4) filtering against the matched normal sample and a local panel of normal samples (Kiel normal samples; n = 55). Normal samples used as reference for germline filtering were processed in the same way as the tumor samples.\n\nAnalysis of microsatellite status from targeted next generation sequencing data\nTo complement immunohistochemical and PCR-based MSI testing, we also assessed the microsatellite status from NGS data by applying MSIsensor on targeted NGS data from tumor and corresponding normal samples (Niu et al. 2014).\n\nAssessment of response, adverse events and survival times\nResponse and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (Eisenhauer et al. 2009; Schwartz et al. 2016). Toxicities were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE, version 5.0, published by the National Cancer Institute/National Institutes of Health in November 2017). Progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan–Meier method. PFS was defined as the time from the date of the initial dose of immune checkpoint inhibition to the date of disease progression or the date of death due to any cause, whichever occurred first. PFS was censored on the date of the last evaluable tumor assessment documenting absence of progressive disease for patients who were alive and progression-free. OS was defined as the time from the initial dose due to death of any cause. For patients who were still alive at the time of analysis, the OS time was censored on the last date the patients were known to be alive. Duration of response was the time of first response as defined by RECIST 1.1 to the time of disease progression and was censored at the last evaluable tumor assessment for patients who had not progressed. Analyses and graphs were generated with GraphPad Prism software (version 8.4.2; San Diego, CA, USA).\n\nResults\nPatient, tumor and treatment characteristics\nOur patient cohort consisted of six patients with mismatch-repair-deficient metastatic cancer of the digestive system (Table 1, Supplementary Table S1). Mismatch repair deficiency was assessed by polymerase chain reaction and/or immunohistochemistry. Cancers comprised three different entities: colorectal adenocarcinoma (4 patients), duodenal adenocarcinoma (1 patient) and cholangiocarcinoma (1 patient). All tumors were diagnosed between 2013 and 2016 in either locally advanced or metastatic stages (UICC stages IIIA-IV). Median age at diagnosis was 50 years (range 37–61). Four of the patients had a positive family history for gastrointestinal cancer and Lynch syndrome diagnosis was confirmed by genetic testing. Before immune checkpoint inhibitor therapy, all patients had received at least one prior line of chemotherapy and presented with metastatic progressive disease. PD-1 inhibition (nivolumab, pembrolizumab) for all patients was started between June 2016 and August 2017. Four patients were treated with pembrolizumab, while one patient received a combination of radiotherapy and nivolumab, and one patient nivolumab alone. Median time under PD-1 inhibition was 17 months (range 4–40). At the data cut-off, PD-1 inhibition is still ongoing in two patients, three patients had discontinued therapy due to excellent response with ongoing remission, and one patient had deceased from tumor progression. Median duration of response was 25 months (range 18–35 months). Patients were followed for a minimum of 25 months (median 27, maximum 40).Table 1 Baseline patient and tumor characteristics\n\nPatient ID\tP1\tP2\tP3\tP4\tP5\tP6\t\nAge at diagnosis (years)\t58\t48\t48\t52\t49\t35\t\nGender\tMale\tFemale\tMale\tFemale\tMale\tMale\t\nECOG performance status\t1\t0\t0\t1\t0\t0\t\nPrimary tumor location\tColon (cecum)\tColon (transverse)\tColon (cecum)\tPortal vein/bile duct/liver\tDuodenum\tColon (ascending)\t\nTumor histology\tUndifferentiated adenocarcinoma with signet ring cell component\tIntestinal-type adenocarcinoma with mucinous component\tMucinous adenocarcinoma\tCholangio-carcinoma\tMucinous adenocarcinoma\tMucinous adenocarcinoma\t\nHistologic differentiation\tPoor\tModerate\tPoor\tPoor\tPoor\tModerate\t\nUICC stage at diagnosis\tIV\tIIIB\tIIIB\tIIIA\tIV\tIIIC\t\nMetastatic sites\tPeritoneum, abdominal lymph nodes\tLiver, abdominal lymph nodes\tRectum\tBone, muscle\tDuodenum, lung, abdominal lymph nodes\tLiver, abdominal lymph nodes\t\nMedian time since\n\ninitial diagnosis (months)\n\n\t21\t5\t23\t47\t3\t20\t\nPrevious primary tumor resection\tYes\tYes\tYes\tYes\tNo\tYes\t\nNumber of prior systemic treatments\t2\t1\t1\t1\t1\t1\t\nPrior therapies received (ctx regimens/agents)\t5-FU/FA + Bevacizumab (palliative 1st line)\n\nFOLFIRI + Bevacizumab (palliative 2nd line)\n\n\tCapecitabine (adjuvant)\tFOLFOX (adjuvant)\tGemcitabine + Cisplatin (palliative 1st line)\tFOLFOXIRI (neoadjuvant)\tFOLFOX + Bevacizumab (additive)\t\nPrior radiotherapy\tNo\tNo\tNo\tYes\tNo\tNo\t\nPrevious malignancies\tN/A\tN/A\tN/A\tEndometrial carcinoma\tN/A\tN/A\t\nLynch syndrome\tYes\tYes\tYes\tYes\tNo\tNo\t\nMMR status (IHC)\tMMR-deficient\tMMR-deficient\tMMR-deficient\tMMR-deficient\tMMR-deficient\tNot done\t\nMMR protein expression (IHC)\tMLH1 + , MSH2 −, MSH6 −, PMS2 +\tMLH1 −, MSH2 + , MSH6 + , PMS2 −\tMLH1 + , MSH2 −, MSH6 −, PMS2 + \tMLH1 −, MSH2 + , MSH6 + , PMS2 −\tMLH1 −, MSH2 + , MSH6 + , PMS2 −\tN/A\t\nMSI status (PCR)\tMSI-high\tNot done\tNot done\tMSI-high\tNot done\tMSI-high\t\nBRAF mutation status\tWild-type\tWild-type\tNot done\tNot done\tNot done\tWild-type\t\nKRAS mutation status\tp.A146T\tp.G13D\tNot done\tNot done\tNot done\tWild-type\t\nNRAS mutation status\tWild-type\tWild-type\tNot done\tNot done\tNot done\tWild-type\t\nPD-L1 expression at baseline\tNot done\t < 1%\tNot done\tNot done\tNot done\tNot done\t\nIHC immunohistochemistry; MMR mismatch repair; MMR mismatch repair; MSI microsatellite instability; PCR polymerase chain reaction\n\n\n\nResponse evaluation, treatment duration and survival\nResponses to PD-1 inhibition were evaluated radiographically in all six patients based on RECIST v1.1 criteria (Fig. 1a, Supplementary Figure S1A). In addition, biomarker levels for CA19-9, CA72-4 and/or CEA were monitored over the course of treatment if they had been elevated at baseline (Fig. 1b, Supplementary Figures S1B-D). Objective radiographic responses (i.e., partial or complete response based on RECIST v1.1 criteria) were noted in all six patients, with two patients achieving a complete response after 2.4 (P3) and 18.5 months (P6), respectively. The time to first objective radiographic response ranged from 1.5 to 8.6 months (median 2.3 months). In three patients (P1, P2, P4) tumor marker level reduction preceded objective radiographic response. However, the progression of patient P5 at 31.8 months after treatment initiation was first indicated by a radiographic increase in tumor size.Fig. 1 Clinical responses to PD-1 inhibition in six patients with mismatch repair-deficient metastatic carcinoma of the digestive system. a Spider plot of radiographic responses to PD-1 inhibition. Tumor responses were measured regularly; values show fractional change of the sum of lesion diameters from the baseline measurements of each measurable target lesion according to RECIST v1.1 criteria. b Spider plot of biochemical responses to anti-PD-1 treatment. Serum levels of protein biomarkers that were higher than the upper limit of normal at baseline were measured repeatedly, and the values represent relative changes from baseline. c Swimmer plot showing the time of objective response in relationship to duration of treatment and time of treatment cessation. CfB change from baseline; CR complete response; PD progressive disease; PR partial response; SLD sum of lesion diameter\n\n\n\nTreatment was discontinued in three of six patients due to excellent response to anti-PD-1 therapy after 7.8 months (P2), 3.8 months (P3), and 4.9 months (P6), respectively, despite some residual disease by imaging in patients P2 and P6 at the time of treatment discontinuation (Fig. 1C and Fig. 2). As of the data cut-off, the time off therapy in these three patients was 31.1 (P2), 22.5 (P3) and 20.3 (P6) months, respectively. None of these three patients has shown evidence of cancer recurrence or progression since discontinuation of pembrolizumab or nivolumab so far. Instead, patient P6, who had partial response when taken off therapy, converted to complete response 13.6 months after treatment cessation.Fig. 2 Radiographic response of the liver metastasis of patient 2 (a), pelvic metastasis of patient 3 (b), and liver metastasis of patient 6 (c). CT scans at baseline prior to PD-1 inhibition and follow-up CT scans are shown for each patient. Circled areas indicate the respective tumor lesions\n\n\n\nImmunotherapy was continued in the other three patients whereby the dose for patient 1 was reduced to 4-weekly cycles after 13.3 months on treatment. Remarkably, the two disease progressions in our cohort (P1, P5) were observed in the patient group that continued with PD-1 inhibition. Patient 1 had the first evidence of progressive disease by imaging 27.1 months after starting PD-1 inhibition. Disease progressed rapidly and despite salvage therapy with FOLFOX, the patient passed away within one month after diagnosis of progressive disease. Patient 5 also had a progressing paraaortic lesion after 31.8 months of immunotherapy. The progressing metastatic lesion was excised by surgery and as of the data cut-off, which was 4.9 months after surgery, the patient is without tumor activity and PD-1 inhibition is continued. None of the patients had primary resistance to PD-1 inhibition, however, acquired resistance was noted in two patients, who developed progressive disease after an initial objective response to pembrolizumab. While one patient (P5) could be treated with local therapy (surgery) and survived and as of the data cut-off continues treatment with pembrolizumab, the other patient (P1) experienced rapid disease progression and died within one month after the first evidence of disease progression by imaging. Taken together, median progression-free survival (PFS) in our small cohort of six patients was 31.8 months (Supplementary Figure S2A); median overall survival (OS) has not yet been reached (median follow-up time of 29.9 months, range 25.2–40.2 months) (Supplementary Figure S2B). The estimates of PFS and OS at 1 and 2 years (12 and 24 months, respectively) were 100% (6 of 6 patients), respectively. The PFS and OS were not strikingly different in patients with colon cancer relative to those with the other GI cancer types. Neither PFS nor OS seemed to be influenced by tumors associated with Lynch syndrome. Adverse events during treatment were manageable and resembled those reported in other clinical studies using PD-1 inhibition (Le et al. 2015). No grade 3 or 4 events were noticed, in particular no immune-related adverse events leading to discontinuation of therapy were observed. Of note, patient P2 developed a reactive thymic hyperplasia under immunotherapy, which has still been present in the latest CT scan (Supplementary Figure S3). Detailed clinical history for each patient is provided in the supplement.\n\nAssessment of tumor mutation burden (TMB)\nIn an attempt to better understand the genetic basis of the good responses to PD-1 inhibition in our small series of six patients, we performed targeted sequencing with a 127 gene panel spanning 0.8 Mb, which is considered suitable for TMB assessment according to current recommendations (Buttner et al. 2019). In addition to non-synonymous (missense), nonsense (stop) and frameshift mutations, we included synonymous mutations into our TMB calculation, following the rationale of Chalmers et al. (2017). Chalmers et al. (2017) reasoned that synonymous mutations, though they are not likely to be involved in creating immunogenicity, are a signal of mutational processes that will also have resulted in non-synonymous mutations and neoantigens elsewhere in the genome. Immunogenicity of particular mutation types and which mutation types should be included into TMB calculation is still a matter of debate and no uniform method exists. When using gene panels biased toward genes with functional mutations in cancer for TMB calculation, exclusion of mutations listed as known somatic alterations in COSMIC (Bamford et al. 2004) has been suggested (Chalmers et al. 2017). Overall, our data shows that MSI-H/dMMR leads to an increased TMB in all our patients, though to a different extent. When including COSMIC listed mutations, mutation counts averaged to 170 mutations per Mb with a range of 42–397 (Fig. 3). When excluding COSMIC listed mutations, an average of 112 mutations was detected per Mb with a range of 20–208. Hence, exclusion of COSMIC listed variants decreased absolute TMB levels by 19–53%, respectively. However, relative TMB levels of samples to one another remained similar.Fig. 3 Tumor mutation burden (TMB) with and without COSMIC mutations. The chart illustrates the contribution of distinct mutation types to overall TMB levels. Shown are mutations with a variant allele frequency (VAF) of greater 10%. Filtering to remove germline variants and sequencing artifacts was against the matched normal sample and a local panel of normal samples (Kiel normal samples; n = 55). Indicated TMB thresholds from the studies of Schrock et al. and Fabrizio et al. are based on counts of nonsynonymous and synonymous mutations with a VAF threshold of 5%\n\n\n\nThe impact of included mutation types and COSMIC variants is critical, in particular with respect to patients with borderline TMB like patient P6 in our cohort, who despite borderline TMB had a durable response and clinical benefit from PD-1 inhibition via nivolumab, which is still ongoing after 25.2 months. In general, TMB levels did not associate with complete or partial response in our small subset of six patients. Moreover, patient P6 achieved complete response after 18.5 months, despite having the lowest TMB in our cohort. The other complete responder, patient P3, had an intermediate TMB level in our cohort. Apart from particular mutations that are included or not, TMB is influenced by a plethora of other factors (Stenzinger et al. 2019, 2020) including but not limited to minimum VAF threshold and method of germline filtering. As expected, the higher the VAF threshold, the lower the mutation count (Supplementary Figure S4). For VAFs below 10%, the method of germline filtering had a considerable impact on mutation counts. If only in silico germline filtering was performed, mutation counts were remarkably higher at VAFs of 5% and 7.5% compared to filtering against a matched normal sample or a local panel of normal samples (Supplementary Figure S4). This implies that thresholds below 10% may not be advisable for samples with solely computational germline filtering due to technical sequencing artifacts and FFPE artifacts, in line with Melendez et al. (2018). As filtering against a local panel of normal samples generated using the same workflow could at least partially resolve this issue, this should be considered as a practical option for routine molecular diagnostics where additional sequencing of a matched normal sample is often not feasible. Of note, for patient 1, who showed rapid progression, no potential genomic target causing this could be identified by the NGS analysis of the primary tumor sample. Due to rapid progression, tumor material from the progressing lesions could not be obtained.\n\nAssessment of microsatellite status by targeted next generation sequencing\nTo evaluate whether MSI status can reliably be assessed by panel sequencing, we applied the MSIsensor software tool (Niu et al. 2014) to our dataset (Supplementary Figure S5). This revealed an MSIsensor score highly suggestive for MSI-H in all five patients, for which a matched normal sample was available, a prerequisite for this tool. From a technical point of view, NGS data nicely confirmed MSI based on the MSIsensor score, making it a potentially useful tool for future studies and clinical purposes.\n\nDiscussion\nCheckpoint inhibitors have shown excellent efficacy in patients with MSI-H/dMMR GI cancers. For instance, in KEYNOTE-164, two cohorts of patients with pretreated mCRC received 3-weekly pembrolizumab (Le et al. 2020). Response rates were 33% in patients pretreated with ≥ 2 (cohort A) or ≥ 1 (cohort B) rounds of pretreatment, respectively. While median survival was 31.4 months in cohort A, it had not been reached in cohort B. Similarly, in CheckMate 142, patients with pretreated MSI-H/dMMR mCRC receiving monotherapy with nivolumab after ≥ 1 line of pretreatment exhibited a response rate of 31% and a 1-year survival rate of about 70% (Overman et al. 2017). However, despite these excellent response rates and long-term disease control, it has to be noticed that the rate of primary progression ranged between 26 and 46% in both studies. Preliminary data of 1st line patients receiving nivolumab in a cohort of the CheckMate 142 study reported 16% patients exhibiting primary progression (Lenz et al. 2019). This data underlines the need for additional biomarkers beyond MSI-H/dMMR to minimize patients exposed to checkpoint inhibitors instead of potentially active chemotherapy regimens, especially for those patients scheduled to receive checkpoint inhibitors in earlier lines of treatment.\n\nRecently, Schrock and coworker (Schrock et al. 2019) suggested that TMB might serve as an additional biomarker in mCRC. In a cohort of 22 patients with mCRC treated with checkpoint inhibitors a cut-point of 37.4 mutations per Mb (range 37–41 mutations per Mb) for TMB was reported to distinguish between responders and non-responders. While all 13 patients with TMB values above this threshold exhibited long term benefit, 6 out of 9 patients with lower values showed primary progression. Their threshold is considerably higher than the 11.7 mutations per Mb threshold published by Fabrizio et al. (Fabrizio et al. 2018) in a previous study to identify MSI-high CRC samples. The stricter threshold suggested by Schrock et al. (Schrock et al. 2019) indeed leads to a more stringent identification of responders, however, at the expense of missing some potential responders since there is an overlap in mutation ranges between responders and non-responders. In other words, though recent evidence has shown that higher TMB scores are generally associated with improved response to immune checkpoint blockade across a wide variety of cancer types (Samstein et al. 2019), some patients still benefit from immune checkpoint blockade despite rather low mutation rates. This is evident in the cohort of Schrock et al. (3 patients) and in our cohort (1 patient; P6 with durable complete response to pembrolizumab). Another issue that needs to be considered when discussing TMB as a clinical biomarker in MSI-H patients, is the high variability and inconsistent reporting of (current) TMB assessment methods across different studies, which can create confusion for oncologists and may impact critical treatment decisions.\n\nOriginally, TMB was determined by whole exome sequencing (WES) and usually calculated as the number of non-synonymous mutations per exome or Mb reflecting the mutation load in all protein coding regions of the genome. Due to the increased interest in TMB for prediction of response to immune checkpoint inhibition and because WES is not yet routinely used in clinic, recent efforts have begun to validate TMB estimation based on targeted NGS panels, which are already implemented in routine molecular diagnostics for oncogenic mutation detection (Stenzinger et al. 2020). Currently, a minimum panel size of 0.8–1 Mb is widely accepted for TMB estimation for clinical purposes (Allgauer et al. 2018; Buttner et al. 2019), although in silico simulations based on TCGA exome data suggest a panel size of 1.5–3 Mb for an optimized cost–benefit ratio (Buchhalter et al. 2019). Overall, accuracy and precision of TMB estimation tend to increase with panel size (Garofalo et al. 2016) while below 0.5 Mb variance rises drastically, in particular for samples with low TMB (Chalmers et al. 2017). However, not only panel size matters but also panel composition as certain differences in TMB estimations have been observed between panels depending on their genomic composition (Xu et al. 2019). With the increased use of gene panels for TMB estimation, TMB definitions started to diverge from the original WES-based definition and other mutation types such as nonsense mutations, synonymous mutations and small indels were included, however, inconsistently across different laboratories and studies (Chan et al. 2019). Due to the enrichment of cancer relevant genes, it is suggested to remove oncogenic driver events by filtering against databases such as COSMIC (Bamford et al. 2004; Chalmers et al. 2017). As illustrated by our data, the mutation types included and removal of potentially oncogenic somatic mutations by exclusion of COSMIC-listed variants has a considerable effect on TMB estimation. However, COSMIC does not only contain oncogenic/cancer-relevant mutations but somatic mutations in general, a fact that may lead to an overcorrection of TMB estimated based on cancer gene panels. Furthermore, COSMIC is an evolving database, i.e., the number of cataloged mutations will increase over time, questioning its value for correcting panel-based TMB estimates for clinical purposes.\n\nTwo other important sources contributing to variability among TMB scores are the method of germline filtering and the minimum VAF threshold. Our data show that if no matched normal sample is sequenced along with the tumor sample, TMB estimation is more robust if filtered against at least a panel of normal samples (PON) that was processed in the same way as the case samples. The PON will not only help augment population frequency databases such as GnomAD, which are highly filtered and curated, but also help remove systematic and assay specific sequencing artifacts, which can be widespread even with matched normal samples. This is even more important when FFPE tissue is used as FFPE material is more artifact prone than fresh/frozen samples. Based on our observations, the commonly used VAF cutpoint of 5% (F1Dx, Oncomine Tumor Mutation Load Assay) may be too low and may thus increase the risk of including false positives, in particular when using FFPE tissue and only computational germline filtering. As filtering against a local PON could at least partially resolve this issue, this should be considered as practical option for routine molecular diagnostics.\n\nGiven the plethora of factors influencing exact TMB values (Stenzinger et al. 2019), exact TMB values are only comparable within individual studies using the exact same preanalytical workflow, sequencing methodology and bioinformatics pipeline. However, some confounding factors such as different levels of tumor cell purity, which significantly influence the number of called mutations even if the exact same workflow is followed, will remain in routine practice and are hard to control. For instance, harmonizing tumor purity would require disintegrating the tissue and enriching for the tumor cells by immunofluorescent markers. However, despite all the discrepancies and uncertainties regarding absolute TMB values, recent data from the QuIP study indicate a reasonable agreement of assignment to TMB categories between different laboratories and panels (Stenzinger et al. 2020). Apart from that, it is evident that the majority of responders with metastatic GI cancers greatly exceeds the currently suggested thresholds of 12 or 37 mutations per Mb, respectively, relatively independent from the specific gene panel used, mutation types included, and specific thresholds applied. The small group of patients with response to immune checkpoint inhibition and only low or borderline TMB, on the other hand, may need a biomarker other than TMB for identification. A potential option could be mutation signatures, which are a reflection of the underlying mutational processes, and other factors such as cell type composition/tumor-infiltrating lymphocytes (Loupakis et al. 2020). Ultimately, multi-omics testing may be the most reliable way to identify responders and non-responders to immune checkpoint inhibition. If TMB is pursued as a clinical biomarker for immunotherapy, consistent standards for TMB estimation and reporting are needed to minimize variability, to ensure reliable and reproducible identification of responders, and to allow comparison across studies (Fancello et al. 2019). To make informed clinical decisions, clinicians/oncologists need to be aware that different methods for TMB testing and reporting exist.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.Supplementary file1 (PDF 1404 kb)\n\n \n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nOpen Access funding provided by Projekt DEAL. The authors would like to thank Regina Fredrik (Institute for Clinical Molecular Biology, Kiel) for help with library preparation, and Yonca Ceribas and Alexandra Eichhorn (Institute of Pathology, University Medical Center Mannheim) for technical assistance. D. Hirsch received an intramural research scholarship (Translational Physician Scientist Program) from the Medical Faculty Mannheim, Heidelberg University.\n\nCompliance with ethical standards\nConflict of interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\nAllgauer M Implementing tumor mutational burden (TMB) analysis in routine diagnostics-a primer for molecular pathologists and clinicians Transl Lung Cancer Res 2018 7 703 715 10.21037/tlcr.2018.08.14 30505715 \nBamford S The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website Br J Cancer 2004 91 355 358 10.1038/sj.bjc.6601894 15188009 \nBoland CR A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer Cancer Res 1998 58 5248 5257 9823339 \nBuchhalter I Size matters: dissecting key parameters for panel-based tumor mutational burden analysis Int J Cancer 2019 144 848 858 10.1002/ijc.31878 30238975 \nButtner R Longshore JW Lopez-Rios F Merkelbach-Bruse S Normanno N Rouleau E Penault-Llorca F Implementing TMB measurement in clinical practice: considerations on assay requirements ESMO Open 2019 4 e000442 10.1136/esmoopen-2018-000442 30792906 \nChalabi M LBA37_PRNeoadjuvant ipilimumab plus nivolumab in early stage colon cancer Ann Oncol 2018 10.1093/annonc/mdy424.047 \nChalmers ZR 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 \nChan TA Yarchoan M Jaffee E Swanton C Quezada SA Stenzinger A Peters S Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic Ann Oncol 2019 30 44 56 10.1093/annonc/mdy495 30395155 \nEisenhauer EA New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774 \nFabrizio DA Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition J Gastrointest Oncol 2018 9 610 617 10.21037/jgo.2018.05.06 30151257 \nFancello L Gandini S Pelicci PG Mazzarella L Tumor mutational burden quantification from targeted gene panels: major advancements and challenges J Immunother Cancer 2019 7 183 10.1186/s40425-019-0647-4 31307554 \nFrampton GM Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing Nat Biotechnol 2013 31 1023 1031 10.1038/nbt.2696 24142049 \nGarofalo A The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine Genome Med 2016 8 79 10.1186/s13073-016-0333-9 27460824 \nHirsch D Camps J Varma S Kemmerling R Stapleton M Ried T Gaiser T A new whole genome amplification method for studying clonal evolution patterns in malignant colorectal polyps Genes Chromosom Cancer 2012 51 490 500 10.1002/gcc.21937 22334367 \nHirsch D Dynamics of genome alterations in Crohn's disease-associated colorectal carcinogenesis Clin Cancer Res 2018 24 4997 5011 10.1158/1078-0432.CCR-18-0630 29967250 \nKandoth C Mutational landscape and significance across 12 major cancer types Nature 2013 502 333 339 10.1038/nature12634 24132290 \nLe DT PD-1 blockade in tumors with mismatch-repair deficiency N Engl J Med 2015 372 2509 2520 10.1056/NEJMoa1500596 26028255 \nLe DT Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade Science 2017 357 409 413 10.1126/science.aan6733 28596308 \nLe DT Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164 J Clin Oncol 2020 38 11 19 10.1200/JCO.19.02107 31725351 \nLenz H-J Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): clinical update J Clin Oncol 2019 37 3521 3521 10.1200/JCO.2019.37.15_suppl.3521 \nLi H Durbin R Fast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics 2009 25 1754 1760 10.1093/bioinformatics/btp324 19451168 \nLoupakis F Prediction of benefit from checkpoint inhibitors in mismatch repair deficient metastatic colorectal cancer: role of tumor infiltrating lymphocytes Oncologist 2020 10.1634/theoncologist.2019-0611 32369650 \nMelendez B Van Campenhout C Rorive S Remmelink M Salmon I D'Haene N Methods of measurement for tumor mutational burden in tumor tissue Transl Lung Cancer Res 2018 7 661 667 10.21037/tlcr.2018.08.02 30505710 \nNebot-Bral L Coutzac C Kannouche PL Chaput N Why is immunotherapy effective (or not) in patients with MSI/MMRD tumors? 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"fulltext_license": "CC BY",
"issn_linking": "0171-5216",
"issue": "147(1)",
"journal": "Journal of cancer research and clinical oncology",
"keywords": "Colorectal cancer; Immunotherapy; Microsatellite instability; Nivolumab; Pembrolizumab; Tumor mutation burden",
"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor; D015996:Survival Rate",
"nlm_unique_id": "7902060",
"other_id": null,
"pages": "263-273",
"pmc": null,
"pmid": "32776177",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "30505715;15188009;9823339;30238975;30792906;28420421;30395155;30151257;31307554;24142049;27460824;22334367;29967250;24132290;26028255;28596308;31725351;2705234;32369650;30505710;30342749;24371154;28734759;29355075;30643254;31038663;27189322;27903500;29773717;30664300;32119917;31383734;31123404;27433843",
"title": "Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system.",
"title_normalized": "clinical responses to pd 1 inhibition and their molecular characterization in six patients with mismatch repair deficient metastatic cancer of the digestive system"
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"abstract": "Neurotoxicity from intrathecally administered chemotherapeutic drugs is frequent, particularly with some agents like methotrexate, which are more prone to developing adverse effects. Myelopathy ranks among the most frequently reported neurological entities; with the diagnosis being straightforward, after ruling out infectious, metabolic, autoimmune or paraneoplastic causes. Scarcity of cases precludes evidence-based recommendations for the management of these complications. The most common therapeutic approach consists of the suspension of chemotherapy, exclusion of infectious and neoplastic causes, with prompt administration of high-dose steroids. We report a 21-year-old patient with acute lymphoblastic leukaemia, who developed acute transverse myelitis and bilateral sensorineural hearing loss, after five rounds of intrathecal methotrexate and cytarabine. Although neurotoxicity from both agents has been documented, this combination has not been previously reported.",
"affiliations": "Servicio de Neurología, Hospital Universitario \"Dr José E. González\", Monterrey, Nuevo León, Mexico sergio.castillotr@uanl.edu.mx.;Servicio de Neurología, Hospital Universitario \"Dr José E. González\", Monterrey, Nuevo León, Mexico.;Servicio de Neurología, Hospital Universitario \"Dr José E. González\", Monterrey, Nuevo León, Mexico.;Servicio de Neurología, Hospital Universitario \"Dr José E. González\", Monterrey, Nuevo León, Mexico.",
"authors": "Castillo-Torres|Sergio A|SA|http://orcid.org/0000-0002-4727-2535;Soto-Rincón|Carlos A|CA|;Villarreal-Montemayor|Héctor J|HJ|;Chávez-Luévanos|Beatriz|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-234076",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(4)",
"journal": "BMJ case reports",
"keywords": "chemotherapy; haematology (incl blood transfusion); neurology (drugs and medicines); spinal cord",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003937:Diagnosis, Differential; D006312:Hearing Loss, Bilateral; D006319:Hearing Loss, Sensorineural; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D009188:Myelitis, Transverse; D009471:Neuromyelitis Optica; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32300035",
"pubdate": "2020-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of neuromyelitis optica: bilateral sensorineural hearing loss and transverse myelopathy following intrathecal chemotherapy.",
"title_normalized": "case of neuromyelitis optica bilateral sensorineural hearing loss and transverse myelopathy following intrathecal chemotherapy"
} | [
{
"companynumb": "MX-MEDEXUS PHARMA, INC.-2020MED00125",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional":... |
{
"abstract": "Chronic graft versus host disease (cGvHD) is a common complication of hematopoietic stem cell transplantation (HSCT). Eosinophilic lung disease is a rare poorly understood complication in HSCT patients with cGvHD. These patients present similarly to those with Acute Eosinophilic Pneumonia (AEP). The purpose of this study is to better elucidate the presentation and potential treatment of this phenomenon.\n\n\n\nWe reviewed over 170 bronchoscopies in post-HSCT patients with respiratory symptoms. Of these, four patients, whose course was complicated by cGvHD, presented with respiratory symptoms, diffuse ground-glass opacities (GGO) on chest computerized tomography (CT), bronchoalveolar lavage (BAL) eosinophilia, and no evidence of infection. The clinical course of these patients was reviewed.\n\n\n\nDespite clinical presentation similar to AEP, not all patients had > 25% eosinophils on BAL, one criterion for AEP, however all improved with steroids. Steroid initiation was often delayed in favor of empiric antibiotics despite negative infectious workup. Several patients had recurrent episodes. Regarding possible associations, we examined but found no link between particular demographics, reason for HSCT, chemotherapy, immunosuppressants, or peripheral eosinophil count and pulmonary eosinophilia in these patients. GGO present on initial CT imaging became chronic in several of these patients.\n\n\n\nWe propose that in post-HSCT patients with GvHD presenting with respiratory symptoms, GGO on CT, BAL eosinophilia of > 10%, and negative respiratory cultures, an autoimmune eosinophilic process may be occurring. Earlier recognition and initiation of corticosteroids in these patients may improve their outcomes as an autoimmune diagnosis was often delayed in favor of antibiotics.",
"affiliations": "Department of Medicine, University of Minnesota, 131 VCRC, 401 E River Pkwy, Minneapolis, 55455, MN, USA. Tawfi004@umn.edu.;Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, 420 Delaware SE, MMC 276, Minneapolis, 55455, MN, USA.",
"authors": "Tawfik|Pierre|P|0000-0003-4693-9163;Arndt|Patrick|P|0000-0003-1875-273X",
"chemical_list": "D000893:Anti-Inflammatory Agents; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1007/s00408-017-0060-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0341-2040",
"issue": "195(6)",
"journal": "Lung",
"keywords": "Acute eosinophilic pneumonia; Bone marrow transplantation; Bronchoalveolar lavage; Corticosteroids; Ground-glass opacities",
"medline_ta": "Lung",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000893:Anti-Inflammatory Agents; D001992:Bronchoalveolar Lavage Fluid; D002908:Chronic Disease; D003937:Diagnosis, Differential; D004804:Eosinophils; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011657:Pulmonary Eosinophilia; D012008:Recurrence",
"nlm_unique_id": "7701875",
"other_id": null,
"pages": "805-811",
"pmc": null,
"pmid": "29058073",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25985921;21441964;12907447;8207996;23334207;18794871;16389562;21601640;11436099;16641398;15062610;18449079;22871762;2912347;7951097;24819788;7994253;7952571;19132457;19525984",
"title": "The Rare Complication and Diagnostic Challenges of Pulmonary Eosinophilia in Graft versus Host Disease Patients after Hematopoietic Stem Cell Transplantation.",
"title_normalized": "the rare complication and diagnostic challenges of pulmonary eosinophilia in graft versus host disease patients after hematopoietic stem cell transplantation"
} | [
{
"companynumb": "PHHY2017US157161",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Oral voriconazole is commonly used for treatment and prophylaxis of invasive fungal disease post-LTx. Development of cutaneous SCC has been described in adult LTx recipients, although it is extremely rare in children. We describe two Caucasian children who developed cutaneous SCC beyond three yr post-LTx. Both developed severe photosensitivity, actinic keratosis and required curative surgical excision of the cutaneous SCC lesions. Neither patient developed metastatic lesions nor had allograft dysfunction as a result of the SCC or the change in medical treatments. The effect of voriconazole on the development of malignant skin lesions is discussed and a recommendation on dermatologic surveillance, preventive measures against phototoxicity and early treatment of SCC are provided.",
"affiliations": "Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.",
"authors": "Wong|Jackson Y|JY|;Kuzel|Paul|P|;Mullen|John|J|;Lien|Dale|D|;Mahmood|Muhammad|M|;Conrad|Carol|C|;Fiorillo|Loretta|L|",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12320",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "18(6)",
"journal": "Pediatric transplantation",
"keywords": "lung transplantation; malignancy; organ transplantation; pediatrics; skin cancer; squamous cell carcinoma; voriconazole",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D002294:Carcinoma, Squamous Cell; D002648:Child; D005260:Female; D006801:Humans; D008172:Lung Diseases, Fungal; D016040:Lung Transplantation; D008297:Male; D010787:Photosensitivity Disorders; D029424:Pulmonary Disease, Chronic Obstructive; D012307:Risk Factors; D012878:Skin Neoplasms; D065819:Voriconazole",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E200-7",
"pmc": null,
"pmid": "25039541",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous squamous cell carcinoma in two pediatric lung transplant patients on prolonged voriconazole treatment.",
"title_normalized": "cutaneous squamous cell carcinoma in two pediatric lung transplant patients on prolonged voriconazole treatment"
} | [
{
"companynumb": "PHHY2014CA114879",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "Temozolomide (TMZ) is a second-generation oral alkylating agent that functions against a number of central nervous system neoplasms, and is generally used to treat high-grade gliomas, including anaplastic astrocytoma and glioblastoma multiforme. Therapy-related secondary myelodysplastic syndrome and acute myeloid leukemia have been reported in patients following prolonged exposure to TMZ. However, TMZ-related acute lymphoblastic leukemia (ALL) is extremely rare. The present study describes the case of an 11-year-old boy with a 3-day history of generalized tonic-clonic seizures and a contrast-enhanced lesion in the left temporooccipital region with focal cystic degeneration, as detected by magnetic resonance imaging. The patient underwent craniotomy and gross-total resection andpathological analysis confirmed the diagnosis of giant cell glioblastoma. Postoperatively, the patient received TMZ-based concurrent chemoradiation during radiotherapy, and developed B-cell ALL 6 months following TMZ treatment. A thorough literature search identified only six published cases of TMZ-related ALL. The chemotherapeutic efficacy of TMZ has been identified, however, its leukemogenic potential should be emphasized among practitioners and patients. Further studies are required to determine the specific pathogenic mechanism of TMZ-related ALL. Close hematological monitoring of patients following TMZ treatment is vital and a high index of suspicion is necessary.",
"affiliations": "Department of Neurosurgery The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China.;Department of Neurosurgery The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China.;Department of Neurosurgery The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China.;Department of Pathology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China.;Department of Neurosurgery The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China.;Department of Neurosurgery, Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China.",
"authors": "Liu|Pengfei|P|;Li|Peiwen|P|;Lei|Ting|T|;Qu|Limei|L|;Huang|Haiyan|H|;Mu|Qingchun|Q|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2018.8422",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "15(6)",
"journal": "Oncology letters",
"keywords": "acute lymphoblastic leukemia; glioblastoma multiforme; temozolomide",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "8663-8668",
"pmc": null,
"pmid": "29805603",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": "11225603;16819506;25118489;11550133;24291476;25920709;16554488;19099199;15735923;20658636;16044311;23519741;25906059;25730188;25189725;17618441;19543728;10520009;26033547;25936680;21518332;20718954;12454741;9874184;26121109;1309379;27354585;10866347;23921765;24850453;24705888;19880768;26483064;21614470",
"title": "Acute lymphoblastic leukemia following temozolomide treatment in a patient with glioblastoma: A case report and review of the literature.",
"title_normalized": "acute lymphoblastic leukemia following temozolomide treatment in a patient with glioblastoma a case report and review of the literature"
} | [
{
"companynumb": "CN-MYLANLABS-2018M1035520",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Since the introduction of combination antiretroviral therapy (ART), the life expectancy has increased for patients infected with human immunodeficiency virus (HIV). This has been associated with reductions in the incidences of some AIDS-defining malignancies, such as Kaposi sarcoma and non-Hodgkin lymphoma, but has coincided with an increased incidence of non-AIDS-defining malignancies, such as anal cancer. However, anal cancers are rare in patients with HIV in Japan. We report the case of an HIV-infected patient with anal cancer treated with chemoradiotherapy. A 37-year-old man receiving ART for HIV infection presented with a 1-month history of left inguinal lymphadenopathy and anal pain. Magnetic resonance imaging and computed tomography revealed a 56-mm mass, left inguinal lymphadenopathy, and left external iliac lymphadenopathy. The mass had infiltrated from the anal canal to the right levator ani and corpus spongiosum. Colonoscopy revealed a tumor with an ulcer in the anal canal. Histological examination of the tumor biopsy specimens confirmed the diagnosis of squamous cell carcinoma. The patient was diagnosed with anal cancer (T4N2M1 stage IV), and he received 5-fluorouracil (1000mg/m(2) on days 1-4 and 29-32) plus mitomycin C (10mg/m(2) on days 1 and 29) and concurrent radiotherapy (total dose, 59.4Gy in 33 fractions) along with ART. The treatment-related adverse events were grade 4 leukopenia and neutropenia, grade 3 thrombocytopenia, and grade 2 radiation dermatitis. Moreover, CD4 suppression was observed:the CD4 count decreased from 190 cells/μl before chemoradiotherapy to 138 cells/μl after 3 months, but increased to 210 cells/μl after 1 year. Because of the grade 4 leukopenia and neutropenia, the dose of 5-fluorouracil was reduced to 800mg/m(2) on days 29-32. A complete response was confirmed on magnetic resonance imaging, and colonoscopy confirmed the disappearance of the anal cancer. The patient is living with no signs of recurrence at 2 years after chemoradiotherapy. When treating HIV-infected patients with anal cancer by chemoradiotherapy and ART, clinicians should be aware of the possibility of CD4 suppression.",
"affiliations": "Department of Gastroenterology and Hepatology, National Hospital Organization, Osaka National Hospital.",
"authors": "Sugimoto|Aya|A|;Nakazuru|Shoichi|S|;Sakakibara|Yuko|Y|;Nishio|Kumiko|K|;Yamada|Takuya|T|;Ishida|Hisashi|H|;Yajima|Keishiro|K|;Uehira|Tomoko|T|;Mori|Kiyoshi|K|;Mita|Eiji|E|",
"chemical_list": "D016685:Mitomycin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.113.254",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "113(2)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D005472:Fluorouracil; D015658:HIV Infections; D006801:Humans; D008297:Male; D016685:Mitomycin",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "254-62",
"pmc": null,
"pmid": "26853985",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Squamous cell carcinoma of the anal canal treated with chemoradiotherapy in a patient with HIV.",
"title_normalized": "squamous cell carcinoma of the anal canal treated with chemoradiotherapy in a patient with hiv"
} | [
{
"companynumb": "JP-BAUSCH-BL-2016-007927",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RALTEGRAVIR POTASSIUM"
},
"drugadditional": n... |
{
"abstract": "Veno-venous extracorporeal membrane oxygenation (ECMO) is typically instituted in severe respiratory failure, defined by Lung Injury Score, and caused either by pulmonary or extra-pulmonary reversible disease processes. These processes will have led to acute worsening of oxygenation and/or respiratory acidosis together with an inability to provide safe, lung protective, mechanical ventilation. Patients with underlying chronic immunosuppression or haematological malignancies treated with ECMO for severe respiratory failure have poor short- and long-term functional and survival outcomes. Consequently, in many centres, a diagnosis of haematological malignancy is considered a contraindication to provision of ECMO support for severe respiratory failure. We present a case of a 51-year-old female who attended her local hospital with symptoms suggestive of community-acquired pneumonia. Within a few days, there was progression to severe respiratory failure, initially managed with invasive mechanical ventilation but rapidly deteriorating respiratory failure triggered referral for ECMO support. Initial investigations on ECMO demonstrated features of acute myeloblastic leukaemia with a superimposed community-acquired pneumonia. This was successfully managed with supportive treatment alongside mechanical respiratory therapy and targeted chemotherapy, achieving complete remission and full functional recovery.",
"affiliations": "Department of Critical Care, Guy's and St Thomas' NHS Foundation Trust, London, UK. manish55pandey@gmail.com.;Department of Critical Care, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Department of Critical Care, Guy's and St Thomas' NHS Foundation Trust, London, UK.",
"authors": "Pandey|Manish|M|http://orcid.org/0000-0001-9132-3515;Peetermans|Marijke|M|;Doyle|Andrew J|AJ|;Dillon|Richard|R|;Meadows|Christopher I S|CIS|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s10047-020-01225-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1434-7229",
"issue": "24(3)",
"journal": "Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs",
"keywords": "Acute myeloblastic leukaemia; Extracorporeal membrane oxygenation; Haematological malignancy",
"medline_ta": "J Artif Organs",
"mesh_terms": "D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008875:Middle Aged; D011014:Pneumonia; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency",
"nlm_unique_id": "9815648",
"other_id": null,
"pages": "387-391",
"pmc": null,
"pmid": "33180228",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31188474",
"title": "Extracorporeal membrane oxygenation in a patient with newly diagnosed acute myeloblastic leukaemia presenting with severe respiratory failure.",
"title_normalized": "extracorporeal membrane oxygenation in a patient with newly diagnosed acute myeloblastic leukaemia presenting with severe respiratory failure"
} | [
{
"companynumb": "GB-drreddys-LIT/UKI/22/0147748",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": "4",
... |
{
"abstract": "We describe one patient and review the literature to define delayed posthypoxic leukoencephalopathy, its etiology, pathophysiology and prognosis. We present a 54-year-old man with confusion and diffuse rigidity following a morphine overdose that had required intubation three weeks previously. A brain CT scan showed bilateral globi pallidi hypodensities and diffusion-weighted brain MRI (DWI) was consistent with acute cerebral anoxia. On day 20 after the initial presentation, the patient insidiously progressed to a state of \"akinetic mutism\". The brain MRI showed diffuse hyperintensity of the white matter on T2-weighted fluid-attenuated inversion recovery sequences. These areas were bright on DWI and were hypointense on the apparent diffusion coefficient map. An extensive autoimmune, metabolic, toxicological, and infectious work-up included arylsulfatase A enzyme levels, which were unremarkable. Therapy with levodopa was initiated with subsequent improvement of the diffuse rigidity. At discharge, the patient continued to be lethargic with moderate rigidity but began to display signs of recovery. He eventually fully recovered with residual mild confusion. Thus, delayed hypoxic leukoencephalopathy is a rare complication of hypoxic-ischemic encephalopathy, occurring in 2.75% of victims of carbon monoxide poisoning. It typically manifests two to 40 days after apparent recovery from an obtunded state. Prognosis is variable, but recovery can be complete. This report brings to light an important syndrome that can easily be misdiagnosed. Patients who present with these clinical and radiographic features should be treated fully and given time to recover without abrupt withdrawal of care.",
"affiliations": "Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA. ricsalmont@hotmail.com",
"authors": "Salazar|R|R|;Dubow|J|J|",
"chemical_list": "D009020:Morphine",
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2012.01.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "19(7)",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": null,
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D038524:Diffusion Magnetic Resonance Imaging; D062787:Drug Overdose; D006801:Humans; D002534:Hypoxia, Brain; D056784:Leukoencephalopathies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009020:Morphine",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "1060-2",
"pmc": null,
"pmid": "22555127",
"pubdate": "2012-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed posthypoxic leukoencephalopathy following a morphine overdose.",
"title_normalized": "delayed posthypoxic leukoencephalopathy following a morphine overdose"
} | [
{
"companynumb": "US-RANBAXY-2012US-59347",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "An 18-year-old woman, gravida 3, para 2, presented at 24 weeks of gestation with preterm premature rupture of membranes. She was started on nifedipine for tocolysis and to facilitate administration of steroids. Two and a half hours later, the patient developed tachycardia and hypotension. Sepsis from chorioamnionitis, acute cardiac event and pulmonary embolism were considered as differential diagnoses. Laboratory and radiological investigations, however, ruled out these possible causes of haemodynamic instability. Her clinical condition deteriorated and hypotension remained intractable despite aggressive fluid resuscitation. An emergency caesarean section at 24 weeks of gestation was carried out in the interest of saving the mother's life. The haemodynamic status of the patient recovered rapidly postcaesarean section. This case report highlights the rare but potentially serious adverse effects of hypotension in administration of nifedipine; and thus reminds us of the importance of judicious prescription and careful titration of nifedipine as a tocolytic.",
"affiliations": "Department of Obstetrics & Gynaecology, KK Hospital, Singapore, Singapore.;Department of Obstetrics & Gynaecology, KK Hospital, Singapore, Singapore.",
"authors": "Khoo|Freda|F|;Mathur|Manisha|M|",
"chemical_list": "D015149:Tocolytic Agents; D009543:Nifedipine",
"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": "D000293:Adolescent; D002585:Cesarean Section; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D005440:Fluid Therapy; D005865:Gestational Age; D006439:Hemodynamics; D006801:Humans; D007022:Hypotension; D009543:Nifedipine; D011247:Pregnancy; D011248:Pregnancy Complications; D015145:Tocolysis; D015149:Tocolytic Agents",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25515131",
"pubdate": "2014-12-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15777455;24276256;9578274;11336775;9241299;14664874;11058528;24090282;18685158",
"title": "Severe resistant maternal hypotension following tocolysis with nifedipine.",
"title_normalized": "severe resistant maternal hypotension following tocolysis with nifedipine"
} | [
{
"companynumb": "SG-ACTAVIS-2015-18040",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIFEDIPINE"
},
"drugadditional": null,
... |
{
"abstract": "Although Mycoplasma genitalium (MG) is an acknowledged cause of nongonococcal urethritis (NGU), access to diagnostic testing is limited. Syndromic management is common, yet little is known about natural history.\n\n\n\nBetween August 2014 and April 2016, 13 heterosexual men aged ≥16 years with MG were identified within a cohort study of men with and without NGU attending an urban sexually transmitted diseases clinic. Men had 6-7 monthly visits. NGU was defined as ≥5 polymorphonuclear leukocytes per high-power field on urethral Gram stain plus either visible urethral discharge or urethral symptoms. Men with NGU received 1 g of azithromycin. Men with persistent NGU received moxifloxacin 400 mg for 14 days. First-void urine was retrospectively tested for MG using transcription-mediated amplification. Resistance-associated mutations were detected by polymerase chain reaction (PCR) and sequencing. Organism load was determined by quantitative PCR.\n\n\n\nSixty-two percent of MG-positive men had macrolide resistance-mediating mutations (MRMM) at enrollment; 31% had parC mutations (all outside the quinolone resistance-determining region). MG persisted after azithromycin in 7 men, 6 of whom had MRMM. The median duration of persistence in the absence of curative therapy was 143 days (range, 21-228). Five men experienced symptom resolution after azithromycin, but MG persisted for another 89-186 days before moxifloxacin. Organism load was somewhat lower in MRMM than wild-type infections (P = .16).\n\n\n\nThe high prevalence of macrolide resistance and long duration of infection after symptom resolution highlights the need for diagnostic MG testing of men with NGU to direct therapy.",
"affiliations": "Department of Epidemiology, University of Washington, Seattle.;Statens Serum Institut, Copenhagen, Denmark.;Public Health-Seattle & King County, University of Washington, Seattle.;Public Health-Seattle & King County, University of Washington, Seattle.;Department of Epidemiology, University of Washington, Seattle.;Department of Epidemiology, University of Washington, Seattle.;Center for AIDS and STD, University of Washington, Seattle.;Center for AIDS and STD, University of Washington, Seattle.;Department of Epidemiology, University of Washington, Seattle.;Department of Epidemiology, University of Washington, Seattle.",
"authors": "Romano|Sarah S|SS|;Jensen|Jørgen S|JS|;Lowens|M Sylvan|MS|;Morgan|Jennifer L|JL|;Chambers|Laura C|LC|;Robinson|Tashina S|TS|;Totten|Patricia A|PA|;Soge|Olusegun O|OO|;Golden|Matthew R|MR|;Manhart|Lisa E|LE|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018942:Macrolides",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciy843",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "69(1)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "\n Mycoplasma genitalium\n ; antibiotic resistance; heterosexual men; urethritis",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D058345:Asymptomatic Infections; D024881:Drug Resistance, Bacterial; D006069:Gonorrhea; D020010:Heterosexuality; D006801:Humans; D018942:Macrolides; D008297:Male; D009175:Mycoplasma Infections; D045704:Mycoplasma genitalium; D012189:Retrospective Studies; D014526:Urethritis; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "113-120",
"pmc": null,
"pmid": "30281079",
"pubdate": "2019-06-18",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "11679571;16940898;16954265;20942656;21734246;22564463;22782815;23588134;23658265;24052013;24280088;24729494;24894419;25537875;25900174;26042815;26240201;26286546;27307460;27331225;27505296;28118803;28472225;28838078;28923377;29281972;29342269;29465649;29883482",
"title": "Long Duration of Asymptomatic Mycoplasma genitalium Infection After Syndromic Treatment for Nongonococcal Urethritis.",
"title_normalized": "long duration of asymptomatic mycoplasma genitalium infection after syndromic treatment for nongonococcal urethritis"
} | [
{
"companynumb": "US-TEVA-2020-US-1827418",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": nu... |
{
"abstract": "OBJECTIVE\nManagement of granulomatosis with polyangiitis (GPA)-associated peripheral ulcerative keratitis (PUK) is challenging and lacks definite guidelines. We aimed to summarize our treatment and outcome experience with patients with GPA-PUK.\n\n\nMETHODS\nThe Massachusetts Eye Research and Surgery Institution patient database was searched from 2005 to 2015 to identify patients with diagnosis of PUK who suffered from GPA. Individual patient histories were examined, and treatment strategies and outcomes were summarized.\n\n\nRESULTS\nThere were 16 patients who started treatment with a mean duration follow-up of 64 months (range: 12-110 mo). Rituximab and cyclophosphamide, either alone or in combination with other agents, were the most successful agents in controlling inflammation. Rituximab was administered in 11 patients with remission being achieved in all. Cyclophosphamide successfully controlled inflammation in 50% (5/10). Two of the patients (2/5, 40%) who had achieved initial control on cyclophosphamide had flares of their PUK. Two of 11 (18%) patients on rituximab had flares of scleritis and orbital inflammation but not PUK. Two patients, one in each treatment group, stopped treatment after achieving remission after 6 months of therapy but suffered disease recurrence within 2 months of treatment cessation.\n\n\nCONCLUSIONS\nRituximab achieved a high rate of disease control in PUK patients with GPA and is the preferred agent in halting disease progression.",
"affiliations": "*Massachusetts Eye Research and Surgery Institution, Waltham, MA; †Ocular Immunology and Uveitis Foundation, Waltham, MA; ‡Massachusetts Eye and Ear Infirmary, Boston, MA; §Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran; and ¶Department of Ophthalmology, Harvard Medical School, Boston, MA.",
"authors": "Ebrahimiadib|Nazanin|N|;Modjtahedi|Bobeck S|BS|;Roohipoor|Ramak|R|;Anesi|Stephen D|SD|;Foster|C Stephen|CS|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000000919",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "35(11)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003320:Corneal Ulcer; D003520:Cyclophosphamide; D005260:Female; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1459-1465",
"pmc": null,
"pmid": "27362884",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful Treatment Strategies in Granulomatosis With Polyangiitis-Associated Peripheral Ulcerative Keratitis.",
"title_normalized": "successful treatment strategies in granulomatosis with polyangiitis associated peripheral ulcerative keratitis"
} | [
{
"companynumb": "US-BAXTER-2017BAX003465",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Cerebral sinus venous thrombosis (CSVT) is a relatively rare but potentially devastating disease. Medical management of CSVT with systemic anticoagulation has been the mainstay treatment strategy with these patients. However, some patients may not respond to this treatment or may present with very severe symptoms indicating more aggressive management strategies. The authors present the case of a pediatric patient who presented with severe CSVT, who underwent successful recanalization with endovascular tissue plasminogen activator (tPA) and abciximab. To the authors' knowledge there are no cases of endovascular thrombolysis for CSVT described in the literature in which abciximab has been used in conjunction with tPA. The authors also review the literature regarding the agents used and outcome in pediatric patients with CSVT after endovascular thrombolysis. The use of abciximab in conjunction with tPA may be considered in patients whose blood is hypercoagulable and in whom the treatment strategy is to obtain acute recanalization and long-term venous patency. However, the use of adjunctive agents increases the risk of hemorrhagic complications and must be done judiciously.",
"affiliations": "Departments of Neurosurgery and.",
"authors": "Khan|Imad S|IS|;Ladner|Travis R|TR|;Satti|Komal F|KF|;Ehtesham|Moneeb|M|;Jordan|Lori C|LC|;Singer|Robert J|RJ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D010959:Tissue Plasminogen Activator; D000077284:Abciximab",
"country": "United States",
"delete": false,
"doi": "10.3171/2013.9.PEDS13335",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1933-0707",
"issue": "13(1)",
"journal": "Journal of neurosurgery. Pediatrics",
"keywords": null,
"medline_ta": "J Neurosurg Pediatr",
"mesh_terms": "D000077284:Abciximab; D000293:Adolescent; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D002544:Cerebral Infarction; D057510:Endovascular Procedures; D006261:Headache; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D008279:Magnetic Resonance Imaging; D008297:Male; D010296:Parietal Lobe; D012851:Sinus Thrombosis, Intracranial; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "101463759",
"other_id": null,
"pages": "68-71",
"pmc": null,
"pmid": "24180679",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Endovascular thrombolysis for pediatric cerebral sinus venous thrombosis with tissue plasminogen activator and abciximab.",
"title_normalized": "endovascular thrombolysis for pediatric cerebral sinus venous thrombosis with tissue plasminogen activator and abciximab"
} | [
{
"companynumb": "US-JNJFOC-20140104776",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABCIXIMAB"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nThis study aimed to report motor tics worsening by prednisolone acute treatment, despite the use of aripiprazole and clonidine. It was also aimed to discuss the mechanisms involved in neuropsychiatric adverse effects with the use of corticosteroids.\n\n\nMETHODS\nIt was reported a 7-year-old boy patient with a history of autism spectrum disorder and motor tics. He has remitted motor tics with an association between aripiprazole and clonidine. However, was registered motor tics' recurrence with acute use of prednisolone.\n\n\nCONCLUSIONS\nThe neuropsychiatric adverse effects mediated by corticosteroid use are low explored, mainly in pediatric clinical practice. The prednisolone prescription is widespread in childhood and, considering some vulnerable conditions to this type of adverse effects, is imperative.",
"affiliations": "D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.",
"authors": "Figueiredo|Tiago|T|",
"chemical_list": "D000068180:Aripiprazole; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000463",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "44(4)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000068180:Aripiprazole; D000067877:Autism Spectrum Disorder; D001321:Autistic Disorder; D002648:Child; D006801:Humans; D008297:Male; D011239:Prednisolone; D020323:Tics",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "145-147",
"pmc": null,
"pmid": "34132672",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Recurrence of Motor Tics Mediated by Oral Prednisolone Use in Autistic Children: A Case Report.",
"title_normalized": "the recurrence of motor tics mediated by oral prednisolone use in autistic children a case report"
} | [
{
"companynumb": "BR-ALKEM LABORATORIES LIMITED-BR-ALKEM-2021-04146",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"dru... |
{
"abstract": "T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that has historically been associated with a very poor prognosis. Nevertheless, despite a lack of incorporation of novel agents, the development of intensified T-ALL-focused protocols has resulted in significant improvements in outcome in children. Through the use of several representative cases, we highlight the key changes that have driven these advances including asparaginase intensification, the use of induction dexamethasone, and the safe omission of cranial radiotherapy. We discuss the results of recent trials to explore key topics including the implementation of risk stratification with minimal residual disease measurement and how to treat high-risk subtypes such as early T-cell precursor ALL. In particular, we address current discrepancies in treatment between different cooperative groups, including the use of nelarabine, and provide rationales for current treatment protocols for both T-ALL and T-lymphoblastic lymphoma.",
"affiliations": "Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.;Department of Haematology, University College London (UCL) Cancer Institute, London, United Kingdom; and.",
"authors": "Teachey|David T|DT|;O'Connor|David|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2019001557",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "135(3)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D018365:Neoplasm, Residual; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "159-166",
"pmc": null,
"pmid": "31738819",
"pubdate": "2020-01-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30842058;20010622;20016537;23889312;22494120;19546402;20007809;19747876;19694717;2902379;24190124;24924991;27114587;30809797;23358966;8151317;24708207;28671688;15908649;9614257;27560110;7949185;10071272;26465987;30209392;25976383;11187917;19147408;19553647;21719599;26853647;27069254;20010625;26109265;28771663;31353059;29051182;27913532;21474675;26485054;25308804;26220040;29938780;28045622;8667921;26755523;28484265;30138085;10627444;31124581;22237106;30466748;25755211",
"title": "How I treat newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in children.",
"title_normalized": "how i treat newly diagnosed t cell acute lymphoblastic leukemia and t cell lymphoblastic lymphoma in children"
} | [
{
"companynumb": "US-SERVIER-S20004054",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGASPARGASE"
},
"drugadditional": "3",
... |
{
"abstract": "Pleural recurrences are a hallmark of thymomas, and represent a challenge for multidisciplinary management. The purpose of this study was to assess the feasibility and the results in terms of morbidity, mortality and survival rates, of Intra-Thoracic Chemo-Hyperthermia (ITCH) for the treatment of pleural recurrences of thymomas.\n\n\n\nRetrospective analysis of 19 consecutives patients between 1997 and 2015 treated by surgical cytoreduction (pleurectomy) followed by ITCH with 25mg/m2 of mitomycin, and 50mg/m2 of Cisplatin.\n\n\n\nThere were 8 men and 11 women with a median age of 44 years. ITCH was combined with pleurectomy alone in 4 (22%) patients, pleurectomy and wedge resections in 14 (74%) patients; 1 (5%) patient had a pleuropneumonectomy. There were no perioperative deaths, and 5 patients (26%) presented with postoperative complication, including 3 (16%) cases related to chemotherapy (one case of reversible grade 2 bone marrow aplasia, and 2 cases of reversible, acute kidney failure). The median length of stay in intensive care unit and hospital were 1day and 10days, respectively. After a median follow-up period of 39 months (range 10-127 months), median disease-free survival was 42 months. Five patients (26%) died during follow-up.\n\n\n\nOur data indicate that ITCH is a feasible option for selected patients with pleural recurrence of thymomas. ITCH clearly provides long local control, without major safety issues, and prolonged survival may be achieved in selected patients. This therapeutic option should be discussed at a multidisciplinary tumor board.",
"affiliations": "Department of Thoracic Surgery, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677 Lyon, France; Université de Lyon, Université Lyon 1, INRA, UMR754, UMS 3444, SFR BioSciences, F-69007 Lyon, France.;Université de Lyon, Université Lyon 1, INRA, UMR754, UMS 3444, SFR BioSciences, F-69007 Lyon, France; Department of Respiratory Medicine, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677 Lyon, France. Electronic address: nicolas.girard@chu-lyon.fr.;Department of Thoracic Surgery, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677 Lyon, France; Department of Surgery, Centre Léon-Berard, Cancer Research Center of Lyon 28, F-69008 Lyon, France.;Department of Thoracic Surgery, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677 Lyon, France.;Université de Lyon, Université Lyon 1, INRA, UMR754, UMS 3444, SFR BioSciences, F-69007 Lyon, France; Department of Pathology, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677 Lyon, France.;Department of Anesthesiology and Reanimation, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677 Lyon, France.;Department of Anesthesiology and Reanimation, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677 Lyon, France.;Université de Lyon, Université Lyon 1, INRA, UMR754, UMS 3444, SFR BioSciences, F-69007 Lyon, France.;Department of Respiratory Medicine, Lyon Sud Hospital, Hospices Civils de Lyon, F-69495 Pierre Benite, France.;Departement of General Surgery, Lyon Sud Hospital, Hospices Civils de Lyon, F-69495 Pierre Benite, France.;Department of Thoracic Surgery, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677 Lyon, France; Université de Lyon, Université Lyon 1, INRA, UMR754, UMS 3444, SFR BioSciences, F-69007 Lyon, France.",
"authors": "Maury|Jean Michel|JM|;Girard|Nicolas|N|;Tabutin|Mayeul|M|;Grima|Renaud|R|;Chalabreysse|Lara|L|;Pavlakovic|Isabelle|I|;Sayag-Beaujard|Annie|A|;Leroux|Caroline|C|;Souquet|Pierre-Jean|PJ|;Glehen|Olivier|O|;Tronc|François|F|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2017.02.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "108()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Chemotherapy; Pleural recurrence; Surgery; Thymoma",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D015897:Comorbidity; D065426:Cytoreduction Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D010997:Pleural Neoplasms; D012189:Retrospective Studies; D016019:Survival Analysis; D013945:Thymoma; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "28625619",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intra-Thoracic Chemo-Hyperthermia for pleural recurrence of thymoma.",
"title_normalized": "intra thoracic chemo hyperthermia for pleural recurrence of thymoma"
} | [
{
"companynumb": "FR-ACCORD-052333",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "Physicians are often guided by laboratory values. When a clinical presentation does not match laboratory values, one must consider the possibility that these values may be falsely increased or decreased. A common cause is analytical interference.\n\n\n\nA 57-year-old male, presenting with fatigue and palpitations, had high TSH and normal FT4 values. Although there were no fitting clinical symptoms for these values, the patient was treated with levothyroxine assuming he had subclinical hypothyroidism. TSH levels remained high, however, whereas FT4 levels increased and the patient developed thyrotoxicosis. Eventually, it was discovered that the TSH was falsely elevated.\n\n\n\nThe patient turned out to have macro TSH, where TSH forms conjunctions with IgG into larger molecules. These conjugates cause a rarely occurring interference during laboratory analysis, resulting in a falsely increased TSH value.",
"affiliations": "Medisch Spectrum Twente, afd. Interne Geneeskunde, Enschede.;Maastricht UMC, Centraal Diagnostisch Laboratorium.;Erasmus MC, afd. Klinische Chemie, Rotterdam.;Medisch Spectrum Twente, afd. Interne Geneeskunde, Enschede.;Medisch Spectrum Twente, afd. Klinische Chemie, Enschede.",
"authors": "Tibben|N E|NE|;Bons|J A P|JAP|;van den Berg|S A A|SAA|;Huisman|J|J|;Krabbe|J G|JG|",
"chemical_list": "D007074:Immunoglobulin G; D013972:Thyrotropin; D013974:Thyroxine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "164()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D005189:False Positive Reactions; D006801:Humans; D006980:Hyperthyroidism; D007037:Hypothyroidism; D007074:Immunoglobulin G; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D013960:Thyroid Function Tests; D013971:Thyrotoxicosis; D013972:Thyrotropin; D013974:Thyroxine",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32757509",
"pubdate": "2020-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Don't be guided purely by numbers: false increased TSH values due to analytical interference.",
"title_normalized": "don t be guided purely by numbers false increased tsh values due to analytical interference"
} | [
{
"companynumb": "NL-IBSA PHARMA INC.-2021IBS000025",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE SODIUM"
},
"drugadditio... |
{
"abstract": "Suicidal intoxication from massive propranolol ingestion is rare. Surprisingly, no reported cases have involved physicians. The author herein reports a case of self-poisoning death due to ingestion of propranolol by a young male physician. A 31-year-old man with major depressive disorder was found dead in his dormitory room. Fifteen empty packages, each having contained ten 40-mg propranolol tablets, were found without any tablets leftover in his room. A suicide note was also found in his room. He was thus alleged to have ingested 6 g of propranolol for self-poisoning. Autopsy findings revealed approximately 150 mL of pink fluid with some partially dissolved pink tablets in the stomach. No anatomic cause of death was found, except for mild dilatation of cerebral ventricles. Toxicologic analysis revealed propranolol in his blood and gastric contents. The cause of death was attributed to acute cardiac arrest due to severe acute propranolol intoxication from self-poisoning caused by major depressive disorder possibly secondary to organic brain syndrome.",
"affiliations": "From the Department of Forensic Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Srettabunjong|Supawon|S|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol",
"country": "United States",
"delete": false,
"doi": "10.1097/PAF.0000000000000332",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "38(3)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000328:Adult; D003865:Depressive Disorder, Major; D005766:Gastrointestinal Contents; D006801:Humans; D008297:Male; D010820:Physicians; D011433:Propranolol; D013405:Suicide",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "266-268",
"pmc": null,
"pmid": "28691951",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal Self-Poisoning With Massive Propranolol Ingestion in a Young Male Physician.",
"title_normalized": "fatal self poisoning with massive propranolol ingestion in a young male physician"
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"abstract": "BACKGROUND\nWe are describing an unusual case of severe hyperglycemia and hypernatremia, resistant to treatment.\n\n\nMETHODS\nA thirty year old female with adenocarcinoma of rectum was admitted with increasing lethargy, headache and drowsiness. She deteriorated rapidly and had cardiac arrest, following which she remained comatose. Her initial serum glucose and sodium were normal, but after receiving dexamethasone and mannitol, the serum glucose progressively increased to 54.7 mmol/L and sodium to 175 mmol/L, despite receiving very high dose of intravenous (IV) insulin infusion. She was evaluated for diabetes insipidus because of continued polyuria even after correction of hyperglycemia. Her serum osmolality was 337 mmol/kg, and urine osmolality was 141 mmol/kg which rose to 382 mmol/kg, after receiving 4 mcg of IV Desmopressin.\n\n\nCONCLUSIONS\nOur patient developed central diabetes insipidus post cardiac arrest and severe dehydration because of diabetes insipidus. Stress of critical illness, dehydration, dexamethasone and IV dextrose infusion were likely responsible for this degree of severe and resistant to treatment hyperglycemia.",
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"authors": "Masood|Muhammad|M|;Kumar|Suneel|S|;Asghar|Ali|A|;Jabbar|Abdul|A|",
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"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central 1756-0500-6-3252394742910.1186/1756-0500-6-325Case ReportAn unusual case of central diabetes insipidus & hyperglycemic hyperosmolar state following cardiorespiratory arrest Masood Muhammad Qamar 1qamar.masood@aku.eduKumar Suneel 2drsuneel69@yahoo.comAsghar Ali 1ali.asghar@aku.eduJabbar Abdul 1haj1960@gmail.com1 Department of Medicine, Section of Endocrinology, Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan2 Department of Medicine, Endocrinology, Sultan Qaboos University Hospital, Muscat, Oman2013 16 8 2013 6 325 325 25 4 2013 12 8 2013 Copyright © 2013 Masood et al.; licensee BioMed Central Ltd.2013Masood et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nWe are describing an unusual case of severe hyperglycemia and hypernatremia, resistant to treatment.\n\nCase presentation\nA thirty year old female with adenocarcinoma of rectum was admitted with increasing lethargy, headache and drowsiness. She deteriorated rapidly and had cardiac arrest, following which she remained comatose. Her initial serum glucose and sodium were normal, but after receiving dexamethasone and mannitol, the serum glucose progressively increased to 54.7 mmol/L and sodium to 175 mmol/L, despite receiving very high dose of intravenous (IV) insulin infusion. She was evaluated for diabetes insipidus because of continued polyuria even after correction of hyperglycemia. Her serum osmolality was 337 mmol/kg, and urine osmolality was 141 mmol/kg which rose to 382 mmol/kg, after receiving 4 mcg of IV Desmopressin.\n\nConclusion\nOur patient developed central diabetes insipidus post cardiac arrest and severe dehydration because of diabetes insipidus. Stress of critical illness, dehydration, dexamethasone and IV dextrose infusion were likely responsible for this degree of severe and resistant to treatment hyperglycemia.\n\nCentralDiabetesInsipidusHyperosmolarHyperglycemicStateCardiopulmonaryArrest\n==== Body\nBackground\nCentral diabetes insipidus (DI) is characterized by decreased release of antidiuretic hormone (ADH), resulting in a variable degree of polyuria. Lack of ADH can be caused by neurosurgery or trauma, primary or secondary tumors, infiltrative diseases, idiopathic DI, hypoxic encephalopathy or severe ischemia. Cases of DI are described in literature in association with cardiopulmonary arrest, severe hypoxia secondary to drug induced respiratory failure as well as carbon monoxide poisoning [1-3].\n\nCase presentation\nOur patient was a 30 year old female recently diagnosed with adenocarcinoma of rectum with metastasis to inguinal lymph nodes. She underwent diversion colostomy. The procedure and hospital course was uneventful, and she was discharged two days later with further plan for chemotherapy and radiation therapy two weeks post surgery.\n\nTwelve days later, she presented in emergency department at 2230 hours with complains of headache and progressive lethargy. She was drowsy but arousable; otherwise her neurological and systemic examination was unremarkable. Laboratory data showed leucocytosis with left shift, mild hypercalcemia and hypokalemia. Serum sodium and glucose were normal (Table 1). She was given IV fluids with normal saline, potassium replacement and Pamidronate infusion. IV hydrocortisone 200 mg, Ceftriaxone and acyclovir were given emperically. MRI Brain and CSF analysis were normal.\n\nTable 1 Laboratory parameters\n\nTest\tEmergency room\tDay 1\tDay 2\tDay 3\t\n \t \t \t0600 hours\t1500 hours\tAfter IV fluids\tAfter desmospressin\t\nGlucose (mmol/L)\t6.7\t“Hi” on CBG\t“Hi” on CBG\t54.7\t9.2\t \t\nSodium (mmol/L)\t146\t165\t170\t175\t164\t140\t\nPotassium (mmol/L)\t2.0\t3.9\t2.4\t2.8\t4.7\t5.3\t\nChloride (mmol/L)\t108\t130\t145\t \t143\t \t\nBircarbonate (mmol/L)\t23.8\t20.7\t19.7\t \t17.7\t \t\nSerum Osmolality (mmol/Kg)\t \t \t \t \t337\t294\t\nUrine Osmolality (mmol/Kg)\t \t \t \t \t141\t382\t\nSpot Urine Na (mmol/L)\t \t \t \t \t52\t136\t\nBUN (mmol/L)\t7.8\t9.6\t10.7\t2.5\t \t\nCreatinine (μmol/L)\t70.7\t88.4\t97.2\t44.2\t \t\nCalcium (mmol/L)\t2.75\t2.92\t \t2.20\t \t\nTotal Intake (Liters per 24 hours)\t \t0.6 (Only 3 hours)\t8.7\t18.8\t \t\nUrine output (Liters per 24 hours)\t \t1.5 (Only 3 hours)\t6.7\t7.2\t \t\nNext day, she deteriorated rapidly with increasing restlessness, incoherent speech, followed by tonic clonic seizure. Later in the evening, she had cardiac arrest for which cardiopulmonary resuscitation (CPR) was done for three minutes.\n\nShe remained comatose after this episode. She was loaded with Phenytoin and started on IV dexamethasone and mannitol. She was also given isotonic saline boluses, plasma expanders (gelatin polypeptide), and dopamine and norepinephrine infusion.\n\nOn the same day, her capillary blood glucose (CBG) was noted to be more than 16 mmol/L. She was started on IV insulin infusion at 10 units per hour via insulin syringe pump, which was progressively increased but CBG remained HI (>27 mmol/L) on glucometer. After 24 hours on IV insulin infusion, her serum glucose (SG) was 54.7 mmol/L while she was still on 60 units per hour IV insulin infusion. Her serum sodium (Na) after cardiac arrest rose to 165 mmol/L. She was given IV Dextrose water 5% (D5W). Despite that, next day Na reached to 170 mmol/L while SG was 54.7 mmol/L (see Table 1). She was making urine about 250–400 mL/hour while receiving similar amount of IV fluids.\n\nAn assessment of hyperosmolar hyperglycemic state with severe dehydration was made. Glucocorticoids and stress of acute illness were thought to be responsible for initial rise in glucose and later osmotic diuresis because of mannitol and glycosuria resulted in severe dehydration and hypernatremia.\n\nPatient was treated with IV 0.45% saline and D5W (total of eight liters overnight). After receiving fluids, her CBG gradually decreased to 9.2 mmol/L and insulin dose was titrated down to 18 units per hour. Her Na also decreased to 164 mmol/L. However after achieving near normal glycemia and alleviating osmotic diuresis, her urine output remained elevated (approximately 400 mL/hour). She was then evaluated for diabetes insipidus.\n\nHer serum osmolality was 337 mmol/kg and urine osmolality was 141 mmol/kg. Urine osmolality rose to 382 mmol/kg after receiving 4 mcg of IV desmopressin. After desmopressin, her urine output dropped and serum Na gradually improved to 140 mmol/L. After desmopressin, her insulin requirement substantially decreased and she was taken off IV insulin. After correction of her metabolic derangements, she remained comatose and totally dependent on ventilator. At that point, the family decided to withdraw the support.\n\nDiscussion\nWe believe that hypoxic damage to the posterior pituitary and/or hypothalamus during cardiac arrest was responsible for the central DI in this patient. A urine osmolality of 141 mmol/kg when serum osmolality was 337 mmol/kg was diagnostic of DI and response to desmopressin confirmed the central cause.\n\nDI following cardiorespiratory arrest is a rare event and has been described in post cardiopulmonary arrest patients [1-4]. In the cases described by Udoshi et al. [4], no lesion was found in the posterior pituitary and hypothalamus on autopsy, however the second patient had infarction of anterior pituitary. Hypothalamic dysfunction i.e. wide fluctuations in heart rate, blood pressure and body temperature were noted in both patients.\n\nDI has also been reported with pituitary tumor apoplexy [5], after moderate to severe traumatic brain injury [6], acute sheehan syndrome [7] and in patients with long standing hypopituitarism secondary to sheehan syndrome [8].\n\nA case of non-ketotic hyperglycemic coma in an 18 year old male, with previously undiagnosed diabetes mellitus, was described in association with hemorrhagic pituitary apoplexy. MRI in this patient revealed a heterogeneous mass, a prolactinoma, arising from an expanded sella turcica and extending into the suprasellar cistern [9]. In the two cases described by Udoshi et al. [4], both developed profound hyperglycemia.\n\nStress and drug induced hyperglycemia was culminated in profound and resistant to treatment hyperglycemia in our patient. This was due to extreme dehydration secondary to DI, and the hyperglycemia mainly responded to fluid resuscitation.\n\nConclusion\nOur patient developed central DI post cardiac arrest manifested as hypernatremia and severe dehydration, responsible for this degree of severe and resistant to treatment hyperglycemia.\n\nConsent\nWritten informed consent was obtained from the patient’s brother (next of kin) for publication of this case report. A copy of the written consent is available for review by the Series Editor of this journal.\n\nAbbreviations\nIV: Intravenous; DI: Diabetes insipidus; ADH: Antidiuretic hormone; CPR: Cardiopulmonary resuscitation; CBG: Capillary blood glucose; SG: Serum glucose; Na: Serum sodium; D5W: Dextrose water 5%.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nQM gave the concept of research paper, and critically reviewed the manuscript. SK led the acquisition of data, review of literature, and drafted the manuscript. AA reviewed the manuscript. AJ critically reviewed the manuscript. All authors read and approved the manuscript.\n\nAuthors’ information\nQM is fellow of the American College of Physicians & the American College of Endocrinology. He is Assistant Professor in Diabetes, Endocrinology & Metabolism, Department of Medicine, Aga Khan University Hospital. He was involved in the medical management of the patient. SK is fellow of the College of Physicians & Surgeons of Pakistan. He is Senior Instructor in Endocrinology, Department of Medicine, Sultan Qaboos University Hospital. He was involved in the medical management of the patient. AA is member of the Royal Colleges of Physicians of the United Kingdom. He is Fellow in Endocrinology, Diabetes & Metabolism, Department of Medicine, Aga Khan University Hospital. He was involved in the medical management of the patient. AJ is fellow of the Royal College of Physicians of London. He is Professor in Diabetes, Endocrinology & Metabolism, Department of Medicine, Aga Khan University Hospital.\n==== Refs\nRothschild M Shenkman L Diabetes insipidus following cardiorespiratory arrest JAMA 1977 238 7 620 621 10.1001/jama.1977.03280070060026 577964 \nArisaka O Arisaka M Ikebe A Niijima S Shimura N Hosaka A Yabuta K Central diabetes insipidus in hypoxic brain damage Childs Nerv Syst 1992 8 2 81 82 10.1007/BF00298445 1591751 \nBeasley EW 3rdPhillips LS Polyuria and refractory hypernatremia after cardiopulmonary arrest Am J Med 1987 82 2 347 349 10.1016/0002-9343(87)90084-2 3812534 \nUdoshi MB Trivedi AD Desai RC Lichtenstein E Diabetes insipidus following cardiorespiratory arrest J Natl Med Assoc 1981 73 9 797 800 7277513 \nSweeney AT Blake MA Adelman LS Habeebulla S Nachtigall LB Duff JM Tully GL 3rdPituitary apoplexy precipitating diabetes insipidus Endocr Pract 2004 10 2 135 138 10.4158/EP.10.2.135 15256331 \nAgha A Thornton E O’Kelly P Tormey W Phillips J Thompson CJ Posterior pituitary dysfunction after traumatic brain injury J Clin Endocrinol Metab 2004 89 12 5987 5992 10.1210/jc.2004-1058 15579748 \nRobalo R Pedroso C Agapito A Borges A Acute Sheehan’s syndrome presenting as central diabetes insipidus BMJ Case Rep 2012 10.1136/bcr-2012-007022 \nAtmaca H Tanriverdi F Gokce C Unluhizarci K Kelestimur F Posterior pituitary function in Sheehan’s syndrome Eur J Endocrinol 2007 156 5 563 567 10.1530/EJE-06-0727 17468192 \nKamboj MK Zhou P Molofsky WJ Franklin B Shah B David R Kohn B Hemorrhagic pituitary apoplexy in an 18 year-old male presenting as non-ketotic hyperglycemic coma (NKHC) J Pediatr Endocrinol Metab 2005 18 6 611 615 16042331\n\n",
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"medline_ta": "BMC Res Notes",
"mesh_terms": "D000328:Adult; D016887:Cardiopulmonary Resuscitation; D003919:Diabetes Insipidus; D005260:Female; D006801:Humans; D006943:Hyperglycemia; D009994:Osmolar Concentration",
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"pubdate": "2013-08-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1591751;16042331;17468192;577964;23131607;3812534;15579748;7277513;15256331",
"title": "An unusual case of central diabetes insipidus & hyperglycemic hyperosmolar state following cardiorespiratory arrest.",
"title_normalized": "an unusual case of central diabetes insipidus hyperglycemic hyperosmolar state following cardiorespiratory arrest"
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"abstract": "Postherpetic neuralgia is a common and potentially debilitating neuropathic pain condition. Current pharmacologic therapy can be inadequate and intolerable for patients. We present a case of a gentleman with refractory postherpetic neuralgia in the intercostobrachial nerve distribution that was successfully treated with cryoneurolysis/cryoanalgesia therapy.",
"affiliations": "Department of Anesthesiology, New York Medical College, Valhalla, NY, USA.;Department of Anesthesiology, New York Medical College, Valhalla, NY, USA.;Department of Anesthesiology, New York Medical College, Valhalla, NY, USA.;Department of Anesthesiology, New York Medical College, Valhalla, NY, USA.",
"authors": "Weber|Garret|G|0000-0002-2947-4942;Saad|Kenneth|K|;Awad|Motaz|M|;Wong|Tiffany H|TH|",
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"fulltext": "\n==== Front\nLocal Reg AnesthLocal Reg AnesthLRAlraLocal and Regional Anesthesia1178-7112Dove 22396110.2147/LRA.S223961Case ReportCase Report Of Cryoneurolysis For The Treatment Of Refractory Intercostobrachial Neuralgia With Postherpetic Neuralgia Weber et alWeber et alhttp://orcid.org/0000-0002-2947-4942Weber Garret 1Saad Kenneth 1Awad Motaz 1Wong Tiffany H 11 Department of Anesthesiology, New York Medical College, Valhalla, NY, USACorrespondence: Garret Weber Department of Anesthesiology, New York Medical College, Westchester Medical Center, 100 Woods Road, Macy Room 2391, Valhalla, NY10595, USA Email garret.weber@wmchealth.org01 11 2019 2019 12 103 107 21 7 2019 18 10 2019 © 2019 Weber et al.2019Weber et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nPostherpetic neuralgia is a common and potentially debilitating neuropathic pain condition. Current pharmacologic therapy can be inadequate and intolerable for patients. We present a case of a gentleman with refractory postherpetic neuralgia in the intercostobrachial nerve distribution that was successfully treated with cryoneurolysis/cryoanalgesia therapy.\n\nKeywords\ncryoneurolysiscryoablationpostherpetic neuralgiaintercostobrachial neuralgianeuropathic painto declareThe authors have no sources of funding to declare for this manuscript.\n==== Body\nIntroduction\nPostherpetic neuralgia (PHN) is one of the most common painful chronic neuropathic pain conditions and it occurs following an acute herpes zoster infection1 herpes zoster, and PHN generally presents along a unilateral thoracic dermatome, with 20% involving multiple adjacent dermatomes.2 The neuropathic pain associated with postherpetic neuralgia is persistent, severe and substantially interferes both with quality of life and recreational and daily activities.1,2 It even can induce the change from independent living to requiring dependent care.1 Unfortunately, there is not a single treatment that is completely effective or disease modifying for PHN.3 Considering that less than half of patients report greater than 50% pain relief with first-line medical therapy, existing medical treatment of postherpetic neuralgia is often refractory to multiple interventions.1,4\n\nWe present a case of a 71-year-old gentleman with postherpetic neuralgia initially in the left upper thoracic dermatomes, but with most severe pain along the distribution of the left intercostobrachial nerve (ICBN), which was refractory to initial treatment attempts. The patient ultimately responded to diagnostic local block followed by cryoneurolysis targeted along the ICBN anatomically. Despite multiple failed prior treatment attempts, the patient demonstrated sustained analgesia subsequent to the cryoneurolysis of the ICBN. To the authors’ knowledge, this is the first reported case of refractory PHN that presented as ICBN neuralgia, which was successfully treated with cryoneurolysis/cryoanalgesia therapy.\n\nCase Report\nFull informed written consent for the procedure and publication of this case report was obtained from the patient. No further institutional approvals were required. A 71-year-old gentleman with a past medical history of coronary artery disease, hyperlipidemia, anxiety and depression presented to the pain clinic with the chief complaint of persistent left back, flank and excruciating left arm pain. The pain started, approximately, 5 months prior to initial presentation, when he was diagnosed with acute herpes zoster in the same distribution (upper thoracic, approximately T2-5 dermatomes on left). The pain was severely limited to the patient’s quality of life and ability to participate in activities of daily living (ADL).\n\nThe patient further described his pain as constant, severe, burning, pins and needles sensation. Average pain severity was reported as >8/10 (on NRS scale 0–10) and significantly interfered with ADLs by impeding exercise, chores, self-care, socializing and sexual relations. The patient’s history and the physical exam revealed his pain and allodynia were mainly located in the left upper arm along the anatomic ICBN distribution.\n\nInitially, the patient’s herpes zoster infection was treated with a course of valacyclovir, with the resolution of his rash. However, the pain persisted subsequently in a similar distribution. Initial treatments included (sequentially) gabapentin, pregabalin, lidocaine patch, amitriptyline and oxycodone. Despite multiple pharmacologic agents, he had limited-to-no relief and found the side effects including drowsiness and cognitive changes to be prohibitive. Epidural steroid injections were also attempted, but yielded minimal and no sustaining pain relief. The patient had attempted trigger point injections, intercostal nerve blocks (ICB), as well as stellate ganglion blocks. He had significant relief from the ICB; however, the pain seemed mainly focused and isolated in severity along the ICBN and there was no sustained analgesia when the local anesthetic had worn off. Given the reproducibility of the majority of his pain along the specific region of the ICBN, the decision was made to specifically target the ICBN for neural blockade and neurolysis. Following two successful diagnostic blocks (>50% pain reduction for the duration of local anesthetic) of the ICBN with local anesthesia only, it was agreed upon with the patient to pursue cryoneurolysis for greater sustained pain relief.\n\nInformed procedural consent was obtained from the patient. In the supine position, the patient's arm was abducted and externally rotated. The area was prepped with a chlorhexidine solution and a 25-gauge needle was used to deposit local anesthetic solution just distal to the axillary fossa, from the deltoid muscle toward the triceps muscle along the anatomic localization of the ICBN (Figure 1). Ten milliliters of a solution containing 5 ml 0.25% bupivacaine, 4 ml of 1% lidocaine and 10 mg of triamcinolone was injected. After adequate anesthesia was obtained, cryoneurolysis was performed using a handheld cryoneurolysis device (Iovera).5 A 3 probe cryoablation tip probe (with three 27 g needles, approximately 7.6 mm in length) was used along the aforementioned treatment line. The tip of the cryoneurolysis probe was placed along the distribution of the ICBN. The device was used on the dotted line shown in Figure 1, moving circumferentially to cover the entire cross-section of the ICBN. The superficial nature of the field block allowed for the use of the cryoablation needles used in this case as described in Figure 2 to cover the length and depth of the intercostobrachial nerve. Nerve stimulation was not used to identify the exact localization as this nerve is generally located via a field block along anatomical landmarks only.Figure 1 Approximate site of injection for local block and treatment line for cryoablation of intercostobrachial nerve (dotted line).\n\nNote: This image is not the actual patient in the case report.\n\nFigure 2 A 3-pronged cryoablation device (with three 27-g needles, approximately 7.6 mm in length) was used along the treatment line shown in Figure 1, moving circumferentially to cover the entire cross-section of the ICBN. Multiple cycles of cryotherapy lasting 60 s in the treatment line as described above were administered with three 27-g needles at a depth of approximately 5.1 mm. The tips of the three-prong needle achieved a cooling temperature of maximum −88 degree Celsius.\n\n\n\nMultiple cycles of cryotherapy lasting 60 s in the treatment line as described above were administered with three 27-g needles at a depth of approximately 5.1 mm. The tip of the three-prong needle (Figure 2) achieved a cooling temperature of maximum −88 degree Celsius. The patient tolerated the procedure well, without any complications reported. At one-month postprocedure, the patient reported greater than 50% pain relief (NRS <4 on the NRS scale) in the ICBN distribution with significant improvement in self-reported quality of life and activity. The patient did not require any further interventions and reported that the quality of life indicators mentioned earlier were no longer significantly debilitating his lifestyle. He did not need any further follow-up due to improved analgesia.\n\nDiscussion\nHerpes zoster is a viral disease caused by reactivation of latent varicella zoster virus (VZV), characterized by a vesicular rash distributing in a dermatomal pattern. The incidence of this disease in the United States is estimated to be 3.4 per 1000 persons, increasing significantly after age 50 to 11 per 1000 persons by age 90.1 Approximately 10–20% of these cases in older individuals will develop PHN.2 PHN is a neuropathic pain condition defined by severe pain often with allodynia in a dermatomal pattern persisting for months after VZV occurrence and resolution.2,3 The pain often precludes functioning, preventing sleep, recreation and can be associated with depression.2 While the reactivation in acute herpes zoster virus is thought to propagate from the dorsal root ganglion, it is thought that chronic pain with PHN is related to an ongoing inflammatory response, which may also lead to injury of the peripheral nerve in addition to the DRG and higher order somatosensory processing6 The authors of this case report hypothesize that this may be the pathophysiologic basis for successful treatment of PHN with cryoablation of the intercostobrachial nerve in the patient presented. This theory has been supported by multiple reported effective peripheral nerve treatments for painful PHN.7,8,15,18 Currently, the usual treatment is multimodal, often including a combination of different pharmacologic classes of medications in addition to topical agents. These include gabapentinoids, tricyclic antidepressants, and opioids.9 Unfortunately, treatment of PHN is often inadequate with less than half of patients reporting greater than 50% pain relief with first-line medical therapy.1,4 Furthermore, the adverse effects of the mentioned standard treatments are often additive which limit dose escalation and tolerability, especially in older patients.9,10\n\nCryoneurolysis/cryoablation/cryoanalgesia therapy has been well described for is a well-established treatment for chronic pain states including neuropathic pain11 Recently cryoanalgesic techniques have even been applied to acute and perioperative pain states.12,13 The concept behind cryoanalgesia/neurolysis involves inducing cold temperature in the proximity of a peripheral nerve by creating ice crystals that will cause reversible axonal degeneration also known as Wallerian degeneration.5,14 The mechanism of analgesia in cryoanalgesia is multifold. There may be reduction of conduction, activation of descending inhibitory modulation, decreased excitatory neurotransmission, generalized sodium channel blockage, and likely a combination of all of the above14 There are several advantages of cryoablative techniques over other neurolytic techniques including surgical, thermal and chemical ablation (eg, alcohol neurolysis). First, in cryoablation, the epineurium, perineurium and endoneurium are generally intact.12–14 This allows for nerve regeneration and reduced risk of neuroma as compared with other neurolytic modalities, which is especially common after surgical neural resection11 Neuroma formation can significantly worsen pre-existing pain. Additionally, cryoablation is much less invasive compared with other techniques. Although pulsed radiofrequency (PRF) ablation has recently been described in setting of PHN, there is a larger probe 22 g for PRF vs 27 g in our case, which can be more painful for patient15 Also in Makharita’s series there was PRF of the intercostal nerves and not specifically the ICBN15 (which will be discussed later). The adverse effects and contraindications to cryoneurolysis include bleeding, skin discoloration and infection. As expected, the treatment area will likely become insensate. In our case, these risks were deemed to be exceedingly minimal due to the superficial nature of the cryoablation and probe used. The contraindications to cryoablation, specifically, include patients who have a history cryoglobulinemia, Raynaud’s syndrome or cold urticaria.5 Our patient had none of these features. Recently a handheld, cryoprobe (Iovera, FDA approved) has been developed and used in a variety of acute and chronic pain states.5,12,13,16 The cryoablation probe produces a focused, extremely cold temperature at its tip via the Joule Thompson effect. The basic principle is when high-pressure gas in the device (nitrous oxide) passes to a low-pressure chamber, there is the production of extremely cold temperature.5 This allows for localized cryoablation that is minimally invasive and an in-office procedure.\n\nWhile cryoablation has been described for PHN as well as intercostal neuralgia and post-thoracotomy pain,11,17,18 to our knowledge this is the first reported case to specifically target the ICBN as a neuralgia, directly related to PHN. The ICBN is often affected/injured postmastectomy and there is literature regarding postmastectomy altered sensitivity with intercostobrachial neuralgia.19 The ICBN is at significant risk for injury postoperatively after procedures involving the axillary region.20 The ICBN is a cutaneous nerve that stems from the second and occasionally third intercostal nerve anatomically.21 One case series by Wisotzky et al demonstrated significant pain relief in patients with ICBN neuralgia, post breast cancer surgery with ICBN blocks.22 However, there were no patients with PHN reported, and the series only looked at 3 patients who were injected with local anesthetic and steroid; no neurolysis was performed.22\n\nGiven the severity of PHN and disabling pain to patients with limited options, we believe that cryoablation offers an alternative that is minimally invasive, with less risk compared to other forms of neurolysis. Our case report demonstrates an ICBN neuralgia related to PHN, which to our knowledge has not been reported in the literature and treated with cryoablation. While we acknowledge that additional studies are necessary and the conflicting data on efficacy of cryoablation with intercostal blocks and with post-thoracotomy pain,17,23 there have been positive results for cryoanalgesia for PHN in the dermatologic literature with cutaneous use18 Additionally, the minimal risk to ICBN cryoablation given the superficial nature, as compared to intercostal blocks, whose risks include pneumothorax and vascular uptake/bleeding, allows for the ICBN cryoanalgesia to be a viable option that should be further explored in patients who present with features of ICBN neuralgia related to PHN.\n\nDisclosure\nThe authors declare no conflicts of interest in this work.\n==== Refs\nReferences\n1. Johnson \nRW , Rice \nAS . Clinical practice. Postherpetic neuralgia . N Engl J Med . 2014 ;371 (16 ):1526 –1533 . doi:10.1056/NEJMcp1403062 25317872 \n2. Sampathkumar \nP , Drage \nLA , Martin \nDP . Herpes zoster (shingles) and postherpetic neuralgia . Mayo Clin Proc . 2009 ;84 (3 ):274 –280 . doi:10.4065/84.3.274 19252116 \n3. Schmader \nK . Herpes zoster . Clin Geriatr Med . 2016 ;32 (3 ):539 –553 . doi:10.1016/j.cger.2016.02.011 27394022 \n4. Cohen \nJI . Clinical practice: herpes zoster . N Engl J Med . 2013 ;369 (3 ):255 –263 . doi:10.1056/NEJMcp1302674 23863052 \n5. Ilfeld \nBM , Preciado \nJ , Trescot \nAM . Novel cryoneurolysis device for the treatment of sensory and motor peripheral nerves . Expert Rev Med Devices . 2016 ;13 (8 ):713 –725 . doi:10.1080/17434440.2016.1204229 27333989 \n6. Hadley \nGR , Gayle \nJR , Ripoll \nJ , et al. Post-herpetic neuralgia: a review . Curr Pain Headache Rep . 2016 ;20 (3 ):17 . doi:10.1007/s11916-016-0548-x 26879875 \n7. Ni \nJ , Wang \nX , Tang \nY , Zeng \nY , Guo \nY . Subcutaneous injection of triamcinolone and lidocaine to prevent postherpetic neuralgia . Pain Physician . 2017 ;20 (5 ):397 –403 .28727702 \n8. Lin \nC , Lin \nY , Lao \nH , Chen \nC . Interventional treatments for postherpetic neuralgia: a systematic review . Pain Physician . 2019 ;22 (3 ):209 –228 .31151330 \n9. Whitley \nRJ . A 70-year-old woman with shingles: review of herpes zoster . JAMA . 2009 ;302 (1 ):73 –80 . doi:10.1001/jama.2009.822 19491172 \n10. Pickering \nG , Leplege \nA . Herpes zoster pain, postherpetic neuralgia, and quality of life in the elderly . Pain Pract . 2011 ;11 (4 ):397 –402 . doi:10.1111/j.1533-2500.2010.00432.x 21199312 \n11. Trescot \nAM . Cryoanalgesia in interventional pain management . Pain Physician . 2003 ;6 (3 ):345 –360 .16880882 \n12. Gabriel \nRA , Finneran \nJJ , Asokan \nD , Trescot \nAM , Sandhu \nNS , Ilfeld \nBM . Ultrasound-guided percutaneous cryoneurolysis for acute pain management: a case report . A A Case Rep . 2017 ;9 (5 ):129 –132 . doi:10.1213/XAA.0000000000000546 28509777 \n13. Gabriel \nRA , Finneran \nJJ \n4th, Trescot \nAM , Ilfeld \nBM . Ultrasound-guided percutaneous cryoneurolysis for postoperative analgesia after limb amputation: a case series . A A Pract . 2019 ;12 (7 ):231 –234 . doi:10.1213/XAA.0000000000000893 30234513 \n14. Bittman \nRW , Peters \nGL , Newsome \nJM , et al. Percutaneous image-guided cryoneurolysis . AJR Am J Roentgenol . 2018 ;210 (2 ):454 –465 . doi:10.2214/AJR.17.18452 29220211 \n15. Makharita \nMY , El Bendary \nHM , Sonbul \nZM , Ahmed \nSES , Latif \nMA . Ultrasound-guided pulsed radiofrequency in the management of thoracic postherpetic neuralgia: a randomized, double-blinded, controlled trial . Clin J Pain . 2018 ;34 (11 ):1017 –1024 . doi:10.1097/AJP.0000000000000629 29757758 \n16. Ilfeld \nBM , Gabriel \nRA , Trescot \nAM . Ultrasound-guided percutaneous cryoneurolysis providing postoperative analgesia lasting many weeks following a single administration: a replacement for continuous peripheral nerve blocks?: a case report . Korean J Anesthesiol . 2017 ;70 (5 ):567 –570 . doi:10.4097/kjae.2017.70.5.567 29046778 \n17. Jones \nMJ , Murrin \nKR . Intercostal block with cryotherapy . Ann R Coll Surg Engl . 1987 ;69 (6 ):261 –262 .2447819 \n18. Calandria \nL . Cryoanalgesia for post-herpetic neuralgia: a new treatment . Int J Dermatol . 2011 ;50 (6 ):746 –750 . doi:10.1111/j.1365-4632.2010.04792.x 21595675 \n19. Couceiro \nTC , Menezes \nTC , Valênça \nMM . Post-mastectomy pain syndrome: the magnitude of the problem . Rev Bras Anestesiol . 2009 ;59 (3 ):358 –365 . doi:10.1590/S0034-70942009000300012 19488550 \n20. Henry \nBM , Graves \nMJ , Pękala \nJR , et al. Origin, branching, and communications of the intercostobrachial nerve: a meta-analysis with implications for mastectomy and axillary lymph node dissection in breast cancer . Cureus . 2017 ;9 (3 ):e1101 .28428928 \n21. Warrier \nS , Hwang \nS , Koh \nCE , et al. Preservation or division of the intercostobrachial nerve in axillary dissection for breast cancer: meta-analysis of randomised controlled trials . Breast . 2014 ;23 (4 ):310 –316 . doi:10.1016/j.breast.2014.01.014 24582033 \n22. Wisotzky \nEM , Saini \nV , Kao \nC . Ultrasound-guided intercostobrachial nerve block for intercostobrachial neuralgia in breast cancer patients: a case series . Pm R . 2016 ;8 (3 ):273 –277 . doi:10.1016/j.pmrj.2015.10.003 26493855 \n23. Khanbhai \nM , Yap \nKH , Mohamed \nS , Dunning \nJ . Is cryoanalgesia effective for post-thoracotomy pain? \nInteract Cardiovasc Thorac Surg . 2014 ;18 (2 ):202 –209 . doi:10.1093/icvts/ivt468 24218494\n\n",
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"keywords": "cryoablation; cryoneurolysis; intercostobrachial neuralgia; neuropathic pain; postherpetic neuralgia",
"medline_ta": "Local Reg Anesth",
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"title": "Case Report Of Cryoneurolysis For The Treatment Of Refractory Intercostobrachial Neuralgia With Postherpetic Neuralgia.",
"title_normalized": "case report of cryoneurolysis for the treatment of refractory intercostobrachial neuralgia with postherpetic neuralgia"
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"abstract": "Imatinib is a specific tyrosine kinase inhibitor which has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukaemia and c-KIT (CD117)-positive gastrointestinal stromal tumours. It has been associated with hepatotoxicity ranging from abnormal liver function tests to acute liver failure along with chronic hepatitis B reactivation. We report the case of a patient who was started on adjuvant treatment with imatinib following resection of a primary gastrointestinal stromal cell tumour of jejunum and developed severe hepatotoxicity. There was no history of risk factors for liver disease, and a search for the underlying causes of hepatotoxicity was unremarkable. Imatinib was stopped and she was treated with steroids which resulted in dramatic improvement of liver function tests. Liver biopsy in this case was not performed because liver function tests improved following discontinuation of imatinib and treatment with steroids. Repeat imaging did not reveal any evidence of tumour recurrence.",
"affiliations": "Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK.;Beatson West of Scotland Cancer Centre, Glasgow, UK.;Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK.",
"authors": "Haq|Mohammad Inamul|MI|;Nixon|Joanna|J|;Stanley|Adrian J|AJ|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D005938:Glucocorticoids; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D008775:Methylprednisolone",
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"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "chemotherapy; gastric cancer; liver disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D056486:Chemical and Drug Induced Liver Injury; D017024:Chemotherapy, Adjuvant; D004379:Duodenal Neoplasms; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D005938:Glucocorticoids; D006801:Humans; D000068877:Imatinib Mesylate; D008111:Liver Function Tests; D008775:Methylprednisolone; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
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"pmid": "30567202",
"pubdate": "2018-12-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Imatinib and liver toxicity.",
"title_normalized": "imatinib and liver toxicity"
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"abstract": "Objective. To describe the clinical, radiological and pathological findings in a patient with methadone-induced delayed posthypoxic encephalopathy (DPHE). Case Report. A Thirty-eight-year-old man was found unconscious for an unknown duration after methadone and diazepam ingestion. His initial vitals were temperature 104 degree Fahrenheit, heart rate 148/minute, respiratory rate 50/minute, and blood pressure 107/72 mmhg. He developed renal failure, rhabdomyolysis, and elevated liver enzymes which resolved completely in 6 days. After 2 weeks from discharge he had progressive deterioration of his cognitive, behavioral and neurological function. Brain MRI showed diffuse abnormal T2 signal in the corona radiata, centrum semiovale, and subcortical white matter throughout all lobes. Extensive work up was negative for any metabolic, infectious or autoimmune disorder. Brain biopsy showed significant axonal injury in the white matter. He was treated successfully with combination of steroids and antioxidants. Follow up at 2 year showed no residual deficits. Conclusion. Our observation suggests that patients on methadone therapy should be monitored for any neurological or psychiatric symptoms, and in suspected cases MRI brain may help to make the diagnosis of DPHE. A trial of steroids and antioxidants may be considered in these patients.",
"affiliations": "Department of Neurology, The University of Kansas Medical Center, Kansas City, KS 66160, USA.",
"authors": "Mittal|Manoj|M|;Wang|Yunxia|Y|;Reeves|Alan|A|;Newell|Kathy|K|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2010/716494",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 2120981710.1155/2010/716494Case ReportMethadone-Induced Delayed Posthypoxic Encephalopathy: Clinical, Radiological, and Pathological Findings Mittal Manoj \n1\n*Wang Yunxia \n1\nReeves Alan \n2\nNewell Kathy \n3\n1Department of Neurology, The University of Kansas Medical Center, Kansas City, KS 66160, USA2Department of Radiology, The University of Kansas Medical Center, Kansas City, KS 66160, USA3Department of Pathology, The University of Kansas Medical Center, Kansas City, KS 66160, USA*Manoj Mittal: dr_chicago2006@yahoo.comAcademic Editor: Marie-Cécile Nassogne\n\n2010 9 12 2010 2010 71649423 9 2010 28 10 2010 11 11 2010 Copyright © 2010 Manoj Mittal et al.2010Copyright © 2010 Manoj Mittal et al.This 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.\nObjective. To describe the clinical, radiological and pathological findings in a patient with methadone-induced delayed posthypoxic encephalopathy (DPHE). Case Report. A Thirty-eight-year-old man was found unconscious for an unknown duration after methadone and diazepam ingestion. His initial vitals were temperature 104 degree Fahrenheit, heart rate 148/minute, respiratory rate 50/minute, and blood pressure 107/72 mmhg. He developed renal failure, rhabdomyolysis, and elevated liver enzymes which resolved completely in 6 days. After 2 weeks from discharge he had progressive deterioration of his cognitive, behavioral and neurological function. Brain MRI showed diffuse abnormal T2 signal in the corona radiata, centrum semiovale, and subcortical white matter throughout all lobes. Extensive work up was negative for any metabolic, infectious or autoimmune disorder. Brain biopsy showed significant axonal injury in the white matter. He was treated successfully with combination of steroids and antioxidants. Follow up at 2 year showed no residual deficits. Conclusion. Our observation suggests that patients on methadone therapy should be monitored for any neurological or psychiatric symptoms, and in suspected cases MRI brain may help to make the diagnosis of DPHE. A trial of steroids and antioxidants may be considered in these patients.\n==== Body\n1. Introduction\nDelayed posthypoxic encephalopathy (DPHE) is a rare clinical entity characterized by delayed neurological deficits seen after an initial hypoxic-ischemic insult. It is commonly described in relation to carbon monoxide (CO) poisoning with prevalence of 0.06%–2.8% and equal sex predilection [1]. Prognosis can be variable, ranging from complete recovery to death. Methadone-induced DPHE is very rare and has been reported in only 5 cases so far: 4 children and 1 adult [2–6]. We report clinical, radiological, and pathological findings of methadone induced DPHE in a 38-year-old man who was successfully treated with methylprednisolone.\n\n2. Case Report\nA 38-year-old righthanded Caucasian male computer engineer presented to the Kansas University Medical Center emergency department (ED) after being unconscious for an unknown duration. His history was notable for prior back and neck pain, for which he had taken methadone and diazepam, prescribed for his father. He had a long history of alcohol abuse, smoking, and hypertension. He had no drug allergies. Family history was notable for a father with schizophrenia, depression, and stimulant abuse. He was unresponsive and comatose on initial examination. His pupils were small (2 mm) and reactive. All four extremities moved in response to painful stimuli, and plantar responses were bilaterally downgoing. He had right basal crackles. His initial vital signs showed a temperature of 104 degree Fahrenheit, heart rate of 148 beats/minute, a respiratory rate of 50/minute, and blood pressure of 107/72 mmhg. Patient did not undergo any cardiopulmonary resuscitation and was intubated for airway protection. Postintubation ABG showed pH 7.4 (reference range (RR): 7.35–7.45), pCO2 37 (RR: 35–45 mmhg), pO2 110 (RR: 85–100 mmhg), and bicarbonate 23 (RR: 22–26 MEQ/L). His blood pressure dropped (78/50 mmhg) requiring intravenous dopamine. Initial blood tests revealed a white blood cell count of 13.1 (RR: 4.5–11.0 K/UL), aspartate transaminase of 233 (RR: 7–40 IU/L), alanine transaminase of 88 (RR: 7–56 IU/L), troponin of 3.98 (RR: 0.0–0.05 NG/ML), and remarkably elevated CPK 3339 (RR: 22 to 198 IU/L). The patient was in acute renal failure with BUN 13 (RR: 8–20 MG/DL), creatinine of 3.2 (RR: 0.4–1.24 MG/DL), and potassium of 6.6 (RR: 3.5–5.1 MMOL/L). Urine toxicological screen was positive for methadone and benzodiazepines, and negative for amphetamines, barbiturates, cannabinoids, cocaine and phencyclidine. His initial CSF exam showed protein 37.2 (15–40 MG/DL), glucose 81 (RR: 40–75 MG/DL), white cells 3 (RR: 0–5/UL), red cells 1 (RR: <1/UL), myelin basic protein (MBP) 2.8 (RR: <1.5 NG/ML), negative cultures, and no oligoclonal bands. A CAT scan without contrast of the head showed loss of distinction between grey and white matter. Patient did not have an initial MRI. Coronary angiogram revealed no abnormalities. \n\nDespite no growth on cultures, he was empirically treated for possible aspiration pneumonia with intravenous antibiotics. He received kayexalate and intravascular hydration along with sodium bicarbonate for acute renal failure. His condition stabilized, and he was extubated after 2 days. He gradually recovered over the next 4 days and was subsequently discharged home after 6 days of hospitalization. At discharge, he had no neurological deficits, and he was able to return to his previous profession as a computer engineer.\n\nHowever, 2 weeks after discharge, his cognitive and behavioral function began to deteriorate. He was brought to the ED 34 days from initial presentation, for subacute onset of difficulties with short-term memory, confusion, impairment of executive function, and lack of motivation. He was admitted to the psychiatry ward. At the time of the second admission, he was alert and oriented to person only. He was able to follow one-step commands. Cranial nerves were intact. He was moving all his extremities spontaneously. He had positive grasp and palmomental reflexes and was hyperreflexic with bilateral plantar extensor response. He continued to deteriorate over the next few days to the point he was totally dependent on others for all activities of daily living.\n\nCSF cytology, protein, cell counts, and glucose were normal. Oligoclonal bands were not detected. MBP was 4.4 (RR: <1.5 NG/ML). CSF 14-3-3 protein was negative. Urine sulfatide, peripheral leukocyte arylsulfatase A assay, serum long chain fatty acids, ELISA for HIV, serum levels of vitamin B12, methylmalonic acid, folate, TSH, vitamin E level, and thiamine were all within normal range. First EEG was done 46 days from initial presentation and showed symmetric bihemispheric dysfunction, and second EEG done on day 60 showed well-developed dominant rhythm of 10 hertz present mainly in the left hemisphere, marked depression of alpha, and medium amplitude of 2-3 hertz waves in the right frontotemporal regions, suggesting possible dysfunction of the right hemisphere. There was no indication of epileptic discharges.\n\nMRI of the brain revealed diffuse abnormal T2 signal in the corona radiata, centrum semiovale, and subcortical white matter throughout all lobes. There was no abnormal contrast enhancement, and no foci of restricted diffusion (Figure 1).\n\nInitial brain biopsy was done 50 days from initial presentation to evaluate for hypoxic encephalopathy, toxic leukoencephlopathy, Creutzfeldt-Jakob disease, and metachromatic leukodystrophy. It was nondiagnostic as there was no white matter on the biopsy sample. A repeat biopsy of the right frontal lobe 12 days later revealed white matter changes including small vacuoles, axonal injury, diffuse reactive astrogliosis, and microglial proliferation. Luxol fast blue myelin stains revealed well-stained and preserved myelin. Immunohistochemical stains revealed immunoreactivity of axons in white matter area to b-APP and NF. White matter also showed strong immunoreactivity with CD 68 and GFAP (Figure 2).\n\nA working diagnosis of DPHE was based on clinical history and neuroimaging findings. Fifty-six days from initial presentation, he was treated with intravenous methylprednisolone 500 mg twice daily for 5 days, amantadine 100 mg twice a day, vitamin C 500 mg twice a day, and vitamin E 800 mg three times a day. Following 5 days of therapy, the patient was more interactive and followed simple commands like open your month and touch examiner's finger. He recognized his wife and regained some long-term memories. He could again feed himself and used more words to interact and speak. After 1 week, methylphenidate was added to increase his participation in rehabilitation. Within 3 days he began having visual hallucinations consisting of spider webs and space ships around him. Both amantadine and methylphenidate were stopped and the visual hallucinations disappeared. He was able to perform his activities of daily living with verbal and procedural cueing. He was started on a slow taper of prednisone 80 mg, with incremental decreases by 20 mg every 2 weeks. He continued to show significant improvement during two weeks of inpatient rehabilitation therapy. At the time of discharge, he was independent in performing all activities of daily living and returned to his job as a computer engineer. A repeat MRI after 2 months was unchanged from his initial MRI (Figure 1). At 6-month followup following hospital discharge, neuropsychiatric testing revealed no deficits. He was doing well at 2-year followup clinic visit.\n\n3. Discussion\nDPHE is characterized by a delayed onset of neurological deterioration after hypoxic-ischemic brain injury [1]. The diagnosis of DPHE is based on typical clinical and radiological presentation, after excluding other conditions that may mimic DPHE [7]. MRI or CT brain studies in DPHE show diffuse periventricular white matter changes [8]. Classic neuropathological findings in DPHE associated with CO poisoning are characterized by diffuse symmetrical demyelination in white matter with preserved axons, U fibers, and perivascular white matter [9]. Although MRI brain in our patient showed diffuse white matter lesions, surprisingly histopathology showed axonal injury with intact myelin structure. Pathological findings in our patient are similar to those seen in toxic leukoencephlopathy including small vacuoles in the white matter, axonal injury, diffuse reactive astrogliosis, and microglial proliferation [10]. Difference in pathological changes in our patient indicates that methadone induced DPHE may be different in underlying pathophysiology from CO-induced DPHE and DPHE may represent a spectrum of disorders rather than a single clinical entity.\n\nEven though impaired oligodendroglial function [11], reduced arylsulphatase A activity [12], altered immune response [13], and mitochondrial dysfunction [14] have been postulated in the etiology of DPHE, the underlying pathophysiology is unknown. In our patient, CSF MBP increased with time (2.8 NG/ML at initial presentation to 4.4 NG/ML at second admission) which may represent slow progressive axonal destruction. Delayed neurological symptoms after initial insult may be explained by this slow axonal destruction.\n\nMethadone induced DPHE may be related to mitochondrial dysfunction as described in heroin-induced leukoencephlopathy. Mitochondrial dysfunction causing opioid related leukoencephlopathy has been suggested by electron microscopy, elevated lactate peak on magnetic resonance spectroscopy, and the clinical improvement following antioxidant therapy in few patients [14, 15]. \n\nThere are no available controlled treatment trials for DPHE. Steroids have occasionally been used with some improvement in treatment of DPHE in children [2, 4]. In an animal study, dexamethasone was found to be effective in preventing histological brain damage and learning and memory impairment caused by hypoxic-ischemic insult [16]. \n\nAutoimmune response against MBP induced by aldehydes from lipid peroxidation [13] may play an important role in the pathophysiology of DPHE which may explain the success of methylprednisolone in our patient. Amantadine 100 mg twice a day may be tried if patient does not respond to intravenous steroids or if patient has prominent features of apathy and abulia [3]. High-dose vitamin C, vitamin E, and coenzyme Q10 may be tried for their possible antioxidant effects and role in mitochondrial disorders [12, 17]. Early and continued vigorous rehabilitation plays a very vital role in the management of these patients as seen in our patient [14]. The recovery and permanent neurological impairment from DPHE varies from series to series. Choi reported 75% full recovery in 1 year, and Shillito and Drinker reported only 50% full recovery within 2 years [1, 18]. Follow up MRI at 2 months was unchanged in our patient despite clinical improvement which goes along with a previous report of earlier clinical improvement and delayed improvement radiologically which may take up to 9 months [8]. As our patient was doing extremely well at 2-year follow up, we did not repeat his MRI brain although it would have been interesting to follow the progression of white matter lesions. \n\nThe usage of methadone has increased significantly during the last decade with methadone-related deaths increasing 390% from 1999 to 2004 [19]. However, despite the widespread use of methadone and unintentional overdose on methadone, only 5 cases of methadone induced DPHE have been reported to date [2–6], suggesting that it is either uncommon or often goes unrecognized or unreported. Out of the 5 cases 4 were reported in children and only 1 was reported in a 24-year-old male. We expect that more DPHE cases will be seen with the widespread usage of methadone in pain clinics. Neurobehavioral changes may be the initial manifestation of DPHE. Clinicians, especially psychiatrists, ER clinicians, and neurologists, should be fully aware of this entity to avoid exposing the patient to extensive invasive diagnostic procedures. The diagnosis of DPHE can be made based on typical clinical presentation and neuroimaging findings without brain biopsy. Patients with DPHE should be considered for a trial of steroids with high doses of antioxidant in order to hasten clinical recovery.\n\nFigure 1 Initial brain MRI illustrates diffuse abnormal T2 FLAIR signal in the corona radiata, centrum semiovale, and subcortical white matter throughout all lobes (a)–(c). Followup MRI brain at 2 months was unchanged (d)–(f).\n\nFigure 2 Cerebral cortex shows apparently normal neuronal density ((a) hematoxylin and eosin, ×200 original magnifications). The histological changes in the biopsy center in the white matter show increased cellularity with reactive gliosis ((b) hematoxylin and eosin, ×400; (c) anti-GFAP, ×200), microglial activation ((d) anti-CD68, ×200), and axonal changes, consistent with recent axonal injury ((e) anti-neurofilament, ×400; (f) anti-B-APP, ×200 all original magnifications) in the presence of abundant well-stained myelin ((g) luxol fast blue with hematoxylin and eosin, ×200). Ultrastructural evaluation confirms axonal degeneration with myelin preservation (h).\n==== Refs\n1 Choi HS Delayed neurologic sequelae in carbon monoxide intoxication Archives of Neurology 1983 40 7 433 435 6860181 \n2 Anselmo M Rainho AC Vale MADOC Methadone intoxication in a child: toxic encephalopathy? Journal of Child Neurology 2006 21 7 618 620 16970857 \n3 Arciniegas DB Frey KL Anderson CA Brousseau KM Harris SN Amantadine for neurobehavioural deficits following delayed post-hypoxic encephalopathy Brain Injury 2004 18 12 1309 1318 15666573 \n4 Mills F MacLennan SC Devile CJ Saunders DE Severe cerebellitis following methadone poisoning Pediatric Radiology 2008 38 2 227 229 17952429 \n5 Riascos R Kumfa P Rojas R Cuellar H Descartes F Fatal methadone intoxication in a child Emergency Radiology 2008 15 1 67 70 17541658 \n6 Zanin A Masiero S Severino MS Calderone M Da Dalt L Laverda AM A delayed methadone encephalopathy: clinical and neuroradiological findings Journal of Child Neurology 2010 25 6 748 751 19808992 \n7 Filley CM Kleinschmidt-DeMasters BK Toxic leukoencephalopathy New England Journal of Medicine 2001 345 6 425 432 11496854 \n8 Chen ZQ Yang WJ Cai L Clinical characteristics, CT and MRI findings for delayed encephalopathy after acute carbon monoxide poisoning Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2005 23 6 438 441 16405778 \n9 Grinker RR Über einen Fall von Leuchtgasvergiftung mit doppelseitiger Pallidumerweichung und schwerer Degeneration des tieferen Großhirnmarklagers Zeitschrift für die gesamte Neurologie und Psychiatrie 1925 98 1 433 456 \n10 Ryan A Molloy FM Farrell MA Hutchinson M Fatal toxic leukoencephalopathy: clinical, radiological, and necropsy findings in two patients Journal of Neurology, Neurosurgery and Psychiatry 2005 76 7 1014 1016 \n11 Plum F Posner JB Hain RF Delayed neurological deterioration after anoxia Archives of Internal Medicine 1962 110 18 25 14487254 \n12 Weinberger LM Schmidley JW Schafer IA Raghavan S Delayed postanoxic demyelination and arylsulfatase-A pseudodeficiency Neurology 1994 44 1 152 154 7904733 \n13 Thom SR Bhopale VM Fisher D Zhang J Gimotty P Delayed neuropathology after carbon monoxide poisoning is immune-mediated Proceedings of the National Academy of Sciences of the United States of America 2004 101 37 13660 13665 15342916 \n14 Kriegstein AR Shungu DC Millar WS Leukoencephalopathy and raised brain lactate from heroin vapor inhalation (“chasing the dragon”) Neurology 1999 53 8 1765 1773 10563626 \n15 Wolters EC Van Wijngaarden GK Stam FC Leucoencephalopathy after inhaling “heroin” pyrolysate Lancet 1982 2 8310 1233 1237 6128545 \n16 Ikeda T Mishima K Yoshikawa T Dexamethasone prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats Behavioural Brain Research 2002 136 1 161 170 12385801 \n17 Przyrembel H Therapy of mitochondrial disorders Journal of Inherited Metabolic Disease 1987 10 1 129 146 3119936 \n18 Shillito FH Drinker CKa Shaughnessy TJ The problem of nervous and mental sequelae in carbon monoxide poisoning Journal of American Medical Association 1936 106 669 674 \n19 National Drug Intelligence Center Methadone Diversion, Abuse, and Misuse: Deaths Increasing at Alarming Rate 2007 Washington, DC, USA U.S. Department of Justice, Ed.\n\n",
"fulltext_license": "CC BY",
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"issue": "2010()",
"journal": "Case reports in medicine",
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"medline_ta": "Case Rep Med",
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"nlm_unique_id": "101512910",
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"pages": "716494",
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"pmid": "21209817",
"pubdate": "2010",
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"references": "16405778;16970857;15965216;17952429;14487254;12385801;15666573;7904733;15342916;17541658;19808992;6128545;6860181;10563626;3119936;11496854",
"title": "Methadone-induced delayed posthypoxic encephalopathy: clinical, radiological, and pathological findings.",
"title_normalized": "methadone induced delayed posthypoxic encephalopathy clinical radiological and pathological findings"
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"abstract": "Patients with hepatitis C virus (HCV) infection and chronic kidney disease (CKD) are a high-priority population for treatment.\nWe performed a post hoc pooled efficacy and safety analysis that included HCV genotype 1-infected patients with compensated liver disease and CKD stages 1 to 3 who received the all-oral 3-direct-acting antiviral regimen of ombitasvir, paritaprevir, ritonavir, and dasabuvir ± ribavirin (OBV/PTV/r + DSV ± RBV) in 11 phase 3 clinical trials. Sustained virologic response rates at posttreatment week 12 (SVR12) and treatment-related adverse events (AEs), serious AEs, and renal-associated AEs are reported. Mean changes from baseline in serum creatinine and estimated glomerular filtration rate (eGFR) were calculated to assess changes in renal function. Factors associated with improved eGFR were assessed by stepwise logistic regression analysis of data from 7 trials in which baseline urinalysis was collected.\nSVR12 rates in patients with stage 1, 2, and 3 CKD were 97% (439/453), 98% (536/547), and 97% (32/33), respectively, with OBV/PTV/r + DSV; and, 96% (1172/1221), 96% (1208/1254), and 93% (55/59), respectively, with OBV/PTV/r + DSV + RBV. Overall rates of serious AEs and renal AEs were 3% (95/3567) and 2% (56/3567), respectively. Factors associated with an eGFR increase of ≥10 ml/min per 1.73 m2 were baseline proteinuria, body mass index, nonblack race, and history of diabetes.\nOBV/PTV/r + DSV ± RBV achieved high SVR rates and was generally well tolerated irrespective of CKD stage.",
"affiliations": "Division of Hepatology, Hofstra Northwell School of Medicine, Manhasset, New York, USA.;Institut National de la Santé et de la Recherche Médicale (INSERM), U1065, Team 8, \"Hepatic Complications in Obesity,\" Nice, F-06204, Cedex 3, France and University Hospital of Nice, Digestive Centre, Nice, F-06202, Cedex 3, France.;Division of Hepatology, School of Medicine, University of Miami, Miami, Florida, USA.;Swedish Medical Center, Seattle, Washington, USA.;Hôpital Saint Joseph, Marseilles, France.;Viral Hepatitis Center, Johns Hopkins University, Baltimore, Maryland, USA.;Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, California, USA.;AbbVie Inc., North Chicago, Illinois, USA.;AbbVie Inc., North Chicago, Illinois, USA.;AbbVie Inc., North Chicago, Illinois, USA.;AbbVie Inc., North Chicago, Illinois, USA.;Mount Sinai Beth Israel, New York, New York, USA.",
"authors": "Bernstein|David E|DE|;Tran|Albert|A|;Martin|Paul|P|;Kowdley|Kris V|KV|;Bourliere|Marc|M|;Sulkowski|Mark S|MS|;Pockros|Paul J|PJ|;Renjifo|Boris|B|;Wang|Deli|D|;Shuster|Diana L|DL|;Cohen|Daniel E|DE|;Jacobson|Ira M|IM|",
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"doi": "10.1016/j.ekir.2018.10.005",
"fulltext": "\n==== Front\nKidney Int RepKidney Int RepKidney International Reports2468-0249Elsevier S2468-0249(18)30227-410.1016/j.ekir.2018.10.005Clinical ResearchOmbitasvir, Paritaprevir, Ritonavir, and Dasabuvir With or Without Ribavirin in Patients With Kidney Disease Bernstein David E. dbernste@northwell.edu1∗Tran Albert 2Martin Paul 3Kowdley Kris V. 4Bourliere Marc 5Sulkowski Mark S. 6Pockros Paul J. 7Renjifo Boris 8Wang Deli 8Shuster Diana L. 8Cohen Daniel E. 8Jacobson Ira M. 91 Division of Hepatology, Hofstra Northwell School of Medicine, Manhasset, New York, USA2 Institut National de la Santé et de la Recherche Médicale (INSERM), U1065, Team 8, “Hepatic Complications in Obesity,” Nice, F-06204, Cedex 3, France and University Hospital of Nice, Digestive Centre, Nice, F-06202, Cedex 3, France3 Division of Hepatology, School of Medicine, University of Miami, Miami, Florida, USA4 Swedish Medical Center, Seattle, Washington, USA5 Hôpital Saint Joseph, Marseilles, France6 Viral Hepatitis Center, Johns Hopkins University, Baltimore, Maryland, USA7 Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, California, USA8 AbbVie Inc., North Chicago, Illinois, USA9 Mount Sinai Beth Israel, New York, New York, USA∗ Correspondence: David E. Bernstein, Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Boulevard, Hempstead, New York 11549, USA. dbernste@northwell.edu16 10 2018 2 2019 16 10 2018 4 2 245 256 5 9 2018 8 10 2018 © 2018 International Society of Nephrology. Published by Elsevier Inc.2018International Society of NephrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nPatients with hepatitis C virus (HCV) infection and chronic kidney disease (CKD) are a high-priority population for treatment.\n\nMethods\nWe performed a post hoc pooled efficacy and safety analysis that included HCV genotype 1–infected patients with compensated liver disease and CKD stages 1 to 3 who received the all-oral 3–direct-acting antiviral regimen of ombitasvir, paritaprevir, ritonavir, and dasabuvir ± ribavirin (OBV/PTV/r + DSV ± RBV) in 11 phase 3 clinical trials. Sustained virologic response rates at posttreatment week 12 (SVR12) and treatment-related adverse events (AEs), serious AEs, and renal-associated AEs are reported. Mean changes from baseline in serum creatinine and estimated glomerular filtration rate (eGFR) were calculated to assess changes in renal function. Factors associated with improved eGFR were assessed by stepwise logistic regression analysis of data from 7 trials in which baseline urinalysis was collected.\n\nResults\nSVR12 rates in patients with stage 1, 2, and 3 CKD were 97% (439/453), 98% (536/547), and 97% (32/33), respectively, with OBV/PTV/r + DSV; and, 96% (1172/1221), 96% (1208/1254), and 93% (55/59), respectively, with OBV/PTV/r + DSV + RBV. Overall rates of serious AEs and renal AEs were 3% (95/3567) and 2% (56/3567), respectively. Factors associated with an eGFR increase of ≥10 ml/min per 1.73 m2 were baseline proteinuria, body mass index, nonblack race, and history of diabetes.\n\nConclusion\nOBV/PTV/r + DSV ± RBV achieved high SVR rates and was generally well tolerated irrespective of CKD stage.\n\nKeywords\nchronic hepatitis Cchronic kidney diseasedirect-acting antiviralhepatitis C virus\n==== Body\nSee Commentary on Page 191\n\n\n\nPatients with HCV infection have an increased risk of developing CKD.1, 2, 3, 4 Moreover, patients with CKD and HCV have a greater risk of CKD progression and end-stage renal disease (ESRD),3, 5 and the prevalence of HCV infection is higher in patients who require hemodialysis than in the general population.6, 7 Furthermore, HCV infection is associated with reduced graft survival after renal transplantation.7 Therefore, it is critical that patients with HCV and CKD receive treatment for HCV.\n\nContemporary HCV treatment guidelines recommend that patients with extrahepatic manifestations of HCV infection be considered a priority for treatment owing to increased risk of disease progression.8, 9 However, few data are available on the safety and efficacy of direct-acting antiviral (DAA) regimens in patients with CKD.\n\nComponents of the 3-DAA regimen of ombitasvir, paritaprevir with the pharmacokinetic enhancer ritonavir, and dasabuvir (OBV/PTV/r + DSV) are primarily metabolized by the liver with minimal renal elimination, with no dose adjustment required in patients with mild to severe renal impairment.8, 9 However, patients with HCV genotype (GT) 1a infection require treatment with ribavirin (RBV), which is renally excreted and requires dose reduction in patients with a creatinine clearance (CrCl) ≤50 ml/min.10 OBV/PTV/r + DSV ± RBV is recommended in guidelines for treatment of HCV in patients with CrCl <30 ml/min or ESRD requiring hemodialysis.8, 9\n\nTo better define the safety and efficacy profile of OBV/PTV/r + DSV ± RBV, we conducted a post hoc pooled analysis of OBV/PTV/r + DSV in HCV GT1-infected patients with CKD stages 1 to 3 across 11 phase 3 studies.\n\nMethods\nStudy Design\nThis is a post hoc pooled analysis of the efficacy and safety of the all-oral 3-DAA regimen of OBV/PTV/r + DSV ± RBV among patients with CKD, as determined by baseline eGFR using the Modification of Diet in Renal Disease equation. Patients from 11 phase 3 studies were included. Patients with a CrCl <30 ml/min were excluded from TURQUOISE-III, TOPAZ-I, and TOPAZ-II, and patients with a CrCl <60 ml/min were excluded from TURQUOISE-I, TURQUOISE-II, PEARL-II, PEARL-III, PEARL-VI, SAPPHIRE-I, and SAPPHIRE-II.\n\nThe study designs and primary outcomes are described elsewhere.11, 12, 13, 14, 15, 16, 17, 18, 19, 20 The studies were conducted in accordance with the International Conference on Harmonisation guidelines, applicable regulations, and the principles of the Declaration of Helsinki; study protocols were approved by independent ethics committees at each study site; and all patients provided written informed consent.\n\nPatient Population\nPatients infected with HCV GT1 without cirrhosis or with Child–Pugh A cirrhosis who had received ≥1 dose of OBV/PTV/r + DSV ± RBV were included in the analysis. Data collected before January 1, 2016 were included. In this analysis, patients were grouped according to baseline eGFR and CKD stage (CKD5: ≤15 ml/min per 1.73 m2; CKD4: >15–30 ml/min per 1.73 m2; CKD3: >30–60 ml/min per 1.73 m2; CKD2: >60–90 ml/min per 1.73 m2; and CKD1 >90 ml/min per 1.73 m2). One patient with CKD5 on hemodialysis received OBV/PTV/r + DSV + RBV.\n\nStudy Medication\nPatients with HCV GT1 infection without cirrhosis received OBV/PTV/r (25/150/100 mg every day) and DSV (250 mg twice a day) for 12 weeks; patients with GT1a infection also received RBV. Patients with compensated cirrhosis received OBV/PTV/r (25/150/100 mg every day) and DSV (250 mg twice a day) with RBV for 12 or 24 weeks for GT1b and GT1a infection, respectively. In the TURQUOISE-III trial, GT1b patients with cirrhosis did not receive RBV and were treated for 12 weeks. RBV was dosed according to body weight (1000 mg: <75 kg; 1200 mg: ≥75 kg) for patients with baseline CrCl ≥50 ml/min and was dose-adjusted for patients with CrCl <50 ml/min.10 Patients with CKD4 to 5 who required RBV received 200 mg every day. Investigators in all studies could reduce, interrupt, or resume RBV based on hemoglobin levels.\n\nVirologic Response\nPlasma HCV RNA levels were determined by a central laboratory using the Roche COBAS TaqMan real-time reverse-transcriptase polymerase chain reaction assay v2.0 (lower limit of quantitation = 25 IU/ml) (Roche, Nutley, NJ) or Roche COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 (lower limit of quantitation = 15 IU/ml) (Roche).\n\nSVR rates at posttreatment week 12 (SVR12; HCV RNA less than lower limit of quantitation) were calculated for all patients, including those who discontinued OBV/PTV/r + DSV ± RBV prematurely.\n\nSafety\nData on all treatment-emergent AEs, as reported by the study investigator, were collected from the start of study drug administration until 30 days after the last dose. AEs were assessed by study investigators for relation to study drug and severity. Serious AEs were collected from the time of signed consent until 30 days after the last dose of OBV/PTV/r + DSV ± RBV. Clinical laboratory chemistry and hematology tests were assessed throughout each study. Renal-associated AEs were defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA version 18.1) Queries Acute Renal Failure and Chronic Kidney Disease and the Custom MedDRA Query (version 18.1.3) Designated Medical Event Acute Renal Failure. Mean changes from baseline to end of treatment (EOT) of serum creatinine (SCr) and eGFR were calculated to assess changes in renal function.\n\nStatistical Analyses\nEfficacy and safety populations included all patients who received at least 1 dose of OBV/PTV/r + DSV ± RBV. Efficacy and safety analyses were performed for CKD stages 1 to 5. Results for patients with CKD4 to 5 are not presented in full owing to low patient numbers. Safety comparisons between treatment groups and CKD subgroups were performed using Fisher exact test. Analysis of covariance was used to assess changes in renal function from baseline to EOT.\n\nChanges in post-baseline eGFR at EOT in 255 patients in the placebo arms were compared with 769 patients in the OBV/PTV/r + DSV + RBV treatment arms of the SAPPHIRE-I and -II trials. Changes in post-baseline eGFR at EOT were assessed in 2663 patients from 7 trials (SAPPHIRE-I, SAPPHIRE-II, TURQUOISE-II, TOPAZ-II, PEARL-II, PEARL-III, PEARL-IV) in which urinalysis was conducted at baseline and baseline factors associated with a ≥10 ml/min per 1.73 m2 increase in eGFR at EOT were examined by stepwise logistic regression.21\n\nResults\nBaseline Patient Demographics and Characteristics\nA total of 3567 patients were included in the pooled analysis; 29% (1033/3567) received OBV/PTV/r + DSV and 71% (2534/3567) received OBV/PTV/r + DSV + RBV. Baseline characteristics are presented in Table 1. Overall, 47% (1674/3567), 50% (1801/3567), and 3% (92/3567) of patients had stage 1, 2, or 3 CKD, respectively. Only 1% (22/3567) of patients had an eGFR <50 ml/min per 1.73 m2 (data not shown).Table 1 Baseline patient demographics and disease characteristics\n\nBaseline characteristic\tOBV/PTV/r + DSV\tOBV/PTV/r + DSV + RBV\tTotal (N = 3567)\t\nCKD1 (n = 453)\tCKD2 (n = 547)\tCKD3 (n = 33)\tSubtotal (n = 1033)\tCKD1 (n = 1221)\tCKD2 (n = 1254)\tCKD3 (n = 59)\tSubtotal (n = 2534)\t\nMale sex, n (%)\t242 (53)\t261 (48)\t10 (30)\t513 (50)\t825 (68)\t704 (56)\t30 (51)\t1559 (62)\t2072 (58)\t\nRace, n (%)\t\t\t\t\t\n White\t406 (90)\t497 (91)\t32 (97)\t935 (91)\t1095 (90)\t1156 (92)\t52 (88)\t2303 (91)\t3238 (91)\t\n Black\t33 (7)\t40 (7)\t1 (3)\t74 (7)\t93 (8)\t72 (6)\t6 (10)\t171 (7)\t245 (7)\t\n Othera\t14 (3)\t9 (2)\t0\t23 (2)\t33 (3)\t26 (2)\t1 (2)\t60 (2)\t83 (2)\t\nHispanic/Latino ethnicity, n (%)\t27 (6)\t36 (7)\t2 (6)\t65 (6)\t108 (9)\t83 (7)\t3 (5)\t194 (8)\t259 (7)\t\nAge, yr, mean±SD\t48.7±12.7\t54.5±10.2\t61.4±9.9\t–\t49.6±10.9\t54.7±9.4\t59.3±4.8\t–\t–\t\nBMI, kg/m2, mean±SD\t26.5±4.7\t26.3±4.3\t27.9±5.2\t–\t26.6±4.9\t26.7±4.3\t27.9±4.3\t–\t–\t\nHCV subgenotype, n (%)b\t\t\t\t\t\n GT1a\t75 (17)\t126 (23)\t4 (12)\t205 (20)\t844 (69)\t847 (68)\t46 (78)\t1737 (69)\t1942 (54)\t\n GT1b\t378 (83)\t421 (77)\t29 (88)\t828 (80)\t376 (31)\t405 (32)\t13 (22)\t794 (31)\t1622 (45)\t\nIL28B non-CC genotype, n (%)\t367 (81)\t422 (77)\t28 (85)\t817 (79)\t970 (79)\t947 (76)\t39 (66)\t1956 (77)\t2773 (78)\t\nHCV RNA ≥800 000 IU/ml, n (%)\t327 (72)\t428 (78)\t26 (79)\t781 (76)\t964 (79)\t1036 (83)\t53 (90)\t2053 (81)\t2834 (79)\t\nFibrosis stage, n (%)c\t\t\t\t\t\n F0–F1\t298 (66)\t331 (61)\t13 (39)\t642 (62)\t650 (53)\t664 (53)\t28 (47)\t1342 (53)\t1984 (56)\t\n F2\t72 (16)\t103 (19)\t8 (24)\t183 (18)\t140 (11)\t173 (14)\t7 (12)\t320 (13)\t503 (14)\t\n F3\t60 (13)\t81 (15)\t3 (9)\t144 (14)\t113 (9)\t142 (11)\t5 (8)\t260 (10)\t404 (11)\t\n F4\t23 (5)\t30 (5)\t9 (27)\t62 (6)\t317 (26)\t275 (22)\t19 (32)\t611 (24)\t673 (19)\t\nTreatment naive, n (%)\t287 (63)\t392 (72)\t19 (58)\t698 (68)\t736 (60)\t783 (62)\t38 (64)\t1557 (61)\t2255 (63)\t\nHistory of hypertension, n (%)\t99 (22)\t163 (30)\t18 (55)\t280 (27)\t284 (23)\t395 (31)\t27 (46)\t706 (28)\t986 (28)\t\nHistory of diabetes mellitus, n (%)\t6 (1)\t11 (2)\t0\t17 (2)\t45 (4)\t34 (3)\t1 (2)\t80 (3)\t97 (3)\t\nAlbumin (g/l), mean±SD\t43.3±3.7\t42.9±3.4\t41.7±3.2\t–\t42.6±3.9\t42.3±3.5\t42.4±3.3\t–\t–\t\nPlatelet count (×109/l), mean±SD\t217.3±60.5\t220.6±65.3\t205.2±55.8\t–\t209.8±72.7\t212.3±68.0\t196.8±66.4\t–\t–\t\neGFR (ml/min per 1.73 m2), mean ± SD\t105.5±14.7\t79.0±7.5\t53.2±6.8\t–\t107.0±14.0\t78.8±7.7\t52.7±6.9\t–\t–\t\n–, not applicable; BMI, body mass index; CKD, chronic kidney disease; DSV, dasabuvir; eGFR, estimated glomerular filtration rate; GT, genotype; HCV, hepatitis C virus; IL28B, interleukin 28B; OBV, ombitasvir; PTV/r; paritaprevir/ritonavir; RBV, ribavirin.\n\na Data missing for 1 patient.\n\nb Non-GT1a/b genotype in 3 patients.\n\nc Data missing for 3 patients.\n\n\n\nEfficacy Outcomes\nAmong patients treated with OBV/PTV/r + DSV without RBV, SVR12 rates were high irrespective of CKD stage (CKD1 97% [439/453]; CKD2 98% [536/547]; CKD3 97% [32/33]) or presence of cirrhosis (Figure 1a). In patients with cirrhosis receiving OBV/PTV/r + DSV without RBV, SVR12 was 100% (62/62), including 61 patients with GT1b infection (Figure 1; Supplementary Figure S1). High SVR12 rates were also achieved with OBV/PTV/r + DSV + RBV. The SVR12 rate was 93% (55/59) in patients with CKD3 and 96% in those with CKD1 or CKD2 (1172/1221 and 1208/1254, respectively; Figure 1b). RBV dose modification was required in 11% (273/2534) of patients with CKD1 to 3; SVR rates were not decreased among patients who had RBV dose reduction (Supplementary Figure S2). SVR12 rates in subgroups were high irrespective of CKD stage and did not differ from the overall SVR12 rates (Figure 1). There were no statistically significant differences among CKD stages 1, 2, and 3.Figure 1 Sustained virologic response rates at posttreatment week 12 in patients treated with OBV/PTV/r + DSV without RBV (a) or with RBV (b) by CKD stage (CKD1: >90 ml/min per 1.73 m2; CKD2: >60–90 ml/min per 1.73 m2; CKD3: >30–60 ml/min per 1.73 m2). The percentage of patients who achieved SVR12 is plotted with 95% confidence intervals. CKD, chronic kidney disease; DSV, dasabuvir; GT, genotype; OBV, ombitasvir; PTV/r; paritaprevir/ritonavir; RBV, ribavirin; SVR12, sustained virologic response rates at posttreatment week 12.\n\n\n\nSafety Outcomes\nAEs and Serious AEs\nPatients with less severe renal dysfunction tended overall to have fewer AEs, and patients treated with RBV tended to have more AEs than those treated without RBV. Of 3567 patients in this analysis, 2870 patients experienced at least 1 AE (80%; Table 2). AEs were significantly associated with CKD stage (CKD1 77% [1285/1674], CKD2 84% [1505/1801], CKD3 87% [80/92]; P < 0.001). The most common AEs were fatigue, headache, and anemia (Table 2 [see Supplementary Table S1 for AEs in ≥10% of patients]). In patients treated with RBV, the frequency of anemia reported as an AE was greater in patients with CKD3 than in those with CKD2 or CKD1 (25% [15/59] vs. 8% [103/1254], and 4% [43/1221], respectively; P < 0.001). Anemia was uncommon among patients who did not receive RBV (CKD3 0% [0/33], CKD2 0.4% [2/547], CKD1 0.2% [1/453]; P = not significant). AEs leading to treatment discontinuation were infrequent and did not differ significantly by CKD stage. Few patients (n = 20) with severe renal impairment (CKD4) or ESRD (CKD5) were included in this analysis, and none of these patients treated with OBV/PTV/r + DSV ± RBV discontinued study drug owing to an AE.Table 2 Treatment-emergent adverse events and renal-associated adverse events by CKD stagea\n\nAE, n (%)\tOBV/PTV/r + DSV\tOBV/PTV/r + DSV + RBV\tOverall (N = 3567)\t\nNo cirrhosis\tCirrhosis\tNo cirrhosis\tCirrhosis\t\nCKD1 (n = 430)\tCKD2 (n = 517)\tCKD3 (n = 24)\tCKD1 (n = 23)\tCKD2 (n = 30)\tCKD3 (n = 9)\tCKD1 (n = 904)\tCKD2 (n = 979)\tCKD3 (n = 40)\tCKD1 (n = 317)\tCKD2 (n = 275)\tCKD3 (n = 19)\t\nAny AE\t274 (64)\t367 (71)\t17 (71)\t18 (78)\t20 (67)\t9 (100)\t722 (80)\t871 (89)\t37 (93)\t271 (85)\t247 (90)\t17 (90)\t2870 (80)\t\nSerious AE\t5 (1)\t7 (1)\t1 (4)\t–\t–\t1 (11)\t19 (2)\t23 (2)\t4 (10)\t19 (6)\t14 (5)\t2 (11)\t95 (3)\t\nAEs leading to discontinuation of study drug\t2 (<1)\t1 (<1)\t–\t–\t–\t–\t3 (<1)\t8 (<1)\t–\t4 (1)\t8 (3)\t1 (5)\t27 (1)\t\nAEs leading to RBV dose reduction\t–\t1 (<1)\t–\t–\t–\t–\t56 (6)\t96 (10)\t17 (43)\t34 (11)\t43 (16)\t6 (32)\t253 (7)\t\nFatal AE\t–\t–\t–\t–\t–\t–\t–\t1 (<1)\t–\t1 (<1)\t–\t–\t2 (<1)\t\nRenal-associated AEs (SMQ/CMQ)\t4 (1)\t10 (2)\t–\t–\t–\t1 (11)\t9 (1)\t15 (2)\t3 (8)\t4 (1)\t9 (3)\t1 (5)\t56 (2)\t\nAEs occurring in ≥15% of patients in any subgroup\t\t\nFatigue\t88 (20)\t121 (23)\t5 (21)\t6 (26)\t6 (20)\t1 (11)\t269 (30)\t351 (36)\t14 (35)\t98 (31)\t112 (41)\t13 (68)\t1084 (30)\t\nHeadache\t88 (20)\t109 (21)\t5 (21)\t2 (9)\t6 (20)\t3 (33)\t203 (22)\t284 (29)\t7 (18)\t71 (22)\t71 (26)\t6 (32)\t855 (24)\t\nNausea\t–\t–\t–\t–\t4 (13)\t–\t150 (17)\t201 (21)\t7 (18)\t54 (17)\t61 (22)\t5 (26)\t482 (14)\t\nPruritus\t27 (6)\t40 (8)\t3 (13)\t1 (4)\t4 (13)\t1 (11)\t113 (13)\t140 (14)\t7 (18)\t49 (15)\t55 (20)\t3 (16)\t443 (12)\t\nInsomnia\t–\t–\t–\t3 (13)\t3 (10)\t1 (11)\t117 (13)\t160 (16)\t8 (20)\t45 (14)\t45 (16)\t5 (26)\t387 (11)\t\nDiarrhea\t–\t–\t–\t4 (17)\t7 (23)\t1 (11)\t75 (8)\t107 (11)\t7 (18)\t41 (13)\t39 (14)\t5 (26)\t286 (8)\t\nCough\t–\t–\t–\t–\t–\t–\t63 (7)\t69 (7)\t7 (18)\t29 (9)\t27 (10)\t1 (5)\t196 (5)\t\nDizziness\t–\t–\t–\t1 (4)\t5 (17)\t–\t48 (5)\t80 (8)\t4 (10)\t18 (6)\t22 (8)\t2 (11)\t180 (5)\t\nAnemia\t1 (<1)\t2 (<1)\t–\t–\t–\t–\t25 (3)\t70 (7)\t12 (30)\t18 (6)\t33 (12)\t3 (16)\t161 (5)\t\nDecreased appetite\t–\t–\t–\t–\t–\t–\t50 (6)\t48 (5)\t6 (15)\t–\t–\t–\t104 (3)\t\nHemoglobin decrease\t–\t–\t–\t–\t–\t–\t23 (3)\t32 (3)\t6 (15)\t15 (5)\t18 (7)\t2 (11)\t96 (3)\t\nRash\t–\t–\t–\t–\t–\t–\t–\t–\t–\t28 (9)\t36 (13)\t5 (26)\t69 (2)\t\nUTI\t–\t–\t–\t–\t–\t–\t18 (2)\t25 (3)\t6 (15)\t–\t–\t–\t49 (1)\t\nAbdominal pain, upper\t–\t–\t–\t1 (4)\t1 (3)\t1 (11)\t–\t–\t–\t21 (7)\t12 (4)\t4 (21)\t40 (1)\t\nDepression\t–\t–\t–\t–\t–\t–\t–\t–\t–\t10 (3)\t11 (4)\t4 (21)\t25 (<1)\t\nBlood bilirubin increase\t–\t–\t–\t–\t–\t–\t–\t–\t–\t8 (3)\t13 (5)\t3 (16)\t24 (<1)\t\nAbdominal pain\t–\t–\t–\t–\t–\t–\t–\t–\t–\t10 (3)\t4 (2)\t3 (16)\t17 (<1)\t\nMyalgia\t–\t–\t–\t4 (17)\t–\t–\t–\t–\t–\t–\t–\t–\t4 (<1)\t\n–, no AE; AE, adverse event; CKD, chronic kidney disease; CMQ, Custom MedDRA Query; DSV, dasabuvir; OBV, ombitasvir; PTV/r; paritaprevir/ritonavir; RBV, ribavirin; SMQ, Standardized MedDRA Query; UTI, urinary tract infection.\n\na CKD1: >90 ml/min per 1.73 m2; CKD2: >60–90 ml/min per 1.73 m2; CKD3: >30–60 ml/min per 1.73 m2.\n\n\n\nFew patients (3% [95/3567]) had serious AEs, which were numerically more frequent in patients treated with (3% [81/2534]) than without RBV (1% [14/1033]; Table 2). More patients with CKD3 who were treated with RBV had serious AEs (10% [6/59]) when compared with those with CKD1 (3%, 38/1221) or CKD2 (3% [37/1254]; P = 0.008), irrespective of cirrhosis status. Only 0.2% of patients (2/1040) treated with OBV/PTV/r + DSV had a serious AE that was considered possibly related to DAA study drug; both had CKD3. In patients treated with RBV, 0.5% of patients (13/2547) had serious AEs possibly related to DAA study drug (CKD2, 8; CKD1, 5). The serious AEs included anemia, acute kidney injury, and acute prerenal failure (each in 1 patient). Serious AEs are provided in Supplementary Table S2.\n\nAEs leading to RBV dose reduction occurred in 10% of patients with CKD1 to 3 (252/2534) with a higher proportion in patients with cirrhosis than without cirrhosis (14% [83/611] vs. 9% [169/1923]; P < 0.001). AEs leading to RBV dose reduction were more frequent in patients with CKD3 than either CKD1 or 2 (CKD1: 7% [90/1221]; CKD2: 11% [139/1254]; CKD3: 39% [23/59]; P < 0.001). RBV dose reductions were not associated with reduced SVR rates (Supplementary Figure S2). Of 13 patients with CKD4 or 5, 9 (64%) had AEs leading to RBV dose reductions; none had cirrhosis.\n\nNone of the 20 patients with CKD4 or 5 discontinued study drug owing to an AE. Four (19%) had serious AEs (none of which were considered possibly related to the study drug).\n\nThree fatal AEs occurred in patients treated with RBV. Two patients died of cancer (metastatic pancreatic cancer in a patient with CKD1; non–small-cell lung cancer in a CKD2 patient), and 1 patient with CKD5 died of left ventricular dysfunction.\n\nAmong patients who received RBV, hemoglobin decreases to <10 g/dl or ≥2 g/dl from baseline to EOT occurred in 49% (593/1220), 61% (764/1250), and 78% (45/58) of patients with CKD1, CKD2, and CKD3, respectively. Fewer patients (2% [22/1032]) who did not receive RBV had comparable hemoglobin reductions. Recipients of RBV had significantly greater hemoglobin reductions (P < 0.001 vs. recipients of 3-DAA without RBV). Mean hemoglobin reductions were significantly greater in patients with CKD1 or 2 versus CKD3: OBV/PTV/r + DSV, P = 0.025; OBV/PTV/r + DSV + RBV, P < 0.001; Figure 2).Figure 2 Mean change in hemoglobin from baseline to EOT by CKD stage (CKD1: >90 ml/min per 1.73 m2; CKD2: >60–90 ml/min per 1.73 m2; CKD3: >30–60 ml/min per 1.73 m2). Mean change from baseline in hemoglobin is plotted with SD. CKD, chronic kidney disease; DAA, direct-acting antiviral; DSV, dasabuvir; EOT, end of treatment; Hgb, hemoglobin; OBV, ombitasvir; PTV/r, paritaprevir/ritonavir; RBV, ribavirin. P values represent a comparison of the 3-DAA with the 3-DAA + RBV regimen. ***, **, and * denote P values statistically significant to 0.001, 0.001, and 0.05 levels, respectively.\n\n\n\nRenal-Associated AEs\nRenal-associated AEs were infrequent, with 67 events occurring in 2% (56/3567) of patients. The frequency of renal-associated AEs increased with decreasing renal function (CKD1: 17/1674 [1%]; CKD2: 34/1801 [2%]; CKD3: 5/92 [5%]; P = 0.001; Table 2). Renal-associated AEs in RBV recipients were reported in 1% (13/1221), 2% (24/1254), and 7% (4/59) of patients with CKD1, 2, and 3, respectively (P = 0.002). Among patients treated without RBV, the incidence was 1% (4/453), 2% (10/547), and 3% (1/33), respectively (P = not significant; Table 2). Most renal-associated AEs were of mild-to-moderate intensity, with 7 patients (0.2%) experiencing severe events. The most common renal-associated AEs were decreased CrCl (33% [22/67]), proteinuria (15% [10/67]), and hyponatremia (13% [9/67]; Table 3). In total, 29 (52%) patients had renal-associated AEs (34 AEs in total) that were considered by the study investigator to be possibly related to either OBV/PTV/r + DSV or RBV. Of 20 patients with CKD4 or 5, 1 recipient (CKD4) of RBV experienced 2 renal-associated AEs (elevated SCr and blood urea nitrogen) during treatment. Two patients discontinued study drug treatment because of renal-associated AEs. Ninety-three percent of renal-associated AEs resolved during or after study drug treatment.Table 3 Renal-associated adverse events by CKD stagea,b\n\nAE, n\tOBV/PTV/r + DSV\tOBV/PTV/r + DSV + RBV\t\nCKD1 (n = 453)\tCKD2 (n = 547)\tCKD3 (n = 33)\tCKD1 (n = 1221)\tCKD2 (n = 1254)\tCKD3 (n = 59)\t\nDecreased CrCl\t–\t5\t1\t5\t9\t2\t\nProteinuria\t1\t–\t–\t6\t3\t–\t\nHyponatremia\t1\t3\t–\t1\t4\t–\t\nHypocalcemia\t–\t1\t–\t–\t3\t–\t\nLeukocyturia\t1\t–\t–\t2\t1\t–\t\nAKI\t–\t–\t–\t–\t3\t–\t\nRenal failure\t–\t–\t–\t–\t1\t2\t\nBlood sodium decrease\t–\t1\t–\t–\t1\t–\t\nEncephalopathy\t–\t–\t–\t–\t2\t–\t\nBlood potassium increase\t–\t–\t–\t–\t1\t–\t\nBlood urea increase\t–\t–\t–\t1\t–\t–\t\nHyperphosphatemia\t–\t–\t–\t–\t1\t–\t\nHypoalbuminemia\t–\t–\t–\t1\t–\t–\t\nMetabolic acidosis\t–\t–\t–\t–\t1\t–\t\nPericarditis\t–\t1\t–\t–\t–\t–\t\nRBC urine positive\t1\t–\t–\t–\t–\t–\t\n–, no AE; AE, adverse event; AKI, acute kidney injury; CKD, chronic kidney disease; CrCl, creatinine clearance; DSV, dasabuvir; OBV, ombitasvir; PTV/r; paritaprevir/ritonavir; RBC, red blood cell; RBV, ribavirin.\n\na Data in the table represent all reported AEs; 1 patient may have had >1 AE.\n\nb CKD1: >90 ml/min per 1.73 m2; CKD2: >60–90 ml/min per 1.73 m2; CKD3: >30–60 ml/min per 1.73 m2.\n\n\n\nEffect of Treatment on Renal Function\nWe observed 2 distinct patterns of changes in kidney function from baseline to EOT among patients with CKD1, CKD2, and CKD3. Mean eGFR decreased among patients with CKD1 but increased among patients with CKD2 to 3 (Figure 3a). Similarly, mean SCr values increased among patients with CKD1 and decreased among patients with CKD2 or 3 (Figure 3b). Importantly, the largest gain in eGFR and decrease in SCr occurred in patients with the lowest baseline eGFR (CKD3). Mean eGFR increased from baseline to EOT in recipients of RBV with CKD2 (1.55 ml/min per 1.73 m2) or CKD3 (5.85 ml/min per 1.73 m2) at baseline and decreased in patients with CKD1 (–4.95 ml/min per 1.73 m2; Figure 3a). Similarly, mean SCr decreased from baseline to EOT with OBV/PTV/r + DSV ± RBV in patients with CKD2 (–0.50 μmol/L) or CKD3 (–5.95 μmol/L), whereas it increased in patients with CKD1 (3.25 μmol/L; Figure 3b). Given that the risk of CKD is higher in patients with cirrhosis,4 we assessed the impact of cirrhosis on renal function (Figure 4). Among patients without cirrhosis with CKD3 at baseline, a mean increase in eGFR of 4.5 ml/min per 1.73m2 and 6.9 ml/min per 1.73 m2 was observed in patients treated with or without RBV, respectively. In patients with cirrhosis with CKD3 at baseline, a mean increase in eGFR of 8.0 ml/min per 1.73 m2 and 3.6 ml/min per 1.73 m2 was observed in patients treated with or without RBV, respectively (Figure 4). By contrast, the largest mean decreases in eGFR were observed in patients with cirrhosis with CKD1. No substantial change was reported in eGFR in patients with CKD4 (0.9 ml/min per 1.73 m2) or CKD5 (–0.4 ml/min per 1.73 m2) treated with or without RBV.Figure 3 Mean change in eGFR (a) and serum creatinine (b) from baseline to end of treatment by CKD stage (CKD1: >90 ml/min per 1.73 m2; CKD2: >60–90 ml/min per 1.73 m2; CKD3: >30–60 ml/min per 1.73 m2). All patients with CKD1 to 3 across 11 clinical trials. Data on eGFR and serum creatinine were missing for 1 patient in the CKD3 group treated with OBV/PTV/r + DSV + RBV. CKD, chronic kidney disease; DSV, dasabuvir; eGFR, estimated glomerular filtration rate; OBV, ombitasvir; PTV/r, paritaprevir/ritonavir; RBV, ribavirin.\n\nFigure 4 Mean change in eGFR (a) and serum creatinine (b) from baseline to end of treatment according to CKD stage (CKD1: >90 ml/min per 1.73 m2; CKD2: >60–90 ml/min per 1.73 m2; CKD3: >30–60 ml/min per 1.73 m2) and presence of cirrhosis. All patients with CKD1 to 3 across 11 clinical trials. Data on eGFR and serum creatinine were missing for 1 patient in the CKD3 group treated with OBV/PTV/r + DSV + RBV. P values represent a comparison with CKD1. ***, **, and * denote P values statistically significant to 0.001, 0.001, and 0.05 levels, respectively. CKD, chronic kidney disease; DSV, dasabuvir; eGFR, estimated glomerular filtration rate; OBV, ombitasvir; PTV/r, paritaprevir/ritonavir; RBV, ribavirin.\n\n\n\nFurthermore, regardless of baseline eGFR, no difference was observed in the proportion of patients with either a decrease (Figure 5a) or increase (Figure 5b) in eGFR by ≥10 ml/min per 1.73 m2 in the placebo (n = 255) and OBV/PTV/r + DSV + RBV (n = 769) arms of the SAPPHIRE-I and -II trials or the OBV/PTV/r + DSV ± RBV (n = 2663) arms of 7 clinical trials in which baseline urinalysis was performed.21Figure 5 Post-baseline decrease (a) and increase (b) in eGFR by ≥10 ml/min per 1.73 m2 at EOT. Patients were from 7 clinical trials (SAPPHIRE-I, SAPPHIRE-II, TURQUOISE-II, TOPAZ-II, PEARL-II, PEARL-III, PEARL-IV). DSV, dasabuvir; eGFR, estimated glomerular filtration rate; EOT, end of treatment; OBV, ombitasvir; PTV/r, paritaprevir/ritonavir; RBV, ribavirin.\n\n\n\nBaseline Factors Associated With eGFR Improvement\nStepwise logistic regression analysis was performed to identify baseline factors associated with ≥10 ml/min per 1.73 m2 improvement in eGFR in 7 clinical trials with baseline urinalysis data. Overall, 18% of patients (486/2663) experienced ≥10 ml/min per 1.73 m2 increase in eGFR at EOT (Figure 5b). Baseline factors significantly associated with this increase were body mass index (P < 0.001), nonblack race (P = 0.021), proteinuria (P < 0.001), and diabetes (P = 0.023; Table 4). When the analysis was done on the placebo group in SAPPHIRE-I and -II, changes in eGFR were not associated with any baseline factors.21Table 4 Baseline factors associated with improvement in eGFRa\n\nVariable\t≥10 ml/min per 1.73 m2 eGFR improvement\t\nOR\t95% CI\tP value\t\nBaseline proteinuria (positive vs. negative)\t1.65\t1.32–2.05\t<0.001\t\nBaseline BMI\t0.95\t0.93–0.97\t<0.001\t\nRace (black vs. nonblack)\t0.60\t0.38–0.92\t0.021\t\nHistory of diabetes (yes vs. no)\t1.51\t1.06–2.16\t0.023\t\nBMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; OR, odds ratio.\n\na Baseline characteristics that were evaluated by linear regression analysis: urine blood (positive or negative), urine protein (positive or negative), fibrosis score (F0–1, F2, F3, F4), BMI (continuous, kg/m2), age (continuous, years), sex (male or female), race (black or nonblack), history of hypertension (yes or no), history of diabetes (yes or no), baseline hepatitis C virus RNA (continuous, log10 IU/ml).\n\n\n\nConclusion\nGiven that HCV infection is implicated in the development and progression of CKD, it is important to identify and treat HCV in patients with CKD. However, given that patients with CKD were generally excluded from registration trials, more data are needed to confirm the safety and efficacy of DAAs in patients with CKD.22\n\nIn the present analysis, the safety and efficacy of OBV/PTV/r + DSV ± RBV were assessed in 3567 GT1-infected patients with CKD stages 1 to 3 across 11 phase 3 studies. It should be noted that some patients received regimens not presently recommended in product labeling. For example, some GT1b-infected patients with cirrhosis received OBV/PTV/r + DSV with RBV for 12 weeks, whereas European Union and US product labeling recommends OBV/PTV/r + DSV alone for all GT1b-infected patients, including those with compensated cirrhosis. Similarly, the approved regimens for GT1a-infected patients are OBV/PTV/r + DSV + RBV for 12 weeks in patients without cirrhosis and 24 weeks in patients with compensated cirrhosis. However, this analysis includes GT1a-infected patients who received OBV/PTV/r + DSV without RBV, in whom the SVR12 rate was 90%. Among patients who received the label-recommended regimen based on HCV subtype, SVR rates across CKD strata were similar to those reported in the registration trials. Regardless of GT1 subgroup or receipt of RBV, high overall SVR rates (93%–98%) were achieved and were similar across CKD stages. In addition, SVR rates were consistently high in subgroups defined by cirrhosis status, irrespective of CKD stage.\n\nOBV/PTV/r + DSV ± RBV was generally well tolerated irrespective of CKD stage. Relatively few patients (3%) had a serious AE, and AEs leading to treatment discontinuation occurred in <1% of patients and did not differ by CKD stage.\n\nThe safety profile of OBV/PTV/r ± RBV in patients with CKD3 was largely similar to that in patients with CKD1 or CKD2. However, serious AEs and renal-associated AEs were more common in patients with CKD3 than in patients with CKD1/2. Many were considered unrelated to DAA therapy, suggesting that this difference reflects the greater underlying morbidity in patients with CKD3.\n\nNo worsening of eGFR was observed with OBV/PTV/r + DSV + RBV, regardless of baseline CKD stage in placebo-controlled trials (SAPPHIRE-I/II). eGFR increased and SCr decreased from baseline to EOT in patients with CKD2 or 3 treated with OBV/PTV/r + DSV ± RBV, suggesting that this regimen does not affect renal function in patients with moderate CKD. Although these parameters improved in patients with CKD3, these data are insufficient to conclude that renal function improves in patients with moderate renal impairment. A large, community-based study showed a correlation between decreasing eGFR and increasing risk of death, cardiovascular events, and hospitalization23; however, it is unknown whether improvements in eGFR observed in this analysis persist after treatment and translate into improved clinical outcomes. Several factors (positive baseline proteinuria, lower baseline body mass index, nonblack race, and a history of diabetes) were associated with improved eGFR in the subanalysis of baseline urinalysis data and may be used to identify patients likely to benefit from treatment. Studies with prolonged observation periods are needed to assess whether eradication of HCV affects the progression of kidney disease and improves survival in patients with renal impairment.\n\nThe results of this study are supported by a German real-world study of more than 1000 GT1- or GT4-infected patients with or without renal impairment who received OBV/PTV/r ± DSV ± RBV.24 The SVR12 rate among patients with moderate-to-severe renal impairment (eGFR <60 ml/min per 1.73 m2) was 100% (34/34), and the safety profile among patients with any degree of renal impairment (eGFR ≤90 ml/min per 1.73 m2; n = 326) was similar to the overall population.24 In addition, no clinically relevant changes in eGFR from baseline to EOT were observed for the overall population or for any CKD subgroup.24\n\nThese results contrast with those obtained with sofosbuvir-based regimens. Sofosbuvir, a nucleoside analog HCV polymerase inhibitor, and its principal metabolite GS-331007 are renally excreted.25 Sofosbuvir and GS-331007 exposures are 171% and 451% higher, respectively, in patients with an eGFR of <30 ml/min per 1.73 m2 than in patients with normal renal function.26 The incidence of serious AEs and worsening renal function in patients with eGFR ≤45 ml/min per 1.73 m2 (moderate renal impairment or worse) was 3.5-fold higher than that in patients with eGFR >45 ml/min per 1.73 m2 in a cohort of 1789 sofosbuvir recipients.25 Similarly, patients with eGFR <60 ml/min per 1.73 m2 were more likely to experience worsening of eGFR than patients with normal renal function after controlling for age, fibrosis stage, and treatment duration in a retrospective study of recipients of ledipasvir/sofosbuvir.27 In another report, sofosbuvir plus simeprevir were well tolerated in patients with severe CKD or ESRD.28 It is not known if sofosbuvir or its metabolite have a pathogenic effect; however, guidelines do not recommend use of sofosbuvir in patients with severe renal impairment (eGFR <30 ml/min per 1.73 m2) or ESRD requiring hemodialysis.8, 9\n\nGrazoprevir (NS3 protease inhibitor) and elbasvir (NS5A inhibitor) are hepatically metabolized; thus, dose adjustments are unnecessary in patients with renal impairment.29 This regimen was well tolerated, with an SVR12 rate of 94% to 99% in GT1-infected patients with CKD4 or 5, including hemodialysis patients.30 In addition, the pan-genotypic regimen of glecaprevir (NS3 protease inhibitor) and pibrentasvir (NS5A inhibitor) is approved for patients with any degree of renal impairment without dosage adjustment31; this regimen achieved an SVR12 rate of 98% in patients infected with GT1 to 6 with CKD4 or 5, including patients requiring hemodialysis, and was well tolerated.32 Separate integrated analyses of grazoprevir plus elbasvir and glecaprevir plus pibrentasvir showed no worsening of eGFR from baseline with either regimen in patients with renal impairment.33, 34\n\nFew patients with CKD4 or 5 were included in this analysis; however, the safety profile of OBV/PTV/r + DSV ± RBV in these patients was generally similar to that in patients with CKD1 to 3. In RUBY-I, OBV/PTV/r + DSV ± RBV achieved an SVR12 rate (by intention-to-treat analysis) of 90% in the initial cohort of GT1-infected patients without cirrhosis with CKD4 or 5.11 The safety profile was generally similar to that in patients with normal renal function, with the exception of a higher incidence of RBV treatment interruptions therapy owing to anemia,11 similar to the current analysis. SVR12 rates of 96% (46/48; 95% in GT1a [35/37] and 100% in GT1b [11/11] patients) were achieved in a second cohort of patients with CKD4 or 5 with or without compensated cirrhosis (including treatment-experienced patients). Most AEs were mild or moderate in severity, and only 1 patient discontinued treatment due to DAA-related serious AE (diarrhea).35 Similarly, real-world studies of OBV/PTV/r ± DSV ± RBV in GT1- and GT4-infected patients with CKD4 or 5, including patients who require hemodialysis, have shown SVR12 rates >95% and good tolerability.36, 37, 38 In this study, the frequency of serious AEs was higher in the small group of patients with CKD4 or 5 than in patients with CKD1 to 3. This was also observed in an integrated analysis of more than 2000 patients with GT1 to 6 treated with glecaprevir and pibrentasvir, with an increased rate of serious AEs, as well as a higher frequency of the AE of pruritus, among patients with CKD4 or 5 (n = 103).34\n\nRBV is eliminated by renal excretion; thus, exposure to RBV and the risk of dose-related AEs is increased in patients with renal impairment. The incidence of renal-associated AEs was generally low across CKD groups, but was higher in patients treated with RBV. For example, anemia occurred in 25% of ribavirin recipients with CKD3, compared with 4% to 8% in those with CKD1 or 2. Similarly, AEs resulting in RBV dose reductions occurred in 39% of patients with CKD3 and 7% to 11% of those with CKD1 or 2. The collective results of the present study and RUBY-I suggest dose adjustments do not completely abrogate the risk of RBV-associated toxicity. Thus, dose reductions and frequent hematologic monitoring are warranted in patients with CKD ≥3 who require RBV. It is noteworthy that SVR12 rates were not affected by RBV dose reductions in any CKD stratum.\n\nRBV-Free Regimens Are Preferred in Patients With ESRD\nIn the exploratory RUBY-II study, in which treatment-naive patients infected with GT1a (n = 13) or GT4 (n = 4) without cirrhosis and with CKD4 or 5 received OBV/PTV/r ± DSV, the SVR12 rate was 100% (excluding 1 GT4-infected patient who withdrew from the study at week 2 for renal transplantation). The RBV-free regimen was well tolerated; no serious AEs were related to the study drugs. These results suggest that RBV may not be required in some GT1a and GT4 patients; however, larger trials are needed to confirm these results.39\n\nIn conclusion, in this pooled analysis of 3567 GT1-infected patients with renal impairment across 11 phase 3 studies treated with OBV/PTV/r + DSV ± RBV for 12 or 24 weeks achieved high SVR rates independent of baseline renal function. Treatment was well tolerated across CKD groups, with low rates of renal-associated AEs and discontinuations. A gain in eGFR at the EOT was observed in patients with CKD2 or 3. Several baseline characteristics were associated with improved eGFR in a subset of 2663 patients who had urinalysis at baseline; however, the long-term benefit and durability of this improvement are yet to be determined. Patients treated with RBV were at higher risk of AEs; consequently, RBV doses should be reduced in and patients should be closely monitored for RBV-associated anemia during treatment with OBV/PTV/r + DSV + RBV.\n\nDisclosure\nDEB received research support from AbbVie, BMS, Gilead, Merck; Consultant/Speaker: AbbVie, BMS, Gilead, Merck. AT: Investigator and Speaker for AbbVie, Gilead, MSD, Janssen, BMS. PM: Investigator: AbbVie, Gilead, Merck; Consultant: AbbVie, Gilead, Merck. KVK: Grant/Research funding: AbbVie, Gilead, Merck; Consultant/Advisor: AbbVie, Gilead, Merck, Trio Health Advisory Group. MB: Board Member and Speaker for Gilead, BMS, MSD, AbbVie, GSK, Janssen. MSS: Research grants with fund paid to Johns Hopkins University: AbbVie, BMS, Gilead, Janssen, Merck; Scientific advisor: AbbVie, BMS, Cocrystal Pharma, Gilead, Janssen, Merck, Trek. PJP: Speaker/Consultant/Advisor: Gilead, AbbVie, Janssen, Bristol-Myers Squibb; Research support: Gilead, AbbVie, Janssen, Bristol-Myers Squibb, Merck, Conatus, Roche Molecular. BR, DW, DLS, and DEC are employees of AbbVie and may hold AbbVie stock or options. IMJ: Research support: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck; Consultant/Advisor: AbbVie, Bristol-Myers Squibb, Gilead, Intercept, Janssen, Merck, Trek; Speaker: AbbVie, Bristol-Myers Squibb, Gilead, Intercept.\n\nSupplementary Material\nTable S1\nAEs in ≥10% of patients in any subgroup.\n\n Table S2\nSerious AEs possibly related to DAA study drug in patients treated with OBV/PTV/r + DSV + RBV.\n\n Figure S1\nSVR12 in patients treated with OBV/PTV/r + DSV without RBV (A) or with RBV (B) by CKD stage and genotype in the presence or absence of cirrhosis.\n\n Figure S2\nSVR12 rates in patients treated with OBV/PTV/r + DSV + RBV stratified by RBV dose modification.\n\n \n\nAcknowledgments\nMedical writing support was provided by Gillian Patman of Medical Expressions, funded by AbbVie. AbbVie sponsored the study (NCT01716585, NCT01715415, NCT01674725, NCT01767116, NCT01833533, NCT01704755, NCT01939197, NCT02219503, NCT02207088, NCT02219490, and NCT02167945); contributed to its design; participated in the collection, analysis, and interpretation of the data; and contributed to the writing, reviewing, and approval of the publication.\n\nTable S1. AEs in ≥10% of patients in any subgroup.\n\nTable S2. Serious AEs possibly related to DAA study drug in patients treated with OBV/PTV/r + DSV + RBV.\n\nFigure S1. SVR12 in patients treated with OBV/PTV/r + DSV without RBV (A) or with RBV (B) by CKD stage and genotype in the presence or absence of cirrhosis.\n\nFigure S2. SVR12 rates in patients treated with OBV/PTV/r + DSV + RBV stratified by RBV dose modification.\n\nSupplementary material is linked to the online version of the paper at http://www.kireports.org/.\n==== Refs\nReferences\n1 Kidney Disease: Improving Global Outcomes (KDIGO) KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease Kidney Int Suppl 109 2008 S1 S99 \n2 Cacoub P. Comarmond C. Domont F. Extrahepatic manifestations of chronic hepatitis C virus infection Ther Adv Infect Dis 3 2016 3 14 26862398 \n3 Lee J.J. Lin M.Y. Chang J.S. Hepatitis C virus infection increases risk of developing end-stage renal disease using competing risk analysis PLoS One 9 2014 e100790 24971499 \n4 Chen Y.C. Lin H.Y. Li C.Y. A nationwide cohort study suggests that hepatitis C virus infection is associated with increased risk of chronic kidney disease Kidney Int 85 2014 1200 1207 24257691 \n5 Molnar M.Z. Alhourani H.M. Wall B.M. Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans Hepatology 61 2015 1495 1502 25529816 \n6 Patel P.R. Thompson N.D. Kallen A.J. Arduino M.J. Epidemiology, surveillance, and prevention of hepatitis C virus infections in hemodialysis patients Am J Kidney Dis 56 2010 371 378 20570422 \n7 Morales J.M. Fabrizi F. Hepatitis C and its impact on renal transplantation Nat Rev Nephrol 11 2015 172 182 25643666 \n8 American Association for the Study of Liver Diseases and Infectious Diseases Society of America. HCV guidance: Recommendations for testing, managing, and treating hepatitis C. Updated 2018. Available at: http://www.hcvguidelines.org/. Accessed August 26, 2018.\n9 European Association for the Study of the Liver (EASL) EASL recommendations on treatment of hepatitis C 2016 J Hepatol 66 2017 153 194 27667367 \n10 Copegus (ribavirin) [package insert]. South San Francisco, CA: Hoffmann-La Roche, Inc. 2011.\n11 Pockros P.J. Reddy K.R. Mantry P.S. Efficacy of direct-acting antiviral combination for patients with HCV genotype 1 infection and severe renal impairment or end-stage renal disease Gastroenterology 150 2016 1590 1598 26976799 \n12 Andreone P. Colombo M.G. Enejosa J.V. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection Gastroenterology 147 2014 359 365 24818763 \n13 Feld J.J. Kowdley K.V. Coakley E. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin N Engl J Med 370 2014 1594 1603 24720703 \n14 Ferenci P. Bernstein D. Lalezari J. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV N Engl J Med 370 2014 1983 1992 24795200 \n15 Poordad F. Hezode C. Trinh R. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis N Engl J Med 370 2014 1973 1982 24725237 \n16 Sulkowski M.S. Eron J.J. Wyles D. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial JAMA 313 2015 1223 1231 25706092 \n17 Zeuzem S. Jacobson I.M. Baykal T. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin N Engl J Med 370 2014 1604 1614 24720679 \n18 Feld J.J. Moreno C. Trinh R. Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12 weeks J Hepatol 64 2016 301 307 26476290 \n19 Dumas E.O. Enejosa J. Ball G. Phase 3B studies to assess long-term clinical outcomes in HCV GT1-infected patients treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin J Hepatol 62 suppl 2015 S855 \n20 Reau N. Poordad F. Enejosa J. Preliminary safety and efficacy results from TOPAZ-II: a phase 3b study evaluating long-term clinical outcomes in HCV genotype 1-infected patients receiving ombitasvir/paritaprevir/r and dasabuvir +/− ribavirin Hepatology 62 suppl 2015 732A \n21 Bernstein D.E. Tran A. Martin P. Predictors of improvement in glomerular filtration rate among patients treated with ombitasvir/paritaprevir/r and dasabuvir with or without RBV Hepatology 64 suppl 2016 456A 26990897 \n22 Fabrizi F. Martin P. Messa P. New treatment for hepatitis C in chronic kidney disease, dialysis, and transplant Kidney Int 89 2016 988 994 27083277 \n23 Go A.S. Chertow G.M. Fan D. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization N Engl J Med 351 2004 1296 1305 15385656 \n24 Welzel T.M. Hinrichsen H. Sarrazin C. Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German hepatitis C registry J Viral Hepat 24 2017 840 849 28342229 \n25 Saxena V. Koraishy F.M. Sise M.E. Safety and efficacy of sofosbuvir-containing regimens in hepatitis C infected patients with impaired renal function Liver Int 36 2016 807 816 26923436 \n26 HARVONI (ledipasvir and sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences, Inc. 2017.\n27 Rosenblatt R. Mehta A. Wagner M. Kumar S. Baseline creatinine clearance is a predictor of worsening renal function while on HCV treatment with sofosbuvir-ledipasvir J Hepatol 64 suppl 2016 S819 \n28 Nazario H.E. Ndungu M. Modi A.A. Sofosbuvir and simeprevir in hepatitis C genotype 1-patients with end-stage renal disease on haemodialysis or GFR Liver Int 36 2016 798 801 26583882 \n29 ZEPATIER (elbasvir and grazoprevir) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc. 2018.\n30 Roth D. Nelson D.R. Bruchfeld A. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study Lancet 386 2015 1537 1545 26456905 \n31 MAVYRET (glecaprevir and pibrentasvir) [package insert]. North Chicago, IL: AbbVie, Inc. 2018.\n32 Gane E. Lawitz E. Pugatch D. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment N Engl J Med 377 2017 1448 1455 29020583 \n33 Reddy K.R. Roth D. Bruchfeld A. Elbasvir/grazoprevir does not worsen renal function in patients with hepatitis C virus infection and pre-existing renal disease Hepatol Res 47 2017 1340 1345 28334495 \n34 Pol S. Pockros P. Pugatch D. Safety and efficacy of glecaprevir/pibrentasvir in adults with chronic hepatitis C virus infection genotype 1–6 as a function of chronic kidney disease stage J Hepatol 66 suppl 2017 S738 \n35 Vierling J.M. Lawitz E. Reddy K.R. RUBY-I: Safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin in adults with genotype 1 chronic hepatitis C virus (HCV) infection with severe renal impairment or end-stage renal disease Hepatology 64 suppl 2016 441A \n36 Munoz-Gomez R. Rincon D. Ahumada A. Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: a multicentre experience J Viral Hepat 24 2017 464 471 27976490 \n37 Sanai F.M. Alghamdi A.S. Afghani A.A. High efficacy of ombitasvir/paritaprevir/ritonavir plus dasabuvir in hepatitis C genotypes 4 and 1-infected patients with severe chronic kidney disease Liver Int 38 2018 1395 1401 29288514 \n38 Sperl J. Kreidlova M. Merta D. Paritaprevir/ritonavir/ombitasvir plus dasabuvir regimen in the treatment of genotype 1 chronic hepatitis C infection in patients with severe renal impairment and end-stage renal disease: a real-life cohort Kidney Blood Press Res 43 2018 594 605 29669332 \n39 Gane E.J. Solà R. Cohen E. RUBY-II: Efficacy and safety of a ribavirin-free ombitasvir/paritaprevir/ritonavir ± dasabuvir regimen in patients with severe renal impairment or end-stage renal disease and HCV genotypes 1a or 4 infection Hepatology 64 suppl 2016 470A 471A\n\n",
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"keywords": "chronic hepatitis C; chronic kidney disease; direct-acting antiviral; hepatitis C virus",
"medline_ta": "Kidney Int Rep",
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"title": "Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir With or Without Ribavirin in Patients With Kidney Disease.",
"title_normalized": "ombitasvir paritaprevir ritonavir and dasabuvir with or without ribavirin in patients with kidney disease"
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"abstract": "Most countries exclude human immunodeficiency virus (HIV)-positive patients from organ donation because of concerns regarding donor-derived HIV transmission. The Swiss Federal Act on Transplantation has allowed organ transplantation between HIV-positive donors and recipients since 2007. We report the successful liver transplantation from an HIV-positive donor to an HIV-positive recipient. Both donor and recipient had been treated for many years with antiretroviral therapy and harbored multidrug-resistant viruses. Five months after transplantation, HIV viremia remains undetectable. This observation supports the inclusion of appropriate HIV-positive donors for transplants specifically allocated to HIV-positive recipients.",
"affiliations": "HIV Unit, Geneva University Hospitals, Geneva, Switzerland.;Transplant Infectious Diseases Unit, Geneva University Hospitals, Geneva, Switzerland.;Division of Transplantation, Geneva University Hospitals, Geneva, Switzerland.;Private Practice, Geneva, Switzerland.;Division of Pathology, Geneva University Hospitals, Geneva, Switzerland.;Virology Laboratory, Geneva University Hospitals, Geneva, Switzerland.;Private Practice, Lausanne, Switzerland.;Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.;Division of Transplantation, Geneva University Hospitals, Geneva, Switzerland.;Division of Gastroenterology and Division of Transplantation, CHUV, Lausanne, Switzerland.;Division of Transplantation, Geneva University Hospitals, Geneva, Switzerland.",
"authors": "Calmy|A|A|;van Delden|C|C|;Giostra|E|E|;Junet|C|C|;Rubbia Brandt|L|L|;Yerly|S|S|;Chave|J-P|JP|;Samer|C|C|;Elkrief|L|L|;Vionnet|J|J|;Berney|T|T|;|||",
"chemical_list": null,
"country": "United States",
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"doi": "10.1111/ajt.13824",
"fulltext": null,
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"issn_linking": "1600-6135",
"issue": "16(8)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; ethics and public policy; immune deficiency; infectious disease; patient safety",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000368:Aged; D006085:Graft Survival; D015658:HIV Infections; D006679:HIV Seropositivity; D015497:HIV-1; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D014019:Tissue Donors; D009927:Tissue and Organ Procurement",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2473-8",
"pmc": null,
"pmid": "27109874",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "HIV-Positive-to-HIV-Positive Liver Transplantation.",
"title_normalized": "hiv positive to hiv positive liver transplantation"
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"abstract": "OBJECTIVE\nThe therapeutic effect of mesalamine is considered to be dose-dependent; however, no consensus has been reached regarding the optimal doses for individual patients. This study aimed to provide new insight for dose optimization using two doses of pH-dependent release mesalamine for induction of remission of moderately active ulcerative colitis (UC).\n\n\nMETHODS\nIn a multicenter, double-blind, randomized study, 110 patients with moderately active UC were assigned to two groups after treatment with a constant dose of mesalamine. Fifty-five patients were treated with a pH-dependent release formulation of 3.6 or 4.8 g/day for 8 weeks. The primary endpoint was a decrease in the UC disease activity index (UCDAI) adjusted by covariates.\n\n\nRESULTS\nIn the full analysis set (n=110), the mean decrease in UCDAI was 3.1 in the 3.6 g/day group and 3.4 in the 4.8 g/day group (P>0.05). In a subgroup analysis, the effectiveness of the 4.8 g/day dose was greater in particular populations, such as those who had been previously treated with a lower dose of mesalamine and those with more severe disease. The safety was comparable between the two groups.\n\n\nCONCLUSIONS\nThe results suggest that treatment with pH-dependent release mesalamine at either 3.6 or 4.8 g/day was effective and safe for the induction of remission in patients with moderately active UC. However, the patients receiving mesalamine at 2.4 g/day but in whom the therapeutic effect is not sufficient and having more severe symptoms (UCDAI 9-10), benefit from higher doses of mesalamine compared to others.",
"affiliations": "Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan.;Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.;Kinshukai Infusion Clinic, Osaka, Japan.;Zeria Pharmaceutical Co., Ltd., Tokyo, Japan.;Kitasato Institute Hospital, Kitasato University, Tokyo, Japan.",
"authors": "Suzuki|Yasuo|Y|;Iida|Mitsuo|M|;Ito|Hiroaki|H|;Saida|Isamu|I|;Hibi|Toshifumi|T|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5217/ir.2016.14.1.50",
"fulltext": "\n==== Front\nIntest ResIntest ResIRIntestinal Research1598-91002288-1956Korean Association for the Study of Intestinal Diseases 10.5217/ir.2016.14.1.50Original ArticleEfficacy and safety of two pH-dependent-release mesalamine doses in moderately active ulcerative colitis: a multicenter, randomized, double-blind, parallel-group study Suzuki Yasuo 1Iida Mitsuo 2Ito Hiroaki 3Saida Isamu 4Hibi Toshifumi 51 Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan.2 Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.3 Kinshukai Infusion Clinic, Osaka, Japan.4 Zeria Pharmaceutical Co., Ltd., Tokyo, Japan.5 Kitasato Institute Hospital, Kitasato University, Tokyo, Japan.Correspondence to Toshifumi Hibi, Kitasato Institute Hospital, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan. Tel: +81-3-5791-6487, Fax: +81-3-5791-6489, thibi@insti.kitasato-u.ac.jp1 2016 26 1 2016 14 1 50 59 20 10 2015 10 12 2015 11 12 2015 © Copyright 2016. Korean Association for the Study of Intestinal Diseases. All rights reserved.2016This 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.Background/Aims\nThe therapeutic effect of mesalamine is considered to be dose-dependent; however, no consensus has been reached regarding the optimal doses for individual patients. This study aimed to provide new insight for dose optimization using two doses of pH-dependent release mesalamine for induction of remission of moderately active ulcerative colitis (UC).\n\nMethods\nIn a multicenter, double-blind, randomized study, 110 patients with moderately active UC were assigned to two groups after treatment with a constant dose of mesalamine. Fifty-five patients were treated with a pH-dependent release formulation of 3.6 or 4.8 g/day for 8 weeks. The primary endpoint was a decrease in the UC disease activity index (UCDAI) adjusted by covariates.\n\nResults\nIn the full analysis set (n=110), the mean decrease in UCDAI was 3.1 in the 3.6 g/day group and 3.4 in the 4.8 g/day group (P>0.05). In a subgroup analysis, the effectiveness of the 4.8 g/day dose was greater in particular populations, such as those who had been previously treated with a lower dose of mesalamine and those with more severe disease. The safety was comparable between the two groups.\n\nConclusions\nThe results suggest that treatment with pH-dependent release mesalamine at either 3.6 or 4.8 g/day was effective and safe for the induction of remission in patients with moderately active UC. However, the patients receiving mesalamine at 2.4 g/day but in whom the therapeutic effect is not sufficient and having more severe symptoms (UCDAI 9-10), benefit from higher doses of mesalamine compared to others.\n\nAsacolpH-dependent-release mesalamineColitis, ulcerativeDouble-blind methodZeria Pharmaceutical Co., Ltd.Kyowa Hakko Kirinhttp://dx.doi.org/10.13039/501100004095\n==== Body\nINTRODUCTION\nThe treatment of UC centers on drug therapy, with mesalamine, steroids, immunomodulators, and biological drugs being the main treatment options. Mesalamine is an antiinflammatory drug with a localized effect on the colon, and it is widely used as first-line treatment for mild-to-moderate UC.1 There are several oral formulations of mesalamine—each of them with different release properties. Mesalamine is considered a safe drug,12 and no difference in the incidence of adverse events (AEs) between the different oral mesalamine formulations has been reported.3\n\nAlthough the therapeutic effect of mesalamine is considered to improve with increasing dose,124 no consensus has been reached with regard to the optimal dose of mesalamine. A textbook on internal medicine states the therapeutic effect of mesalamine on UC shows a dose–response relationship of up to 4.8 g/day,5 whereas the practice guidelines published by the American College of Gastroenterology recommend that patients with mild-to-moderate extensive colitis be started on treatment with a maximum of 4.8 g/day of mesalamine.1 On the other hand, according to a systematic review by the Cochrane Collaboration,3 a daily dosage of 2.4 g appears to be a safe and effective induction therapy for patients with mildly to moderately active UC. The Cochrane Collaboration review also states that among patients with mildly active UC, a dosage of 4 to 4.8 g/day does not appear to provide any additional benefit over a dosage of 2 to 2.4 g/day. That differs from patients with moderate disease, who may benefit from an initial dose of 4.8 g/day. According to the same review, a pooled analysis of the ASCEND trials found no statistically significant difference in the clinical improvement of mild-to-moderate UC in patients administered with pH-dependent-release oral mesalamine (Asacol®) at 4.8 g/day and 2.4 g/day;678 however, a subgroup analysis found that moderate cases may benefit from 4.8 g/day. Moreover, a study that compared 4 g/day and 2.25 g/day doses of time-dependent-release mesalamine (Pentasa® tablets) in patients with moderate UC found no statistically significant difference in failure to induce remission.9\n\nDue to there being only limited evidence regarding the benefit of exceeding 4 g/day of mesalamine in the treatment of patients with moderately active UC, the aim of the present study was to compare the efficacy and safety of oral pHdependent-release mesalamine at 3.6 g/day and 4.8 g/day in patients with moderately active UC.\n\nMETHODS\n1. Study Design\nThis was a multicenter, randomized, double-blind, parallel group study conducted at 38 facilities in Japan from September 2012 to October 2013. Patients were randomly assigned to study groups through a central registration by dynamic allocation with biased-coin minimization. The allocation factors were severity of UC (UC disease activity index [UCDAI] of 6-8 and 9-10), inflamed areas (ulcerative proctitis and other), and prior dose of oral mesalamine (<3.6 g/day and ≥3.6 g/day). Balance within the study site was also considered. The person responsible for the allocation, who was independent from the study, prepared the study drug allocation table and randomly allocated the study drug (3.6 g/day and 4.8 g/day groups) by way of a permutation block method for sets of four patients (two patients/group). The same person sealed the study drug allocation table immediately after allocation and securely retained the table until key code breaking. The screening period was 3 to 14 days after informed consent was obtained. Eligible subjects received one of the following combinations of the study drug orally (four tablets per dosing, three times daily after each meal for 8 weeks): 4.8 g/day (four pH-dependent-release mesalamine tablets per dosing) or 3.6 g/day (three pH-dependent-release mesalamine tablets and one placebo tablet per dosing).\n\nAll procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the 1975 Declaration of Helsinki, as revised in 2013. Documented approval by appropriate institutional review boards was obtained for all participating sites. All subjects provided written informed consent prior to participating in the study. The trial was registered in the JapicCTI under registration no. JapicCTI-121943.\n\n2. Subjects\nPatients with moderately active UC who met all of the following inclusion criteria were enrolled in the study: UCDAI score of 6 to 10 and rectal bleeding score of ≥1, relapsingremitting-type UC, and age of 16 to 64 years at the time of informed consent. Patients with any of the following criteria were excluded: (1) daily dose of oral mesalamine <2.0 g or >4.0 g (for salazosulfapyridine, the amount equivalent to mesalamine was calculated by multiplying the dose by 0.5) within 14 days prior to screening; (2) clinical course classified as the first attack, chronic continuous, or acute fulminating; (3) comorbid intestinal stenosis, intestinal perforation, toxic megacolon, or septicemia; (4) comorbid infectious enteritis; (5) time from onset of UC ≤6 months; (6) treatment with antidiarrheal medication or laxatives within 3 days prior to screening; (7) treatment with mesalamine (enema or suppository) or corticosteroid (oral, enema, suppository, or injection) within 14 days prior to screening; (8) treatment with azathioprine or 6-mercaptopurine (oral) within 21 days prior to screening; (9) cytapheresis or endoscopic mucosal or submucosal dissection within 28 days prior to screening; (10) laparotomy, laparoscopic surgery, endoscopic enteroplasty, or surgery for hemorrhoids or perianal abscess within 56 days prior to screening; (11) use of cyclosporine or tacrolimus (oral or injection), infliximab or adalimumab (injection), or other study drugs within 84 days prior to screening; (12) history of resection of the small intestine, appendix, colon, or rectum; (13) moderate comorbid hepatic or renal disorder; (14) serious comorbid disease such as hematologic, respiratory, or circulatory disorders, psychiatric or neurological diseases, or metabolic or electrolyte abnormality; (15) treatment for malignant tumor or a follow-up duration <5 years; (16) hypersensitivity to mesalamine or salicylic acid drugs; and (17) pregnancy or lactation.\n\n3. Study Drug\nPatients were administered pH-dependent-release mesalamine (Asacol® tablets; Tillotts Pharma AG, Ziefen, Switzerland) consisting of Eudragit-S® coated pH-dependent-release mesalamine containing 400 mg of mesalamine per tablet. Eudragit-S® dissolves at a pH ≥7, and the study drug (Asacol® 400-mg tablets) is designed to release mesalamine at the terminal ileum, where pH exceeds 7. The placebo and the Asacol® tablets were indistinguishable from each other. The Asacol® and placebo tablets used in this study were supplied by Zeria Pharmaceutical Co., Ltd. (Tokyo).\n\nThe following drugs and therapies were prohibited—from the study's start to final assessment (at week 8 or discontinuation): mesalamine drugs (oral, enema, and suppository), including salazosulfapyridine; corticosteroids (oral, enema, suppository, and injection); drugs containing azathioprine or 6-mercaptopurine (oral); drugs containing cyclosporine or tacrolimus (oral and injection); drugs containing infliximab or adalimumab (injection); other study drugs; endoscopic mucosal resection or endoscopic submucosal dissection; laparotomy, laparoscopic surgery, or endoscopic enteroplasty; surgery for hemorrhoids or perianal abscess; and cytapheresis.\n\nThe following drugs were restricted—from the study's start to final assessment (at week 8 or discontinuation): antidiarrheal medications or laxatives taken 3 days prior to visit and nonsteroidal anti-inflammatory drugs taken for 3 or more consecutive days.\n\n4. Efficacy Assessment\nThe primary endpoint was a decrease in UCDAI from screening to final assessment. Secondary endpoints were the proportion of patients in remission (remission proportion) and the proportion of patients in remission or showing improvement (efficacy proportion).\n\nThe UCDAI is the sum of the mucosal-appearance score (based on colonoscopy findings), stool frequency score, rectal-bleeding score, and physician's global assessment score (each score has four items ranging from 0 to 3).10 Throughout the study, each patient visited the study site every 2 weeks and in addition, separately recorded the state of rectal bleeding, stool frequency, and drug compliance in a patient diary. The stool frequency score and the rectal-bleeding score were based on patient diary entries from 3 days before the visit. Each score of the UCDAI was assessed at each visit—except for the mucosal-appearance score. Patients with a UCDAI ≤2 and a rectal-bleeding score of 0 at final assessment were defined as being in remission. Patients who did not achieve remission but whose UCDAI decreased by ≥2 at final assessment were defined as showing improvement. Efficacy was defined as either remission or improvement. Colonoscopy was performed at screening and final assessment (at week 8 or discontinuation), and the UCDAI was calculated each time.\n\n5. Safety Assessment\nLaboratory data were collected at screening, at week 4, and at final assessment (at week 8 or discontinuation); and vital signs were recorded at screening and final assessment. The presence or absence of AEs and adverse drug reactions was recorded by the study doctor at each visit. AEs were coded and tabulated using MedDRA/J terminology (Med-DRA/J Ver.16.1).\n\n6. Statistical Analysis\nAs primary analysis, analysis of covariance was performed using the following allocation factors: UCDAI at screening (continuous), inflamed areas (ulcerative proctitis or other), and dose of prior oral mesalamine (<3.6 g/day or ≥3.6 g/day) as covariates. If any of the UCDAI scores were missing, the UCDAI was handled as missing and was excluded from the analysis. Moreover, if any of the UCDAI scores were missing at final assessment, the subject was considered not remitted/not improved. Secondary and subgroup analyses were performed without adjusting the allocation factors. For the safety endpoint, the frequency distribution and incidence of AEs and adverse drug reactions were compared. A significance level of 0.05 (two-sided) was used for statistical tests, and P<0.05 was considered statistically significant. A confidence level of 0.95 (two-sided) was used to calculate the CI. There was no statistical rationale for the sample size set for this study.\n\nThe safety analysis set was the population used for safety assessment and included subjects who took at least one tablet of the study drug, but it excluded patients who had goodclinical-practice noncompliance or had no safety data after the start of the study treatment. The full-analysis set was the primary analysis set, which included all subjects in the safety analysis set—except for those who had no efficacy data after the start of the study treatment or who, after the start of the study treatment, were determined not to have UC. The perprotocol set included all subjects in the full-analysis set—except for those who did not meet the inclusion criteria—who fell under the exclusion criteria, used restricted or prohibited concomitant drugs, had treatment compliance <80%, or discontinued within 3 days from the start of the study treatment. The statistical analysis plan was finalized after the blind review prior to key code breaking, and the statistical analyses were performed at Zeria Pharmaceutical Co., Ltd. All statistical calculations were performed with SAS Release 9.2 (SAS Institute Inc., Cary, NC, USA).\n\nRESULTS\n1. Subjects\nAmong the 131 patients who provided informed consent, 110 eligible subjects (3.6 g/day group, 55; 4.8 g/day group, 55) received the study drug. Of those, 13 subjects (3.6 g/day group, 7; 4.8 g/day group, 6) discontinued the study. There were no between-group differences in reasons for discontinuation. The most common reason for discontinuation was aggravation of UC. The disposition of each analysis set is shown in Fig. 1. Because the analysis results of the full-analysis set and per-protocol set were similar, the analysis results of the full-analysis set are shown later.\n\nPatient baseline characteristics are shown in Table 1. Most of the participants were men (62.7%), and mean age, body weight, and other characteristics were similar among the two dose groups. No adjustments were made other than the allocation factors in the efficacy analysis.\n\n2. Efficacy\n1) UCDAI at Final Assessment\nThe decrease in UCDAI (primary endpoint) was 3.1 in the 3.6 g/day group and 3.4 in the 4.8 g/day group. The difference in the decrease in UCDAI between the two groups was 0.3 (95% CI, -0.7–1.3) and was not statistically significant. In the secondary analysis, the decreases in UCDAI without adjustment for covariates were 2.3 in the 3.6 g/day group (95% CI, 1.6–3.1) and 2.7 in the 4.8 g/day group (95% CI, 2.0–3.5); and a marked decrease from the time of screening was observed in both groups (Table 2).\n\n2) Secondary Endpoints\nThe proportions of subjects in remission were 18.2% in the 3.6 g/day group and 25.5% in the 4.8 g/day group, and the proportions of subjects showing efficacy were 56.4% in the 3.6 g/day group and 60.0% in the 4.8 g/day group. The differences in the percentages of subjects who were in remission and showing efficacy were 7.3% (95% CI, -8.1–22.6) and 3.6% (95% CI,-14.7–22.0), respectively (Table 3).\n\n3) Subgroup Analysis\nThe difference between the 3.6 g/day and 4.8 g/day groups with respect to disease severity at screening, inflamed areas, and dose of prior oral mesalamine was investigated. In the subgroup with UCDAI scores of 6–8 at screening, the decrease in UCDAI was 2.1 in both the 3.6 g/day group and the 4.8 g/day group (95% CI, -1.2–1.2). In the subgroup with UCDAI scores of 9–10, the decreases in UCDAI were 3.1 in the 3.6 g/day group and 4.3 in the 4.8 g/day group, with a difference of 1.3 (95% CI, -1.2–3.7) between the two groups. In both subgroups, according to inflamed areas and dose of prior oral mesalamine, the decrease in UCDAI was higher in the 4.8 g/day group than in the 3.6 g/day group (Table 4).\n\nPatients who received 2.0 to 4.0 g of oral mesalamine within 14 days prior to screening as a prior therapy were included in the present study; this included types of oral mesalamine other than pH-dependent-release mesalamine, such as salazosulfapyridine. (The amount equivalent to mesalamine was calculated by multiplying the dose by 0.5.)\n\nIn Table 4, in the subgroup with dose of prior oral mesalamine of <3.6 g/day, the decreases in UCDAI were 3.6 in the 3.6 g/day group and 3.8 in the 4.8 g/day group, with a difference of 0.2 (95% CI, -1.8–2.2) between the two groups. In the subgroup with dose of prior oral mesalamine of ≥3.6 g/day, the decreases in UCDAI were 1.9 in the 3.6 g/day group and 2.4 in the 4.8 g/day group, with a difference of 0.5 (95% CI, -0.8–1.8) between the two groups. There was no significant difference between the 3.6 g/day and 4.8 g/day groups in decrease in UCDAI according to dose of prior oral mesalamine (<3.6 g/day or ≥3.6 g/day).\n\nPatients whose pH-dependent-release mesalamine dose at screening was 2.4 g/day or 3.6 g/day were analyzed to determine the effect of changing the dose. In the subgroup whose mesalamine dose at screening was 2.4 g/day, the decreases in UCDAI were 2.3 in the 3.6 g/day group and 4.5 in the 4.8 g/day group, with a difference of 2.2 (95% CI, –3.1–7.4) between the groups. In the subgroup whose mesalamine dose at screening was 3.6 g/day, the decrease in UCDAI was 2.1 in both the 3.6 g/day group and the 4.8 g/day group (Table 5).\n\n3. Safety\nThe incidences of AEs were 43.6% (24/55 subjects) in the 3.6 g/day group and 45.5% (25/55 subjects) in the 4.8 g/day group. The incidences of adverse drug reactions were 14.5% (8/55 subjects) in the 3.6 g/day group, and 20.0% (11/55 subjects) in the 4.8 g/day group. There was no clear difference in the incidences of AEs and adverse drug reactions between the two groups.\n\nAEs with incidences ≥5% in either group were nasopharyngitis (7.3% in the 3.6 g/day group and 12.7% in the 4.8 g/day group) and increased beta-N-acetyl-D-glucosaminidase (NAG) (12.7% in the 3.6 g/day group and 7.3% in the 4.8 g/day group). A causal relationship with the study drug was ruled out for all nasopharyngitis events; however, it could not be ruled out in many cases of increased NAG. The incidences of adverse drug reactions are shown in Table 6.\n\nRegarding serious AEs, aggravation of UC occurred in one subject in the 3.6 g/day group, and acute pancreatitis and colon dysplasia occurred in one subject each in the 4.8 g/day group. Aggravation of UC and acute pancreatitis were determined to be related to the study drug. Moreover, herpes zoster oticus occurred in one subject in the 3.6 g/day group, and acute pancreatitis occurred in one subject in the 4.8 g/day group; they were determined as AEs leading to discontinuation of the study treatment.\n\nDISCUSSION\nOral pH-dependent-release mesalamine is widely used for the treatment of UC worldwide. In Japan, pH-dependent-release mesalamine at 3.6 g/day has been approved as the maximum dose for patients with active UC; however, the use of up to 4.8 g/day is approved in many other countries. To date, no study has compared 3.6 g/day and 4.8 g/day doses of pH-dependent-release mesalamine. Thus, this study, which directly compared the therapeutic effects of those two dose levels, may provide valuable new evidence.\n\nBecause of the exploratory aspect of this study, there was no statistical rationale for the sample size, and as a result, it is difficult to draw a definite conclusion. Nevertheless, there was a marked decrease in UCDAI at final assessment in both the 3.6 g/day group and the 4.8 g/day group, and the percentages of patients showing efficacy were comparable to those found in studies performed in Japan and overseas.67810 Therefore, both dose levels were considered to induce remission in patients with moderately active UC. However, there was no significant difference between the 3.6 g/day and 4.8 g/day groups in decrease in UCDAI at final assessment. Therefore, in Japanese patients with moderately active UC, the benefit gained from the 4.8 g/day dose compared with the 3.6 g/day dose was considered minimal. Ito et al. investigated pH-dependent-release mesalamine induction of remission at doses of 2.4 g/day and 3.6 g/day and without adjustment for covariates;10 the difference in the decrease in UCDAI at final assessment was 1.4 (1.5 in the 2.4 g/day group and 2.9 in the 3.6 g/day group). In the present study, the difference in the decrease in UCDAI was 0.4 (2.3 in the 3.6 g/day group and 2.7 in the 4.8 g/day group). Although it is not possible to simply compare the results from the two studies, the difference in the decrease in UCDAI between the 3.6 g/day and 4.8 g/day groups found in the present study was smaller than the difference between the 2.4 g/day and 3.6 g/day groups in the previous study.\n\nThe results of subgroup analysis suggested that some patients may benefit from 4.8 g/day of pH-dependent-release mesalamine. In the subgroup analysis based on the dose of oral mesalamine in prior therapy, the decrease in UCDAI in patients who had received 2.4 g/day was 2.2 points higher in the 4.8 g/day group (group with a 2.4 g dose increase) than in the 3.6 g/day group (group with a 1.2 g dose increase). Meanwhile, the decrease in UCDAI in patients who had received 3.6 g/day did not differ between the 3.6 g/day (group with no dose change) and 4.8 g/day (group with a 1.2 g dose increase) groups. Thus, the increase in dose by 1.2 g appeared to have no effect. Although the therapeutic effect of mesalamine has been proposed to improve with increasing dose,12 those results showed that patients receiving oral mesalamine at 2.4 g/day but in whom the therapeutic effect is not sufficient could benefit from increasing the dose up to 4.8 g/day. However, increasing the dose of oral mesalamine to 4.8 g/day may not be appropriate for patients with moderately active UC who are receiving up to 3.6 g/day. Furthermore, in the subgroup analysis based on disease severity, there was no difference in the decrease in UCDAI between the two groups in patients whose UCDAIs at screening were 6-8, whereas the decrease in UCDAIs in patients with scores of 9-10 was 1.3 points higher in the 4.8 g/day group than in the 3.6 g/day group.\n\nPatients may be classified as severe when their UCDAIs are ≥11.11 Therefore, it seemed that patients with moderate UC whose disease severities were milder (UCDAI 6-8) were less likely to benefit from 4.8 g/day of pH-dependent-release mesalamine, and those with more-severe symptoms (UCDAI 9-10) were more likely to benefit from 4.8 g/day than from 3.6 g/day. However, because the numbers of subjects in those subgroups were small, it is not appropriate to draw a conclusion based solely on trends identified from the results of that study.\n\nRegarding safety, there was no clear difference in incidences of AEs or adverse drug reactions between the two groups. Incidences of adverse drug reactions did not tend to be markedly higher in the 4.8 g/day group. Mesalamine is generally considered a safe drug,12 and 4.8 g/day of pH-dependent-release mesalamine has been reported to be a safe dose in patients with mild-to-moderate UC.789 Thus, the results from this study were in accordance with those of previous reports. However, in the present study, acute pancreatitis in one subject in the 4.8 g/day group was determined to be a serious adverse drug reaction. Pancreatitis is a known adverse reaction of mesalamine. Physicians should be aware of patients' symptoms and relevant clinical laboratory data.\n\nOur results suggest that the safety risk of the 4.8 g/day dose is not higher than that of the 3.6 g/day dose. However, patients who did not respond sufficiently to treatment with 3.6 g/day were believed to benefit little from an increase in the dose to 4.8 g/day and may benefit more from a treatment other than oral mesalamine. Meanwhile, the results suggested that treatment with 4.8 g/day may bring benefit to particular populations, such as (1) patients who are not responding sufficiently because of the low dose of mesalamine and (2) patients with more-severe disease. However, further investigation is required to determine the optimal dose for each patient.\n\nWe must conduct more-detailed assessments of patients' backgrounds to determine which findings from the subgroup analysis of the present study can be generalized. An understanding of the limitations of mesalamine treatment based on patients' backgrounds will potentially lead to optimization of UC treatment.\n\nA limitation of the present study was that no statistical rationale was established for the sample size of the present study, which was relatively small.\n\nIn conclusion, stand-alone treatment with pH-dependent-release mesalamine at 3.6 g/day and 4.8 g/day was effective for the induction of remission in patients with moderately active UC. The benefit from a dose exceeding 3.6 g/day—namely, 4.8 g/day—was not apparent for all patients with active UC. Safety risks were considered to be comparable between the 4.8 g/day and 3.6 g/day doses.\n\nACKNOWLEDGEMENTS\nWe thank all of the study participants, doctors, and staff who supported this study. We thank Hikaru Ito (Zeria Pharmaceutical Co., Ltd., Tokyo) for help in writing this paper and Michelle Belanger, MD, on behalf of inScience Communications for editorial support, which was funded by Zeria Pharmaceutical Co., Ltd. All named authors meet International Committee of Medical Journal Editors criteria for authorship for this manuscript; they take responsibility for the integrity of the work as a whole; and they have given final approval to the version to be published.\n\nFinancial support: This study was funded and supported by Zeria Pharmaceutical Co., Ltd., and Kyowa Hakko Kirin Co., Ltd. (Tokyo).\n\nConflict of interest: Hiroaki Ito has received consulting fees from Zeria Pharmaceutical Co., Ltd. Isamu Saida is an employee of Zeria Pharmaceutical Co., Ltd. Toshifumi Hibi has received advisory, speaker fees and grant support from Zeria Pharmaceutical Co., Ltd., speaker fees from Kyorin Pharmaceutical Co., Ltd., and consulting fees from Pfizer Japan Inc.\n\nFig. 1 Enrollment, randomization, and analysis of the study subjects. SAF, safety analysis set; FAS, full-analysis set; PPS, per-protocol set.\nTable 1 Patient Baseline Characteristics\nCharacteristic\t3.6 g/day group (n=55)\t4.8 g/day group (n=55 )\t\nSex\t\t\t\n Male\t30\t39\t\n Female\t25\t16\t\nAge (yr)\t40.2±12.5\t37.9±10.2\t\nBody weight (kg)\t61.4±12.1\t62.3±10.7\t\nDuration of disease (yr)\t\t\t\n <2\t7\t9\t\n ≥2 to <5\t15\t17\t\n ≥5 to <10\t14\t13\t\n ≥10\t19\t16\t\nInflamed areas\t\t\t\n Ulcerative proctitis\t11\t9\t\n Left-sided colitis\t28\t26\t\n Right-sided or segmental colitis\t2\t1\t\n Extensive colitis\t14\t19\t\nNo. of normal stools\t\t\t\n 1\t41\t35\t\n 2\t8\t13\t\n 3\t4\t6\t\n ≥4\t2\t1\t\nTime from most recent relapse (wk)\t\t\t\n <2\t2\t3\t\n ≥2 to <4\t10\t10\t\n ≥4 to <8\t13\t23\t\n ≥8 to <24\t22\t15\t\n ≥2\t8\t4\t\nSeverity of disease (UCDAI at initial assessment)\t\t\t\n 6-8\t41\t40\t\n 9-10\t14\t15\t\nDose of prior oral mesalaminea (g/day)\t\t\t\n <3.6\t14\t14\t\n ≥3.6\t41\t41\t\nValues are presented as mean±SD or n.\n\naOral mesalamine drugs included oral salazosulfapyridine. If salazosulfapyridine was used, the amount equivalent to mesalamine was calculated by multiplying the dose by 0.5.\n\nUCDAI, Ulcerative Colitis Disease Activity Index.\n\nTable 2 Decrease in Ulcerative Colitis Disease Activity Index\nCharacteristic\t3.6 g/day group (n=52)\t4.8 g/day group (n=53)\tP-value\t\nUCDAI at screening\t7.4±1.2\t7.6±1.3\t\t\nUCDAI at final assessmenta\t5.1±2.9\t4.9±2.9\t\t\nDecrease in UCDAIb (adjusted by covariates), mean (95% CI)\t3.1 (2.3–4.0)\t3.4 (2.5–4.3)\t\t\nDifference in decrease in UCDAIc (adjusted by covariatesd) difference (95% CI)\t0.3 (−0.7–1.3)\t0.598\t\nDecrease in UCDAI, mean (95% CI)\t2.3 (1.6–3.1)\t2.7 (2.0–3.5)\t\t\nDifference in decrease in UCDAI (95% CI)\t0.4 (−0.7–1.5)\t0.494\t\nValues are mean±SD.\n\nMissing values were excluded from the analysis.\n\naFinal assessment was at week 8 or at discontinuation.\n\nbDecrease in UCDAI = UCDAI at screening – UCDAI at final assessment.\n\ncDifference in decrease in UCDAI = decrease in UCDAI in the 4.8 g/day group – decrease in UCDAI in the 3.6 g/day group.\n\ndCovariates were UCDAI at screening (continuous), inflamed areas (ulcerative proctitis, other), and dose of prior oral mesalamine (<3.6 g/day, ≥3.6 g/day).\n\nUCDAI, Ulcerative Colitis Disease Activity Index.\n\nTable 3 Remission Proportion and Efficacy Proportion\nCharacteristic\t3.6 g/day group (n=55)\t4.8 g/day group (n=55)\t\nEffectivea\t\t\t\n Remittedb\t10\t14\t\n Improved\t21\t19\t\nNot effective\t24\t22\t\nRemission proportionc (%) (95% CI)\t18.2 (9.1–30.9)\t25.5 (14.7–39.0)\t\nDifference in remission proportiond, difference (95% CI)\t7.3 (−8.1–22.6)\t\nEfficacy proportione (%) (95% CI)\t56.4 (42.4–69.6)\t60.0 (46.0–72.9)\t\nDifference in efficacy proportionf, difference (95% CI)\t3.6 (−14.7–22.0)\t\nValues are presented as n or y.\n\nMissing values were handled as \"Not effective.\"\n\naEffective was remitted and improved.\n\nbRemitted was UCDAI ≤2 and rectal-bleeding score of 0 at final assessment.\n\ncRemission proportion = % of patients remitted.\n\ndDifference in remission proportion = remission proportion in the 4.8 g/day group – remission proportion in the 3.6 g/day group.\n\neEfficacy proportion = % of patients with effective treatment.\n\nfDifference in efficacy proportion = efficacy proportion in the 4.8 g/day group – efficacy proportion in the 3.6 g/day group.\n\nTable 4 Subgroup Analysis According to Disease Severity, Inflamed Areas, and Dose of Prior Oral Mesalamine\nCharacteristic\t3.6 g/day group (n=52)\t\t4.8 g/day group (n=53)\t\nUCDAI at initial assessment\t\t\t\t\n 6–8\t39\t\t38\t\n Decrease in UCDAIa, mean (95% CI)\t2.1 (1.2–3.0)\t\t2.1 (1.3–2.8)\t\n Difference in decrease in UCDAIb, difference (95% CI)\t\t0.0 (−1.2–1.2)\t\t\n 9–10\t13\t\t15\t\n Decrease in UCDAI, mean (95% CI)\t3.1 (1.5–4.6)\t\t4.3 (2.4–6.3)\t\n Difference in decrease in UCDAI, difference (95% CI)\t\t1.3 (−1.2–3.7)\t\t\nDecrease in UCDAI inflamed areas\t\t\t\t\n Ulcerative proctitis\t11\t\t9\t\n Decrease in UCDAI, mean (95% CI)\t2.9 (1.1–4.7)\t\t3.1 (0.9–5.3)\t\n Difference in decrease in UCDAI, difference (95% CI)\t\t0.2 (−2.4–2.8)\t\t\n Other\t41\t\t44\t\n Decrease in UCDAI, mean (95% CI)\t2.2 (1.3–3.1)\t\t2.6 (1.8–3.5)\t\n Difference in decrease in UCDAI, difference (95% CI)\t\t0.5 (−0.8–1.7)\t\t\nDose of prior oral mesalaminec\t\t\t\t\n <3.6 g/day\t13\t\t13\t\n Decrease in UCDAI, mean (95% CI)\t3.6 (2.2–5.0)\t\t3.8 (2.2–5.3)\t\n Difference in decrease in UCDAI, difference (95% CI)\t\t0.2 (−1.8–2.2)\t\t\n ≥3.6 g/day\t39\t\t40\t\n Decrease in UCDAI, Mean (95% CI)\t1.9 (1.0–2.8)\t\t2.4 (1.5–3.3)\t\n Difference in decrease in UCDAI, difference (95% CI)\t\t0.5 (−0.8–1.8)\t\t\nFinal assessment was at week 8 or at discontinuation.\n\nMissing values were excluded from the analysis.\n\naDecrease in UCDAI = UCDAI at screening – UCDAI at final assessment.\n\nbDifference in decrease in UCDAI = decrease in UCDAI in the 4.8 g/day group – decrease in UCDAI in the 3.6 g/day group.\n\ncOral mesalamine drugs included oral salazosulfapyridine. If salazosulfapyridine was used, the amount equivalent to mesalamine was calculated by multiplying the dose by 0.5.\n\nUCDAI, Ulcerative Colitis Disease Activity Index.\n\nTable 5 Subgroup Analysis According to the Prior Dose of pH-Dependent-release Mesalamine\nCharacteristic\t3.6 g/day group (n=33)\t\t4.8 g/day group (n=35)\t\nPrior dose of oral mesalamine\t\t\t\t\n 2.4 g/day\t3\t\t6\t\n Decrease in UCDAIa, mean (95% CI)\t2.3 (−4.8– 9.5)\t\t4.5 (1.1–7.9)\t\n Difference in decrease in UCDAIb, difference (95% CI)\t\t2.2 (−3.1–7.4)\t\t\n 3.6 g/day\t30\t\t29\t\n Decrease in UCDAI, mean (95% CI)\t2.1 (1.1–3.1)\t\t2.1 (1.1–3.2)\t\n Difference in decrease in UCDAI, difference (95% CI)\t\t0.0 (−1.4–1.5)\t\t\nFinal assessment was at week 8 or at discontinuation.\n\nMissing values were excluded from the analysis.\n\naDecrease in UCDAI = UCDAI at screening – UCDAI at final assessment.\n\nbDifference in decrease in UCDAI = decrease in UCDAI in the 4.8 g/day group – decrease in UCDAI in the 3.6 g/day group.\n\nUCDAI, Ulcerative Colitis Disease Activity Index.\n\nTable 6 List of Adverse Drug Reactions\nCharacteristic\t3.6 g/day group (n=55)\t4.8 g/day group (n=55)\t\nAll events\t8 (14.5)\t11 (20.0)\t\nAbdominal discomfort\t0 (0.0)\t1 (1.8)\t\nAggravation of UC\t1 (1.8)\t0 (0.0)\t\nAcute pancreatitis\t0 (0.0)\t1 (1.8)\t\nIncreased amylase\t0 (0.0)\t1 (1.8)\t\nIncreased beta-N-acetyl-D-glucosaminidase\t6 (10.9)\t4 (7.3)\t\nIncresed conuated bilirubin\t0 (0.0)\t1 (1.8)\t\nIncresed bilirubin\t1 (1.8)\t1 (1.8)\t\nIncreased urinc acid\t0 (0.0)\t1 (1.8)\t\nIncreased gamma-glutamyltransferase\t1 (1.8)\t0 (0.0)\t\nAbnormal liver function test\t0 (0.0)\t2 (3.6)\t\nDecresed white blood cell count\t0 (0.0)\t1 (1.8)\t\nIncresed white blood cell count\t0 (0.0)\t1 (1.8)\t\nValues are presented as n (%).\n\nEvent term based on MedDRA/J Ver.16.1.\n\nAdverse events were evaluated as related or unrelated. If assessed as related, the event was counted as an adverse drug reaction.\n==== Refs\n1 Kornbluth A Sachar DB Practice Parameters Committee of the American College of Gastroenterology Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology Practice Parameters Committee Am J Gastroenterol 2004 99 1371 1385 15233681 \n2 Carter MJ Lobo AJ Travis SP; British Society Guidelines for the management of inflammatory bowel disease in adults Gut 2004 53 Suppl 5 V1 V16 15306569 \n3 Feagan BG Macdonald JK Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis Cochrane Database Syst Rev 2012 10 CD000543 10.1002/14651858.CD000543.pub3 23076889 \n4 Friedman S Blumberg RS Inflammatory bowel disease Kasper DL Braunwald E Fauci AS Hauser SL Longo DL Jameson JL Harrison's principles of internal medicine 16th ed New York McGraw-Hill 2004 1776 1789 \n5 Friedman S Blumberg RS Inflammatory bowel disease Longo DL Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo J Harrison's principles of internal medicine 18th ed New York McGraw-Hill 2011 2477 2495 \n6 Hanauer SB Sandborn WJ Dallaire C Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial Can J Gastroenterol 2007 21 12 827 834 18080055 \n7 Hanauer SB Sandborn WJ Kornbluth A Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: The ASCEND II trial Am J Gastroenterol 2005 100 2478 2485 16279903 \n8 Sandborn WJ Regula J Feagan BG Delayed-release oral mesalamine 4.8 g/day (800-mg) tablet is effective for patients with moderately active ulcerative colitis Gastroenterology 2009 137 1934 1943 19766640 \n9 Hiwatashi N Suzuki Y Mitsuyama K Clinical trial: Effects of an oral preparation of mesalazine at 4 g/day on moderately active ulcerative colitis. A phase III parallel-dosing study J Gastroenterol 2011 46 46 56 20878425 \n10 Ito H Iida M Matsumoto T Direct comparison of two different mesalamine formulations for the induction of remission in patients with ulcerative colitis: A double-blind, randomized study Inflamm Bowel Dis 2010 16 1567 1574 20049950 \n11 Hirai F Mayo score. Disease activity index of inflammatory bowel disease Research Group for Intractable Inflammatory Bowel Disease (Watanabe Group) Health and labour science research grants from the Japanese Ministry of Health, Labour and Welfare and research on measures for intractable disease; 2007–2009 research report 2010 640\n\n",
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"issue": "14(1)",
"journal": "Intestinal research",
"keywords": "Asacol; Colitis, ulcerative; Double-blind method; pH-dependent-release mesalamine",
"medline_ta": "Intest Res",
"mesh_terms": null,
"nlm_unique_id": "101572802",
"other_id": null,
"pages": "50-9",
"pmc": null,
"pmid": "26884735",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": "16279903;20878425;15233681;23076889;15306569;20049950;19766640;18080055",
"title": "Efficacy and safety of two pH-dependent-release mesalamine doses in moderately active ulcerative colitis: a multicenter, randomized, double-blind, parallel-group study.",
"title_normalized": "efficacy and safety of two ph dependent release mesalamine doses in moderately active ulcerative colitis a multicenter randomized double blind parallel group study"
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"abstract": "There is little evidence around Camrelizumab combined with cytoreductive nephrectomy (CN) and radiotherapy (RT) as a treatment option for metastatic renal cell carcinoma (mRCC). The influence of CN on immune responses and the abscopal effect are not well understood. In this paper, we report a case of anti-programmed cell death-1 (PD-1) treated with combined RT once CN reduced the primary tumor burden (TB). This patient also encountered an increased response to targeted radiotherapy after immune resistance. We also observed a macrophage-to-lymphocyte ratio (MLR) peak, which may be correlated with subsequent pseudoprogression after thoracic radiotherapy. Consequently, even with the disease, this patient has remained stable. This peculiar instance suggests there is a need to investigate the underlying mechanisms of CN in promoting the abscopal effect during immunotherapy when combined with RT. It also suggests that there is a need for further investigation into the role of RT in overcoming immune resistance, and the value of MLR in predicting pseudoprogression. We hypothesize that a heavy tumor burden might suppress the abscopal effect, thereby ensuring that CN promotes it. However, radiotherapy may overcome immune resistance during oligoprogression.",
"affiliations": "Cheeloo College of Medicine, Shandong University, Jinan, China.;Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.;Health Research, Faculty of Health and Medicine, Lancaster University, City of Lancaster, United Kingdom.;Cheeloo College of Medicine, Shandong University, Jinan, China.;Cheeloo College of Medicine, Shandong University, Jinan, China.",
"authors": "Wu|Min|M|;Liu|Jie|J|;Seery|Samuel|S|;Meng|Xue|X|;Yue|Jinbo|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000082082:Immune Checkpoint Inhibitors; D016693:Receptors, Antigen, T-Cell, alpha-beta; C000631724:camrelizumab",
"country": "Switzerland",
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"doi": "10.3389/fimmu.2021.646085",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.646085\nImmunology\nCase Report\nCytoreductive Nephrectomy Promoted Abscopal Effect of Camrelizumab Combined With Radiotherapy for Metastatic Renal Cell Carcinoma: A Case Report and Review of the Literature\nWu Min 1 2\nLiu Jie 2\nSeery Samuel 3\n\nMeng Xue 1 2 *\n\nYue Jinbo 1 2 *\n\n1 Cheeloo College of Medicine, Shandong University, Jinan, China\n2 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China\n3 Health Research, Faculty of Health and Medicine, Lancaster University, City of Lancaster, United Kingdom\nEdited by: Ilaria Marigo, Veneto Institute of Oncology (IRCCS), Italy\n\nReviewed by: Weidong Han, Sir Run Run Shaw Hospital, China; Georgi Guruli, Virginia Commonwealth University, United States; Wan Xiangbo, The Sixth Affiliated Hospital of Sun Yat-sen University, China\n\n*Correspondence: Xue Meng, mengxuesdzl@163.com; Jinbo Yue, jbyue@sdfmu.edu.cn\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n15 6 2021\n2021\n12 64608525 12 2020\n28 5 2021\nCopyright © 2021 Wu, Liu, Seery, Meng and Yue\n2021\nWu, Liu, Seery, Meng and Yue\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nThere is little evidence around Camrelizumab combined with cytoreductive nephrectomy (CN) and radiotherapy (RT) as a treatment option for metastatic renal cell carcinoma (mRCC). The influence of CN on immune responses and the abscopal effect are not well understood. In this paper, we report a case of anti-programmed cell death-1 (PD-1) treated with combined RT once CN reduced the primary tumor burden (TB). This patient also encountered an increased response to targeted radiotherapy after immune resistance. We also observed a macrophage-to-lymphocyte ratio (MLR) peak, which may be correlated with subsequent pseudoprogression after thoracic radiotherapy. Consequently, even with the disease, this patient has remained stable. This peculiar instance suggests there is a need to investigate the underlying mechanisms of CN in promoting the abscopal effect during immunotherapy when combined with RT. It also suggests that there is a need for further investigation into the role of RT in overcoming immune resistance, and the value of MLR in predicting pseudoprogression. We hypothesize that a heavy tumor burden might suppress the abscopal effect, thereby ensuring that CN promotes it. However, radiotherapy may overcome immune resistance during oligoprogression.\n\nclear cell renal cell carcinoma\ncamrelizumab\nabscopal effect\npseudoprogression\nMLR\nFoundation for Innovative Research Groups of the National Natural Science Foundation of China10.13039/501100012659\n==== Body\nIntroduction\n\nRenal cell carcinoma (RCC) accounts for approximately 85% of all pathological renal carcinomas. Among all of these cases, 70% are clear cell renal cell carcinomas (ccRCC) (1). Approximately 30% of all kidney carcinoma patients have multiple distant metastases such as lung, bone, brain, and other organs upon diagnosis, of which the 5-year survival rate is only around 8% (2). Renal carcinoma has strong immunogenicity. Cytokine therapy was generally offered before the discovery of a number of targeted therapies, which eventually became standard first-line interventions for ccRCC (3). However, immunotherapies have now become the first-line therapy and have gradually become a new treatment mode for metastatic, inoperable, medium-high risk ccRCC (4–6).\n\nBased on the results of various clinical trials, immune monotherapy combined with CN or RT appear to prolong survival (7, 8). CN therefore appears to reduce the tumor burden so that the immunotherapeutic effect is enhanced. Immunotherapy combined with RT also improves survival, although the abscopal effect is infrequent (9–11). The abscopal effect is a rare phenomenon associated with radiotherapy (11). It refers to the release of immunocompetent molecules from apoptosing tumor cells after local radiotherapy and the stimulation of immune responses, which leads to the reduction and control of tumor lesions without RT (12). Multiple studies have revealed that combined radiotherapy and immunotherapy can be more effective at overcoming tumor immunosuppression and increasing the incidence of abscopal effect compared to RT alone, regardless of the type of immune checkpoint inhibitor combined with either CTLA-4 or PD-1/PD-L1 inhibitors (13, 14).\n\nHowever, there is no data on the effect of CN in immunotherapeutics when combined with RT or the potential abscopal effect that comes with it. This is the first report of a patient who was administered Camrelizumab combined with CN and radiotherapy as a second-line treatment for mRCC. In this instance, CN appeared to promote the abscopal effect when receiving immunotherapy and RT. RT plays an important role in oligoprogressive metastasis and may be useful in overcoming immune resistance.\n\nCase Description\n\nA 65-year-old man presented at an outpatient clinic with a chief complaint of excruciating pain around his waist and lower left limb for more than 10 months. Physical examination revealed a left lumbar mass, which warranted further examination. On June 22, 2016, positron emission tomography-computed tomography (PET/CT) enabled clinicians to identify a 6.1 cm mass located in the left kidney with multiple bone and double lung metastases. The largest lesion was approximately 1.2 cm and was located in the inferior lobe of the right lung. Lumbar magnetic resonance imaging (MRI) highlighted the existence of a soft mass near the fifth lumbar vertebra (L5) ( Figure 1 ).\n\nFigure 1 Disease status timeline and PET/CT scan of primary and metastatic lesions accompanied by treatment regimens. CN, cytoreductive nephrectomy; RT, radiotherapy; PET/CT, positron emission tomography-computed tomography/computed tomography; PD, progressive disease; PR, partial response; Point-in-time filled with color represents continuous use of Camrelizumab.\n\nTo relieve the patient’s pain, lumbosacral adnexal tumor resection from the fourth lumbar vertebra to the first sacral vertebra with internal fixation and pyramidal plasty of the first sacral vertebra was performed on June 28, 2016. Post-operative pathology determined metastatic ccRCC. Tissue-based genetic testing also showed high VEGFR1 mRNA expression; consequently, treatment with Sunitinib was initiated in mid-August 2016. However, serum creatinine level rose from a pre-Sunitinib level of 74 μmol/L to a high of 202 μmol/L over approximately two years. Thyroid function appeared normal prior to receiving the targeted therapy, but thyroid stimulating hormone levels also progressively rose to 85.23 mIU/L while the T4 thyroid hormone decreased to 7.10 pmol/L until Sunitinib was discontinued.\n\nOn May 30, 2018, when the patient first underwent a routine examination in our hospital, CT scans revealed that the left renal mass had enlarged to 10.4 cm with the largest 2.2 cm lesion transforming into the left lung, and vertebral metastases had recurred. These findings met the standard definition for progressive disease (PD) according to RECIST guidelines (15). Programmed cell death receptor ligand 1 (PD-L1) expression tests were negative ( Figure 2 ). We recommended a combined dose of axitinib and pembrolizumab as a second-line treatment. However, this patient declined and preferred a single dose of Camrelizumab (AiRuiKa™) instead, a programmed cell death 1 (PD-1) inhibitor at 200 mg q2W for four cycles in step with helical tomotherapy at 45 Gy in 15 fractions for the L5 metastasis lesion.\n\nFigure 2 FFPE tissue photomicrograph from metastatic lesion stained for negative PD-L1 assessment. PD-L1, programmed cell death receptor-ligand 1.\n\nOn August 14, 2018, CT re-examination showed that the disease had progressed globally, with the left renal primary lesion enlarging once more from 10.4 cm to 10.9 cm. The left pulmonary metastasis had also increased from 2.2 cm to 2.9 cm, with new metastases appearing in both lungs. It was suspected that this was due to heavy renal tumor burden; therefore, this patient underwent CN to the left renal mass on September 10, 2018. Post-operative pathological diagnosis confirmed ccRCC. The patient continued receiving 200 mg q3W Camrelizumab after CN.\n\nOn December 17, 2018, CT revealed that the size of the largest metastasis in the left lung was reduced to 1.0 cm after two post-operative cycles of Camrelizumab, which suggested a substantial disease response. This first abscopal effect manifesting through combined radiotherapy and immunotherapy occurred after CN. Subsequent re-examination reflected relative disease stability with regular immunotherapy; however, the lesion in the left inferior lobar bronchus increased to 2.8 cm even after 20 post-operative cycles of Camrelizumab, indicating disease progression according to the imRECIST standard (16).\n\nOn November 22, 2019, oligoprogressive lesion-targeted radiotherapy was commenced at 45 Gy in 15 fractions with an MLR peak during radiation ( Figure 2 ). RT was completed on December 12, 2019 without severe adverse reactions or discontinuation of Camrelizumab. Unfortunately, CT scans taken on the March 16, 2020 showed that the targeted metastatic lesion continued to grow to 6.4 cm even after radiation. Interestingly, the density of another small metastatic nodule theoretically outside the field of radiation was lower than previously recorded.\n\nAccording to the imRECIST standard (16), we recommended a tissue biopsy to determine whether there was pseudoprogression of the disease. However, the patient declined. The patient continued Camrelizumab treatment, resulting in a second abscopal effect which showed that the superior lobe of left lung metastasis had shrunk ( Figure 1 ). After seven further cycles of Camrelizumab, CT revealed that the lesion in the left inferior lobe had also shrunk in size from 6.4 cm to 3.6 cm, which appeared to confirm suspected pseudoprogression. Until now, the patient’s disease has remained stable with Camrelizumab maintenance. The efficacy of Camrelizumab in this patient was unaffected by negative PD-1/PD-L1 expression, and all adverse reactions caused by Sunitinib diminished without additional severe immune-related adverse events (irAEs) except for minor renal function damage.\n\nThe patient also had normal fasting blood glucose levels from November 2018 to August 2019, which is peculiar for a man with a history of diabetes for more than ten years without discontinuing insulin. Hematological indices, including white blood cell (WBC), neutrophil (N), and lymphocyte (L) levels, remained stable throughout the treatment. However, the number of monocytes and the macrophage-to-lymphocyte ratio (MLR) peaked during radiotherapy for lung metastasis, which may be correlated with subsequent pseudoprogression ( Figures 1 and 4 ).\n\nDiscussion\n\nAs the most common pathological type of renal carcinoma, ccRCC is associated with a dismal prognosis. Furthermore, the median PFS of mRCC ranges from six to ten months (1). Current evidence suggests that ccRCC is a highly immunogenic tumor and should therefore be subjected to immune checkpoint inhibitor-based interventions (4, 6). Our report highlights the remarkable effect of Camrelizumab when combined with CN and radiotherapy regardless of PD-L1 expression. Abscopal effects associated with RT combined with immunotherapy occurred twice during treatment after CN. Local radiotherapy for oligoprogressive lesions was also beneficial for immune resistance and pseudoprogression and was probably associated with the MLR peak in blood.\n\nAccording to various animal models, the immune microenvironment changes after hypofractionated RT because PD-L1 expression is upregulated in tumors, weakening the immunosuppressive effect and activating cytotoxic T cells; this in turn reduces tumor invasive myeloid-derived suppressor cells (MDSCs) (17). In two previous retrospective studies, researchers have found that the overall survival of melanoma patients with signs of the abscopal effect after radiotherapy combined with CTLA-4 inhibitors was significantly longer than for those without (12, 18). Some studies have also reported an abscopal effect in mRCC during radiation with checkpoint inhibitor immunotherapies such as nivolumab or pembrolizumab (19–21).\n\nOur patient encountered abscopal effects twice, which may be related to the aforementioned mechanisms involved in the immune microenvironment. He was treated with Camrelizumab after Sunitinib resistance, which is the first report focusing on a Chinese PD-1 monoclonal antibody for ccRCC in addition to tirelizumab (22). However, after four cycles of Camrelizumab immunotherapy and irradiation, the disease continued to progress slowly. We then supplemented the strategy with CN; unexpectedly, the efficiency evaluation measure highlighted a partial response and the first abscopal effect occurred. We infer that CN reduced the number of tumor cells so that there were sufficient PD-1 proteins combined with PD-L1. This in turn activated T cells, enabling them to avoid being suppressed. Physiological memory accumulated over the previous RT six months, and there was a transformation in the remaining M1 macrophages in distant metastases which may lead to the first abscopal effect.\n\nCytoreductive nephrectomy always plays an unpredictable role for patients with mRCC (23). There are both advantages and futilities associated with this intervention (24). As immune checkpoint inhibitors are rapidly becoming the standard treatment for mRCC, the synergistic effect of CN combined with ICIs has been questioned once more. A previous retrospective study suggested that the median overall survival in the CN plus IO group was not attained, while the median OS in the IO arm was 11.6 months with an HR of 0.23 (7). Other similar studies exploring CN in the treatment with immunotherapy are yet to be initiated; therefore, the evidence base is relatively immature. Unfortunately, there are still no relevant studies that report CN promoting the abscopal effect. Our patient benefited from CN combined with immunotherapy and radiotherapy because of the accelerated abscopal effect experienced with this treatment. Although RT is known to stimulate immunotherapy and reduce tumor burden as well, the disease still progressed after RT for L5 metastasis in advance. However, after CN the disease response was PR immediately. It does have the possibility that CN reduced tumor burden with the accumulative effect of RT for L5. But we couldn’t evaluate the effect of CN and L5 radiotherapy on reducing the number of tumor cells respectively because we hadn’t detected TB timely. However, Patients with heavy tumor burden may be more capable of coping with CN, immunotherapy, and RT combinations, thereby providing a window of opportunity; however, further research is required.\n\nSeveral previous studies have found that the level of CRP negatively correlates with both OS and cancer-specific survival (25–28). Reichle et al. suspected that tumor cells produce CRP, which is thought to be the reason why patients with larger tumor volumes have higher CRP levels (29). Tatokoro et al. also hypothesized that CRP could be used to accurately reflect tumor burden as a biomarker (30). In this case, the patient’s serum CRP level significantly reduced from 36 mg/L to 2.69 mg/L since Camrelizumab and RT for L5 metastasis intervention, as well as CN afterwards, which may reflect the combination therapy of ICI and RT does reduce the tumor burden. Another study found that tumor burden is associated with baseline T‐cell receptor β‐chain (TCRB) diversity, and that high diversity of TCRB increases the accumulation of CD4+ and CD8+ T cells. This in turn initiates further immune response and increases the likelihood of an improved prognosis (31). During radiotherapy, TCRB was enriched with tumor-associated antigens that enhanced the immune efficiency. RT indirectly activates T cells that infiltrate tumor lesions and increases TCRB diversity, which accelerates the efficacy of immune checkpoint inhibitors. Therefore, the combination of RT and immunotherapy can greatly enhance the anti-tumor effect.\n\nThis patient developed an acquired immune resistance after receiving Camrelizumab for more than one year. As a matter of course, we commenced RT even if the targeted lesion continued to grow, while the density of another small metastatic nodule outside the field of radiation lessened. After continuous immunotherapy, CT revealed that the radiated lesion decreased in size, which confirmed pseudoprogression and the abscopal effect. Immunotherapy resistance against PD-1/PD-L1 has been observed in different solid tumors (32). Patients with low expression of PD-L1 or TMB are more likely to acquire adaptive resistance to ICI. If OP refers to no more than two progressive metastases, more than 56% of the progression in solid tumors is oligoprogression in acquired resistance during ICI, which can easily be addressed with local RT (33). There is one previous report of a woman with metastatic anorectal mucosal melanoma who received CR after radiotherapy before encountering oligoprogression during nivolumab immunotherapy (34). Therefore, RT reversing acquired immune resistance is substantial.\n\nA prospective study by Welsh et al. found that adjuvant radiation therapy can overcome resistance to anti-PD-1 treatment by inducing IFN-β production and elevating MHC class I expression (35). They also found that RT combined with OXPHOS inhibition not only reverses PD-1 resistance in non-small-cell lung cancer, but also enhances anti-tumor immunity (36). In 2019, researchers discovered that resistance to PD-1 checkpoint blockade may be overcome by ADAR1 loss (32). However, another study found that resistance to PD-1 blockade is associated with an inactivation of antigen presentation (37). Our patient had a negative PD-L1 expression and benefited from a second course of radiotherapy when he incurred Camrelizumab resistance, suggesting that there was an underlying acquired immune resistance. RT clearly reversed resistance to Camrelizumab, after which pseudoprogression and a second abscopal effect were observed. This peculiar occurrence presents several unknowns, and the role of RT in overcoming immune resistance requires further investigation.\n\nCT imaging suggested that pseudoprogression manifests with temporary tumor enlargement or new lesions, which can actually be an indicator for improved prognosis (38). The overall incidence of pseudoprogression is approximately 6% in solid tumors and between 5.7 to 8.8% in renal carcinoma (9, 10). Radiotherapy changes the tumor microenvironment and enhances anti-tumor responses by inducing T lymphocyte aggregation in lesions (39). Another new pattern of progression within eight weeks of initial treatment of immunotherapy is called hyperprogression, which has several different definitions (40–42). The incidence of hyperprogression in lung cancer ranges from 5% to 19.2% (43) and generally predicts poor prognosis (44). Patients have a higher possibility of incurring hyperprogression when they are older (70+ years), have EGFR/ALK/MDM2/MDM4 mutations, or have multiple metastases (42, 44, 45). The factors with which we differentiate pseudoprogression and hyperprogression include patients’ clinical symptoms, serum levels of IL-8, ctDNA, and PET-CT (46).\n\nWe observed a peak MLR in our patient’s regular blood work during radiotherapy, in which the number of monocytes was ten times greater than normal ( Figure 3 ). In recent years, the role of macrophages in tumor immunotherapy has become controversial. We know that there are various sources of macrophages within different organs, while tumor-related macrophages (TAMs) are often considered to originate from circulatory monocytes (47). This constitutes what is known as an immunosuppressive triangle with Treg cells and MDSCs within the tumor microenvironment (48). TAMs can be divided into two distinct phenotypes according to different polarizations. Dormant M0-TAMs can be driven toward classical (M1) or alternative (M2) activation under the stimulation of the microenvironment (49). M1 type macrophages enhance immune responses and play an important anti-tumor role via pro-inflammatory cytokines, inducible nitric oxide synthase 2, and MHC class II molecules (50). M2 type macrophages are enriched in the hypoxic region of tumor tissues, expressing functions such as promoting angiogenesis, remodeling matrices, and suppressing adaptive immunity. The number of M2 type macrophages positively correlates with the progression of tumors, with many studies showing that TAMs predominantly display an M2-like phenotype (51).\n\nFigure 3 (A) Hematological indexes remained stable except the number of monocytes peaked during radiotherapy; (B) MLR remained stable and then peaked during radiotherapy; (C) Serum CRP level significantly reduced after Camrelizumab and RT. WBC, white blood cell; N, neutrophil; L, lymphocyte; M, macrophage; MLR, macrophage-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; CRP, C-reactive protein.\n\nFor surface biomarkers however, CD80 and MHC II expression in M1 type macrophages were particularly high. Although this is not the case for CD206, which appears similar to M0 macrophages; the level of CD206 expression in M2 type macrophages is considerably higher. Under continuous immune microenvironment stimulation, low or intermediate radiation doses can influence changes in macrophage phenotype by the expression of surface molecular markers (52). An original study revealed that low-dose irradiation can program macrophages into an M1 phenotype, which leads to the normalization of tumor vasculature and aggregation of immune cells in tumor sites (53). Our patient probably underwent more M1 type macrophage transformation after RT. Then, with a residual memory of RT, tumor cells decreased during CN, and extra M1 macrophages had the opportunity to gather distant metastases through blood vessels, providing a possible reason for the MLR peak and pseudoprogression after radiotherapy ( Figures 1 and 4 ).\n\nFigure 4 Hypothesis for the mechanism of Camrelizumab combined with CN and RT. RT destroys tumor cells so that more tumor-associated antigens can be released and recognized by tissue-resident DCs, accelerating the activation of T cells which increases the rate of activated T cells. With CN decreasing the TB, enough Camrelizumab could combine with PD-L1 expressed on tumor cells, so that T cells avoid being suppressed and work. During Camrelizumab prescription, radiation may change the microenvironment which might convert more M0-macrophages into M1-macrophages. More activated T cells and M1-macrophages wandered in blood vessels, which can account for pseudoprogression and abscopal effect. CN, cytoreductive nephrectomy; RT, radiotherapy; DCs, dendritic cells; TB, tumor burden; PD-L1, programmed cell death receptor-ligand 1.\n\nTo the best of our knowledge, this is the first reported case in which a patient apparently encountered temporary diabetes remission while receiving immunotherapy. All previous studies have found that type I diabetes is a common temporary side effect of immune checkpoint inhibitors (54, 55). Anti-PD-1/PD-L1 monoclonal antibody can induce insulin-dependent diabetes as one severe side effect (56, 57). A basic study found that low PD-L1 expression is associated with type I diabetes, where diabetes was reverted by upregulating PD-L1 expression to inhibit autoimmune response (58). Therefore, our case is peculiar and unprecedented, providing the first clinical evidence of this phenomenon. As such, we ought to consider the mechanisms that may be involved, specifically PD-L1 expression during treatment.\n\nIn conclusion, we observed a remarkable effect of CN combined with Camrelizumab and radiotherapy, regardless of PD-L1 expression. Interestingly, the abscopal effect associated with RT and immunotherapy occurred twice during treatment. CN also reduced the tumor burden, which may have promoted the first abscopal effect during RT. Local radiotherapy was again added when the patient encountered immune resistance, after which pseudoprogression and the second abscopal effect were observed. MLR during RT may also be a useful biomarker for predicting radiotherapeutic efficacy and prognosis. This is the first clinical evidence of this nature; therefore, we ought to consider the molecular mechanisms involved in radiation-related pseudoprogression, abscopal effect, and immune resistance. It is therefore of paramount importance that clinicians working in this field take the time to report any instances that may provide further insight.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nMW, JL, SS, XM, and JY contributed to the study. JY designed the manuscript and approved the final manuscript. XM made critical appraisal. JL is responsible for providing patient information and overall framework arrangements. SS modified and edited this report. MW collected the CT images, analyzed data, and drafted the article. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported by the following grants: National Natural Science Foundation of China (Grant No. 81871895),Young Taishan Scholars and Academic Promotion Program of Shandong First Medical University (Grant No. 2019RC003).\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\n\nI really appreciate for what Jie Liu, Samuel Seery, Xue Meng, and Jinbo Yue contributed to the study, as well as Editage edited my manuscript.\n==== Refs\nReferences\n\n1 Barata PC Rini BI . Treatment of Renal Cell Carcinoma: Current Status and Future Directions. CA Cancer J Clin (2017) 67 :507–24. 10.3322/caac.21411\n2 Rana R McKay MD Nils Kroeger MD Wanling Xie P Jae-Lyun Lee M . 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"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "12()",
"journal": "Frontiers in immunology",
"keywords": "MLR; abscopal effect; camrelizumab; clear cell renal cell carcinoma; pseudoprogression",
"medline_ta": "Front Immunol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D002292:Carcinoma, Renal Cell; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007680:Kidney Neoplasms; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D009362:Neoplasm Metastasis; D009392:Nephrectomy; D011879:Radiotherapy Dosage; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000084582:Tumor-Associated Macrophages",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "646085",
"pmc": null,
"pmid": "34211459",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "25083318;26261262;32583235;32529147;28624829;30658932;28961310;30559380;32253116;23219372;16520032;29341833;14767273;24869795;29070816;23962746;21478036;28043983;29449659;31908886;27169994;20570887;19105661;21459570;23989537;22857740;19139884;27821490;30977778;24382348;32581056;32349930;29141886;30657859;24209604;26095785;30115069;30184160;27330803;25805871;27827313;27425038;28665741;27905824;32540858;32073142;29937434;32749204;33072598;30193240;18550105;30327274;31485459;29439857;30718830;22437938",
"title": "Cytoreductive Nephrectomy Promoted Abscopal Effect of Camrelizumab Combined With Radiotherapy for Metastatic Renal Cell Carcinoma: A Case Report and Review of the Literature.",
"title_normalized": "cytoreductive nephrectomy promoted abscopal effect of camrelizumab combined with radiotherapy for metastatic renal cell carcinoma a case report and review of the literature"
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"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-316530",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
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"abstract": "OBJECTIVE\nTo investigate the continuation rate with a reduced lubiprostone dose (12 mcg twice daily, BD) after the onset of adverse events (AEs) in patients with chronic constipation (CC).\n\n\nMETHODS\nIn this exploratory, open-label, multicenter study, patients with CC received lubiprostone 24 mcg BD and the dose was reduced to 12 mcg BD in subjects experiencing AEs. The primary objective was the continuation rate after dose reduction due to nausea/vomiting. Secondary objectives included the continuation rate after dose reduction due to diarrhea/any AE and efficacy, including changes in number of weekly bowel movements and Bristol Stool Form Scale.\n\n\nRESULTS\nOf the 146 patients included in the study, 42 (28.8%) received lubiprostone 12 mcg BD (dose-reduced group) due to any AE. Thirty-six (85.7%) subjects in the dose-reduced group continued treatment and completed the study. 22/27 (81.5%) and 17/19 (89.5%) patients in whom the dose was reduced due to nausea/vomiting or diarrhea, respectively, continued treatment. There was no clinically relevant difference in efficacy after dose reduction.\n\n\nCONCLUSIONS\nThese results suggest that treatment withdrawal due to AEs associated with lubiprostone 24 mcg BD could be minimized in patients with CC after dose reduction to 12 mcg BD, thus resulting in improved long-term outcomes.\n\n\nBACKGROUND\nJapan Registry of Clinical Trials (https://jrct.niph.go.jp/latest-detail/jRCTs031180069).",
"affiliations": "Department of Allergy and Respiratory Medicine, Tohno-Chuo Clinic , Mizunami, Gifu, Japan.;Department of Gastroenterology, Sato Clinic , Shibuya- ku, Tokyo, Japan.;Department of Internal Medicine, Kanauchi Medical Clinic , Shinjuku- ku, Tokyo, Japan.;Department of Allergy and Respiratory Medicine, Tohno-Chuo Clinic , Mizunami, Gifu, Japan.;Department of Internal Medicine, Kanauchi Medical Clinic , Shinjuku- ku, Tokyo, Japan.;Department of Gastroenterology, Kimuranaika-ichonaika , Yokohama, Kanagawa, Japan.",
"authors": "Ohbayashi|Hiroyuki|H|;Sato|Yasuo|Y|;Kiuchi|Mari|M|;Asano|Takamitsu|T|;Nagazumi|Atsushi|A|;Kimura|Takazumi|T|",
"chemical_list": "D065101:Chloride Channel Agonists; D000068238:Lubiprostone",
"country": "England",
"delete": false,
"doi": "10.1080/17474124.2021.1833714",
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"issue": "15(3)",
"journal": "Expert review of gastroenterology & hepatology",
"keywords": "Lubiprostone; adverse events; chronic constipation; nausea; vomiting",
"medline_ta": "Expert Rev Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D065101:Chloride Channel Agonists; D002908:Chronic Disease; D003248:Constipation; D003967:Diarrhea; D000084862:Drug Tapering; D005260:Female; D006801:Humans; D000068238:Lubiprostone; D008297:Male; D008875:Middle Aged; D009325:Nausea; D014839:Vomiting; D028761:Withholding Treatment",
"nlm_unique_id": "101278199",
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"pages": "333-342",
"pmc": null,
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"pubdate": "2021-03",
"publication_types": "D000068397:Clinical Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Open-label study to evaluate the treatment continuation rate after a dose reduction of lubiprostone due to onset of adverse events.",
"title_normalized": "open label study to evaluate the treatment continuation rate after a dose reduction of lubiprostone due to onset of adverse events"
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"abstract": "Although infection with Strongyloides stercoralis is often subclinical, some infections persist for decades due to the parasite's autoinfective lifecycle. Hyperinfection syndrome, however, characterized by a massive increase in parasite burden as a result of host immunosuppression causes a myriad of clinical symptoms and is associated with high mortality. Use of corticosteroids and infection with HTLV-1 virus are the biggest traditional risk factors for hyperinfection syndrome, though its development can occur with virtually any degree of immunosuppression. Recurrent hyperinfection syndrome, though rare, has also been demonstrated in persons with ongoing immunosuppression, prompting many experts to recommend continued prophylactic treatment in at risk populations. We present the case of a recurrent S. stercoralis hyperinfection occurring four years after previous treatment with anti-helminthic therapy in a patient with AIDS with intermittent adherence to antiretroviral therapy (ART), highlighting diagnostic and treatment issues in the management of recurrent S. stercoralis infection.",
"affiliations": "University of Texas at Austin Dell Medical School, Department of Internal Medicine, 1500 Red River St, Austin, TX 78701, USA.;University of Texas at Austin Dell Medical School, Department of Internal Medicine, 1500 Red River St, Austin, TX 78701, USA.;University of Texas at Austin Dell Medical School, Department of Infectious Diseases, 1500 Red River St, Austin, TX 78701, USA.",
"authors": "Bagwell|Kelli|K|;Vasudevan|Jaya|J|;Mondy|Kristin|K|",
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"doi": "10.1016/j.idcr.2021.e01325",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00281-X\n10.1016/j.idcr.2021.e01325\ne01325\nCase Report\nRecurrent Strongyloides stercoralis infection in an HIV+ patient\nBagwell Kelli Kelli.bagwell@ascension.org\na⁎\nVasudevan Jaya Jaya.vasudevan@ascension.org\na\nMondy Kristin kemondy@ascension.org\nb\na University of Texas at Austin Dell Medical School, Department of Internal Medicine, 1500 Red River St, Austin, TX 78701, USA\nb University of Texas at Austin Dell Medical School, Department of Infectious Diseases, 1500 Red River St, Austin, TX 78701, USA\n⁎ Correspondence to: 1500 Red River St, Austin, TX 78701, USA. Kelli.bagwell@ascension.org\n01 11 2021\n2021\n01 11 2021\n26 e0132525 10 2021\n29 10 2021\n29 10 2021\n© 2021 The Authors. Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAlthough infection with Strongyloides stercoralis is often subclinical, some infections persist for decades due to the parasite’s autoinfective lifecycle. Hyperinfection syndrome, however, characterized by a massive increase in parasite burden as a result of host immunosuppression causes a myriad of clinical symptoms and is associated with high mortality. Use of corticosteroids and infection with HTLV-1 virus are the biggest traditional risk factors for hyperinfection syndrome, though its development can occur with virtually any degree of immunosuppression. Recurrent hyperinfection syndrome, though rare, has also been demonstrated in persons with ongoing immunosuppression, prompting many experts to recommend continued prophylactic treatment in at risk populations. We present the case of a recurrent S. stercoralis hyperinfection occurring four years after previous treatment with anti-helminthic therapy in a patient with AIDS with intermittent adherence to antiretroviral therapy (ART), highlighting diagnostic and treatment issues in the management of recurrent S. stercoralis infection.\n\nKeywords\n\nHIV\nAIDS\nRecurrent Strongyloides stercoralis hyperinfection\n==== Body\npmcIntroduction\n\nAlthough endemic in the tropics and subtropics, infection with the intestinal nematode S. stercoralis is becoming increasingly common in non-endemic regions due to increased travel and immigration. In immunocompetent hosts, infection is typically indolent and asymptomatic, persisting for years due to the parasite’s unique lifecycle that allows for perpetual host autoinfection [1]. With any insult to the immune system, however, a massive increase in parasitic burden ensues, resulting in a clinical syndrome known as hyperinfection, with symptoms resulting from increased parasitic dissemination throughout the body. Rapidly fatal if unrecognized, hyperinfection can result in gastrointestinal bleeding, respiratory distress and frequent development of polymicrobial bacteremia and sepsis, as enteric organisms translocate through the gut wall during parasitic invasion [2], [3].\n\nCase presentation\n\nA 44-year-old African woman with a history of advanced HIV complicated by intermittent adherence to ART presented to the hospital with progressive, severe abdominal pain as well as fever, anorexia and diarrhea for over one week. Shortly after her immigration to the United States from Southern Africa four years prior, she had required hospitalization for treatment of S. stercoralis hyperinfection, diagnosed via positive stool studies, with resolution of infection after two weeks of anti-helminthic therapy and initiation of ART. At the time of this initial infection, a serum S. stercoralis antibody was negative, though a CD4 count was only 36 cells/µL. After completion of two weeks of combination therapy with albendazole and ivermectin, a subsequent stool study was negative and no further anti-helminthic therapy was given. The patient unfortunately had frequent lapses in her HIV care and had poor medication adherence. Upon readmission four years later, the patient was febrile to 39.1C, but had otherwise stable vital signs. She denied recent travel outside of the United States. Physical exam revealed cachexia and a distended, diffusely tender abdomen, though without peritoneal signs. Complete blood count revealed no leukocytosis or eosinophilia. A complete metabolic panel showed a sodium level of 121 mm/dL and albumin of 2.6 g/dL. Serum and urine studies were consistent with the syndrome of inappropriate antidiuretic hormone (SIADH). Other metabolic parameters were within normal limits. CD4 count was 72 cells/µL. A serum S. stercoralis antibody level was not checked due to the patient’s prior negativity with active infection and persistently low CD4 count. Interestingly, an initial stool study for ova and parasites was only notable for Blastocystis hominis with no evidence of S. stercoralis larvae, though only one stool sample was sent for evaluation. CT scan of the abdomen and pelvis revealed cardiomegaly, enterocolitis and a distended stomach and proximal duodenum (Fig. 1).Fig. 1 CT Chest/Abdomen/Pelvis revealing distended stomach (red arrow) and proximal duodenum, consistent with SMA syndrome. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 1\n\nBroad spectrum antibacterials were initiated. Escherichia coli and Citrobacter sp. promptly grew in the aerobic bottles of two sets of blood cultures drawn at admission. Esophagogastroduodenoscopy (EGD) revealed a distended stomach with multiple nodular duodenal erosions from which biopsies were taken. Despite antibacterials and subsequent clearance of her blood cultures, the patient’s abdominal pain continued to worsen, as did her abdominal distension and anorexia. In addition, new systolic cardiac murmurs were detected in multiple valvular regions. Finally, pathology from endoscopic biopsies returned, revealing S. stercoralis in the stomach and duodenum (Fig. 2). Transthoracic echocardiogram demonstrated vegetations up to 1.3 cm in size involving the tricuspid, aortic and mitral valves, suspicious for Loeffler’s endocarditis given her biopsy results and negative repeat blood cultures (Fig. 3). These findings, indicative of parasitic involvement in both the gastrointestinal tract and cardiac system, suggested the diagnosis of S. stercoralis hyperinfection. Two weeks after antimicrobial and anti-helminthic therapies were initiated, her symptoms had resolved and repeat duodenal biopsies were negative for S. stercoralis. The patient was discharged on ART with bictegravir-emtricitabine-tenofovir alafenamide, trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis and monthly ivermectin for secondary S. stercoralis prophylaxis. After hospitalization, the patient was followed by the local community HIV clinic for further care. Repeat endoscopic biopsies two months after hospital discharge revealed no evidence of persistent infection, however, she remains on continued monthly antiparasitic therapy as her CD4 count has not been reliably above 200 cells/µL.Fig. 2 Gastric biopsy pathology slide revealing Strongyloides stercoralis larvae (see red asterisks). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 2\n\nFig. 3 Transthoracic echocardiogram parasternal long axis view with sterile mitral valve vegetations (red arrow) suggestive of Loeffler’s endocarditis. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 3\n\nDiscussion\n\nAlthough previously considered an AIDS-defining illness, S. stercoralis hyperinfection syndrome in persons with AIDS is fairly uncommon, and is more typically seen in persons with either HTLV-1 infection or chronic steroid use [1], [2], [4]. Though S. stercoralis hyperinfection itself is not infrequent, recurrent hyperinfection is rare. A few cases of recurrent S. stercoralis hyperinfection in other immunocompromising conditions have been previously described in persons with HTLV-1 infections and malignancy, but review of those reports demonstrated recurrence within weeks to months of original treatment, suggesting more of a primary treatment failure [5], [6].\n\nOur case demonstrates a recurrence of S. stercoralis hyperinfection several years after completion of a previous course of appropriate anti-helminthic therapy. We postulate this was due to a lack of regular adherence to ART and failure to maintain immune reconstitution, as the patient had no risk factors to suggest new infection, such as travel to region in which S. stercoralis is endemic. To our knowledge, such a relapse years after initial infection has not been previously reported.\n\nThis case highlights the complexity of S. stercoralis infection in immunocompromised persons, especially those who may have variable immune reconstitution as seen with HIV/AIDS. As prompt diagnosis and initiation of early therapy can greatly improve disease outcomes, this case demonstrates the need to consider recurrent hyperinfection in the differential diagnosis of those patients with AIDS presenting with typical clinical features and to obtain swift diagnosis, which is notoriously difficult. An initial stool examination in this patient was negative, which is not uncommon given the irregular shedding of larvae, even in hyperinfection, with most studies suggesting that at least four successive stool studies are required to effectively rule out infection [2], [7]. This case also highlights the importance of documenting clearance of parasites after appropriate treatment through endoscopic biopsy, multiple stool examinations, or serology trends, if previously positive, and to consider secondary prophylaxis in persons with ongoing or relapsed immunocompromise. Due to the low sensitivity of stool examinations and invasiveness of endoscopic procedures, the use of monitoring sequential serum S. stercoralis antibody titers has been suggested as a means of evaluating efficacy of treatment in those at high risk for treatment failure [8]. Though adequate research is still lacking regarding the true sensitivity of serum antibody assays, most studies report a sensitivity of 70–100% in those currently available [7], [9]. Interestingly, during our patient’s initial hospitalization for S. stercoralis hyperinfection, her S. stercoralis serum IgG levels were negative, which we attribute to her low absolute CD4 count of 36 cells/µL at admission causing an inability to mount an antibody response. This false negativity has also been reported in other studies evaluating serologic methods of S. stercoralis detection, again attributable to overall reduced antibody production in those with HIV or other immunocompromising conditions [7], [8], [9]. Still, for patients with a demonstrable antibody titer, there is some evidence to suggest the use of monitoring patients serially at least 1–2 years post treatment to ensure sustained serologic trend of cure [8].\n\nReview of current literature also supports the use of ongoing suppressive anti-parasitic therapy after initial treatment for hyperinfection in those patients with continued immunosuppression, in part due to the difficulty in assuring complete eradication of infection in this population. Most of this literature, however, is focused on a patient population either with malignancy and need for continued chemotherapy or those patients requiring ongoing treatment with corticosteroids [1], [5], [10]. We chose to extrapolate this recommendation to our patient with recurrent hyperinfection due to AIDS as she was at high risk of reinfection due to her history of adherence issues with taking ART. Based on this case, we would recommend that patients diagnosed with S. stercoralis hyperinfection be closely monitored (potentially over years) for signs or symptoms of recurrent infection, and that those who have persistent or recurrent immunosuppression be considered as candidates for secondary prophylaxis.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.\n\nConsent\n\nNo written informed consent was obtained for this case report as it does not contain any patient identifiers in order to protect patient anonymity.\n\nCRediT authorship contribution statement\n\nKB: Data collection, Writing, Editing. JV: Writing, Editing. KM: General conceptualization, Editing.\n\nConflicts of interest\n\nNo author has any conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Krolewiecki A. Nutman T.B. Strongyloidiasis: a neglected tropical disease Infect Dis Clin 33 2019 135 151\n2 Keiser P.B. Nutman T.B. Strongyloides stercoralis in the immunocompromised population Clin Microbiol Rev 17 2004 208 217 14726461\n3 Potter A. Stephens D. De Keulenaer B. Strongyloides hyper-infection: a case for awareness Ann Trop Med Parasitol 97 2003 855 860 14754498\n4 Mejia R. Nutman T.B. Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis Curr Opin Infect Dis 25 2012 458 463 22691685\n5 Krishnan S. Barger G. Chandrasekar P. Recurrent strongyloides stercoralis hyperinfection syndrome: case report and a brief review Infect Dis Clin Pract 14 2006 240 243\n6 Peters L. McCarthy A.E. Faught C. Secondary strongyloides stercoralis prophylaxis in patients with human T-cell lymphotropic virus type 1 infection: report of two cases Int J Infect Dis 13 2009 501 503\n7 Bon B. Houze S. Talabani H. Magne D. Belkadi G. Develoux M. Senghor Y. Chandenier J. Ancelle T. Hennequin C. Evaluation of a rapid enzyme-linked immunosorbent assay for diagnosis of strongyloidiasis J Clin Microbiol 48 2010 1716 1719 20335415\n8 Greaves D. Coggle S. Pollard C. Aliyu S.H. Moore E.M. Strongyloides stercoralis infection Bmj 347 2013 f4610 23900531\n9 Requena-Méndez A. Chiodini P. Bisoffi Z. Buonfrate D. Gotuzzo E. Muñoz J. The laboratory diagnosis and follow up of strongyloidiasis: a systematic review PLoS Negl Trop Dis 7 2013 e2002\n10 Lowe R.C. Chu J.N. Pierce T.T. Weil A.A. Branda J.A. Case 3-2020: a 44-year-old man with weight loss, diarrhea and abdominal pain N Engl J Med 382 2020 365 374 31971683\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "26()",
"journal": "IDCases",
"keywords": "AIDS; HIV; Recurrent Strongyloides stercoralis hyperinfection",
"medline_ta": "IDCases",
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"pages": "e01325",
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"pmid": "34786343",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "22691685;23900531;30712758;19501008;14726461;31971683;20335415;23350004;14754498",
"title": "Recurrent Strongyloides stercoralis infection in an HIV+ patient.",
"title_normalized": "recurrent strongyloides stercoralis infection in an hiv patient"
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"abstract": "Tramadol is an opioid analgesic that binds to mu-opioid receptors and inhibits the uptake of norepinephrine and serotonin. Through its activation of these receptors, it has potential to increase the utilization of glucose and/or decrease hepatic gluconeogenesis.\nA 55-year-old male presents to the Emergency Department (ED) via Emergency Medical Services (EMS) following a self-reported overdose of alprazolam, lorazepam, acetaminophen with codeine, and tramadol. During EMS transport, the patient was found to be hypoglycemic with a glucose of 30 mg/dL and was administered 25 grams of intravenous (IV) dextrose 50% in water. The patient had no past medical history of diabetes mellitus, hypoglycemia, or hyperglycemia and was normoglycemic on his prior presentations to our facility 3 months and 2 years prior. Subsequent analysis found that the patient was negative for acetaminophen, ethanol, salicylates, tricyclics, and lithium. His urinalysis was positive for opiates and benzodiazepines. Upon arrival to the ED, the patient's blood glucose was 131 mg/dL but subsequently dropped to 73 mg/dL, necessitating the initiation of continuous IV fluids containing dextrose. These fluids were discontinued 3.5 hrs later and the patient was discharged 16 days later.\nThis case illustrates that hypoglycemia can be a presenting symptom in patients with an acute overdose of tramadol with no previous history of glycemic dysregulation. Upon presentation it is important to closely monitor serum glucose concentrations to identify hypoglycemia early in order to initiate necessary hypoglycemia protocols.",
"affiliations": "Department of Clinical Pharmacy and Outcome Sciences, University of South Carolina College of Pharmacy, Columbia, SC, USA.;Department of Emergency Medicine, Medical University of South Carolina, Charleston, SC, USA.;Department of Emergency Medicine, Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Weant|Kyle A|KA|https://orcid.org/0000-0003-0835-7955;Clendening|Alexander M|AM|;Bush|Jeffrey S|JS|",
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"journal": "Journal of pharmacy practice",
"keywords": "emergency medicine; hypoglycemia; overdose; tramadol",
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"pmid": "33736525",
"pubdate": "2021-03-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Case Report of Hypoglycemia Following a Tramadol Overdose in a Non-Diabetic Patient.",
"title_normalized": "a case report of hypoglycemia following a tramadol overdose in a non diabetic patient"
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"abstract": "Purpose: To report a Candida endogenous endophthalmitis in a pregnant woman with a prior history of in-vitro fertilization (IVF).Methods: Case report.Results: 21-year-old healthy woman within the first trimester of her pregnancy of a successful IVF developed a focal retinitis and panuveitis. Ocular findings suggested fungal endophthalmitis. The patient was treated with pars plana vitrectomy and repeated intravitreal antifungal injections. No systemic therapy was given. Cultures showed Candida albicans. IVF procedure was the only identifiable risk factor for endogenous endophthalmitis.Conclusions: In-vitro fertilization appeared as a possible risk factor for endogenous endophthalmitis during pregnancy. In the absence of systemic fungal infection, local intravitreal antifungal injections seem to be effective options to treat endogenous candida endophthalmitis, especially in the first trimester.",
"affiliations": "Department of Ophthalmology, School of Medicine, Gazi University, Ankara, Turkey.;Byers Eye Institute, Stanford University, Palo Alto, California, USA.;Ulucanlar Eye Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Ulucanlar Eye Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Byers Eye Institute, Stanford University, Palo Alto, California, USA.;Byers Eye Institute, Stanford University, Palo Alto, California, USA.;Byers Eye Institute, Stanford University, Palo Alto, California, USA.",
"authors": "Hasanreisoglu|Murat|M|https://orcid.org/0000-0001-9885-5653;Mahajan|Sarakshi|S|;Ozdemir|Huseyin Baran|HB|https://orcid.org/0000-0002-5585-253X;Ozdal|Pinar Cakar|PC|;Halim|M Sohail|MS|;Hassan|Muhammad|M|;Nguyen|Quan Dong|QD|",
"chemical_list": null,
"country": "England",
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"issue": "29(2)",
"journal": "Ocular immunology and inflammation",
"keywords": "Fungal endogenous endophthalmitis; IVF; in-vitro fertilization; pars plana vitrectomy; pregnancy",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D002176:Candida albicans; D002177:Candidiasis; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012160:Retina; D041623:Tomography, Optical Coherence; D014822:Vitreous Body; D055815:Young Adult",
"nlm_unique_id": "9312169",
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"pages": "308-311",
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"pubdate": "2021-02-17",
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"title": "Fungal Endogenous Endophthalmitis during Pregnancy as a Complication of In-Vitro Fertilization.",
"title_normalized": "fungal endogenous endophthalmitis during pregnancy as a complication of in vitro fertilization"
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"abstract": "Primary mucinous adenocarcinoma of the appendix is a rare gastrointestinal malignancy. Fistulous tract formation is a complication that is cited in literature. An 85-year-old man with multiple comorbidities presented with several weeks of persistent non-bloody diarrhea. Laboratory work-up was non-diagnostic. Abdominal imaging with barium contrast showed an enterocolonic fistulous tract extending from the duodenum to the cecum involving an enlarged appendiceal mass. Subsequent biopsy confirmed mucinous appendiceal neoplasm with peritoneal spread to the liver and mesentery. This is the first report describing an enterocolonic fistula formation resulting from this malignancy.",
"affiliations": "Department of Internal Medicine/Pediatrics, Brown University Alpert Medical School, Providence, RI.;Department of Gastroenterology, Saint Louis University School of Medicine, Saint Louis, MO.;Department of Gastroenterology, Saint Louis University School of Medicine, Saint Louis, MO.;Department of Pathology, Saint Louis University School of Medicine, Saint Louis, MO.",
"authors": "Aung|Su|S|;Cheung|Amanda|A|;Prather|Charlene|C|;Lai|Jinping|J|",
"chemical_list": null,
"country": "United States",
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"doi": "10.14309/crj.2017.3",
"fulltext": "\n==== Front\nACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2017.310.14309/crj.2017.3Case ReportColonDiarrhea Concealing a Duodenal-Cecal Fistula Secondary to Appendiceal Mucinous Neoplasm Aung et alAppendiceal Mucinous NeoplasmAung Su MD, MPH1Cheung Amanda MD2Prather Charlene MD, MPH2Lai Jinping MD, PhD31 Department of Internal Medicine/Pediatrics, Brown University Alpert Medical School, Providence, RI2 Department of Gastroenterology, Saint Louis University School of Medicine, Saint Louis, MO3 Department of Pathology, Saint Louis University School of Medicine, Saint Louis, MOCorrespondence: Su Aung, Department of Internal Medicine/Pediatrics, 245 Chapman St., Suite 100, Providence, RI 02905 (sunandar.aung@lifespan.org).2017 4 1 2017 4 e318 1 2016 9 6 2016 Copyright © Aung et al.2017This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Primary mucinous adenocarcinoma of the appendix is a rare gastrointestinal malignancy. Fistulous tract formation is a complication that is cited in literature. An 85-year-old man with multiple comorbidities presented with several weeks of persistent non-bloody diarrhea. Laboratory work-up was non-diagnostic. Abdominal imaging with barium contrast showed an enterocolonic fistulous tract extending from the duodenum to the cecum involving an enlarged appendiceal mass. Subsequent biopsy confirmed mucinous appendiceal neoplasm with peritoneal spread to the liver and mesentery. This is the first report describing an enterocolonic fistula formation resulting from this malignancy.\n==== Body\nIntroduction\nPrimary appendiceal neoplasms are rare, accounting for less than 0.5% of all gastrointestinal (GI) malignances.1-3 The most common clinical presentation is acute appendicitis.4 Typically, this type of tumor is incidentally diagnosed at the time of operation or once it has progressed with mucinous implants in other abdominal organs or the peritoneum leading to mucinous ascites, known as pseudomyxoma peritonei. Isolated case reports have been published describing fistula formations on the skin, bladder, vagina, and colon secondary to this rare malignancy. This is the first report of mucinous appendiceal neoplasm presenting with an enterocolonic fistula.\n\nCase Report\nAn 84-year-old man presented to the hospital after 3 weeks of diarrhea. He appeared healthy and had stable vital signs. He had an unremarkable abdominal exam, including the absence of tenderness to palpation, palpable masses, and peritoneal signs. He was able to ambulate without assistance and did not exhibit any weakness, tremors, abnormal reflexes, or neurological deficits.\n\nThe patient had a history of chronic myelogenic leukemia in molecular remission, interstitial lung disease, coronary artery disease, chronic kidney disease, hypertension, and lumbar back disease. He reported liquid bowel movements occurring two to four times per hour with occasional stool incontinence. He described a concomitant 4.5-kg weight loss in the month prior to presentation. A full review of systems was otherwise negative, including the absence of hematochezia, melena, nausea, vomiting, abdominal pain, fevers, chills, or appetite change. He reported no recent travel, unusual food ingestion, or new environmental exposures. He lived with his wife, who did not have similar symptoms.\n\nOne year prior to this presentation the patient had a surveillance colonoscopy, which was performed despite his relatively advanced age as he was otherwise healthy and had a personal history of high-risk polyps. Remarkable findings on that colonoscopy included two 3–4 mm sessile polyps in the ascending and sigmoid colon, diverticulosis, and a focal patch of erythematous mucosa at the appendiceal orifice (Figure 1). The polyps were removed with cold biopsy forceps and pathologic examination showed colonic mucosa with focal hyperplastic changes. Biopsies from the abnormal mucosa at the appendiceal orifice revealed a mildly active focal chronic colitis. At that time, clinical suspicion for inflammatory bowel disease was low because laboratory workup did not show elevated inflammatory markers or abnormal blood counts, and the patient was asymptomatic, specifically denying diarrhea, blood in stool, or weight loss.\n\nFigure 1 Focal erythematous patch at the appendiceal orifice seen on colonoscopy 1 year prior to presentation.\n\nA detailed infectious workup was unremarkable including negative results for stool cultures, Clostridium difficile toxin, Giardia, parasite exam, and cytomegalovirus culture. Inflammatory stool markers including leukocytes, lactoferrin, and calprotectin were unremarkable. Calculated stool osmotic gap was elevated at 156 mOsm/kg. Stool pH was low at 4.5. Both neutral and split fecal fat products were elevated.\n\nThe patient was taking imatinib for 5 years to treat chronic myelogenic leukemia with no prior adverse effects. Nonetheless, given the potential side effect profile, the medication was discontinued. He was taking doxycycline for a dermatological condition, but this too was discontinued. Despite these medication changes and the regular use of loperamide, the patient had no relief in the frequency or volume of liquid bowel movements.\n\nThe current presentation with diarrhea was the first time in the ensuing year that the patient reported any symptoms to suggest a need for repeat colon evaluation. Diagnostic colonoscopy was notable for severely ulcerated nonbleeding mucosa within an enlarged appendiceal orifice (Figure 2). Biopsies obtained from this region at the time of the colonoscopy were nondiagnostic, showing only necrotic tissue.\n\nFigure 2 Endoscopic view of appendiceal lumen showing ulcerated mucosa.\n\nSubsequent evaluation with computed tomography imaging revealed a midline abdominal mass measuring 7.6 cm in its largest dimension. It appeared to lie inferiorly to the duodenum and superiorly to the colon (Figure 3). There were fluid collections adjacent to the liver as well as the mesentery. Interventional radiology performed fine-needle aspirations and core biopsies of the peritoneal lesions. The histopathology and cytopathology findings were consistent with a low-grade mucinous neoplasm originating from the appendix with pseudomyxoma peritonei syndrome (Figure 4).\n\nFigure 3 Computed tomography of the abdomen demonstrating a midline appendiceal mass extending superiorly and communicating with the proximal bowel.\n\nFigure 4 Cytopathology and histopathology of the peritoneal implant showing clusters of epithelial cells of low-grade mucinous neoplasm in a thick mucinous background. (A) Papanicolaou stain, 400x. (B) Diff-quick stain, 400x. (C) Hematoxylin and eosin stain, 100x. (D) Hematoxylin and eosin stain, 400x.\n\nThe computed tomography scan further suggested communication between the appendiceal mass and the proximal small intestine and colon. This abnormal anatomy explained the patient’s persistent diarrhea. A small-bowel follow-through demonstrated a fistulous communication from the third portion of the duodenum to the cecum (Figure 5).\n\nFigure 5 Small bowel follow-through demonstrating a fistulous tract extending from the third part of the duodenum to the cecum.\n\nThe duodenal-cecal fistula allowed contents to bypass nearly the entire small intestine, which explained the elevation of the stool osmotic gap. Small bowel fistula formation additionally increases the risk for small intestinal bacterial overgrowth and fat malabsorption. Therefore, the low stool pH and increased fecal fat products can be explained by the patient’s unusual anatomy.\n\nMedical oncology and surgical oncology were consulted to discuss treatment options. Due to the patient’s advanced age and comorbidities as well as the relatively slow growth of this type of tumor, the patient opted to forgo both surgical intervention and treatment with chemotherapy. He was managed symptomatically with antidiarrheal agents and antibiotics for bacterial overgrowth.\n\nDiscussion\nMalignancies of the appendix are rare, with a reported incidence of 0.12 cases per 1,000,000 people per year based on population data from the SEER program.1-3 Primary neoplasm of the appendix constitutes less than 0.5% of all GI neoplasms,2 and the most common histologic type is mucinous neoplasm, accounting for more than one-third of these cases.1\n\nThe diagnosis of appendiceal mucinous neoplasm is challenging, and preoperative diagnosis is rarely made. Abdominal imaging may show a right lower quadrant soft-tissue mass with curvilinear mural calcification, but this finding is evident in less than half of cases.4 The diagnosis is often made at the time of operation because the most common clinical presentation is luminal obstruction leading to acute appendicitis.5,6 Other reported presentations include appendicular abscess, palpable abdominal mass, intestinal obstruction, and intussusception.4 Pseudomyxoma peritonei may be seen as the disease progresses with mucocele rupture or transmural extension.7\n\nMucinous appendiceal neoplasm follows an indolent and progressive course, eventually leading to mortality secondary to lymph node and solid organ metastasis. Implantation of mucinous material into the peritoneum is an uncommon condition known as pseudomyxoma peritonei.4 Fistula formation as a complication of primary mucinous appendiceal neoplasm is rare. A number of case reports have been published within the past several decades describing various types of fistulous tracts. The most common organs involved include skin,8-12 bladder,13-20 vagina,21,22 and colon.23,24 In the majority of the cases reviewed, patients were symptomatic from the fistula formation, and this eventually led to the diagnosis of appendiceal mucinous neoplasm upon further investigation via imaging, endoscopy, or surgical exploration. History of abdominal surgery was a prevailing risk factor for development of a fistulous tract in these case reports and is known to be the most common cause for fistulas in the GI tract, accounting for up to 85% of cases.25 Other causes for spontaneous fistula formation in the GI tract include inflammatory diseases (including inflammatory bowel disease, diverticular disease, appendicitis, and peptic ulcer disease), infection, malignancy, and radiation exposure. Medications with antiangiogenic properties, including tyrosine kinase inhibitors like imatinib, have been reported to cause decreased blood supply to large tumors resulting in tumor necrosis, perforation, and fistula formation.26 The incidence of this phenomenon is unknown given its relatively rare occurrence.\n\nThe recommended treatment for mucinous appendiceal neoplasm varies on the extent of the malignancy. Patients with low-grade histology have a predicted 5-year survival rate of 75%.4 The recommended treatment for mucinous appendiceal neoplasm is a right hemicolectomy.5 Mucinous ascites (pseudomyxoma peritonei) is a late finding, presence of which necessitates more aggressive therapy with surgical debulking followed by intraperitoneal and/or systemic chemotherapy.6\n\nDisclosures\nAuthor contributions: All of the authors participated in writing the manuscript. S. Aung is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1. McCusker ME , Coté TR , Clegg LX , Sobin LH \nPrimary malignant neoplasms of the appendix: A population-based study from the surveillance, epidemiology and end-results program, 1973-1998 . Cancer . 2002 ;\n94 :3307 –12 .12115365 \n2. Nitecki SS , Wolff BG , Schlinkert R , Sarr MG \nThe natural history of surgically treated primary adenocarcinoma of the appendix . Ann Surg . 1994 ;\n219 :51 –7 .8297177 \n3. Connor SJ , Hanna GB , Frizelle FA \nAppendiceal tumors: Retrospective clinicopathologic analysis of appendiceal tumors from 7,970 appendectomies . Dis Colon Rectum . 1998 ;\n41 :75 –80 .9510314 \n4. Lam-Himlin D , Montgomery E , Torbenson M \nNon-neoplastic and neoplastic disorders of the appendix . In: Iacobuzio-Donahue C , Montgomery E , eds. Gastrointestinal and Liver Pathology 2 ed. \nPhiladelphia, PA : \nElsevier Saunders ; 2012 :257 –96 .\n5. Reichle FA , Brigham MP , Fleegler EJ , Rosemond GP \nAdenocarcinoma of the vermiform appendix . Am Surg . 1971 ;\n37 :344 –50 .4325336 \n6. Rutledge RH , Alexander JW \nPrimary appendiceal malignancies: Rare but important . Surgery . 1992 ;\n111 :244 –50 .1542852 \n7. Stevens KJ , Dunn WK , Balfour T \nPseudomyxoma extraperitonei: A lethal complication of mucinous adenocarcinoma of the appendix . Am J Gastroenterol . 1997 ;\n92 :1920 –2 .9382067 \n8. Sayles M , Courtney E , Younis F , O'Donovan M , Ibrahim A , Fearnhead NS \nAppendiceal mucinous adenocarcinoma presenting as an enterocutaneous fistula in an incisional hernia . BMJ Case Reports . 2010 ;\n2010 .\n9. Nakao A , Sato S , Nakashima A , et al \nAppendiceal mucocele of mucinous cystadenocarcinoma with a cutaneous fistula . J Int Med Res . 2002 ;\n30 :452 –6 .12235932 \n10. Koizumi J , Noguchi H \nPseudomyxoma retroperitonei with spontaneous skin fistula . Abdom Imaging . 1999 ;\n24 :193 –5 .10024411 \n11. Nishitani K , Nishitani H , Shimoda Y \nCutaneous invasion of mucinous adenocarcinoma of the appendix . J Dermatol . 1987 ;\n14 :167 –9 .3038981 \n12. Mehzad M , Aflaki B , Afghari H \nAdenocarcinoma of the appendix: Report of an unusual case . Dis Colon Rectum . 1978 ;\n21 :205 –6 .648308 \n13. Ikeda I , Miura T , Kondo I \nCase of vesico-appendiceal fistula secondary to mucinous adenocarcinoma of the appendix . J Urol . 1995 ;\n153 :1220 –1 .7869505 \n14. Dalton DP , Dalkin BL , Sener SF , et al \nEnterovesical fistula secondary to mucinous adenocarcinoma of appendix . J Urol . 1987 ;\n138 :617 –8 .3041057 \n15. Desantis M , Bereder JM , Benchimol D \nVesico-appendiceal fistula revealing pseudomyxoma peritonei . J Visc Surg . 2014 ;\n151 :61 –3 .24462837 \n16. Vidarsdottir H , Moller PH , Benediktsdottir KR , Geirsson G \nAdenocarcinoma of the appendix with a fistula to the urinary bladder . Scand J Urol Nephrol . 2010 ;\n44 :354 –6 .20509819 \n17. Mistry R , Ananthakrishnan K , Hamid BN , et al \nAppendiceal carcinoma masquerading as recurrent urinary tract infections: Case report and review of literature . Urology . 2006 ;\n68 :428.e1 –3 .\n18. Chen KT , Spaulding RW \nAppendiceal carcinoma masquerading as primary bladder carcinoma . J Urol . 1991 ;\n145 :821 –2 .1848640 \n19. Dahms SE , Hohenfellner M , Eggersmann C , et al \nAppendix carcinoma invading the urinary bladder . Urol Int . 1997 ;\n58 :124 –7 .9096277 \n20. Bartholomew LG , Farrow GM , DeWeerd JH \nAdenocarcinoma of the appendix simulating primary bladder carcinoma . Dig Dis Sci . 1984 ;\n29 :371 –5 .6705651 \n21. Tucker ON , Madhavan P , Healy V , et al \nUnusual presentation of an appendiceal malignancy . Int Surg . 2006 ;\n91 :57 –60 .16706105 \n22. Kneece SM , Wackym PA , Dudley BS , et al \nAppendicovaginal fistula and primary appendiceal cystadenocarcinoma . South Med J . 1987 ;\n80 :914 –6 .3603115 \n23. Miyakura Y , Iwai H , Togashi K , et al \nMucinous cystadenocarcinoma of the appendix invading the ascending colon with fistula formation: Report of a case . Surg Today . 2007 ;\n37 :806 –10 .17713739 \n24. Nitschke J , Richter H , Herguth D , Hamelmann H \nAcute appendicitis and postoperative fecal fistula: Symptoms of an unrecognized carcinoma of the colon . Dis Colon Rectum . 1976 ;\n19 :605 –10 .185027 \n25. Sleisenger MH , Feldman M , Friedman LS , Brandt LJ \nSleisenger and Fordtran's gastrointestinal and liver disease: Pathophysiology, diagnosis, management . 9th ed \nPhiladelphia, PA : \nSaunders/Elsevier ; 2010 .\n26. Thornton E , Howard SA , Jagannathan J , et al \nImaging features of bowel toxicities in the setting of molecular targeted therapies in cancer patients . Br J Radiol . 2012 ;\n85 :1420 –6 .22674709\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "4()",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "e3",
"pmc": null,
"pmid": "28138447",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "7869505;12115365;648308;17713739;6705651;12235932;24462837;185027;8297177;22789695;1848640;9382067;16706105;9096277;3038981;20509819;9510314;4325336;1542852;16904475;22674709;3041057;10024411;3603115",
"title": "Diarrhea Concealing a Duodenal-Cecal Fistula Secondary to Appendiceal Mucinous Neoplasm.",
"title_normalized": "diarrhea concealing a duodenal cecal fistula secondary to appendiceal mucinous neoplasm"
} | [
{
"companynumb": "US-APOTEX-2017AP008568",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "Adverse effects on muscles occur in approximately 5 to 10% of patients taking statins. Drug interactions, associated diseases, agedness, low body weight, high statin dose and hereditary factors increase the risk of adverse effects. In most cases the muscle effects are mild and disappear upon discontinuation of the medication. Rhabdomyolysis is a severe though rare complication that can possibly result in renal damage. A totally different muscle-related adverse effect, necrotizing myopathy, has recently been linked to the use of statins. Its characteristic feature is progression of the symptoms in spite of discontinuation of the statin.",
"affiliations": null,
"authors": "Pohjola-Sintonen|Sinikka|S|;Julkunen|Heikki|H|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors",
"country": "Finland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-7183",
"issue": "130(16)",
"journal": "Duodecim; laaketieteellinen aikakauskirja",
"keywords": null,
"medline_ta": "Duodecim",
"mesh_terms": "D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009135:Muscular Diseases; D009336:Necrosis; D012206:Rhabdomyolysis; D012307:Risk Factors",
"nlm_unique_id": "0373207",
"other_id": null,
"pages": "1622-7",
"pmc": null,
"pmid": "25269368",
"pubdate": "2014",
"publication_types": "D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Muscle-related adverse effects of statins.",
"title_normalized": "muscle related adverse effects of statins"
} | [
{
"companynumb": "FI-PFIZER INC-2019114618",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ESOMEPRAZOLE MAGNESIUM"
},
"drugadditional": ... |
{
"abstract": "Neuromuscular blocking agents have been implicated in 60-70% of anaphylactic events associated with anaesthesia. We report two cases of probable hypersensitivity reaction to sugammadex and an additional suspected but less supported case of possible immune-mediated reaction or other adverse reaction. The patients were given a bolus of sugammadex 100 mg immediately before extubation. In all three patients, a possible allergic reaction was suspected within 4 min of sugammadex administration, but with different degrees of severity. Skin testing was positive in two of these patients. Hypersensitivity to sugammadex unaccompanied by cardiovascular or respiratory symptoms might be missed during the course of anaesthesia. Careful monitoring for possible allergic responses is required in patients who have received sugammadex.",
"affiliations": "Department of Anaesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.",
"authors": "Godai|K|K|;Hasegawa-Moriyama|M|M|;Kuniyoshi|T|T|;Kakoi|T|T|;Ikoma|K|K|;Isowaki|S|S|;Matsunaga|A|A|;Kanmura|Y|Y|",
"chemical_list": "D000732:Androstanols; D003473:Neuromuscular Nondepolarizing Agents; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D000077123:Rocuronium",
"country": "England",
"delete": false,
"doi": "10.1093/bja/aes137",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0912",
"issue": "109(2)",
"journal": "British journal of anaesthesia",
"keywords": null,
"medline_ta": "Br J Anaesth",
"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D000732:Androstanols; D000768:Anesthesia, General; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008875:Middle Aged; D003473:Neuromuscular Nondepolarizing Agents; D000077123:Rocuronium; D012882:Skin Tests; D000077122:Sugammadex; D047408:gamma-Cyclodextrins",
"nlm_unique_id": "0372541",
"other_id": null,
"pages": "216-8",
"pmc": null,
"pmid": "22617091",
"pubdate": "2012-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three cases of suspected sugammadex-induced hypersensitivity reactions.",
"title_normalized": "three cases of suspected sugammadex induced hypersensitivity reactions"
} | [
{
"companynumb": "JP-MSD-1709JPN002837J",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SUGAMMADEX"
},
"drugadditional": "4",
"... |
{
"abstract": "Primary Immune thrombocytopenia (ITP) in the elderly is a major clinical challenge which is increasingly frequent due to global ageing population.\n\n\n\nTo describe baseline ITP features, management, and outcome, a centralized electronic database was established, including data of 451 patients aged ≥60 years that were treated from 2000 onwards and were observed for ≥1 year (total observation of 2704 patient-years).\n\n\n\nAt ITP diagnosis, median age was 71.1 years (age ≥ 75: 42.8%); 237 (53.9%) patients presented with haemorrhages (grade ≥ 3: 7.5%). First-line therapy included prednisone (82.9%), dexamethasone (14.6%), thrombopoietin-receptor agonists (TRAs, 1.3%), and oral immunosuppressive agents (1.1%). Prednisone starting dose ≥1 mg/kg/d (p = .01) and dexamethasone 40 mg/d (p < .001) were mainly reserved to patients aged 60-74, who were more treated with rituximab (RTX, p = .02) and splenectomy (p = .03) second-line. Overall response rates to first and second-line therapies were 83.8% and 84.5%, respectively, regardless of age and treatment type/dose. A total of 178 haemorrhages in 101 patients (grade ≥ 3: n. 52, 29.2%; intracranial in 6 patients), 49 thromboses in 43 patients (grade ≥ 3: n. 26, 53.1%) and 115 infections in 94 patients (grade ≥ 3: n. 23, 20%) were observed during follow-up. Incidence rates of complications per 100 patient-years were: 4.5 (haemorrhages, grade ≥ 3: 1.7), 1.7 (thromboses, grade ≥ 3: 0.9), and 3.9 (infections, grade ≥ 3: 0.7). TRAs use were associated with reduced risk of bleeding and infections, while cardiovascular risk factors (particularly, diabetes) significantly predicted thromboses and infections.\n\n\n\nAge-adapted treatment strategies are required in elderly and very elderly patients.",
"affiliations": "Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy. Electronic address: francesca.palandri@unibo.it.;Hematology Division, Sapienza University, Policlinico Umberto I, Rome, Italy.;Hematology Division, Ospedale San Gerardo, ASST Monza, Monza, Italy.;Division of Hematology, ASST Niguarda Hospital, Oncohematology, Milan, Italy.;Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.;Hematology Project Foundation and Department of Hematology, San Bortolo Hospital, Vicenza, Italy.;Hematology Department, Careggi University Hospital, Florence, Italy.;Institute of Hematology, Catholic University School of Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Department of Hematology, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.;Hematology Unit, Infermi Hospital Rimini, Rimini, Italy.;Hematology Division, Sapienza University, Policlinico Umberto I, Rome, Italy.;Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.;Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.;Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.;Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.;Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.;Institute of Hematology, Catholic University School of Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.;Hematology Project Foundation and Department of Hematology, San Bortolo Hospital, Vicenza, Italy.;Hematology Division, Sapienza University, Policlinico Umberto I, Rome, Italy.;Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.;Hematology Project Foundation and Department of Hematology, San Bortolo Hospital, Vicenza, Italy.;Institute of Hematology \"L. and A. Seràgnoli\", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.",
"authors": "Palandri|Francesca|F|;Santoro|Cristina|C|;Carpenedo|Monica|M|;Cantoni|Silvia|S|;Barcellini|Wilma|W|;Carli|Giuseppe|G|;Carrai|Valentina|V|;Rossi|Elena|E|;Rivolti|Elena|E|;Lucchesi|Alessandro|A|;Rotondo|Francesco|F|;Baldacci|Erminia|E|;Auteri|Giuseppe|G|;Sutto|Emanuele|E|;Di Pietro|Christian|C|;Catani|Lucia|L|;Bartoletti|Daniela|D|;De Stefano|Valerio|V|;Ruggeri|Marco|M|;Mazzucconi|Maria Gabriella|MG|;Cavo|Michele|M|;Rodeghiero|Francesco|F|;Vianelli|Nicola|N|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.thromres.2019.11.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0049-3848",
"issue": "185()",
"journal": "Thrombosis research",
"keywords": "Elderly; ITP; Immune thrombocytopenia; TPO-receptor agonists; Toxicity",
"medline_ta": "Thromb Res",
"mesh_terms": "D000368:Aged; D006801:Humans; D007166:Immunosuppressive Agents; D016553:Purpura, Thrombocytopenic, Idiopathic; D000069283:Rituximab; D013156:Splenectomy; D013921:Thrombocytopenia",
"nlm_unique_id": "0326377",
"other_id": null,
"pages": "88-95",
"pmc": null,
"pmid": "31783273",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Management of elderly patients with immune thrombocytopenia: Real-world evidence from 451 patients older than 60 years.",
"title_normalized": "management of elderly patients with immune thrombocytopenia real world evidence from 451 patients older than 60 years"
} | [
{
"companynumb": "IT-AMGEN-ITASP2019207982",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ROMIPLOSTIM"
},
"drugadditional": null,
... |
{
"abstract": "Cytomegalovirus (CMV) infections are asymptomatic in immunocompetent patients but in immunocompromised patients, CMV infections have varying manifestations depending on their location. Patient who are organ transplant recipients, taking immunosuppressive therapy for a long time are at increased risk of CMV infections. CMV-induced gastric ulcer is very rare but many cases have been reported in the literature. No case describing association between CMV-related gastric ulcer and glomerulonephritis has been reported in the literature so far. In this article, we describe a case of pauci immune crescentic glomerulonephritis in a patient who was on rituximab and long-term steroid therapy and found to have CMV-related gastric ulcer. The association of small vessel vasculitis and CMV-related gastrointestinal infection has not been studied in the literature. Pauci immune crescentic glomerulonephritis is a subtype of rapidly progressive glomerulonephritis manifested by continuous loss of renal functions with features of dysmorphic red blood cells and glomerular proteinuria. Treatment of such condition is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen known as Rituximab. We also discussed the pathogenesis of CMV- induced gastric ulcer after rituximab therapy. This case emphasizes the importance of opportunistic infections in glomerulonephritis patients and raises the awareness that glomerunephritis patients are at increased risk of opportunistic infections as well. Rituximab was considered to be a safer drug but over the years, the incidence if opportunistic infections in patients on rituximab has been increasing.",
"affiliations": "Internal Medicine Residency Program, Mercy St. Vincent Medical Center, Toledo, OH, USA.;Gastroenterology, Mercy St. Vincent Medical Center, Toledo, OH, USA.;Gastroenterology, Mercy St. Vincent Medical Center, Toledo, OH, USA.",
"authors": "Ishtiaq|Rizwan|R|;Wilhelm|Darlene M|DM|;Ahmad|Sumair|S|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1080/00325481.2019.1667211",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-5481",
"issue": "131(8)",
"journal": "Postgraduate medicine",
"keywords": "CMV; gastric ulcer; glomerulonephritis; rituximab",
"medline_ta": "Postgrad Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D003586:Cytomegalovirus Infections; D005921:Glomerulonephritis; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D000069283:Rituximab; D013276:Stomach Ulcer",
"nlm_unique_id": "0401147",
"other_id": null,
"pages": "619-622",
"pmc": null,
"pmid": "31506001",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "CMV gastric ulcer in a patient with pauci immune crescentic glomerulonephritis on rituximab - a rare combination.",
"title_normalized": "cmv gastric ulcer in a patient with pauci immune crescentic glomerulonephritis on rituximab a rare combination"
} | [
{
"companynumb": "US-ROCHE-2506364",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "CTLA4-haploinsufficiency is a complex disease of immune dysregulation presenting with a broad spectrum of clinical manifestations. CTLA4-Fc fusion proteins such as abatacept have been described to alleviate immune dysregulation in several adult cases of CTLA4-haploinsufficiency. However, until now only few cases of pediatric CTLA4-haploinsufficiency treated with abatacept have been described. Here we present two pediatric cases of severe CTLA4-haploinsufficiency refractory to conventional immunosuppressive therapies that responded rapidly to treatment with abatacept. No side effects were observed during a follow-up period of 7-15 months. While one patient has successfully undergone HSCT the second patient continues to receive abatacept. Our cases demonstrate safe medium-term use of abatacept in the pediatric population.",
"affiliations": "Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Radiology, Pediatric Radiology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany; German Centre for Infection Research (DZIF), Munich, Germany; Munich Centre for Rare Diseases (M-ZSE), University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.;Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany; German Centre for Infection Research (DZIF), Munich, Germany; Munich Centre for Rare Diseases (M-ZSE), University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address: fabian.hauck@med.uni-muenchen.de.",
"authors": "Lanz|Anna-Lisa|AL|;Riester|Martin|M|;Peters|Philipp|P|;Schwerd|Tobias|T|;Lurz|Eberhard|E|;Hajji|Mohammad Samer|MS|;Rohlfs|Meino|M|;Ley-Zaporozhan|Julia|J|;Walz|Christoph|C|;Kotlarz|Daniel|D|;Klein|Christoph|C|;Albert|Michael H|MH|;Hauck|Fabian|F|",
"chemical_list": "D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007166:Immunosuppressive Agents; D000069594:Abatacept",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clim.2021.108779",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1521-6616",
"issue": "229()",
"journal": "Clinical immunology (Orlando, Fla.)",
"keywords": "Abatacept; CTLA4-fc fusion protein; CTLA4-haploinsufficiency; Immune dysregulation; Inborn error of immunity",
"medline_ta": "Clin Immunol",
"mesh_terms": "D000069594:Abatacept; D000293:Adolescent; D060908:CTLA-4 Antigen; D005260:Female; D057895:Haploinsufficiency; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007154:Immune System Diseases; D007166:Immunosuppressive Agents; D008297:Male; D020125:Mutation, Missense; D050378:T-Lymphocytes, Regulatory",
"nlm_unique_id": "100883537",
"other_id": null,
"pages": "108779",
"pmc": null,
"pmid": "34116213",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Abatacept for treatment-refractory pediatric CTLA4-haploinsufficiency.",
"title_normalized": "abatacept for treatment refractory pediatric ctla4 haploinsufficiency"
} | [
{
"companynumb": "DE-PFIZER INC-202101447747",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Carcinoid tumours are often difficult to diagnose because of non-specific symptoms, mimicking those of irritable bowel disease of Crohn's disease. The authors describe a 57-year-old patient with clinical and radiological features, suggestive of Crohn's disease, in whom the diagnosis was proved to be a carcinoid tumour involving the terminal ileum. This case report illustrates that ileal carcinoid should be considered in the differential diagnosis of Crohn's disease, particularly in older patients.",
"affiliations": "Department of Gastroenterology, Atrium Medical Centre, Heerlen, The Netherlands. bakker@atriummc.nl",
"authors": "Bakker|C M|CM|;Sosef|M N|MN|;Vliegen|R A|RA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2011()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002276:Carcinoid Tumor; D003424:Crohn Disease; D003937:Diagnosis, Differential; D006801:Humans; D007078:Ileal Neoplasms; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "22715273",
"pubdate": "2011-01-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19161610;14531542;18097129;12569593;9362193",
"title": "A wolf in sheep's clothing.",
"title_normalized": "a wolf in sheep s clothing"
} | [
{
"companynumb": "US-009507513-2105USA006245",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAlthough locally advanced head and neck squamous cell carcinoma (HNSCC) can be effectively treated using chemoradiotherapy (CRT) with docetaxel (DTX), and cisplatin (CDDP) plus 5-fluorouracil (TPF-CRT), severe adverse events (especially neutropenia) can limit treatment adherence. Therefore, we evaluated the safety and efficacy of a new chemotherapy regimen that consisted of DTX and CDDP plus cetuximab (Cmab) with concurrent radiotherapy.\n\n\nMETHODS\nBio-chemoradiotherapy (B-CRT) using DTX, CDDP, and Cmab was administrated to patients with locally advanced HNSCC, and its safety and efficacy were evaluated.\n\n\nRESULTS\nInterim analysis of nine patients revealed severe neutropenia in five patients (56 %) and leukopenia in seven patients (78 %); hence, the study was terminated. One patient experienced disease-free survival using only B-CRT.\n\n\nCONCLUSIONS\nNeutropenia was equally severe for B-CRT, compared to TPF-CRT. Based on the limited sample size, it is impossible to conclude that B-CRT has non-inferior efficacy, compared to TPF-CRT.",
"affiliations": "Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. gnishimu@yokohama-cu.ac.jp.;Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.;Department of Otorhinolaryngology, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.;Department of Radiology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.",
"authors": "Nishimura|Goshi|G|;Taguchi|Takahide|T|;Takahashi|Masahiro|M|;Shiono|Osamu|O|;Komatsu|Masanori|M|;Sano|Daisuke|D|;Yabuki|Kenichiro|K|;Arai|Yasuhiro|Y|;Takahashi|Hideaki|H|;Hata|Masaharu|M|;Oridate|Nobuhiko|N|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D000068818:Cetuximab; D002945:Cisplatin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-016-3052-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "77(6)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Bio-chemoradiotherapy; Cetuximab; Cisplatin; Docetaxel; Head and neck squamous cell carcinoma",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D059248:Chemoradiotherapy; D002945:Cisplatin; D018572:Disease-Free Survival; D000077143:Docetaxel; D057239:Early Termination of Clinical Trials; D006258:Head and Neck Neoplasms; D006801:Humans; D007970:Leukopenia; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia; D011829:Radiation Dosage; D012720:Severity of Illness Index; D043823:Taxoids",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1315-9",
"pmc": null,
"pmid": "27154176",
"pubdate": "2016-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Phase II trial of concurrent bio-chemoradiotherapy using docetaxel, cisplatin, and cetuximab for locally advanced head and neck squamous cell carcinoma.",
"title_normalized": "phase ii trial of concurrent bio chemoradiotherapy using docetaxel cisplatin and cetuximab for locally advanced head and neck squamous cell carcinoma"
} | [
{
"companynumb": "JP-PFIZER INC-2016492979",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial.\n\n\n\nThis single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m2, nab-paclitaxel 150 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 and oral capecitabine 1250 mg/m2 on days 1-28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed.\n\n\n\nBetween April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group.\n\n\n\nDespite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma.\n\n\n\nCelgene.",
"affiliations": "Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Radiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.;Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.;Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.;Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.",
"authors": "Reni|Michele|M|;Zanon|Silvia|S|;Peretti|Umberto|U|;Chiaravalli|Marta|M|;Barone|Diletta|D|;Pircher|Chiara|C|;Balzano|Gianpaolo|G|;Macchini|Marina|M|;Romi|Silvia|S|;Gritti|Elena|E|;Mazza|Elena|E|;Nicoletti|Roberto|R|;Doglioni|Claudio|C|;Falconi|Massimo|M|;Gianni|Luca|L|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; D000069287:Capecitabine; C056507:gemcitabine; D017239:Paclitaxel; D002945:Cisplatin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2468-1253(18)30196-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "3(10)",
"journal": "The lancet. Gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Lancet Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000418:Albumins; D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069287:Capecitabine; D021441:Carcinoma, Pancreatic Ductal; D002945:Cisplatin; D003841:Deoxycytidine; D005221:Fatigue; D005260:Female; D006801:Humans; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009503:Neutropenia; D017239:Paclitaxel; D010190:Pancreatic Neoplasms; D000077982:Progression-Free Survival",
"nlm_unique_id": "101690683",
"other_id": null,
"pages": "691-697",
"pmc": null,
"pmid": "30220407",
"pubdate": "2018-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial.",
"title_normalized": "nab paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma pact 19 a randomised phase 2 trial"
} | [
{
"companynumb": "IT-PFIZER INC-2018292712",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "The aim of the current work was to report the effect of imatinib on pregnancy in patients with chronic myeloid leukemia (CML).\n\n\n\nData were collected between January 1998 and December 2014. One hundred four patients met inclusion criteria, and we report the results of 104 pregnancies-conceived by the participant or partner-while being on imatinib therapy for CML.\n\n\n\nFifty-eight patients were male and 46 were female. Eighty-three patients, 20 patients, and one patient were had CML in the chronic phase, accelerated phase, or blast phase, respectively. Of 46 female patients, 21 underwent abortion (spontaneous, n = 36.9; elective termination, n = 8.6%). In the case of full-term pregnancy in the female partners of male patients with CML, all outcomes were uneventful. Of 46 female patients, 25 had full-term pregnancy outcomes. During the pre-imatinib era (total n = 6), patients were treated with hydroxyurea, interferon-alpha, and therapeutic leukapheresis. A total 10 of 19 pregnant patients continued on imatinib until their delivery and experienced the following outcomes: normal full-term deliveries (n = 7), preterm delivery (n = 1), omphalocele (n = 1), and craniosynostosis (n = 1). Of those who discontinued imatinib after counseling (n = 9), eight patients had full-term normal delivery, of which two patients required leukapheresis and one patient expired. All patients who continued on imatinib while pregnant were in complete cytogenetic response and major molecular response (MMR) before pregnancy, during pregnancy, and postpregnancy. Of nine patients who discontinued imatinib, two lost MMR during the third trimester and all of these patients were in complete cytogenetic response and MMR before pregnancy.\n\n\n\nIt is clear that there is no standard of care for the best treatment of CML in the case of pregnancy. Interferon and/or leukapheresis will be included as treatment options. Patients can have normal pregnancies even with the administration of imatinib at the risk of congenital anomalies, intervention for which can be done after birth.",
"affiliations": "Kerudi Cancer Hospital, Bagalkot, India.;Indira Gandhi Medical College, Shimla, India.;Gujarat Cancer and Research Institute, Ahmedabad, India.;Basaveshwara Engineering College, Bagalkot, India.",
"authors": "Madabhavi|Irappa|I|;Sarkar|Malay|M|;Modi|Mitul|M|;Kadakol|Nagaveni|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1200/JGO.18.00211",
"fulltext": "\n==== Front\nJ Glob OncolJ Glob OncoljgojgoJGOJournal of Global Oncology2378-9506American Society of Clinical Oncology 180021110.1200/JGO.18.00211Bone Marrow TransplantationHematologic MalignanciesImmunotherapyOriginal ReportPregnancy Outcomes in Chronic Myeloid Leukemia: A Single Center Experience CML in Pregnancy: An Indian ExperienceMadabhavi Irappa MBBS, MD, DM1Sarkar Malay MD2Modi Mitul MD3Kadakol Nagaveni 41 Kerudi Cancer Hospital, Bagalkot, India2 Indira Gandhi Medical College, Shimla, India3 Gujarat Cancer and Research Institute, Ahmedabad, India4 Basaveshwara Engineering College, Bagalkot, IndiaIrappa Madabhavi, MBBS, MD, DM, Department of Medical Oncology and Hematology, Kerudi Cancer Hospital, Bagalkot, Karnataka, India; e-mail: irappamadabhavi@gmail.com2019 4 10 2019 5 JGO.18.0021120 8 2019 © 2019 by American Society of Clinical Oncology2019American Society of Clinical OncologyCreative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/PURPOSE\nThe aim of the current work was to report the effect of imatinib on pregnancy in patients with chronic myeloid leukemia (CML).\n\nMETHODS\nData were collected between January 1998 and December 2014. One hundred four patients met inclusion criteria, and we report the results of 104 pregnancies—conceived by the participant or partner—while being on imatinib therapy for CML.\n\nRESULTS\nFifty-eight patients were male and 46 were female. Eighty-three patients, 20 patients, and one patient were had CML in the chronic phase, accelerated phase, or blast phase, respectively. Of 46 female patients, 21 underwent abortion (spontaneous, n = 36.9; elective termination, n = 8.6%). In the case of full-term pregnancy in the female partners of male patients with CML, all outcomes were uneventful. Of 46 female patients, 25 had full-term pregnancy outcomes. During the pre–imatinib era (total n = 6), patients were treated with hydroxyurea, interferon-alpha, and therapeutic leukapheresis. A total 10 of 19 pregnant patients continued on imatinib until their delivery and experienced the following outcomes: normal full-term deliveries (n = 7), preterm delivery (n = 1), omphalocele (n = 1), and craniosynostosis (n = 1). Of those who discontinued imatinib after counseling (n = 9), eight patients had full-term normal delivery, of which two patients required leukapheresis and one patient expired. All patients who continued on imatinib while pregnant were in complete cytogenetic response and major molecular response (MMR) before pregnancy, during pregnancy, and postpregnancy. Of nine patients who discontinued imatinib, two lost MMR during the third trimester and all of these patients were in complete cytogenetic response and MMR before pregnancy.\n\nCONCLUSION\nIt is clear that there is no standard of care for the best treatment of CML in the case of pregnancy. Interferon and/or leukapheresis will be included as treatment options. Patients can have normal pregnancies even with the administration of imatinib at the risk of congenital anomalies, intervention for which can be done after birth.\n\n SJS Export v1\n==== Body\nINTRODUCTION\nIt has been observed that, during pregnancy, the prevalence of leukemia is less than one in 10,000 pregnancies.1 Today, for patients with chronic myeloid leukemia (CML), imatinib mesylate has become the standard therapy. If a patient wants to get pregnant, it is advisable to plan the pregnancy and to aim for a response as deep as possible, at least a major molecular response (MMR). Therapy should then be interrupted, with a preference for a 3-month washout before conception and for the duration of the pregnancy. Therapy should be resumed immediately after birth; however, if there is an unplanned pregnancy or if the patient is diagnosed while pregnant, the issue is more complicated. Although there have been some instances reported in which patients continued therapy throughout pregnancy with no problems for the baby, it is not recommend to use a tyrosine kinase inhibitor (TKI) at all during pregnancy.2 In the current study, we report the outcomes of imatinib therapy in pregnant patients or their female partners—for male patients with CML—conceived while receiving imatinib for CML.\n\nMETHODS\nIn this retrospective analysis from a single center in India from January 1998 to December 2014, a total of 2,008 patients with CML were treated at our center. Of 2,008 patients, 5.1% met the inclusion criteria for this study. This study was permitted by our institution review board and written informed consent was obtained from all eligible patients. Data on age, sex, symptoms, signs, and laboratory parameters were extracted from the medical record department of our center and entered into Excel (Microsoft, Redmond, WA). From January 1998 to February 2002, patients were treated with non–TKI-based treatments, including hydroxyurea, interferon-alpha, and/or leukapheresis. After US Food and Drug Administration (FDA) approval of imatinib, most patients were treated with this TKI.\n\nInclusion Criteria\nWe included pregnant patients and male patients with female partners who conceived while taking imatinib who were diagnosed with Ph chromosome–positive CML (CP or AP or BC) by conventional cytogenetics, fluorescence in situ hybridization (FISH) for BCR-ABL or by reverse transcript quantitative polymerase chain reaction (RT-qPCR) for BCR-ABL.\n\nExclusion Criteria\nNo pregnant patients were excluded.\n\nAssessment\nAt our tertiary care center, any patients with suspected CML underwent assessment, including CBC, renal function test, liver function test, lactate dehyrogenase, serum uric acid, serum electrolytes, abdominal sonography, bone marrow aspiration, and conventional cytogenetics. If marrow cytogenetic assessment failed, then FISH or RT-qPCR was performed from peripheral blood. Immunophenotyping was performed if blast crisis was present.\n\nTreatment\nAll pregnant patients who were taking imatinib at the time of diagnosis during the first, second, or third trimester of the conception were counseled regarding teratogenicity, toxicity, and safety data of imatinib and advised to stop imatinib and undergo therapeutic abortion if possible and, if at near term, were advised to undergo preterm delivery after consulting with an expert gynecologist. If the patient wanted to continue the pregnancy at her own risk and was not willing to undergo leukapheresis and interferon-alpha therapy, she was allowed to take imatinib at a dose of 400 mg per day. All male patients with CML were allowed to take imatinib at a dose of 400 mg per day.\n\nLeukapheresis is offered in all three trimesters and interferon alpha is advised in second and third trimester. Hydroxyurea 25 mg/kg was continued in pre–imatinib era.\n\nDiagnostic Criteria for Different Phases of CML\nPeripheral blood can be used to diagnose CML. Typical indications of CML are an elevated WBC count with left shift, frequently with basophilia, and an enlarged spleen. For proper workup, a bone marrow aspiration along with cytogenic analysis is mandatory, although FISH or polymerase chain reaction for BCR-ABL can be used to confirm the presence of BCR-ABL.\n\nResponse Evaluation\nWe used European LeukemiaNet guidelines to assess the response of imatinib and for additional monitoring of patients. Response was assessed with standardized RT-qPCR and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels of 10% or less at 3 months, less than 1% at 6 months, and 0.1% or less from 12 months onward define optimal response, whereas levels of more than 10% at 6 months and more than 1% from 12 months onward define failure, requiring a deviation from current path of treatment. Similarly, partial cytogenetic response at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no cytogenic response (Ph positive > 95%) at 3 months, less than partial cytogenetic response at 6 months, and less than CCyR from 12 months onward define failure.\n\nRESULTS\nClinical characteristics of patients at presentation are as follows: Median age at presentation for males was 36 years (range, 25 to 45 years) and for females was 27 years (range, 21 to 36 years); 55.7% of patients (n = 58) were male and 44.3% (n = 46) were female. We noted common initial clinical symptoms in patients, such as generalized weakness (67.3%), heaviness of the left hypochondriac region (65.3%), abdominal pain (62.5%), fever (54.8%), and bleeding (1%). The hematologic profile of the study population is as follows: Average hemoglobin was 8.4 g/dL (range, 6 to 14 g/dL), WBC per cubic millimeter was 32,000 (range, 4,500 to 120,000/cubic mm), and platelet count per cubic millimeter was 290,000 (range, 19,000 to 940,000/cubic mm). The disease profile at presentation was CML-CP in 79.8% (n = 83), CML-AP in 19.2% (n = 20), and CML-BC in 1% (n = 1) of patients. Distribution of pregnant female patients (n = 46) according to the trimester of the pregnancy are as follows: first trimester, 45% to 6% (n = 21); second trimester, 32.6% (n = 15); and third trimester, 21.7% (n = 10). Of 46 female patients, 21 patients underwent therapeutic abortion (Table 1).\n\nTABLE 1 Landmark Studies of Imatinib in Pregnant Patients With CML\n\nOutcomes in Male Patients\nOutcomes of full-term pregnancy in female partners of male patients with CML were uneventful and without any congenital malformations to infants.\n\nOutcomes in Female Patients\nOf 46 female patients, 25 had full-term pregnancy outcomes. During the pre–imatinib era, of six patients, three were treated with hydroxyurea, interferon alpha (n = 1), and/or therapeutic leukapheresis (n = 2), and all patients had normal full-term deliveries without any complications. Nineteen pregnant patients were receiving imatinib at the time of enrollment and were counseled regarding the safety of the drug and advised to discontinue. Even after proper counseling, 10 of 19 patients continued imatinib until the time of delivery. Of 10 patients, seven had normal full-term delivery, there was one preterm delivery, one with omphalocele, and another infant had craniosynostosis. Of those who discontinued imatinib (n = 9), eight patients had full-term normal delivery, of which two patients required leukapheresis. One patient expired from multiorgan failure as a result of septic shock during the perinatal period because of postpartum sepsis, which was determined to be unrelated to CML because her hematologic profile and RT-qPCR were normal except neutrophilia with left shift. All patients who continued imatinib even after counseling while pregnant were in CCyR and MMR prepregnancy, during pregnancy, and postpregnancy (Table 2).\n\nTABLE 2 Outcome of Pregnancy in All Patients\n\nObservation of Newborns\nNewborns of male patients with CML who are receiving imatinib: All newborns (age range, newborn to 11 years old), toddlers, and children were doing well with normal development of all milestones (gross motor, fine motor, language, cognitive, social skills, vision, and hearing).\n\nNewborns of female patients with CML in the pre–imatinib era: All six newborns (age range, 13 to 22 years old), toddlers, and children were doing well with normal development of all milestones.\n\nNewborns of female patients with CML in the post–imatinib era:Newborns of female CML patients who discontinued imatinib after proper counseling: All nine newborns (age range, 4 to 8 years old), toddlers, and children were doing well with normal development of all milestones.\n\nNewborns of female patients with CML who continued imatinib after proper counseling: All eight newborns (age range, 4 to 8 years old), toddlers, and children were doing well with normal development of all milestones.\n\nNewborn with omphalocele: Primary surgical repair was performed on the second day of the neonatal period. The child had manageable feeding problems and was doing well. He is now 6 years old studying at the first standard.\n\nNewborn with craniosynostosis: The newborn was having scaphocephaly, and total cranial vault remodeling intervention was performed at the fifth month of infancy. The child is now 2.5 years old with normal milestone development to date.\n\n\n\n\n\nRecommendations for Female Patients With CML Receiving Imatinib and Planning Pregnancy or Diagnosed With CML During Pregnancy\nFigures 1 and 2 show suggested algorithms for the management of pregnancy in patients with CML who are on treatment with imatinib with unplanned pregnancy or diagnosis of CML in pregnancy (Fig 1), and who are on treatment with imatinib and planning an elective pregnancy or planned pregnancy (Fig 2). Generally, RT-qPCR increases if the patient is taken off treatment, but this increase does not necessitate the treatment to be intervened. When the patient is taken off treatment, the first measurement should be performed after 2 to 3 three months. However, the frequency of additional monitoring will be decided by the rate at which the full blood count of the patient increases initially and RT-qPCR. Another treatment approach that considers leukemic burden and pregnancy terms may be helpful for avoiding interventions in treatment in the case of favorable situations and takes into account the interests of both the child and mother when treatment initiation becomes necessary. For female patients with CML, this treatment approach can significantly increase the chances of having children. Even so, both the patient and physician should understand the possible risks. Managing CML at pregnancy with huge leukemic mass is still a complicated task; pregnancy with CML should be thoroughly planned at deep remission. In patients with less than 15 weeks of gestation, TKIs should be stopped and patients should be observed without treatment. After 15 weeks of gestation, if BCR-ABL is less than 1% we can observe without any treatment, and if BCR-ABL is more than 1% we can restart therapy with imatinib, nilotinib, and no dasatinib.\n\nFIG 1 Suggested algorithm for management of pregnancy in patients with chronic myeloid leukemia (CML) who are on treatment with imatinib with unplanned pregnancy or diagnosis of CML in pregnancy. IFN-α, interferon alpha; TKI, tyrosine kinase inhibitor; WCC, white cell count.\n\nFIG 2 Suggested algorithm for management of pregnancy in patients with chronic myeloid leukemia (CML) who are on treatment with imatinib and planning an elective pregnancy or planned pregnancy. CHR, complete hematological response; CMR, complete molecular response; IFN-α, interferon alpha; IVF, in vitro fertilization; MMR, major molecular response; TKI, tyrosine kinase inhibitor.\n\nDISCUSSION\nThe most common malignancies associated with pregnancy are cervical cancer, breast cancer, melanoma, lymphomas, and acute leukemia.3 CML presents as approximately 10% cases of pregnancy-associated leukemia. CML in pregnancy is not associated with an increase in premature infants, low birth weight, or abortion rates, which were concerns previously. The disease course is akin to that in nonpregnant females.4\n\nManagement options for CML diagnosed in pregnancy are imatinib, hydroxyurea, interferon alfa, and leukapheresis.5 During the pre–imatinib era, literature has revealed reasonably varied facts regarding hydroxyurea, but not enough to be endorsed by the FDA.6 Hydroxyurea was used as a cytotoxic agent before the discovery of TKI and has been documented to cause fetal growth restriction, intrauterine death, and craniofacial and spinal defects.7,8 Cytotoxic chemotherapy, such as busulphan, is significantly associated with fetal malformations.9 Interferon alpha works slowly but the FDA has approved interferon alpha as category C during pregnancy. There are several case series that have demonstrated that leukapheresis may be considered a safe procedure in situations when protection of the fetus is preferred, mainly during hyperleukocytosis.10,11 As compelling data do not exist at present, use of TKIs and other cytotoxic agents could not be suggested for regular use. Interferon alpha has a higher molecular weight—unable to cross the placenta—and does not inhibit DNA synthesis. Hence, it is considered safe in pregnancy.7,12\n\nImatinib has changed a mortal disease with a median survival of 6 to 7 years into a chronic condition for a large number of patients. Apart from inhibiting the BCR-ABL1 protein, TKIs also reduce stem-cell factor (c-kit), platelet-derived growth factor receptors, arg, c-fms, and src—especially by dasatinib—proteins, which are pertinent to implantation, fetal maturation, and gonadal development, at least revealed by animal studies.5,13\n\nImatinib in Men\nThere is no increased jeopardy of congenital malformations or increased abortion with usual and higher doses of imatinib.9,14-16 Previous studies have shown that imatinib can potentially hamper postnatal testicular development and sperm capacitation in animal studies.13,17 Newer studies have shown that imatinib exposure leads to a significant decline in testosterone levels in adult patients with CML18,19; however, outcomes of pregnancy in more than 150 patients were uneventful, excluding the malrotation of the intestine and single stillbirth with malformations.20 An imatinib-treated patient with hyper eosinophilic syndrome developed oligospermia.21 No special safety measures are relevant for male patients receiving TKIs.22\n\nImatinib in Women\nImatinib use in pregnancy comes under category D according to FDA. Women should be well informed about the impending danger to the fetus if used during pregnancy or if the patient becomes pregnant while taking this drug. It is recommended that female patients follow adequate contraception. With imatinib, the majority of patients achieve deep, long-lasting responses, which is associated with normal life expectancy. Mammalian ovaries express c-kit, c-abl, and platelet-derived growth factor, which are inhibited by TKI, that are imperative in the growth and maturity of oocytes and follicles.23-25 When CML is diagnosed in the first trimester, termination of pregnancy is considered harmless for the mother; however, TKIs are associated with fetal malformations if used in the second trimester. Platelet-derived growth factor A inhibition of imatinib resulted in teratogenicity in mice.26\n\nDistinguishing congenital abnormalities have occurred after the administration of imatinib in early pregnancy. These include exomphalos, omphaloceles, pulmonary hypoplasia, duplex kidneys, renal agenesis, skeletal malformations (craniosynostosis, shoulder anomaly, and scoliosis), and spontaneous abortion.22 The incidence of exomphalos is approximately 100-fold greater than predictable. Once pregnancy has been documented, if the patient is receiving imatinib it should be stopped. Close monitoring of fetal growth, especially a nuchal scan, should be performed for fetal anomalies. No trial has demonstrated cumulative toxicity of imatinib and fetal malformations.3 Cole et al27 studied the cases of 215 women who became pregnant while taking imatinib until 2009. Of 215 women, 171 sustained their pregnancy to term—62 of them had unknown outcomes, whereas 109 pregnancies had known outcomes: 33% (n = 36) had complications, such as spontaneous abortion (n = 24), stillbirth (n = 1), malformations (n = 9), and low birth weight (n = 2).27 Imatinib does not have any effect on folliculogenesis or spermatogenesis.28 Until now, the number of cases of pregnant women with CML reported in the literature is more than 200; however, with the exception of imatinib, there are no data available on the use of targeted agents nor various landmark studies of imatinib in pregnant patients with CML (Table 1).\n\nSecond-Generation TKI During Pregnancy20,29 (Table 3)\nNilotinib for men: Little has been reported regarding conception during nilotinib treatment.30\n\nNilotinib for women: As for men, little has been reported for women who become pregnant while being treated with nilotinib. One patient at the 3-month ultrasound showed a large omphalocele, which resulted in the pregnancy interruption, and another patient’s fetus was exposed to nilotinib for 5 weeks before stopping therapy and pregnancy was unremarkable, with the delivery of a healthy girl.\n\nDasatinib for men: Cortes et al30a studied the effects of dasatinib on pregnant partners of nine male patients who conceived children while receiving dasatinib. Of these patients, one mother experienced preeclampsia but eventually delivered a healthy baby at 37 weeks, free of any birth defects or neonatal complications.30,31\n\nDasatinib for women: To study the effect of dasatinib on pregnant women, 13 pregnant patients were observed. Of these patients, only one normal newborn was delivered; one patient gave birth to a premature newborn, four women had to undergo induced abortions, another two had spontaneous abortions, and five women were pregnant at last reported follow-up. In conclusion, temporarily discontinuing TKIs nilotinib and dasatinib, then observing or intervening with interferon alpha and/or leukapheresis, can be considered to be the safest and thus the best potential therapeutic options for the management of CML in pregnancy.31\n\nOther TKIs: No conceptions/pregnancies have been reported while receiving ponatinib.\n\n\n\nTABLE 3 CML in Pregnancy Outcomes After 2G-Tyrosine Kinase Inhibitor Therapy\n\nBreast Feeding\nImatinib and its active metabolite are excreted into human milk.\n\nFuture Perspectives\nSome stopping imatinib studies (TWISTER [A phase II study to determine relapse-free interval after withdrawal of imatinib therapy in adult patients with chronic phase chronic myeloid leukaemia in stable complete molecular remission] and STIM [Stop Imatinib] trials) have demonstrated that even after discontinuing imatinib and attaining complete molecular response for 2 years, nearly 40% of patients maintain a deep response with undetectable BCR-ABL1 transcripts.30,31 On the basis of existing data, female patients with CML who have a desire become pregnant should be advised to wait until persistent MMR is achieved for a minimum of 2 years with monitoring of CBC and RT-qPCR. For future assisted conception in patients who at least achieve complete hematologic response and who plan for future pregnancy, it is advised to collect oocytes. Start in vitro fertilization drugs 7 days after stopping TKI and resume TKI after the oocytes collection (Table 4).\n\nTABLE 4 Management of a Female Patient With CML Planning a Pregnancy20\n\nImpact of Imatinib and Other 2G-TKIs on Pregnancy in Patients With CML\nPhysiologic changes, which also include changes in hematologic parameters accompanying pregnancy, may complicate the diagnosis of CML during pregnancy as they may mask the symptoms.\n\nAs the prothrombotic proteins and hemostatic factors increase physiologically, and the venous blood flow is obstructed physically, the prothrombotic potential of a normal pregnancy is recognized. Hence, it is clear that thrombosis can be considered to be the most common cause of maternal morbidity. In the case of myeloproliferative diseases, this may be compounded where there is an associated increase in blood platelet count.5,13\n\nAll TKIs have similar class effects as they inhibit BCR-ABL1. TKIs also have a lot of off-target effects as a result of the inhibition of c-kit, platelet-derived growth factor receptors, arg, and c-fms. Furthermore, it should be noted that one of the 2G-TKIs, dasatinib, also inhibits src and related proteins, which are relevant to gonadal development, embryonic implantation, and fetal maturation.5,13\n\nLess experience has been reported with 2G-TKIs36-42 (Table 3; bosutinib, dasatinib, nilotinib, and ponatinib) in pregnancy. Dual BCR-ABL/src kinase inhibitor dasatinib crosses the placenta and results in considerable levels of fetal plasma. It has been reported that, in the first trimester, dasatinib causes fetal hydrops and severe fetal bicytopenia; however, there have been reports of some pregnancies as well.\n\nIn conclusion, the management of CML during pregnancy poses a therapeutic dilemma because of the potential teratogenic effect of therapy and requires the contemplation of both maternal and fetal life. Imatinib use during pregnancy is a double-edged sword, because discontinuation of the drug is associated with a loss of cytogenetic and molecular response, as well as consequences of the disease and, if continued, results in fetal jeopardy. Several treatment approaches have been used for CML with pregnancy, including hydroxyurea, leukapheresis, and interferon alpha. There are various adverse pregnancy outcomes with TKIs, such as spontaneous abortion, miscarriage, stillbirth, preterm delivery, and malformed child. The various malformations of TKIs are omphalocele, craniosynostosis, clinodactyly, short fifth fingers, slightly downward slanting palpebral fissures, renal and vertebral anomalies, as in our case (right renal agenesis and hemivertebrae), and low birth weight.\n\nACKNOWLEDGMENT\nThe authors thank Nagaveni Irappa Madabhavi (lecturer, Government Polytechnic Zalaki, Bijapur, Karnataka, India) for drawing the figures.\n\nAUTHOR CONTRIBUTIONS\nConception and design: Irappa Madabhavi, Mitul Modi\n\nProvision of study material or patients: Irappa Madabhavi, Malay Sarkar, Mitul Modi\n\nCollection and assembly of data: Irappa Madabhavi, Nagaveni Kadakol\n\nData analysis and interpretation: All authors\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jgo/site/ifc.\n\nOpen Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).\n\nNo potential conflicts of interest were reported.\n==== Refs\nREFERENCES\n1. Pentheroudakis G Orecchia R Hoekstra HJ et al Cancer, fertility and pregnancy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 21 suppl. 5 v266 v273 2010 20555095 \n2. Cortes J Kantarjian H How I treat newly diagnosed chronic phase CML Blood 120 1390 1397 2012 22613793 \n3. Pentheroudakis G Orecchia R Hoekstra HJ et al Cancer, fertility and pregnancy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 21 v266 v273 2010 suppl 5 20555095 \n4. Apperley J CML in pregnancy and childhood Best Pract Res Clin Haematol 22 455 474 2009 19959094 \n5. Milojkovic D Apperley J State-of-the-art in the treatment of chronic myeloid leukaemia Curr Opin Oncol 20 112 121 2008 18043265 \n6. Fadilah SA Ahmad-Zailani H Soon-Keng C et al Successful treatment of chronic myeloid leukemia during pregnancy with hydroxyurea Leukemia 16 1202 1203 2002 12040456 \n7. Harrison C Pregnancy and its management in the Philadelphia negative myeloproliferative diseases Br J Haematol 129 293 306 2005 15842653 \n8. Thauvin-Robinet C Maingueneau C Robert E et al Exposure to hydroxyurea during pregnancy: A case series Leukemia 15 1309 1311 2001 11480579 \n9. Breccia M Cannella L Montefusco E et al Male patients with chronic myeloid leukemia treated with imatinib involved in healthy pregnancies: Report of five cases Leuk Res 32 519 520 2008 17804066 \n10. Apperly J Pye S Chapter 19: The haematological malignancies Kehoe S Jauniaux E Martin-Hirsch P et alCancer and Reproductive Health. London United Kingdom RCOG Press 243 256 2008 \n11. Strobl FJ Voelkerding KV Smith EP Management of chronic myeloid leukemia during pregnancy with leukapheresis J Clin Apher 14 42 44 1999 10355663 \n12. Yazdani Brojeni P Matok I Garcia Bournissen F et al A systematic review of the fetal safety of interferon alpha Reprod Toxicol 33 265 268 2012 22200624 \n13. Nurmio M Kallio J Toppari J et al Adult reproductive functions after early postnatal inhibition by imatinib of the two receptor tyrosine kinases, c-kit and PDGFR, in the rat testis Reprod Toxicol 25 442 446 2008 18472395 \n14. Ault P Kantarjian H O’Brien S et al Pregnancy among patients with chronic myeloid leukemia treated with imatinib J Clin Oncol 24 1204 1208 2006 16446320 \n15. Hensley ML Ford JM Imatinib treatment: Specific issues related to safety, fertility, and pregnancy Semin Hematol 40 suppl 2 21 25 2003 12783371 \n16. Ramasamy K Hayden J Lim Z et al Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy Br J Haematol 137 374 375 2007 17408403 \n17. Baker MA Hetherington L Curry B et al Phosphorylation and consequent stimulation of the tyrosine kinase c-Abl by PKA in mouse spermatozoa; its implications during capacitation Dev Biol 333 57 66 2009 19560455 \n18. Ghalaut VS Prakash G Bansal P et al Effect of imatinib on male reproductive hormones in BCR-ABL positive CML patients: A preliminary report J Oncol Pharm Pract 20 243 248 2014 23966360 \n19. Bay K Bjerrum OW Olsson-Strömberg U et al Reproductive hormone profiles during imatinib therapy in men with chronic myeloid leukemia Andrology 2 2167 0250 2013 \n20. Abruzzese E Trawinska MM Perrotti AP et al Tyrosine kinase inhibitors and pregnancy Mediterr J Hematol Infect Dis 6 e20140282014 24804001 \n21. Seshadri T Seymour JF McArthur GA Oligospermia in a patient receiving imatinib therapy for the hypereosinophilic syndrome N Engl J Med 351 2134 2135 2004 15537917 \n22. Zhou L You JH Wu W et al Pregnancies in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitor Leuk Res 37 1216 1221 2013 23937984 \n23. Christopoulos C Dimakopoulou V Rotas E Primary ovarian insufficiency associated with imatinib therapy N Engl J Med 358 1079 1080 2008 18322295 \n24. Schmandt RE Broaddus R Lu KH et al Expression of c-ABL, c-KIT, and platelet-derived growth factor receptor-beta in ovarian serous carcinoma and normal ovarian surface epithelium Cancer 98 758 764 2003 12910520 \n25. Hutt KJ McLaughlin EA Holland MK Kit ligand and c-Kit have diverse roles during mammalian oogenesis and folliculogenesis Mol Hum Reprod 12 61 69 2006 16481408 \n26. Garderet L Santacruz R Barbu V et al Two successful pregnancies in a chronic myeloid leukemia patient treated with imatinib Haematologica 92 e9 e10 2007 17405743 \n27. Cole S Kantarjian H Ault P et al Successful completion of pregnancy in a patient with chronic myeloid leukemia without active intervention: A case report and review of the literature Clin Lymphoma Myeloma 9 324 327 2009 19717385 \n28. Schultheis B Nijmeijer BA Yin H et al Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model Leuk Res 36 271 274 2012 22018447 \n29. Barkoulas T Hall PD Experience with dasatinib and nilotinib use in pregnancy J Oncol Pharm Pract 24 121 128 2018 29284357 \n30. Ross DM Branford S Seymour JF et al Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: Results from the TWISTER study Blood 122 515 522 2013 23704092 \n30a. Cortes J O’Brien S Ault P et alPregnancy outcomes among patients with chronic myeloid leukemia treated with dasatinib Blood (abstr 3230) Poster presented at the 50th American Society of Hematology Annual Meeting December 6–9, 2008; San Francisco, CA \n31. Mahon FX Réa D Guilhot J et al Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial Lancet Oncol 11 1029 1035 2010 20965785 \n32. Pye SM Cortes J Ault P et al The effects of imatinib on pregnancy outcome Blood 111 5505 5508 2008 18322153 \n33. Nomura RM Igai AM Faciroli NC et al Maternal and perinatal outcomes in pregnant women with leukemia [in Portuguese] Rev Bras Ginecol Obstet 33 174 181 2011 22159617 \n34. Alizadeh H Jaafar H Rajnics P et al Outcome of pregnancy in chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors: Short report from a single centre Leuk Res 39 47 51 2015 25455655 \n35. Iqbal J Ali Z Khan AU et al Pregnancy outcomes in patients with chronic myeloid leukemia treated with imatinib mesylate: Short report from a developing country Leuk Lymphoma 55 2109 2113 2014 24237577 \n36. Cortes J O’Brien S Ault P et al Pregnancyoutcomes among patients with chronic myeloid leukemia treated with dasatinib Blood 112 3230 2008 abstr \n37. Conchon M Sanabani SS Bendit I et al Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: Case study J Hematol Oncol 2 42 2009 19807918 \n38. Berveiller P Andreoli A Mir O et al A dramatic fetal outcome following transplacental transfer of dasatinib Anticancer Drugs 23 754 757 2012 22421368 \n39. Kroll T Ames MB Pruett JA et al Successful management of pregnancy occurring in a patient with chronic myeloid leukemia on dasatinib Leuk Lymphoma 51 1751 1753 2010 20629520 \n40. Conchon M Sanabani SS Serpa M et al Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy Adv Hematol 2010 1362522010 20224653 \n41. Bayraktar S Morency B Escalón MP Successful pregnancy in a patient with chronic myeloid leukaemia exposed to dasatinib during the first trimester BMJ Case Rep 2010 bcr05201029752010 \n42. He K Lago MW Iyer RA et al Lacteal secretion, fetal and maternal tissue distribution of dasatinib in rats Drug Metab Dispos 36 2564 2570 2008 18787054 \n43. Hadiji Mseddi S Kallel F Amouri H et al Delivery of two normal twins exposed to imatinib and nilotinib during the first trimester of pregnancy in a woman with chronic myeloid leukemia J Hematol Malig 2 838 2012 \n44. Fadhilla R Ardiansyah IR Sucipto MCR et al A case study: Exposure of nilotinib in pregnancy with chronic myeloid leukemia: Is it safe? ESMO Asia 2016 Congress Singapore December 18, 2016 \n45. Sweany SJ TKIs and the treatment of CML in pregnant women HemOnc Today, October 25, 2011 https://www.healio.com/hematology-oncology/leukemia/news/print/hemonc-today/%7Bff202790-727e-43aa-9d19-d403b622c670%7D/tkis-and-the-treatment-of-cml-in-pregnant-women\n46. Arnall J Muluneh B Loss of pregnancy in a patient with chronic myeloid leukemia during treatment with nilotinib J Hematol Oncol Pharm 6 22 27 2016 \n47. Cortes JE Gambacorti-Passerini C Deininger MW et al Pregnancy outcomes in patients treated with bosutinib Blood 132 1729 2018 abstr 30206114 \n48. Cortes JE Abruzzese E Chelysheva E et al The impact of dasatinib on pregnancy outcomes Am J Hematol 90 1111 1115 2015 26348106 \n49. Cortes J O’Brien S Ault P et al Pregnancy outcomes among patients with chronic myeloid leukemia treated with dasatinib Blood 112 3230 2008 abstr\n\n",
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"journal": "Journal of global oncology",
"keywords": null,
"medline_ta": "J Glob Oncol",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D055815:Young Adult",
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"pages": "1-11",
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"pmid": "31584851",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": "10355663;22018447;22791487;26348106;17405743;18472395;25455655;18787054;22159617;22200624;16481408;11480579;18043265;19807918;12040456;24237577;15537917;22613793;23966360;18322153;16446320;15842653;20965785;18322295;12910520;29284357;19959094;23704092;17408403;19560455;12783371;20224653;17804066;20629520;22421368;20555095;19717385;24804001;23937984",
"title": "Pregnancy Outcomes in Chronic Myeloid Leukemia: A Single Center Experience.",
"title_normalized": "pregnancy outcomes in chronic myeloid leukemia a single center experience"
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"abstract": "Intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy in vitrectomized eyes remains a challenge due to the reduced half-life of these agents. Aflibercept may have stronger binding activity and a longer intravitreal half-life compared to bevacizumab and ranibizumab, but its use in postvitrectomy eyes has not been reported. We present a case of an 89-year-old female, with recurrent choroidal neovascularization 10 years following prior macular translocation vitrectomy surgery for neovascular age-related macular degeneration, successfully treated with monthly aflibercept injections initiated following poor response to a single initial bevacizumab injection. This report suggests that aflibercept may be an important treatment option for vitrectomized eyes requiring anti-VEGF treatment.",
"affiliations": "Duke Eye Center, Duke University Medical Center, Durham, NC, USA.",
"authors": "Hahn|Paul|P|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OPTH.S73265",
"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S73265opth-8-2129Case ReportSuccessful treatment of neovascular age-related macular degeneration following single bevacizumab failure using aflibercept in a vitrectomized eye Hahn Paul Duke Eye Center, Duke University Medical Center, Durham, NC, USACorrespondence: Paul Hahn, Duke Eye Center, DUMC 3802, Durham, NC 27710, USA, Tel +1 919 684 5631, Fax +1 919 681 6474, Email paul.s.hahn@duke.edu2014 17 10 2014 8 2129 2131 © 2014 Hahn. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy in vitrectomized eyes remains a challenge due to the reduced half-life of these agents. Aflibercept may have stronger binding activity and a longer intravitreal half-life compared to bevacizumab and ranibizumab, but its use in postvitrectomy eyes has not been reported. We present a case of an 89-year-old female, with recurrent choroidal neovascularization 10 years following prior macular translocation vitrectomy surgery for neovascular age-related macular degeneration, successfully treated with monthly aflibercept injections initiated following poor response to a single initial bevacizumab injection. This report suggests that aflibercept may be an important treatment option for vitrectomized eyes requiring anti-VEGF treatment.\n\nKeywords\nanti-VEGFvitrectomizedafliberceptneovascular age-related macular degeneration\n==== Body\nIntroduction\nThe treatment of neovascular age-related macular degeneration (NVARMD) and other retinal diseases has been transformed by the development of intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy. These agents effectively stabilize and can even reverse the natural course of vision loss. Reduced efficacy of these agents has been observed in vitrectomized eyes, in which more rapid diffusion and clearance of intravitreal therapies compared to nonvitrectomized eyes poses a challenge in treatment of retinal diseases in eyes having undergone vitrectomy.1\n\nAflibercept, the newest of the anti-VEGF agents, may have stronger binding activity with a longer half-life compared to bevacizumab and ranibizumab.2 Given these potential pharmacokinetic advantages, aflibercept may be better suited for treatment of retinal diseases in vitrectomized eyes.\n\nCase description\nAn 89-year-old Caucasian female presented with acute-onset metamorphopsia and vision loss in the left eye. She had a history of NVARMD, with a longstanding, stable disciform scar and finger-counting vision in the right eye and a history of macular translocation surgery (with concurrent cataract extraction and subsequent strabismus surgery and silicone oil removal) 10 years prior in the left eye. Over the ensuing 10 years following macular translocation, she maintained regular follow-up examinations, with stable left-eye vision at the 20/32–20/50 level without active choroidal neovascularization (CNV) or need for subsequent treatment. Three months following an examination recording 20/40 vision and stable findings (10 years following macular translocation), she reported awakening with “blurry, dark, and wavy” vision loss in the left eye. On exam, her visual acuity measured 20/100. Her anterior-segment examination including intraocular pressure was unremarkable. Her fundus examination demonstrated geographic atrophy along the inferior arcade, consistent with prior macular translocation surgery, without any ophthalmoscopically visible heme, fluid, or exudates (Figure 1). Fluorescein angiography demonstrated leakage consistent with CNV (Figure 1), and optical coherence tomography (OCT) imaging demonstrated a subretinal CNV lesion without associated fluid (Figure 2). This lesion was not present on OCT imaging at her recent visit 3 months prior.\n\nGiven these findings, prompt anti-VEGF treatment to the left eye was recommended, and the patient was treated that day with intravitreal injection of bevacizumab 1.25 mg. She returned 4 weeks later as scheduled reporting worsening of her visual acuity, which had deteriorated to 20/160. Her ophthalmoscopic and imaging findings remained essentially unchanged. Given the absence of appropriate response in a functionally monocular patient, the decision was made to switch treatment to aflibercept 2.0 mg. One month after a single aflibercept injection, her visual acuity dramatically improved to 20/80. An additional aflibercept injection was administered, and her visual acuity further improved 1 month later to 20/50. Ongoing monthly aflibercept injections were administered, with improvement of visual acuity to 20/32 after four consecutive aflibercept injections. OCT imaging was repeated at 3-month intervals after aflibercept initiation, resulting in fibrosis and moderate shrinkage of her CNV.\n\nDiscussion\nWhile intravitreal pharmacotherapy has revolutionized the clinical treatment of retinal diseases, management of eyes following prior vitrectomy has been challenging due to the altered pharmacokinetics of intravitreal agents, which have a shorter half-life and reduced efficacy in the vitrectomized eye. Investigations with a sustained-release dexamethasone intravitreal implant (Ozurdex; Allergan, Irvine, CA, USA) have demonstrated successful treatment of macular edema associated with central retinal vein occlusion, uveitis, and diabetic retinopathy in vitrectomized eyes,3–5 but novel anti-VEGF treatment options beyond higher or more frequent dosing have not been described. Aflibercept, the newest of the anti-VEGF agents, has stronger binding activity and extended half-life compared to bevacizumab and ranibizumab, and successful treatment of diseases recalcitrant to prior bevacizumab or ranibizumab injections has been reported.6 Similarly, this pharmacokinetic profile may be favorable for the treatment of vitrectomized eyes despite the challenges initially identified with bevacizumab and ranibizumab. To the author’s knowledge, there are no reports of intravitreal treatment in vitrectomized eyes using aflibercept described in the literature.\n\nIn the case reported herein, a monocular patient with acute loss of vision and new-onset CNV secondary to NVARMD in a vitrectomized eye was poorly responsive with worsening visual acuity after a single injection with bevacizumab, but demonstrated dramatic improvement in visual acuity after a single aflibercept injection, with continued improvement in retinal architecture and return to baseline visual acuity following serial aflibercept injections. It is certainly possible that the favorable response seen in this patient would have occurred with ongoing bevacizumab injections. However, given the stronger binding activity and extended half-life with a similar safety profile, the author advocates consideration of aflibercept for treatment of postvitrectomy eyes. This case represents proof of concept that the theoretical pharmacokinetic advantages of aflibercept may allow for successful treatment of vitrectomized eyes, and further studies are warranted to test this hypothesis.\n\nDisclosure\n\nThe author reports no conflicts of interest in this work.\n\nFigure 1 Fundus photograph (A) at presentation demonstrates stable findings following macular translocation for age-related macular degeneration, with geographic atrophy along the inferior arcades and no visible heme, fluid, or exudates. Early (B) and mid-phase (C) fluorescein angiograms at presentation demonstrate a small leaking juxtafoveal choroidal neovascularization lesion (orange arrow). A window defect corresponding to the inferior atrophy is also noted. No ophthalmoscopic evidence for active choroidal neovascularization is visible (orange arrow, A).\n\nFigure 2 Horizontal (left column) and vertical (right column) individual B-scan images from indicated time points.\n\nNotes: At the patient’s stable visit 3 months prior to presentation (A, B), her fovea is intact without evidence of neovascularization. At presentation (C, D), a new subfoveal choroidal neovascularization lesion is identified. No appreciable change is noted after a single bevacizumab injection (month 1) (E, F), but progressive shrinkage of the choroidal neovascularization lesion with visual improvement to baseline is noted at month 4 (G, H) and month 7 (I, J), following aflibercept treatment.\n\nAbbreviations: BCVA, best-corrected visual acuity; s/p, status post.\n==== Refs\nReferences\n1 Yanyali A Aytug B Horozoglu F Nohutcu AF Bevacizumab (Avastin) for diabetic macular edema in previously vitrectomized eyes Am J Ophthalmol 2007 144 1 124 126 17601433 \n2 Stewart MW Rosenfeld PJ Penha FM Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor Trap-eye) Retina 2012 32 3 434 457 22374154 \n3 Boyer DS Faber D Gupta S Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients Retina 2011 31 5 915 923 21487341 \n4 Reibaldi M Russo A Zagari M Resolution of persistent cystoid macular edema due to central retinal vein occlusion in a vitrectomized eye following intravitreal implant of dexamethasone 0.7 mg Case Rep Ophthalmol 2012 3 1 30 34 22615698 \n5 Adán A Pelegrín L Rey A Dexamethasone intravitreal implant for treatment of uveitic persistent cystoid macular edema in vitrectomized patients Retina 2013 33 7 1435 1440 23514796 \n6 Grewal DS Gill MK Sarezky D Lyon AT Mirza RG Visual and anatomical outcomes following intravitreal aflibercept in eyes with recalcitrant neovascular age-related macular degeneration: 12-month results Eye (Lond) 2014 28 7 895 899 24833178\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "8()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "aflibercept; anti-VEGF; neovascular age-related macular degeneration; vitrectomized",
"medline_ta": "Clin Ophthalmol",
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"nlm_unique_id": "101321512",
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"pages": "2129-31",
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"title": "Successful treatment of neovascular age-related macular degeneration following single bevacizumab failure using aflibercept in a vitrectomized eye.",
"title_normalized": "successful treatment of neovascular age related macular degeneration following single bevacizumab failure using aflibercept in a vitrectomized eye"
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"abstract": "Strongyloidiasis is caused by a soil-transmitted helminth that is endemic in tropical and subtropical countries. The parasite can complete its life cycle without leaving the host, allowing autoinfection and persistence. The risk of infection in travelers is low, but the disease may become lethal following immunosuppression. In case of solid organ transplantation, the risk of donor transmission has been suspected for several years. However, the management of live donors in this context has only recently been considered, and no guidelines exist for the management of deceased donors. To highlight the complexity of diagnosing, treating, and preventing strongyloidiasis donor transmission, we describe a case of possible transmission of severe strongyloidiasis to a kidney transplant recipient with limited travel history. Taking into account the difficulty of diagnosing chronic strongyloidiasis infection and the increase in travel and immunosuppressive treatments, we recommend pragmatic management guidelines to limit the risks of infection.",
"affiliations": "Service des Maladies Infectieuses et Tropicales, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière Charles Foix, Paris, France.;Département d'Urologie, Néphrologie et Transplantation, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière Charles Foix, Paris, France.;Département d'Urologie, Néphrologie et Transplantation, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière Charles Foix, Paris, France.;Laboratoire de Parasitologie-Mycologie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière Charles Foix, Paris, France.;Département d'Urologie, Néphrologie et Transplantation, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière Charles Foix, Paris, France.;Assistance Publique-Hôpitaux de Paris, Service de Pneumologie et Réanimation médicale, Hôpital Pitié-Salpêtrière Charles Foix, Paris, France.;Service des Maladies Infectieuses et Tropicales, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière Charles Foix, Paris, France.;Département d'Urologie, Néphrologie et Transplantation, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière Charles Foix, Paris, France.",
"authors": "Eperon|Gilles|G|;Tourret|Jerome|J|;Ailioaie|Oana|O|;Paris|Luc|L|;Mercadal|Lucile|L|;Mayaux|Julien|J|;Caumes|Eric|E|;Barrou|Benoit|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.17-0234",
"fulltext": null,
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"issn_linking": "0002-9637",
"issue": "98(4)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000368:Aged; D000818:Animals; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D014019:Tissue Donors; D066027:Transplant Recipients; D014195:Travel",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "941-944",
"pmc": null,
"pmid": "29363441",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18321548;15635962;27121364;21358367;15337730;12869094;21532747;19530103;20335415;24636427;16410894;16282302;497706;11718124;23783760;15996452;19807271;21366799;23919410;22691685;24615130;17940124;7694965;17524878",
"title": "Severe Strongyloidiasis in Solid Organ Transplant Recipients: Should We Preventively Treat the Recipient, the Donor, or Both?",
"title_normalized": "severe strongyloidiasis in solid organ transplant recipients should we preventively treat the recipient the donor or both"
} | [
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"abstract": "A 50-year-old woman developed a human herpes virus 6 limbic encephalitis characterized by memory loss and somnolence, 3 weeks after a cord blood-derived stem cell transplantation. Sequential scalp electroencephalogram failed to detect seizure activity. Cerebrospinal fluid polymerase chain reaction assay demonstrated human herpes virus 6 deoxyribonucleic acid (positive, 3.74 log). Acute phase FDG PET imaging showed bilateral intense FDG uptake in both hippocampi and amygdalae. After antiviral treatment (gancyclovir followed by foscarnet), neurologic symptoms disappear gradually. Late phase FDG PET imaging showed a regression in FDG uptake representing hippocampal hypometabolism because of hippocampal sclerosis.",
"affiliations": "Service de Biophysique et Médecine Nucléaire, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, and Université de Strasbourg/CNRS, UMR 7237, France.",
"authors": "Hubele|Fabrice|F|;Bilger|Karin|K|;Kremer|Stéphane|S|;Imperiale|Alessio|A|;Lioure|Bruno|B|;Namer|Izzie Jacques|IJ|",
"chemical_list": "D019788:Fluorodeoxyglucose F18",
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"mesh_terms": "D005260:Female; D019788:Fluorodeoxyglucose F18; D015654:Herpesvirus 6, Human; D006801:Humans; D020363:Limbic Encephalitis; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D049268:Positron-Emission Tomography; D019349:Roseolovirus Infections",
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"title": "Sequential FDG PET and MRI findings in a case of human herpes virus 6 limbic encephalitis.",
"title_normalized": "sequential fdg pet and mri findings in a case of human herpes virus 6 limbic encephalitis"
} | [
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"companynumb": "FR-CLINIGEN GROUP PLC/ CLINIGEN HEALTHCARE LTD-E2B_00005382",
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"abstract": "We present a case of benzodiazepine withdrawal delirium in a middle-aged man undergoing spinal surgery. Benzodiazepines were stopped prior to surgery and on postoperative day 4, the patient exhibited significant paranoia, hyperarousal and ideas of reference. Patient's symptoms resolved after reintroduction of his benzodiazepines. It is important to include benzodiazepine withdrawal in the differential diagnosis for acute delirium even in those patients taking low or moderate doses. Benzodiazepine withdrawal delirium typically responds rapidly to restarting benzodiazepines. In patients with known discontinuation issues, early consultation with consult-liaison psychiatry and preoperative planning for early medication re-initiation is paramount.",
"affiliations": "Behavioral Health, Walter Reed National Military Medical Center, Bethesda, Maryland, USA eric.w.lutz3.mil@mail.mil.;Behavioral Health, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.",
"authors": "Lutz|Eric William|EW|;Hines|Christopher|C|",
"chemical_list": "D001569:Benzodiazepines; D002998:Clonazepam",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240804",
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"issue": "14(6)",
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"keywords": "delirium; drug therapy related to surgery; neurosurgery; psychiatry (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001569:Benzodiazepines; D002998:Clonazepam; D003693:Delirium; D006801:Humans; D008297:Male; D008875:Middle Aged; D011184:Postoperative Period; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "101526291",
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"pubdate": "2021-06-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent clonazepam withdrawal delirium in a postoperative neurosurgical patient: a case report.",
"title_normalized": "recurrent clonazepam withdrawal delirium in a postoperative neurosurgical patient a case report"
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"companynumb": "US-TEVA-2021-US-1944744",
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"abstract": "Sorafenib, a multi-kinase inhibitor, is approved for the treatment of patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). This study evaluated the efficacy and safety of sorafenib in real-world clinical practice and compared the results to those of the DECISION trial. The clinical features associated with better clinical outcomes after sorafenib treatment were also evaluated.\n\n\n\nThis multicenter, retrospective cohort study evaluated 98 patients with progressive RAI-refractory DTC who were treated with sorafenib in six tertiary hospitals in Korea. The primary objective was the progression-free survival (PFS) according to Response Evaluation Criteria In Solid Tumors v1.1. Overall survival, response rate (defined as the best objective response according to Response Evaluation Criteria In Solid Tumors v1.1), and safety were also evaluated.\n\n\n\nThe median PFS was 9.7 months; median overall survival was not reached during follow-up. Partial responses and stable disease were achieved in 25 (25%) and 64 (65%) patients, respectively. Stable disease of >6 months was achieved in 41 (42%) patients. Subgroup analyses identified several prognostic indicators of a better PFS: absence of disease-related symptoms (hazard ratio [HR] = 0.5; p = 0.041), lung-only metastasis (HR = 0.4; p = 0.048), a daily maintenance dose ≥600 mg (HR = 0.3; p = 0.005), and a thyroglobulin reduction ≥60% (HR = 0.4; p = 0.012). The mean daily dose of sorafenib was 666 ± 114 mg, and drug withdrawals due to adverse events (AEs) occurred in 13% of patients. AEs and serious AEs were reported in 93 (95%) and 40 (41%) patients, respectively. The most frequent AE was hand-foot skin reaction (76%).\n\n\n\nThe PFS of progressive RAI-refractory DTC patients treated with sorafenib was consistent with the findings of the DECISION trial. Disease-related symptoms, lung-only metastasis, a daily maintenance dose, and thyroglobulin reduction were significantly associated with PFS. These results suggest that sorafenib is an effective treatment option for patients with progressive RAI-refractory DTC.",
"affiliations": "1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.;2 Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Korea.;3 Division of Endocrinology and Metabolism, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine , Seoul, Korea.;4 Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea , Seoul, Korea.;5 Department of Endocrinology, Dongnam Institute of Radiological and Medical Sciences Cancer Center , Busan, Korea.;1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.;2 Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul, Korea.;1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.;6 Division of Endocrinology and Metabolism, Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital , Busan, Korea.;1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.",
"authors": "Kim|Mijin|M|;Kim|Tae Hyuk|TH|;Shin|Dong Yeob|DY|;Lim|Dong Jun|DJ|;Kim|Eui Young|EY|;Kim|Won Bae|WB|;Chung|Jae Hoon|JH|;Shong|Young Kee|YK|;Kim|Bo Hyun|BH|;Kim|Won Gu|WG|;|||",
"chemical_list": "D000970:Antineoplastic Agents; D000077157:Sorafenib",
"country": "United States",
"delete": false,
"doi": "10.1089/thy.2017.0356",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1050-7256",
"issue": "28(3)",
"journal": "Thyroid : official journal of the American Thyroid Association",
"keywords": "progression-free survival; radioactive iodine refractory; real-world clinical practice; sorafenib; thyroid neoplasm",
"medline_ta": "Thyroid",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077982:Progression-Free Survival; D056910:Republic of Korea; D012189:Retrospective Studies; D000077157:Sorafenib; D016019:Survival Analysis; D015996:Survival Rate; D063128:Tertiary Healthcare; D013964:Thyroid Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9104317",
"other_id": null,
"pages": "340-348",
"pmc": null,
"pmid": "29350109",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "24424318;26097811;25505208;3410936;24768112;9445411;17215530;28318881;15972576;9874472;18650514;16684830;26462967;17404173;18852116;21649472;28463599;21508143;25040494;27491718;1286158;25548522;23758653;8410272",
"title": "Tertiary Care Experience of Sorafenib in the Treatment of Progressive Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Korean Multicenter Study.",
"title_normalized": "tertiary care experience of sorafenib in the treatment of progressive radioiodine refractory differentiated thyroid carcinoma a korean multicenter study"
} | [
{
"companynumb": "KR-BAYER-2018-091672",
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"patient": {
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"activesubstancename": "LEVOTHYROXINE"
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... |
{
"abstract": "Background: Candida prosthetic joint infection (PJI) is a rare complication of total knee arthroplasty (TKA). The literature regarding its diagnosis and management is scarce. Case summary: We present the case of a 79-year-old woman with history of TKA and femoral intramedullary nailing, who developed PJI caused by Candida lusitaniae. A two-stage exchange arthroplasty was performed. She underwent implant removal, debridement and placement of temporary antibiotic impregnated spacer. Postoperatively, the patient received treatment with micafungin for 24 weeks. Eleven months after the first stage, the spacer was removed and a new knee prosthesis was placed. Complete eradication of infection was demonstrated by negative culture of cement spacer, synovial fluid and periprosthetic tissue. Histology of surgical samples was unremarkable. Empiric treatment with micafungin was given for 6 weeks after placement of the new prosthesis. At 6-month follow-up, there was no evidence of recurrent infection. Conclusion: To our knowledge, this is the first reported case of Candida lusitaniae PJI.",
"affiliations": "a Division of Infectious Diseases, Department of Medicine, Miller School of Medicine , University of Miami , Miami , FL , USA.;a Division of Infectious Diseases, Department of Medicine, Miller School of Medicine , University of Miami , Miami , FL , USA.;a Division of Infectious Diseases, Department of Medicine, Miller School of Medicine , University of Miami , Miami , FL , USA.",
"authors": "Bini Viotti|Julia|J|http://orcid.org/0000-0002-8145-9440;Corzo-Pedroza|Monica|M|http://orcid.org/0000-0003-1914-3952;Gonzales Zamora|Jose Armando|JA|http://orcid.org/0000-0002-2768-9712",
"chemical_list": "D000935:Antifungal Agents; D000077551:Micafungin",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2018.1511264",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "74(4)",
"journal": "Acta clinica Belgica",
"keywords": "Prosthetic joint infection; fungal infection; total knee arthroplasty",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000368:Aged; D000935:Antifungal Agents; D019645:Arthroplasty, Replacement, Knee; D002175:Candida; D003646:Debridement; D020878:Device Removal; D005260:Female; D006801:Humans; D007720:Knee Prosthesis; D000077551:Micafungin; D020370:Osteoarthritis, Knee; D016459:Prosthesis-Related Infections; D012086:Reoperation; D016896:Treatment Outcome",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "286-291",
"pmc": null,
"pmid": "30136635",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prosthetic joint infection caused by Candida lusitaniae: report of a unique case.",
"title_normalized": "prosthetic joint infection caused by candida lusitaniae report of a unique case"
} | [
{
"companynumb": "US-TEVA-2019-US-1077856",
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"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
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"abstract": "BACKGROUND\nHemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease characterized by hyperactivation of the immune system that causes hypercytokinemia and potentially multi organ failure. HLH can occur in patients with underlying rheumatic or autoinflammatory disorders. Additionally, HLH can develop in patients during infections or malignancies without a known genetic predisposition.\n\n\nMETHODS\nWe herein report a patient, who presented with fever, both acute kidney and liver injury, anemia, thrombocytopenia and HSV stomatitis. HLH was diagnosed based on clinical criteria and qPCR revealed an acute parvovirus B19 infection as potential underlying infectious trigger. Treatment was started with both IVIG and dexamethasone. Subsequently, kidney biopsy demonstrated TMA.\n\n\nCONCLUSIONS\nIn rare cases both HLH and aHUS can occur simultaneously in a patient as a consequence of viral infections. Insights from this unusual case might help physicians understand this complex symptom constellation.",
"affiliations": "Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Nephropathology, Friedrich-Alexander University, Erlangen, Nürnberg, Germany.;Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany. adrian.schreiber@charite.de.",
"authors": "Steffen|C J|CJ|;Koch|N|N|;Eckardt|K U|KU|;Amann|K|K|;Seelow|E|E|;Schreiber|A|A|http://orcid.org/0000-0003-1244-6379",
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"doi": "10.1186/s12882-021-02538-0",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369\nBioMed Central London\n\n2538\n10.1186/s12882-021-02538-0\nCase Report\nHemophagocytic lymphohistiocytosis and thrombotic microangiopathy after parvovirus B19 infection and renal transplantation: a case report\nSteffen C. J. 1\nKoch N. 1\nEckardt K. U. 1\nAmann K. 2\nSeelow E. 1\nhttp://orcid.org/0000-0003-1244-6379\nSchreiber A. adrian.schreiber@charite.de\n\n1\n1 grid.6363.0 0000 0001 2218 4662 Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Berlin, Germany\n2 grid.5330.5 0000 0001 2107 3311 Department of Nephropathology, Friedrich-Alexander University, Erlangen, Nürnberg, Germany\n12 10 2021\n12 10 2021\n2021\n22 33712 2 2021\n22 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nHemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease characterized by hyperactivation of the immune system that causes hypercytokinemia and potentially multi organ failure. HLH can occur in patients with underlying rheumatic or autoinflammatory disorders. Additionally, HLH can develop in patients during infections or malignancies without a known genetic predisposition.\n\nCase presentation\n\nWe herein report a patient, who presented with fever, both acute kidney and liver injury, anemia, thrombocytopenia and HSV stomatitis. HLH was diagnosed based on clinical criteria and qPCR revealed an acute parvovirus B19 infection as potential underlying infectious trigger. Treatment was started with both IVIG and dexamethasone. Subsequently, kidney biopsy demonstrated TMA.\n\nConclusions\n\nIn rare cases both HLH and aHUS can occur simultaneously in a patient as a consequence of viral infections. Insights from this unusual case might help physicians understand this complex symptom constellation.\n\nKeywords\n\nHemophagocytic Lymphohistiocytosis (HLH)\nAtypical hemorrhagic uremic syndrome (aHUS)\nParvovirus B19\nCase report\nCharité - Universitätsmedizin Berlin (3093)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nHemophagocytic lymphohistiocytosis (HLH) is a rare clinical condition (1/800000 adults per year, 1–10/Million children per year) with excessive immune activation and inflammation, eventually leading to multi organ failure. It can be divided into primary (genetic) forms which mostly affect children and secondary forms which are subclassified as viral, autoimmune, or paraneoplastic [1, 2].\n\nThrombotic microangiopathies (TMA) are a group of disorders characterized by microthrombi causing microangiopathic hemolytic anemia, thrombocytopenia and ischemic tissue injury [3]. TMAs encompass primary forms which occur spontaneously and secondary forms which develop in the context of pregnancy, autoimmune disease, malignancy, infection, malignant hypertension, bone marrow transplantation or the use of certain medications [4].\n\nHere we report a case of simultaneous HLH and TMA after acute infection with parvovirus B19 (PVB19) in a kidney transplant recipient.\n\nCase presentation\n\nIn September 2020, a 50-year-old female was admitted to our hospital with PCR-diagnosed HSV-1 stomatitis and refractory anemia. The patient had received a cadaveric donor kidney transplantation for kidney failure due to IgA vasculitis in 2007 and was on triple immunosuppressive therapy including prednisolone (2.5 mg daily), mycophenolate mofetil (1500 mg daily) and cyclosporine A (100 mg daily). Laboratory testing on admission showed chronic allograft dysfunction (creatinine 3.1 mg/dl), anemia (Hb 5.9 g/dl) with low reticulocytes (32/nl) and low markers of systemic inflammation (CRP 1.9 mg/l, ferritin 324 μg/l). Transferrin saturation, vitamin B12 and folic acid levels, cyclosporine A through concentrations (48 ng/ml) as well as haptoglobin were within the normal range. There was no clinical sign of blood loss. Serum PCR-testing was negative for HSV-1/2, varicella zoster, CMV, EBV, HIV and parvovirus B19 (PVB19) respectively. A nasopharyngeal swab for SARS-CoV-2 was negative.\n\nThe patient was initially treated with intravenous acyclovir for 14 days, and immunosuppression was reduced by pausing mycophenolate mofetil and reducing cyclosporine A. Reticulocytes and hemoglobin levels recovered consequently and stomatitis resolved.\n\nEleven days after admission the patient suddenly developed fever up to 40 °C, low oxygen saturation (92%) and a cough. The lab results indicated acute on chronic allograft dysfunction (creatinine 4.1 mg/dl), acute hepatitis (ASAT 249 U/l, ALAT 300 U/l, bilirubin 4.1 mg/dl), moderately elevated CRP (29 mg/l) and an extremely high ferritin level (20,659 μg/l). Additionally, the patient showed thrombocytopenia (92/μl), elevated LDH (1170 U/l) and reduced haptoglobin (< 0.1 g/l), elevated d-dimer (8.8 mg/l), elevated soluble IL-2 receptor (12,458 IU/ml), elevated triglycerides (255 mg/dl) and low fibrinogen (1.0 g/l), reduced C3 and C4 (620 and 140 mg/l respectively). Coombs test was negative and a blood smear was negative for schistocytes. A chest CT scan ruled out pneumonia and pulmonary embolism. Abdominal ultrasound revealed ascites and moderate splenomegaly. Multiple urine and blood cultures did not show bacterial infection. A second PCR for SARS-CoV-2 was negative.\n\nThe diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made based on the patient’s extremely high ferritin levels, presence of 6 out of 8 HLH diagnostic criteria and an HScore of 269 indicating a 99% probability of HLH. Treatment with dexamethasone 20 mg daily was started on day 13. Bone marrow aspiration and biopsy were conducted on day 14 and revealed no pathological findings (no evidence of HLH).\n\nFever subsided 1 day after starting dexamethasone, kidney function improved, and the levels of ferritin, transaminases and bilirubin decreased.\n\nPCR for hepatitis B, C, D and E as well as for EBV and CMV were negative. Repeated PCR testing for PVB19 revealed > 10 million copies/ml. Treatment with intravenous immunoglobulins (100 g cumulative) was started over a course of 3 days to address the PVB19 infection. Dexamethasone dose was tapered to 8 mg on the day of discharge. PCR testing of the bone marrow sample revealed > 9 million copies/ml of PVB19. Serologic testing of blood samples was positive for IgM and negative IgG suggesting primary infection with PVB19.\n\nIn the following days the patient’s condition further improved, the viral load fell to 16,400 copies/ml at the time of discharge and ferritin levels decreased to 298 μg/l.\n\nOn day 35, the patient was re-admitted after a hypertensive crisis and a suspected seizure. Magnetic resonance imaging of the brain (including diffusion weighted imaging and fluid-attenuated inversion recovery sequences) as well as EEG did not show any pathological findings (e.g. posterior reversible leukoencephalopathy syndrome, intracranial hemorrhage). Laboratory testing showed worsening hemolysis, thrombocytopenia, complement consumption, schistocytes of 0.1% and further increasing albuminuria (UACR > 5 g/g). Ferritin, serum albumin levels and cyclosporine A through concentrations (40 ng/ml) were within the normal range and creatinine was stable at the patient’s previous baseline concentration. A renal allograft biopsy was performed, which showed glomerular TMA without vascular rejection, glomerulitis or peritubular capillaritis as well as tubular atrophy and 20% interstitial fibrosis (Fig. 1). ADAMTS13 diagnostic ruled out a TTP. On a follow up visit in our outpatient clinic on day 48 the patient was in good clinical condition. Ferritin was within the normal range and albuminuria was decreasing (UPCR 1.5 g/g), creatinine concentration was 3,5 mg/dl. Considering the gradual improvement we decided against therapeutic plasma exchange and complement inhibiting therapy Table 1.Fig. 1 Characteristic histological findings in the renal biopsy. A-C: A Tubular atrophy and interstitial fibrosis with mild lymphoplasmacellular interstitial inflammation and acute tubular damage; no peritubular capillaritis, no eosinophils. B,C: Glomerular thrombotic microangiopathy (TMA) with swelling of endothelia cells, lumen obliteration, influx of inflammatory cells, some double contours of the basement membrane and some fibrin within glomerular capillaries (B, arrow). PAS staining, magnifications × 10 (A), × 20 (B) and × 40 (C). D-F Immunohistochemical findings: Granular mesangiocapillary immune deposits of IgA (D), IgG (E) and most prominently C3c (F) indicating a parainfectious glomerulonephritis. G-J Electron micrographs of different magnification showing the characteristic ultrastructural changes in thrombotic microangiopathy, e.g. endothelial cell swelling with subendothelial cleft formation and some podocyte damage. No specific osmiophilic deposits, no fibrils. G: × 2000, H: × 5000, J: × 8000\n\nTable 1 Laboratory findings during hospitalization\n\n\tNormal range\tDay 1\tDay 13\tDay 14\tDay 16\tDay 36\t\nCreatinine (mg/dl)\t0.5–0.9\t3.2\t3.7\t4.1\t3.7\t2.3\t\nUrea (mg/dl)\t17–48\t137\t70\t143\t166\t110\t\nCRP (mg/l)\t< 0.5\t4.4\t21.5\t29.2\t19\t2.6\t\nBilirubin (mg/dl)\t< 1.2\t0.2\t4.1\t2.1\t0.8\t0.5\t\nAlanine aminotransferase (U/l)\t< 31\t12\t300\t201\t121\t85\t\nAspartate aminotransferase (U/l)\t< 35\t13\t249\t143\t43\t35\t\nLactate dehydrogenase (U/l)\t135–250\t203\t679\t974\t763\t454\t\nSerum ferritin (μg/l)\t13–150\t324\t2644\t20,659\t2563\t194\t\nHaptoglobin (g/l)\t0.3–2.0\t1.6\t< 0.1\t< 0.1\t0.14\t< 0.1\t\nC3 (mg/l)\t900–1800\t\t550\t620\t\t470\t\nC4 (mg/l)\t100–400\t\t130\t140\t\t80\t\nTriglyceride (mg/dl)\t< 200\t\t\t211\t255\t\t\nFibrinogen (g/l)\t1.6–4.0\t\t\t\t1.1\t\t\nHb (g/dl)\t12.0–15.6\t5.9\t7.4\t8.3\t7.8\t8.8\t\nLeukocytes (n/nl)\t3.9–10.5\t3.4\t3.2\t3.1\t6.5\t6.2\t\nThrombocytes (n/nl)\t150–370\t302\t187\t162\t92\t91\t\nReticulocytes (n/nl)\t25–105\t32\t169\t145\t\t212\t\nUrinary Albumin/Creatinine (mg/gCrea)\t< 20\t169\t\t\t\t5307\t\n\nThe clinical course, lab values and treatment are depicted in Fig. 2. Genetic screening did not reveal a pathogenic variant in complement genes. However the patient revealed to be homozygous for the known CFH-H3 (alias CFHtgtgt) risk haplotye as well as heterozygous carrier of the CFHR1*B risk allele.Fig. 2 Clinical course, treatment milestones, ferritin levels and parvovirus B19 copies. Red dots indicate parvovirus B19 copies. The viral load was under the limit of detection on day 1 and day 3. Viral load declined following treatment with IVIGs. Serologic testing was negative for both IgM and IgG on day 1 and positive IgM on day 11, IgG stayed negative. Blue squares show ferritin levels\n\nDiscussion and conclusion\n\nIn the present case, suspicion for HLH was raised by otherwise unexplained multi organ failure and extremely high ferritin levels. The diagnosis of HLH was established by the 2004 diagnostic criteria [1]. The patient fulfilled 6 out of 8 criteria, 5 are considered sufficient for diagnosis (fever, splenomegaly, cytopenia of two lineages, hypertriglyceridemia and hypofibrigenemia, elevated sIL-2Receptor and hyperferritinemia). The absence of single clinical features, even a negative bone marrow biopsy, does not exclude HLH [1]. Other authors have proposed alternative diagnostic criteria such as the HScore, because the aforementioned HLH criteria were specifically developed for the pediatric population and other common laboratory findings such as elevated LDH, elevated liver enzymes, hepatic dysfunction and coagulopathy were not considered [5]. The HScore uses additional values such as immunosuppression, transaminases and LDH to calculate a probability score between 0 and 337 with values > 167 to classify > 90% of secondary HLH [5]. Our patient had an HScore of 267 indicating a 99% probability of HLH.\n\nGlomerular TMA compatible with renal involvement was confirmed by renal allograft biopsy. Complement consumption, hypertension as well as seizures can be explained by aHUS, since EEG and MRI did not hint at an alternative diagnosis. Increasing albuminuria reflects glomerular damage. Cases of TMA triggered by PVB19 infection in both healthy and immunocompromised patients in the absence of an alternative cause have previously been reported [6–8]. The diagnosis of the PVB19 infection was made by both serum and bone marrow PCR testing. The results suggested a primary infection, indicated by the presence of specific IgM and the absence of specific IgG. When we tested the patient for viral infections on first admission, multiple PCR assays for PVB19 were negative. However other authors demonstrated that in some individuals PVB19 infection is only detectable in bone marrow samples whereas serum diagnostic can still be negative [9, 10]. In our case it is likely that PVB19 infection was already ongoing when the patient was admitted to our hospital.\n\nSecondary HLH is typically a sequela of infections (usually EBV, but also CMV or HIV), rheumatic diseases (e.g. systemic lupus erythematosus) or malignancies [2]. A few cases of HLH due to PVB19 infection have previously been described, including one patient who had received renal transplantation [7, 10, 11].\n\nEven though the incidence of acute kidney injury in HLH is high, the exact pathophysiologic mechanism of renal damage in HLH remains unclear and is probably multifactorial [12]. It has been proposed that PVB19 directly infects glomerular endothelium by using the same receptor (glycosphinoglipid globoside Gb4) used to infect erythroid progenitor cells. Subsequently it causes endothelial cell dysfunction or cell death leading to aHUS [6, 8]. Other studies suggest that aHUS and nephrotic proteinuria may have been caused primarily by HLH and only indirectly by PVB19 infection [13, 14]. A disease mechanism in HLH might be that high levels of inflammatory cytokines (particularly TNFα) can injure podocytes, thereby leading to glomerular collapse and tubular necrosis with subsequent proteinuria and renal dysfunction [13, 14]. Another recently proposed mechanism suggests coactivation of interferon gamma and complement activation as culprit in the evolution of TMA in patients with HLH [15]. In our patient the TMA should be classified as secondary aHUS triggered by parvovirus B19 Infection as well as by concomittant HLH. The risk haplotypes revealed by genetic screening display a high minor allele frequency in the general healthy population. In the absence of pathogenic complement variants they do not explain occurrence of aHUS. At most, they may have acted as additional disease modifiers in the setting of marked complement activation [16] .\n\nA few limitations of our study are important to mention. First, a genetic testing for HLH risk haplotypes as well as functional complement assays (AH50; alternative pathway hemolytic assays) were not performed in this patient. Second, a long-term follow up for several years is still missing, therefore we cannot evaluate the likelihood of HLH relapses.\n\nTreatment of HLH secondary to PVB19 infection in a transplant patient poses a challenge to balance immunosuppressive therapy to both address HLH and to fight PVB19 infection. In the present case, treatment with dexamethasone was initiated when HLH was suspected. After a positive PCR result for PVB19, intravenous immunoglobulins were added. Mycophenolat mofetil was discontinued and cyclosporine was reduced to a trough level of 50 ng/ml. In contrast to current recommendations for secondary HLH, we decided to taper dexamethasone relatively fast and did not prescribe etoposide [17]. We assumed PVB19 to be the underlying cause of aHUS. In summary, we observed the rare combination of HLH and TMA associated with parvovirus B19 that escaped initial PCR testing.\n\nAbbreviations\n\nHLH Hemophagocytic Lymphohistiocytosis\n\naHUS Atypical hemorrhagic uremic syndrome\n\nTMA Thrombotic microangiopathy\n\nPVB19 Parvovirus B19\n\nAcknowledgements\n\nWe appreciate the patient for participating in this study.\n\nAuthors’ contributions\n\nCJS, NK, ES, and AS collected the data, carried out the analysis of the patient’s clinical course and outcome and were also involved in drafting the manuscript. KA was responsible for the pathology images and legends. CJS, NK, ES, KUE, and AS established the diagnosis and revised and approved the final manuscript. Each author contributed important intellectual content during the drafting and revision of the manuscript. All the authors read and approved the final version of the manuscript to be published.\n\nFunding\n\nThis study was supported by the Open-Access-Fund of the Charité. The funder supported the fees upon acceptance for publication. Open Access funding enabled and organized by Projekt DEAL.\n\nAvailability of data and materials\n\nThe datasets used in this study are not publicly accessible because they contain identifying patient data. They can be provided by the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe patient was informed about the availability and importance of the data, including the clinical data, images, and health information, described in this article.\n\nConsent for publication\n\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 of this journal.\n\nCompeting interests\n\nAll authors report no conflict of interest.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Henter J-I Horne A Aricó M Egeler RM Filipovich AH Imashuku S HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer. 2007 48 124 131 10.1002/pbc.21039 16937360\n2. Ramos-Casals M Brito-Zerón P López-Guillermo A Khamashta MA Bosch X Adult haemophagocytic syndrome Lancet 2014 383 1503 1516 10.1016/S0140-6736(13)61048-X 24290661\n3. Tsai H-M Untying the knot of thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome Am J Med. 2013 126 200 209 10.1016/j.amjmed.2012.09.006 23410558\n4. Arnold DM Patriquin CJ Nazy I Thrombotic microangiopathies: a general approach to diagnosis and management Can Med Assoc J. 2017 189 E153 E159 10.1503/cmaj.160142 27754896\n5. Fardet L Galicier L Lambotte O Marzac C Aumont C Chahwan D Development and validation of the hscore, a score for the diagnosis of reactive hemophagocytic syndrome: score for reactive hemophagocytic syndrome Arthritis Rheumatol. 2014 66 2613 2620 10.1002/art.38690 24782338\n6. Murer L Zacchello G Bianchi D Dall’Amico R Montini G Andreetta B Thrombotic microangiopathy associated with parvovirus b19 infection after renal transplantation J Am Soc Nephrol 2000 11 6 1132 1137 10.1681/ASN.V1161132 10820178\n7. Ardalan MR Shoja MM Tubbs RS Esmaili H Keyvani H Postrenal Transplant Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy Associated with Parvovirus B19 Infection Am J Transplant. 2008 8 1340 1344 10.1111/j.1600-6143.2008.02244.x 18522549\n8. Prasad B, St. Onge J. Parvovirus leading to thrombotic microangiopathy in a healthy adult: Table 1. BMJ Case Rep. 2016;bcr2015213492.\n9. Heegaard ED Petersen BL Heilmann CJ Hornsleth A Prevalence of Parvovirus B19 and Parvovirus V9 DNA and Antibodies in Paired Bone Marrow and Serum Samples from Healthy Individuals J Clin Microbiol. 2002 40 933 936 10.1128/JCM.40.3.933-936.2002 11880419\n10. Kalmuk J Matar S Feng G Kilb E Lim MY Parvovirus B19-induced hemophagocytic lymphohistiocytosis: Case report and review of the literature Clin Case Rep. 2019 7 2076 2081 10.1002/ccr3.2401 31788255\n11. Yuan C, Asad-Ur-Rahman F, Abusaada K. A Rare Case of Hemophagocytic Lymphohistiocytosis Associated with Parvovirus B19 Infection. Cureus. 2016. 10.7759/cureus.897.\n12. Aulagnon F Lapidus N Canet E Galicier L Boutboul D Peraldi M-N Acute Kidney Injury in Adults With Hemophagocytic Lymphohistiocytosis Am J Kidney Dis. 2015 65 851 859 10.1053/j.ajkd.2014.10.012 25480521\n13. Thaunat O Delahousse M Fakhouri F Martinez F Stephan J-L Noël L-H Nephrotic syndrome associated with hemophagocytic syndrome Kidney Int. 2006 69 1892 1898 10.1038/sj.ki.5000352 16557222\n14. Bae MN Kwak DH Park SJ Choi BS Park CW Choi YJ Acute kidney injury induced by thrombotic microangiopathy in a patient with hemophagocytic lymphohistiocytosis BMC Nephrol. 2016 17 4 10.1186/s12882-015-0217-z 26739581\n15. Gloude NJ Dandoy CE Davies SM Myers KC Jordan MB Marsh RA Thinking Beyond HLH: Clinical Features of Patients with Concurrent Presentation of Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy J Clin Immunol. 2020 40 699 707 10.1007/s10875-020-00789-4 32447592\n16. Fremeaux-Bacchi V Fakhouri F Garnier A Bienaimé F Dragon-Durey M-A Ngo S Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults Clin J Am Soc Nephrol CJASN. 2013 8 554 562 10.2215/CJN.04760512 23307876\n17. Henter J-I Chow C-B Leung C-W Lau Y-L Cytotoxic therapy for severe avian influenza A (H5N1) infection Lancet 2006 367 870 873 10.1016/S0140-6736(06)68232-9 16530581\n\n",
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"keywords": "Atypical hemorrhagic uremic syndrome (aHUS); Case report; Hemophagocytic Lymphohistiocytosis (HLH); Parvovirus B19",
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"title": "Hemophagocytic lymphohistiocytosis and thrombotic microangiopathy after parvovirus B19 infection and renal transplantation: a case report.",
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"abstract": "OBJECTIVE\nTreatment options for recurrent or progressive hormone receptor-positive (HR+) advanced breast cancer include chemotherapy and everolimus plus exemestane (EVE + EXE). This study estimates the costs of managing adverse events (AEs) during EVE + EXE therapy and single-agent chemotherapy in Western Europe.\n\n\nMETHODS\nAn economic model was developed to estimate the per patient cost of managing grade 3/4 AEs for patients who were treated with EVE + EXE or chemotherapies. AE rates for patients receiving EVE + EXE were collected from the phase III BOLERO-2 trial. AE rates for single-agent chemotherapy, capecitabine, docetaxel, or doxorubicin were collected from published clinical trial data. AEs with at least 2% prevalence for any of the treatments were included in the model. A literature search was conducted to obtain costs of managing each AE, which were then averaged across Western European countries (when available). Per patient costs for managing AEs among patients receiving different therapies were reported in 2012 euros (€).\n\n\nRESULTS\nThe EVE + EXE combination had the lowest average per patient cost of managing AEs (€730) compared to all chemotherapies during the first year of treatment (doxorubicin: €1230; capecitabine: €1721; docetaxel: €2390). The most costly adverse event among all patients treated with EVE + EXE was anemia (on average €152 per patient). The most costly adverse event among all patients treated with capecitabine, docetaxel, or doxorubicin was lymphocytopenia (€861 per patient), neutropenia (€821 per patient), and leukopenia (€382 per patient), respectively.\n\n\nCONCLUSIONS\nThe current model estimates that AE management during the treatment of HR+ advanced breast cancer will cost one-half to one-third less for EVE + EXE patients than for chemotherapy patients. The consideration of AE costs could have important implications in the context of healthcare spending for advanced breast cancer treatment.",
"affiliations": "Centre René Gauducheau, Service Oncologie Médicale , Nantes Saint-Herblain , France.",
"authors": "Campone|Mario|M|;Yang|Hongbo|H|;Faust|Elizabeth|E|;Kageleiry|Andrew|A|;Signorovitch|James E|JE|;Zhang|Jie|J|;Gao|Haitao|H|",
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"title": "Cost of adverse events during treatment with everolimus plus exemestane or single-agent chemotherapy in patients with advanced breast cancer in Western Europe.",
"title_normalized": "cost of adverse events during treatment with everolimus plus exemestane or single agent chemotherapy in patients with advanced breast cancer in western europe"
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"abstract": "OBJECTIVE\nDetermine toxicity and efficacy of autologous hematopoietic stem cell transplantation (HSCT) for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are dependent on intravenous immunoglobulins or plasmapheresis.\n\n\nMETHODS\nUnselected peripheral blood stem cells were re-infused on day 0 after conditioning with cyclophosphamide 200 mg/kg/intravenously (IV), rATG (thymoglobulin) 5.5 mg/kg/IV, and rituximab 1000 mg/IV.\n\n\nRESULTS\nSixty-six patients underwent HSCT for CIDP. Data on sixty patients with a mean follow-up of 4.5 years (range 2-5 years) were available for analysis. There were no treatment-related deaths, and overall survival was 97%. Post-transplant immune medication-free remission was 80%, 78%, 76% 78%, and 83% at 1, 2, 3, 4, and 5 years. Ambulation without assistance improved from 33% pre-HSCT to 82% 82%, 81%, 86%, and 83% at 1, 2, 3, 4, and 5 years, respectively. Mean right/left hand grip strength (kg) improved significantly (all p values < 0.01) from 18.1/16.5 pre-HSCT to 26.3/25.4, 29.2/28.2, 28.8/28.6, 30.3/25.5, and 30.8/29.1 at 1, 2, 3, 4, and 5 years, respectively. Average nerve conduction velocity (NCV) (m/s) improved significantly (all p values ≤ 0.001) from a mean of 27.2 pre-HSCT to 33.5, 33.8, 37.7, 38.2, and 38.3 at 1, 2, 3, 4, and 5 years, respectively. Average compound motor action potential (CMAP) (mv) improved significantly (p values ≤ 0.001) from a mean of 3.6 pre-HSCT to 4.6, 4.6, 5.0, 5.1, and 4.1 at 1, 2, 3, 4, and 5 years, respectively.\n\n\nCONCLUSIONS\nA randomized trial is indicated to verify these results and confirm that HSCT reverses disability and offers long-term immune therapy independence.",
"affiliations": "Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Axis Bldg, 446 East Ontario, Suite 10-1000, Chicago, IL, 60611, USA. rburt@northwestern.edu.;Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.;Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.;Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Axis Bldg, 446 East Ontario, Suite 10-1000, Chicago, IL, 60611, USA.;Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.;Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.;Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.;Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Axis Bldg, 446 East Ontario, Suite 10-1000, Chicago, IL, 60611, USA.;Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Axis Bldg, 446 East Ontario, Suite 10-1000, Chicago, IL, 60611, USA.;Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.;Academic Department of Neuroscience and Sheffield, NIHR Translational Neuroscience BRC, Sheffield Teaching Hospitals, NHS Foundation Trust, University of Sheffield, Sheffield, UK.",
"authors": "Burt|Richard K|RK|http://orcid.org/0000-0002-0922-4145;Balabanov|Roumen|R|;Tavee|Jinny|J|;Han|Xiaoqiang|X|;Sufit|Robert|R|;Ajroud-Driss|Senda|S|;Jovanovic|Borko|B|;Quigley|Kathleen|K|;Arnautovic|Indira|I|;Helenowski|Irene|I|;Sharrack|Basil|B|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
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"doi": "10.1007/s00415-020-10010-6",
"fulltext": null,
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"issn_linking": "0340-5354",
"issue": "267(11)",
"journal": "Journal of neurology",
"keywords": "Chronic inflammatory demyelinating polyradiculoneuropathy; Efficacy; Hematopoietic stem cell transplantation; Toxicity",
"medline_ta": "J Neurol",
"mesh_terms": "D018737:Hand Strength; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; D014182:Transplantation, Autologous",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyradiculoneuropathy.",
"title_normalized": "hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyradiculoneuropathy"
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"abstract": "Recurrent respiratory papillomatosis is a human papillomavirus-mediated condition characterised by the development of benign squamous papillomata of the respiratory tract. Malignant transformation of recurrent respiratory papillomatosis, while rare, carries a poor prognosis and there are limited data surrounding treatment options, particularly in inoperable disease. We present the case of a 64-year-old male who developed malignant airway obstruction secondary to primary tracheal squamous cell carcinoma in the setting of a 5-year history of recurrent laryngotracheal papillomatosis, requiring placement of tracheostomy while on veno-venous extracorporeal membranous oxygenation. He was managed with cisplatin-based definitive chemoradiotherapy and had a complete metabolic response on post-treatment positron emission tomography/computed tomography, and remains free of recurrent squamous cell carcinoma at 16 months following treatment. This case supports the use of combined chemoradiotherapy as a potential therapeutic option for patients with primary tracheal squamous cell carcinoma, and emphasises the challenges associated with the long-term management of recurrent respiratory papillomatosis.",
"affiliations": "Department of ENT/Head and Neck Surgery, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.;Department of ENT/Head and Neck Surgery, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.;Department of ENT/Head and Neck Surgery, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.;Department of ENT/Head and Neck Surgery, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.;GenesisCare Radiotherapy, St Vincent's Hospital Melbourne, Melbourne, VIC, Australia.",
"authors": "Kovacs|Aaron C|AC|https://orcid.org/0000-0002-2684-942X;Vodanovich|Domagoj|D|;Mogridge|Emily K|EK|;Wun|Lisa|L|;Corry|June|J|",
"chemical_list": null,
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"doi": "10.1177/2050313X211054623",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211054623\n10.1177_2050313X211054623\nCase Report\nA case of primary tracheal squamous cell carcinoma arising from malignant transformation of recurrent respiratory papillomatosis, with a complete response to concurrent chemoradiotherapy\nhttps://orcid.org/0000-0002-2684-942X\nKovacs Aaron C 1\nVodanovich Domagoj 1\nMogridge Emily K 1\nWun Lisa 1\nCorry June 23\n1 Department of ENT/Head and Neck Surgery, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia\n2 GenesisCare Radiotherapy, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia\n3 Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia\nAaron C Kovacs, Department of ENT/Head and Neck Surgery, St Vincent’s Hospital Melbourne, 41 Victoria Parade, Fitzroy, Melbourne, VIC 3123, Australia. Email: aaronckovacs@gmail.com\n21 10 2021\n2021\n9 2050313X21105462331 8 2021\n5 10 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ 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 page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nRecurrent respiratory papillomatosis is a human papillomavirus-mediated condition characterised by the development of benign squamous papillomata of the respiratory tract. Malignant transformation of recurrent respiratory papillomatosis, while rare, carries a poor prognosis and there are limited data surrounding treatment options, particularly in inoperable disease. We present the case of a 64-year-old male who developed malignant airway obstruction secondary to primary tracheal squamous cell carcinoma in the setting of a 5-year history of recurrent laryngotracheal papillomatosis, requiring placement of tracheostomy while on veno-venous extracorporeal membranous oxygenation. He was managed with cisplatin-based definitive chemoradiotherapy and had a complete metabolic response on post-treatment positron emission tomography/computed tomography, and remains free of recurrent squamous cell carcinoma at 16 months following treatment. This case supports the use of combined chemoradiotherapy as a potential therapeutic option for patients with primary tracheal squamous cell carcinoma, and emphasises the challenges associated with the long-term management of recurrent respiratory papillomatosis.\n\nRecurrent respiratory papillomatosis\nhuman papillomavirus\nsquamous cell carcinoma\nprimary tracheal malignancy\nchemotherapy\nradiotherapy\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\npmcIntroduction\n\nRecurrent respiratory papillomatosis (RRP) is a rare human papillomavirus (HPV)-mediated disease of adults and children, characterised by the development of benign squamous papillomata of the respiratory tract. Papillomata most commonly involve the larynx, but can affect the tracheobronchial tree and lung parenchyma. Malignant transformation of RRP is even rarer still, associated exclusively with squamous cell carcinoma (SCC) and occurring in 3%–7% of cases in adults and less than 1% in children.1,2\n\nThe aetiologic role of HPV in RRP is well-established, and most commonly associated with the so-called low-risk virotypes HPV-6 and HPV-11.1,3 Due to the refractory nature of the disease, its current management focuses on regular resection of disease, typically with CO2 laser. In a minority of cases, spontaneous remission can occur.3,4 Systemic bevacizumab, a recombinant monoclonal antibody and VEGF-A inhibitor, has shown some promise in small-scale case series as an adjuvant therapeutic for treatment-resistant disease. 5\n\nThe exact pathogenesis behind malignant transformation into SCC is poorly understood, but key risk factors include HPV-16 or HPV-18 infection, juvenile onset, smoking, previous radiotherapy or cytotoxic drug use and high disease severity score.2,4,6 Cases with pulmonary involvement appear to have particularly high rates of malignant transformation, at an estimated 16%. 7\n\nPrimary subglottic and tracheal malignancies are very uncommon, representing less than 1% of all malignant tumours, with the predominant histology being SCC (45%) followed by adenoid cystic carcinoma (ACC, 16.3%). 8 Current best practice consists of surgical resection where possible,8–11 but owing to their rarity, there are limited data available on optimal management in inoperable cases. We report on our experience with management of a 64-year-old man with unresectable tracheal SCC through the use of cisplatin-based chemoradiotherapy.\n\nCase report\n\nA 64-year-old male presented to a regional emergency department acutely stridulous and short of breath. His medical history was significant for recurrent laryngotracheal papillomatosis associated with HPV-11, diagnosed over 5 years prior and managed jointly by private ENT and thoracic surgeons. He had more than 50 prior laser debulking procedures but no history of irradiation or malignancy. He was an ex-smoker of 50 pack-years with comorbid hypertension and hyperlipidaemia. Computed tomography (CT) of the chest demonstrated a 23 mm× 15 mm endotracheal lesion causing severe tracheal stenosis.\n\nHe commenced on adrenaline and dexamethasone while awaiting transfer to a metropolitan tertiary hospital. After transfer, he proceeded to microlaryngoscopy and bronchoscopy while on veno-venous extracorporeal membranous oxygenation (ECMO), due to the inability to safely intubate. The airway was subsequently secured via tracheostomy, and tracheal biopsies were taken. Intraoperative findings included multiple non-obstructive papillomatoid lesions of the supraglottis, vocal cords and subglottis, as well as an atypical circumferential lesion extending from subglottis to 3 cm from the carina (Figure 1). There was no apparent involvement of the main bronchi. He was subsequently decannulated from ECMO and transferred to intensive care unit (ICU) on mechanical ventilation.\n\nFigure 1. Pre-treatment microlaryngoscopy and microlaryngoscopy 1 year after completion of treatment (left and right, respectively).\n\nHistopathology of the tracheal biopsies revealed well-differentiated SCC arising on a background of squamous papilloma. Staging positron-emission tomography (PET) demonstrated intense FDG avidity associated with the circumferential tracheal mass (Figure 2) but no evidence of nodal or distant metastases. After discussion in the hospital’s head and neck oncology multidisciplinary meeting, it was deemed that the disease was inoperable due to its size and concerns regarding feasibility of anastomosis after resection. He was consequently referred for combined chemoradiotherapy.\n\nFigure 2. Axial PET/CT, pre-treatment and 10 weeks after completion of treatment (left and right, respectively).\n\nThe patient commenced radiotherapy of 60 Gy over 27 fractions over 5.2 weeks (Figure 3) with high-dose cisplatin (100 mg/m2) in weeks 1 and 4. He tolerated treatment very well, with just the expected painful radiation mucositis and tracheitis necessitating narcotic analgesia. He required a two-night unplanned hospital admission for management of cisplatin-associated anaemia and non-neutropaenic aspiration pneumonia.\n\nFigure 3. Radiation dosimetry.\n\nRed line denotes the PET avid disease, blue denotes 60 Gy, and green denotes 56 Gy (prophylactic nodal coverage).\n\nRestaging PET 10 weeks following completion of chemoradiotherapy demonstrated marked reduction of metabolic activity in the primary site and no new nodal disease or distant metastatic disease (Figure 1). It was unclear whether the residual FDG avidity was related to inflammation around the tracheotomy site or residual disease. Repeat microlaryngoscopy revealed non-obstructive granulation tissue adjacent to tracheostomy insertion site; biopsy of this site showed no evidence of residual SCC. Two weeks later, the patient was electively readmitted for tracheostomy decannulation on the basis of patient wishes; he was successfully decannulated and discharged home after one night of inpatient observation.\n\nSurveillance microlaryngoscopy and bronchoscopy at 9 months post-completion of treatment demonstrated marked subglottic and proximal tracheal stenosis secondary to irradiation, as well as non-obstructive recurrent laryngeal papillomata. There was no clinical or histological evidence of recurrent SCC (Figure 1). Subsequent to this, he required 3–6-weekly balloon dilation for worsening stridor associated with his airway stenosis. At 13 months following completion of chemoradiotherapy, he required re-tracheostomy for upper airway control of critical subglottic stenosis; repeat biopsy at this time again showed no evidence of malignancy. Definitive management of his proximal tracheal stenosis is necessary before future decannulation can be considered. He remains free of malignant recurrence at 16 months following treatment.\n\nDiscussion\n\nMalignant transformation of RRP has historically proven challenging to treat, and its management has only been described in individual case reports. In a similar case of RRP-associated tracheal SCC, Kanazawa et al. 6 reported treatment with primary radiotherapy by accelerated hyperfractionation with good local control, but the patient ultimately died from metastasis to the lung. Another report 12 described use of primary interferon-α2b and cisplatin in a patient with RRP-associated bronchogenic SCC without significant response. Further cases13,14 of RRP-associated pulmonary SCC describe primary surgical approaches to management. To our knowledge, our case represents the first successful use of primary chemoradiotherapy in the management of SCC arising from malignant transformation of RRP. He will require close surveillance for disease recurrence as well as ongoing management of recurrent papillomatous disease and his severe subglottic and proximal tracheal stenosis.\n\nPrimary tracheal malignancies are rare, with only 2.6 new cases per 1,000,000 people each year. 8 The associated prognosis is grave. The largest population-based study of primary tracheal carcinoma to date utilised the US-based National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database from 1973 to 2004, identifying 578 separate cases; overall 5-year survival was 27.1%, with SCC carrying the worst prognosis with a 5-year survival of only 12.6%. 8 The authors noted a statistically significant improvement in survival with cases that underwent surgery; however, this finding must be interpreted with caution due to the inherent biases in treatment allocation, and thus outcomes in retrospective series. Unfortunately, the database did not capture data about the use of chemotherapy.\n\nIndeed, owing to the rarity of primary tracheal SCC, there are very limited data available surrounding the potential benefit of adjuvant radiotherapy following multiple surgical excisions, or definitive chemoradiotherapy in unresectable disease. There are no prospective studies, with the existing literature consisting entirely of individual case reports and small-scale retrospective reviews.10,11,15–17 Videtic et al. 15 found success in the use of cisplatin-based chemoradiotherapy in a 64-year-old man with primary tracheal SCC. He was administered two cycles for induction, followed by concurrent administration of two further cycles alongside external beam radiotherapy (60 Gy over 30 fractions). He had complete response on post-treatment CT at 6 weeks, and remained disease-free after 2 years. Joshi et al. 17 reported their use of concurrent chemoradiotherapy in a 50-year-old man with basaloid SCC of the trachea, administering a dose of 60 Gy over 37 fractions with seven doses of weekly paclitaxel and carboplatin. Surveillance PET/CT at 2 years following treatment had no evidence of local or distant disease, although he went on to develop bone and lung metastases by the third year of follow-up.\n\nMore recently, Jiang et al. 10 observed a 5-year survival of 13.8% in 49 patients with malignant primary tracheal tumours in Changsha, China, identified retrospectively over the period of 2009–2019. The longest survival time was observed in patients treated with complete surgical resection where viable (seven patients, 22.6%). 10 Of the non-surgical group, two received symptomatic treatment only (6.5%), four patients (12.9%) underwent radiotherapy only, eight patients (25.8%) underwent concurrent chemoradiotherapy, and a further eight patients (25.8%) underwent concurrent chemoradiotherapy with additional bronchoscopic intervention. The addition of bronchoscopic intervention had a statistically significant benefit on survival outcomes when compared to chemoradiotherapy alone. Unfortunately, this study also did not capture data about the specifics of chemoradiotherapy regimens, but nevertheless suggests that bronchoscopic intervention may be a useful adjunct in management of patients with inoperable primary tracheal malignancies.\n\nOur choice of chemoradiotherapy regimen, in particular the use of a platinum-based chemotherapy agent, was on the basis of extrapolation from its proven efficacy in other head and neck SCCs. The addition of concurrent cisplatin to radiotherapy has been well-demonstrated to improve locoregional control and overall survival in stage 3 and 4 mucosal head and neck SCCs. 18 Our early success in this case lends further credence to this modality of treatment, and highlights it as an area that warrants further research.\n\nConclusion\n\nRRP remains a challenging entity to manage with significant associated morbidity. Malignant transformation, while rare, is an important consideration in the long-term management of affected patients. Our preliminary success with the use of combined chemoradiotherapy for the treatment of inoperable tracheal SCC suggests that this is a viable treatment option in this rare disease.\n\nThe subject of this case report provided written informed consent for its publication, including the use of clinical photography and medical imaging. The authors thank the subject and his family for their support in putting together this paper.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymised information to be published in this article.\n\nORCID iD: Aaron C Kovacs https://orcid.org/0000-0002-2684-942X\n==== Refs\nReferences\n\n1 Can NT Tretiakova MS Taxy JB . Natural history and malignant transformation in recurrent respiratory papillomatosis: human papillomavirus (HPV), dysplasia and an autopsy review. Fetal Pediatr Pathol 2015; 34 (2 ): 80–90.25353697\n2 Fortes HR Von Ranke FM Escuissato DL , et al . Recurrent respiratory papillomatosis: a state-of-the-art review. Respir Med 2017; 126 : 116–121.28427542\n3 Carifi M Napolitano D Morandi M , et al . Recurrent respiratory papillomatosis: current and future perspectives. Ther Clin Risk Manag 2015; 11 : 731–738.25999724\n4 Dedo HH Yu KC . CO(2) laser treatment in 244 patients with respiratory papillomas. Laryngoscope 2001; 111 (9 ): 1639–1644.11568620\n5 Evers G Schliemann C Beule A , et al . Long-term follow-up on systemic bevacizumab treatment in recurrent respiratory papillomatosis. Laryngoscope 2021; 131 (6 ): E1926–E1933.33382105\n6 Kanazawa T Fukushima N Imayoshi S , et al . Rare case of malignant transformation of recurrent respiratory papillomatosis associated with human papillomavirus type 6 infection and p53 overexpression. Springerplus 2013; 2 (1 ): 153.23641321\n7 Gélinas JF Manoukian J Côté A . Lung involvement in juvenile onset recurrent respiratory papillomatosis: a systematic review of the literature. Int J Pediatr Otorhinolaryngol 2008; 72 (4 ): 433–452.18281102\n8 Urdaneta AI Yu JB Wilson LD . Population based cancer registry analysis of primary tracheal carcinoma. Am J Clin Oncol 2011; 34 (1 ): 32–37.20087156\n9 Madariaga MLL Gaissert HA . Overview of malignant tracheal tumours. Cardiothorac Surg 2018; 7 : 11.\n10 Jiang M Lei Q Lv X , et al . Clinical features and prognosis analysis of 57 patients with primary tracheal tumors. Transl Cancer Res 2020; 9 : 613–619.\n11 Honings J Van Dijck JA Verhagen AF , et al . Incidence and treatment of tracheal cancer: a nationwide study in The Netherlands. Ann Surg Oncol 2007; 14 (2 ): 968–976.17139460\n12 Rady PL Schnadig VJ Weiss RL , et al . Malignant transformation of recurrent respiratory papillomatosis associated with integrated human papillomavirus type 11 DNA and mutation of p53. Laryngoscope 1998; 108 (5 ): 735–740.9591556\n13 Hasegawa Y Sato N Niikawa H , et al . Lung squamous cell carcinoma arising in a patient with adult-onset recurrent respiratory papillomatosis. Jpn J Clin Oncol 2012; 43 (1 ): 78–82.23110763\n14 Dominguez DA Martin DT Velotta JB . A case of video-assisted thoracoscopic resection of malignant transformation of pulmonary recurrent respiratory papillomatosis. J Thorac Dis 2017; 9 (4 ): E364–E366.28523179\n15 Videtic GMM Campbell C Vincent MD . Primary chemoradiation as definitive treatment for unresectable cancer of the trachea. Can Respir J 2003; 10 (3 ): 143–144.12712222\n16 Webb BD Walsh GL Roberts DB , et al . Primary tracheal malignant neoplasms: the University of Texas MD Anderson Cancer Center experience. J Am Coll Surg 2006; 202 (2 ): 237–246.16427548\n17 Joshi NP Haresh KP Das P , et al . Unresectable basaloid squamous cell carcinoma of the trachea treated with concurrent chemoradiotherapy: a case report with review of literature. J Cancer Res Ther 2010; 6 (3 ): 321–323.21119264\n18 Blanchard P Baujat B Holostenco V , et al . Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011; 100 (1 ): 33–40.21684027\n\n",
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"keywords": "Recurrent respiratory papillomatosis; chemotherapy; human papillomavirus; primary tracheal malignancy; radiotherapy; squamous cell carcinoma",
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"title": "A case of primary tracheal squamous cell carcinoma arising from malignant transformation of recurrent respiratory papillomatosis, with a complete response to concurrent chemoradiotherapy.",
"title_normalized": "a case of primary tracheal squamous cell carcinoma arising from malignant transformation of recurrent respiratory papillomatosis with a complete response to concurrent chemoradiotherapy"
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"abstract": "BACKGROUND\nAcute graft-versus-host-disease (GVHD) in kidney recipients is extremely rare. Knowledge about its clinical manifestations, diagnosis, treatment, and prognosis is limited and needs to be increased.\n\n\nRESULTS\nOne male kidney transplant recipient developed diarrhea and suffered kidney function damage. Primarily diagnosed with acute rejection, he was given methylprednisolone (MP) bolus treatment. Meanwhile, intravenous immunoglobulin (IVIG) and decreased immunosuppressive agents were applied for the corresponding infection. During the treatment, skin rashes occurred over his whole body. Biopsies were then taken. The pathology of the kidney graft showed no rejection, while the skin pathology revealed typical GVHD. Furthermore, fluorescence in situ hybridization proved the presence of donor-derived cells in the skin lesions, and infiltrating cytotoxic T cells and NK cells were identified in the rash.\n\n\nRESULTS\nBased on the clinical presentations, pathological findings, and chimerism detection, GVHD after kidney transplantation was confirmed as the final diagnosis. The recipient responded well to treatment. His kidney function recovered, and the skin lesions were completely resolved. He has been followed for 1 year without any further episodes.\n\n\nCONCLUSIONS\nGVHD after kidney transplantation has its own characteristics. In the presence of a highly immunocompromised state, diarrhea and rashes, a diagnosis of GVHD needs to be considered. Kidney function impairment may be involved. Pathological changes and detection of chimerism and immunocyte infiltration are required for diagnosis. MP bolus, IVIG, and decreased immunosuppression could be beneficial to the clinical outcome. Kidney recipients have a prognosis superior to recipients of organs bearing large numbers of lymphocytes.",
"affiliations": "Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Department of Transplantation, Central Hospital of Yiyang, Yiyang Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"authors": "Guo|Yanhua|Y|;Ding|Shouyang|S|;Guo|Hui|H|;Li|Shenqiu|S|;Lu|Xia|X|;Chen|Zhishui|Z|;Chen|Zhonghua Klaus|ZK|;Ming|Changsheng|C|;Gong|Nianqiao|N|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28658148MD-D-16-0771010.1097/MD.0000000000007333073333600Research ArticleClinical Case ReportGraft-versus-host-disease after kidney transplantation A case report and literature reviewGuo Yanhua MDaDing Shouyang MDbGuo Hui MDaLi Shenqiu MD, PhDcLu Xia MD, PhDaChen Zhishui MD, PhDaChen Zhonghua Klaus MD, PhDaMing Changsheng MD, PhDa∗Gong Nianqiao MD, PhDa∗Kukla. Aleksandra a Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhanb Department of Transplantation, Central Hospital of Yiyang, Yiyangc Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.∗ Correspondence: Nianqiao Gong, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China (e-mail: nqgong@tjh.tjmu.edu.cn); Changsheng Ming (e-mail: chshming@tom.com).6 2017 30 6 2017 96 26 e733330 12 2016 24 5 2017 3 6 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nAcute graft-versus-host-disease (GVHD) in kidney recipients is extremely rare. Knowledge about its clinical manifestations, diagnosis, treatment, and prognosis is limited and needs to be increased.\n\nClinical Findings:\nOne male kidney transplant recipient developed diarrhea and suffered kidney function damage. Primarily diagnosed with acute rejection, he was given methylprednisolone (MP) bolus treatment. Meanwhile, intravenous immunoglobulin (IVIG) and decreased immunosuppressive agents were applied for the corresponding infection. During the treatment, skin rashes occurred over his whole body. Biopsies were then taken. The pathology of the kidney graft showed no rejection, while the skin pathology revealed typical GVHD. Furthermore, fluorescence in situ hybridization proved the presence of donor-derived cells in the skin lesions, and infiltrating cytotoxic T cells and NK cells were identified in the rash.\n\nOutcome:\nBased on the clinical presentations, pathological findings, and chimerism detection, GVHD after kidney transplantation was confirmed as the final diagnosis. The recipient responded well to treatment. His kidney function recovered, and the skin lesions were completely resolved. He has been followed for 1 year without any further episodes.\n\nConclusion:\nGVHD after kidney transplantation has its own characteristics. In the presence of a highly immunocompromised state, diarrhea and rashes, a diagnosis of GVHD needs to be considered. Kidney function impairment may be involved. Pathological changes and detection of chimerism and immunocyte infiltration are required for diagnosis. MP bolus, IVIG, and decreased immunosuppression could be beneficial to the clinical outcome. Kidney recipients have a prognosis superior to recipients of organs bearing large numbers of lymphocytes.\n\nKeywords\nchimerismgraft-versus-host-disease (GVHD)immunosuppressionkidney transplantationpathologyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAcute graft-versus-host-disease (GVHD) is a rare but fatal complication following transplantation.[1] After liver transplantation, acute GVHD occurs with an incidence of 0.1% to 1%[2] and the mortality rate exceeds 75%.[3] The onset of GVHD needs functioning donor-derived T cells that cause a local inflammatory reaction.[4] Generally, the transplant requires a large volume or enrichment of lymphocytes. For example, a liver has 109 donor-derived lymphocytes to transfer to the recipient.[5] GVHD also occurs after other kinds of solid organ transplantation such as lung, intestine, and pancreas-kidney.[6–8] The occurrence of GVHD after kidney transplantation is extremely rare. To date, only 5 cases have been reported.[9–13] With so few cases, knowledge about clinical manifestation, diagnosis, treatment, and prognosis of GVHD after kidney transplantation is limited and needs to be increased.\n\n2 Case presentation\nA 57-year-old man underwent kidney transplantation due to uremia. The kidney was procured from a donor who was brain dead due to a cerebrovascular accident. The donor's HLA typing was A:2,-; B:13,15; DR:7,15 while the recipient's was A:2,11; B:13,60; DR:7,8. The recipient's panel reactive antibody (PRA) level before the transplant was negative. The cross-match was negative. The donation and transplantation were approved by the committee of ethics at Central Hospital of Yiyang.\n\nThe recipient received induction therapy with rabbit-antithymocyte globulin 100 mg/d for 6 days and a triple immunosuppressive regimen including tacrolimus (Tac) + Mycophenolate mofetil (MMF) + prednisone (Pred). On POD20, his serum creatinine (Scr) level was 113 μmol/L. On POD28, the Scr increased to 203 μmol/L while the Tac trough level was 10.6 ng/L. Given concerns about tacrolimus-related renal toxicity and rejection due to the decreased Tac level, the recipient's immunosuppressive regimen was converted to low-dose Tac + rapamycin + MMF + Pred in a local follow-up clinic. One week later, the Scr was 126 μmol/L with the Tac trough level at 10.6 ng/L and rapamycin 1 mg Qd. On POD37, the recipient developed a cough, expectoration, decreased appetite, diarrhea, and cachexia, with urine output decreased to 600 mL. A sputum smear indicated the presence of fungi in the sputum. Afterward, the recipient was treated with voriconazole 200 mg/d orally.\n\nOn POD41, the recipient was admitted to our institute. His urine output was 100 mL and his Scr was 316 μmol/L. His liver function was normal. His blood work showed WBC 5.21×109/L (N: 92.7%), HB 80.0 g/L, and platelet count 176.0 × 109/L. The Tac trough level was 5.4 ng/L and MPA AUC was 91.73 mg × h/L. Based on an increased Scr, decreased urine output, and a relatively low Tac trough level, the patient's primary diagnosis was acute rejection. Following an immediate renal biopsy, MP bolus treatment was given: 500 mg/d for 2 days, 300 mg on the third day, and 20 mg/d for maintenance. Meanwhile, to treat the diarrhea and cachexia, the patient was given fluid treatment and nutritional support. He responded well, with his urine output increasing to 1000 mL within 1 day. The output subsequently increased to more than 2000 mL per day, and the Scr gradually decreased to a normal range within 10 days.\n\nOn the second day after admission (POD42), a lung CT showed interstitial pneumonia. In addition to MP bolus treatment, Tac was thereafter maintained at a trough level of 5 to 6 ng/mL, and MMF and rapamycin were withdrawn immediately. IVIG at 10 g/d was given for 10 doses. Moreover, a broad-spectrum antibiotic was administered for 29 days. To treat the possible pathogens that may have induced the interstitial pneumonia, gancyclovir was used for 14 days (without positive virus pathogen findings) and trimethoprim-sulfamethoxazole was given on POD45 for 90 days against a possible pneumocystis carinii infection that may have been related to rapamycin. Additionally, micafungin sodium was given for 23 days although neither aspergillus nor candida was identified by fungi culture or CT scan.\n\nAlso on POD42, rashes developed sporadically on the recipient's face and back. A rash biopsy was taken. Thereafter, more rashes were distributed over his whole body, mainly on the face and abdomen (Fig. 1A and B). Seven days after occurrence, the rashes began to scab and were completely resolved by POD90.\n\nFigure 1 Development of skin rashes after kidney transplantation. A and B, Three weeks after occurrence, skin rashes (arrow) were distributed on the face and abdomen. C and D, Six weeks after occurrence, skin rashes (arrow) were resolving.\n\nOn POD47, the pathological results were reported. Strikingly, the renal pathology gave a normal finding without any sign of rejection (Fig. 2A). The rash pathology showed typical grade III acute GVHD based on the histology criteria:[8] peripheral lymphocytes infiltrating around the branches of the arteriole (arteriole vasculitis in the dermis); necrosis of the basal cells and cleft formation; acanthocytes in the basal cells; more superficial layers resulting in separation and demo-epidermal junction; focal spongiosis, dyskeratosis and eosinophilic necrosis of the epidermal cells; and moderate mononuclear infiltration of the papillary dermis (Fig. 2B–D). The rash tissue was detected by fluorescence in situ hybridization (FISH), and the presence of donor-derived HLA loci B15+ and DR1+ cells was determined (Fig. 2E and F). Moreover, infiltrating cytotoxic CD8+T cells and CD56+ NK cells were identified in the skin rashes by immunofluorescence (Fig. 2G and H).\n\nFigure 2 Detection on the kidney graft and skin rash. A, Renal allograft biopsy showed normal structure and no signs of allograft rejection. H&E, ×200. B, Grade III acute GVHD: peripheral lymphocytes infiltrating around the branches of the arteriole (arteriole vasculitis in the dermis). H&E, ×200. C, Grade III acute GVHD: necrosis of basal cells and acanthocytes in the basal cells resulting in cleft formation; more superficial layers resulting in separation and demo-epidermal junction (arrowhead). H&E, ×100. D, Grade III acute GVHD: the focal spongiosis and dyskeratosis (arrow), eosinophilic necrosis of the epidermal cells (double arrows), and moderated mononuclear infiltration of the papillary dermis (aster). H&E, ×200. E, B15 locus in the nucleus was stained by a specific DNA probe with green fluorescence (arrow). FISH ×400. F, DR15 locus in the nucleus was stained (arrow). FISH ×400. G, CD8 + cytotoxic T cells were shown with red fluorescence in (arrow). immunofluorescence, ×200. H, CD56 + NK cells were shown (arrow). Immunofluorescence, ×200. FISH = fluorescence in situ hybridization, GVHD = acute graft-versus-host-disease.\n\nOn POD60, the recipient's clinical symptoms recovered; the sputum, blood, and virus assays all reported negative, and he was returned to a triple immunosuppressive regimen (Tac + MMF + Pred) with regular Tac trough level monitoring (8–10 ng/dL). On POD90, his Scr was 132 μmol/L, and the skin lesions were completely resolved (Fig. 1C and D). He was followed for 1 year without any further episodes.\n\n3 Discussion\nBefore the onset of GVHD, the recipient had received ATG induction + classical triple immunosuppression and even a short-term quadruple regime. Although his Tac trough level showed a temporary decrease, the patient generally experienced a highly immunocompromised state that may have been responsible for the following pneumonia, suggesting a susceptibility to GVHD.[14]\n\nThe diagnosis of GVHD of the recipient was delayed, as happened in each of the 5 reported cases, although the patients were showing typical manifestations (diarrhea and rashes). Limited experience and lack of awareness were the main reasons. Another reason was that the recipient's primary diagnosis was thought to be acute rejection because of the temporarily low Tac trough level and kidney damage (urine output decrease and Scr increase). Retrospectively, 2 of the 5 reported cases had already experienced kidney damage, which seems to be a marked characteristic of GVHD after kidney transplantation. Interestingly, a kidney biopsy proved no rejection, and a skin biopsy exhibited typical pathological features of GVHD. Based on the clinical presentations and pathological findings, the diagnosis of GVHD was formed.\n\nNotably, the differential diagnosis of toxic epidermal necrolysis (TEN) needs to be excluded. TEN could happen under exposure to medicines such as anti-infection drugs or immunosuppressive agents, with a pathological presentation of separation at the dermo-epidermal junction. These TEN features also existed in the current case. Therefore, we further investigated 3 supportive evidences for GVHD. First, the pathology identified the manifestation of arteriole vasculitis in the dermis. This only occurs under immune response such as acute rejection but not TEN. Second, our case is the first kidney recipient diagnosed as GVHD based on the findings of chimerism of donor-derived cells in the recipient's tissue (skin rash). All of the prior GVHD diagnoses on kidney recipients were based only on the integration of clinical findings and biopsy pathology,[9–13] although FISH or short tandem repeat (STR) has been used for chimerism detection in liver and pancreas transplantation.[15,16] Third, we identified the infiltration of cytotoxic T cells and NK cells in the lesions, which points to an ongoing cellular immunity but not TEN. Combined with the clinical presentations, pathological findings, and chimerism detection, the diagnosis of GVHD in this case was finally confirmed.\n\nThe recipient received treatments including MP bolus, IVIG, decreased immunosuppression, and anti-infection medication. The therapy was aimed to treat acute rejection and infection. Fortunately, he obtained a quick response because this strategy is also effective on GVHD. The reasons for reversion to GVHD are deduced as follows: MP bolus treatment destroyed the activated donor-derived lymphocytes; decreased immunosuppression was beneficial to delete donor-derived lymphocytes by the host's native immune system; IVIG may have modulated the immune reaction while also having an effect on the infection. The recovery of kidney function should have been due to the fluid treatment and the adjustment of gastrointestinal disorder-related immunosuppressants that corrected the diarrhea-induced hypovolemia, which only resulted in transient acute kidney injury without pathological changes.\n\nThe prognosis of GVHD after kidney transplantation is relatively superior to that after other solid transplantation. To date, only 2 of 6 kidney recipients have died, compared with 75% of liver recipients.[3] The reason for this may be that a kidney graft bears much fewer passenger lymphocytes than the liver or other organs. The outcome also could be partly related to timely clinical diagnosis and treatments.\n\nIn conclusion, the current case shows specific characteristics of GVHD after kidney transplantation: with the presence in the recipient of a highly immunocompromised state, diarrhea and rashes, the diagnosis of GVHD needs to be considered; kidney function impairment may be involved; besides clinical manifestations and pathological changes, chimerism and immunocyte infiltrating should be detected; MP bolus, IVIG, and decreased immunosuppression could be beneficial to the clinical outcome; kidney recipients have a prognosis superior to recipients of organs bearing large numbers of lymphocytes.\n\nAbbreviations: AUC = area under the concentration–time curve, FISH = fluorescence in situ hybridization, GVHD = acute graft-versus-host-disease, HB = hemoglobin, HLA = human leukocyte antigen, IVIG = intravenous immunoglobulin, MMF = mycophenolate mofetil, MP = methylprednisolone, POD = postoperation day, PRA = panel reactive antibody, Pred = prednisone, Scr = serum creatinine, STR = short tandem repeat, Tac = tacrolimus, TEN = toxic epidermal necrolysis, WBC = white blood cell.\n\nYG, SD, and HG contributed equally to this work.\n\nNG and CM designed the research. YG, SD, HG, SL, and XL performed all the clinical and pathological work. ZC and ZKC provided continuous support and conceptual advice for this study. NG and YG wrote the paper.\n\nThis work was supported by grants to NG from the National Natural Science Foundation of China (No. 81570678), to XS Sun from the Major State Basic Research Development Program of China (No. 2013CB530803, 973), to CM from the National High-Tech Research and Development Program of the Ministry of Science and Technology of China (2012AA021010, 863), and to NG from the Clinical Research Physician Program of Tongji Medical College, HUST.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Sharma A Armstrong AE Posner MP \nGraft-versus-host disease after solid organ transplantation: a single center experience and review of literature . Ann Transplant \n2012 ;17 :133 –9 .\n[2] Jeanmonod P Hubbuch M Grunhage F \nGraft-versus-host disease or toxic epidermal necrolysis: diagnostic dilemma after liver transplantation . Transpl Infect Dis \n2012 ;14 :422 –6 .22650490 \n[3] Taylor AL Gibbs P Sudhindran S \nMonitoring systemic donor lymphocyte macrochimerism to aid the diagnosis of graft-versus-host disease after liver transplantation . Transplantation \n2004 ;77 :441 –6 .14966423 \n[4] Jamieson NV Joysey V Friend PJ \nGraft-versus-host disease in solid organ transplantation . Transpl Int \n1991 ;4 :67 –71 .1910431 \n[5] Norris S Collins C Doherty DG \nResident human hepatic lymphocytes are phenotypically different from circulating lymphocytes . J Hepatol \n1998 ;28 :84 –90 .9537869 \n[6] Gulbahce HE Brown CA Wick M \nGraft-vs-host disease after solid organ transplant . Am J Clin Pathol \n2003 ;119 :568 –73 .12710129 \n[7] Luckraz H Zagolin M McNeil K \nGraft-versus-host disease in lung transplantation: 4 case reports and literature review . J Heart Lung Transplant \n2003 ;22 :691 –7 .12821167 \n[8] Zhang Y Ruiz P \nSolid organ transplant-associated acute graft-versus-host disease . Arch Pathol Lab Med \n2010 ;134 :1220 –4 .20670147 \n[9] Kato T Yazawa K Madono K \nAcute graft-versus-host-disease in kidney transplantation: case report and review of literature . Transplant Proc \n2009 ;41 :3949 –52 .19917421 \n[10] Kim JM Kim SJ Joh JW \nGraft-versus-host disease after kidney transplantation . J Korean Surg Soc \n2011 ;80 (suppl 1) :S36 –9 .22066080 \n[11] Ohtsuka Y Sakemi T Ichigi Y \nA case of chronic graft-versus-host disease following living-related donor kidney transplantation . Nephron \n1998 ;78 :215 –7 .9496741 \n[12] Smith DM Agura ED Levy MF \nGraft vs host disease following kidney transplantation using an ’0 HLA antigen mismatched’ donor . Nephrol Dial Transplant \n2006 ;21 :2656 –9 .16627604 \n[13] Zacharias N Gallichio MH Conti DJ \nGraft-versus-host disease after living-unrelated kidney transplantation . Case Rep Transplant \n2014 ;2014 :971426 .24812587 \n[14] Taylor AL Gibbs P Bradley JA \nAcute graft versus host disease following liver transplantation: the enemy within . Am J Transplant \n2004 ;4 :466 –74 .15023138 \n[15] Matsukuma KE Wei D Sun K \nDiagnosis and differential diagnosis of hepatic graft versus host disease (GVHD) . J Gastrointest Oncol \n2016 ;7 (suppl 1) :S21 –31 .27034810 \n[16] Shulman HM Kleiner D Lee SJ \nHistopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report . Biol Blood Marrow Transplant \n2006 ;12 :31 –47 .\n\n",
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"mesh_terms": "D057210:Delayed Diagnosis; D003937:Diagnosis, Differential; D006086:Graft vs Host Disease; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged",
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"title": "Graft-versus-host-disease after kidney transplantation: A case report and literature review.",
"title_normalized": "graft versus host disease after kidney transplantation a case report and literature review"
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"abstract": "Rituximab can cause late-onset neutropenia that may result in serious life-threatening complications. The author describes the pathophysiology, incidence, and management of this adverse reaction and presents two case histories.",
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"title": "Drug-Induced Neutropenia: A Focus on Rituximab-Induced Late-Onset Neutropenia.",
"title_normalized": "drug induced neutropenia a focus on rituximab induced late onset neutropenia"
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"abstract": "BACKGROUND\nGilteritinib is a multitargeted tyrosine kinase inhibitor (TKI) approved by the Food and Drug Administration (FDA) for acute myeloid leukemia (AML) with a FMS-related tyrosine kinase 3 (FLT3) mutation. The pharmacokinetics of gilteritinib in the setting of severe renal impairment (creatinine clearance [CrCl] 15-29 mL/min utilizing Cockcroft-Gault method) and end-stage renal disease are unknown. Gilteritinib is primarily metabolized by the liver through the CYP3A4 enzyme and is eliminated in both the feces and urine. Its excretion is primarily through the fecal route, accounting for 64.5% of the recovered dose. Only about 16.4% of the recovered dose has been detected in the urine of human subjects.\n\n\nMETHODS\nWe describe our patient case documenting the administration of gilteritinib in the setting of end-stage renal disease (ESRD) and hemodialysis (HD).Management and Outcomes: Our patient was initiated on single agent gilteritinib 120 mg by mouth once daily for relapse FLT3-TDK positive AML. Treatment course was complicated by pancytopenia, neutropenic fever, and staphylococcus lugdunensis bacteremia requiring temporary interruption of therapy.\n\n\nCONCLUSIONS\nGiven that gilteritinib is metabolized by the liver and eliminated primarily in the feces, one does not expect an increase in toxicity related to impaired renal function. Although this report describes the successful utilization of gilteritinib, caution should be exercised when administering in patient populations with end organ disease, and patient comorbidities should be taken into account.",
"affiliations": "College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.;College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.;Division of Pharmacy, Rush University Medical Center, Chicago, IL, USA.",
"authors": "Tollkuci|Eris|E|https://orcid.org/0000-0002-4760-5256;Tran|Tiffany|T|;Myers|Rebecca|R|",
"chemical_list": "D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C000609080:gilteritinib",
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"keywords": "AML; FLT3 inhibitor; Gilteritinib; acute myeloid leukemia; hemodialysis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000814:Aniline Compounds; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D015470:Leukemia, Myeloid, Acute; D009154:Mutation; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D012008:Recurrence; D006435:Renal Dialysis",
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"title": "Gilteritinib administration in a hemodialysis patient.",
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"abstract": "Primary splenic angiosarcoma is a rare and fatal neoplasm arising from vascular endothelial cells within the spleen. With an incidence of 2 cases per 10 million people worldwide, the diagnosis and treatment of this rare entity is unfamiliar and challenging. We describe the case of a previously healthy 45-year-old woman who presented with vague upper-abdominal pain and was found to have a splenic mass on computed tomography. The patient underwent laparoscopic splenectomy and was found to have splenic angiosarcoma on microscopic evaluation. Although specific radiologic diagnosis is not possible, bringing the possibility of primary splenic angiosarcoma to the ordering clinician's attention has the potential to hasten treatment and improve patient outcomes. This case highlights the importance for radiologists to be aware of this rare neoplasm and to consider it in the differential when encountering a heterogeneously enhancing splenic mass.",
"affiliations": "Department of Radiology, Allegheny Health Network, Pittsburgh, PA. Electronic address: abatouli@wpahs.org.;Department of Radiology, Allegheny Health Network, Pittsburgh, PA.;Department of Pathology, Allegheny Health Network, Pittsburgh, PA.;Department of Pathology, Allegheny Health Network, Pittsburgh, PA.;Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, PA.;Department of Radiology, Allegheny Health Network, Pittsburgh, PA.;Department of Surgery, Allegheny Health Network, Pittsburgh, PA.;Department of Radiology, Allegheny Health Network, Pittsburgh, PA.",
"authors": "Batouli|Ali|A|;Fairbrother|Samuel W|SW|;Silverman|Jan F|JF|;Muniz|Maria De Los Angeles|Mde L|;Taylor|Kevin B|KB|;Welnick|Mark A|MA|;Mancini|Sheri A|SA|;Hartman|Matthew S|MS|",
"chemical_list": null,
"country": "United States",
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"issn_linking": "0363-0188",
"issue": "45(4)",
"journal": "Current problems in diagnostic radiology",
"keywords": null,
"medline_ta": "Curr Probl Diagn Radiol",
"mesh_terms": "D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006394:Hemangiosarcoma; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D013154:Spleen; D013156:Splenectomy; D013160:Splenic Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7607123",
"other_id": null,
"pages": "284-7",
"pmc": null,
"pmid": "26321379",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary Splenic Angiosarcoma: Clinical and Imaging Manifestations of This Rare Aggressive Neoplasm.",
"title_normalized": "primary splenic angiosarcoma clinical and imaging manifestations of this rare aggressive neoplasm"
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{
"abstract": "PurposeTo evaluate safety and efficacy of difluprednate 0.05% ophthalmic emulsion for treatment of postoperative inflammation after cataract surgery in pediatric patients.MethodsThis was a phase 3B, multicentre, randomized, double-masked, active-controlled study of patients aged 0-3 years who underwent uncomplicated cataract surgery in one eye, with/without intraocular lens implantation. Patients were randomized to receive difluprednate 0.05% four times daily or prednisolone acetate 1% for 14 days post surgery, followed by tapering for 14 days. Safety included evaluation of adverse events. Primary efficacy was the proportion of patients with an anterior cell grade of 0 (no cells) at day 14; secondary efficacy was a global inflammation score.ResultsForty patients were randomized to each treatment group. Adverse drug reactions included corneal oedema (difluprednate 0.5%, n=1; prednisolone acetate 1%, n=0) and increased intraocular pressure or ocular hypertension (n=2/group). Mean intraocular pressure values during treatment were 2-3 mm Hg higher with difluprednate 0.05% compared with prednisolone acetate 1%; mean values were similar between groups by the first week after treatment cessation. At 2 weeks post surgery, the incidence of complete clearing of anterior chamber cells was similar between groups (difluprednate 0.05%, n=30 (78.9%); prednisolone acetate 1%, n=31 (77.5%). Compared with prednisolone acetate 1%, approximately twice as many difluprednate 0.05%-treated patients had a global inflammation assessment score indicating no inflammation on day 1 (n=12 (30.8%) vs n=7 (17.5%) and day 8 (n=18 (48.7%) vs n=10 (25.0%).ConclusionsDifluprednate 0.05% four times daily showed safety and efficacy profiles similar to prednisolone acetate 1% four times daily in children 0-3 years undergoing cataract surgery.",
"affiliations": "Storm Eye Institute, Medical University of South Carolina, Charleston, SC, USA.;Rady Children's Hospital, San Diego, CA, USA.;Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.;Department of Ophthalmology, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA.;Indiana University Medical Center, Indianapolis, IN, USA.;Alcon Research Ltd, Fort Worth, TX, USA.;Alcon Research Ltd, Fort Worth, TX, USA.;Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA.",
"authors": "Wilson|M E|ME|;O'Halloran|H|H|;VanderVeen|D|D|;Roarty|J|J|;Plager|D A|DA|;Markwardt|K|K|;Gedif|K|K|;Lambert|S R|SR|",
"chemical_list": "D005938:Glucocorticoids; D009883:Ophthalmic Solutions; C009935:prednisolone acetate; D005477:Fluprednisolone; D011239:Prednisolone; C015808:difluprednate",
"country": "England",
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"doi": "10.1038/eye.2016.132",
"fulltext": "\n==== Front\nEye (Lond)Eye (Lond)Eye0950-222X1476-5454Nature Publishing Group eye201613210.1038/eye.2016.13227367745Clinical StudyDifluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients: a randomized safety and efficacy study Difluprednate for postsurgery inflammationWilson M E 1*O'Halloran H 2VanderVeen D 3Roarty J 4Plager D A 5Markwardt K 6Gedif K 6Lambert S R 71 Storm Eye Institute, Medical University of South Carolina, Charleston, SC, USA2 Rady Children's Hospital, San Diego, CA, USA3 Boston Children's Hospital, Harvard Medical School, Boston, MA, USA4 Department of Ophthalmology, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA5 Indiana University Medical Center, Indianapolis, IN, USA6 Alcon Research Ltd, Fort Worth, TX, USA7 Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA* Storm Eye Institute, Medical University of South Carolina, Charleston, SC 29425, USA Tel: +1 843 792 7622; Fax: +1 843 792-8289. E-mail: wilsonme@musc.edu09 2016 01 07 2016 1 9 2016 30 9 1187 1194 01 04 2016 06 05 2016 Copyright © 2016 The Author(s)2016The Author(s)This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Purpose\nTo evaluate safety and efficacy of difluprednate 0.05% ophthalmic emulsion for treatment of postoperative inflammation after cataract surgery in pediatric patients.\n\nMethods\nThis was a phase 3B, multicentre, randomized, double-masked, active-controlled study of patients aged 0–3 years who underwent uncomplicated cataract surgery in one eye, with/without intraocular lens implantation. Patients were randomized to receive difluprednate 0.05% four times daily or prednisolone acetate 1% for 14 days post surgery, followed by tapering for 14 days. Safety included evaluation of adverse events. Primary efficacy was the proportion of patients with an anterior cell grade of 0 (no cells) at day 14; secondary efficacy was a global inflammation score.\n\nResults\nForty patients were randomized to each treatment group. Adverse drug reactions included corneal oedema (difluprednate 0.5%, n=1; prednisolone acetate 1%, n=0) and increased intraocular pressure or ocular hypertension (n=2/group). Mean intraocular pressure values during treatment were 2–3 mm Hg higher with difluprednate 0.05% compared with prednisolone acetate 1% mean values were similar between groups by the first week after treatment cessation. At 2 weeks post surgery, the incidence of complete clearing of anterior chamber cells was similar between groups (difluprednate 0.05%, n=30 (78.9%); prednisolone acetate 1%, n=31 (77.5%). Compared with prednisolone acetate 1%, approximately twice as many difluprednate 0.05%-treated patients had a global inflammation assessment score indicating no inflammation on day 1 (n=12 (30.8%) vs n=7 (17.5%) and day 8 (n=18 (48.7%) vs n=10 (25.0%).\n\nConclusions\nDifluprednate 0.05% four times daily showed safety and efficacy profiles similar to prednisolone acetate 1% four times daily in children 0–3 years undergoing cataract surgery.\n==== Body\nIntroduction\nIn children with congenital cataract who are otherwise healthy, early cataract surgery can result in good corrected visual acuity and binocular function.1, 2 However, compared with older children and adults, young children tend to have a more substantial inflammatory response to cataract surgery.3, 4 This inflammatory response, which is characterized by the presence of cells and flare in the anterior chamber, occurs when the blood–aqueous barrier is compromised.5 If left untreated, inflammation can interfere with the child's visual rehabilitation and may lead to further complications.6, 7, 8 Treatment with anti-inflammatory agents during the postoperative period allows for more rapid resolution of inflammatory symptoms and improved patient comfort.9, 10\n\nControlled studies have demonstrated that topical steroids are effective and have a favourable safety profile in suppressing ocular inflammation and reducing the long-term likelihood of vision impairment when administered at the time of surgery and during the weeks afterwards.10, 11\n\nDifluprednate ophthalmic emulsion 0.05% is a topical ocular corticosteroid that has been approved since 2008 for use in adults, initially for treatment of inflammation and pain associated with ocular surgery, and subsequently for treatment of endogenous anterior uveitis.12, 13 Recent studies in adults have shown that difluprednate treatment is associated with rapid resolution of both inflammation and pain associated with ocular surgery.9 Phase 3 studies in adults have shown that difluprednate 0.05% four times daily is well tolerated and noninferior to prednisolone acetate 1% eight times daily for treatment of endogenous anterior uveitis.12, 14\n\nChildren have a greater propensity for postoperative inflammation than adults.3, 8, 15 The safety of topical difluprednate after ocular surgery in children has not been previously established.16 The current study was designed in response to a written request by the US Food and Drug Administration in February 2009 to evaluate the safety of difluprednate 0.05% in children aged 0–3 years for treatment of postoperative inflammation following cataract surgery. In our study, prednisolone acetate 1% was selected for comparison because it is currently widely accepted in the United States as standard care in the treatment of inflammation following ocular surgery in children and adults.\n\nPatients and methods\nStudy design\nThis was a phase 3B, multicentre, randomized, double-masked, parallel-group, active-controlled study (NCT01124045) initiated in August 2010 and completed in April 2012. It was designed to compare the safety and efficacy of difluprednate 0.05% (Durezol ophthalmic emulsion, Alcon Laboratories, Inc., Fort Worth, TX, USA) and prednisolone acetate 1% (Pred Forte ophthalmic suspension, Allergan, Inc., Irvine, CA, USA) in the treatment of inflammation following cataract surgery in children aged 0–3 years.\n\nAll investigative sites were located in the United States. Institutional Review Board/Ethics Committee approval was obtained before the start of the study. The study was performed in compliance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice, and informed consent was obtained from a parent or legal guardian before enrolment of each patient.\n\nPatients were randomly assigned to treatment groups in accordance to a planned ratio of 1 : 1. Randomization numbers were generated using computer software (PROC PLAN, SAS Institute, Inc., Cary, NC, USA). The protocol was amended to include stratification by race (white and non-white) in randomization procedures to ensure a balance across treatment group. Patients, caregivers, and investigators were masked to the medication being instilled. Because prednisolone acetate 1% is a suspension that needs to be shaken before instillation, parents or legal guardians of patients were instructed to shake the assigned medication bottle before instillation to preserve masking.\n\nPatients\nChildren (age 0–3 years) enrolled in the study were scheduled to undergo uncomplicated cataract surgery in one eye, with or without intraocular lens implantation. Use of contact lenses for postsurgery refractive correction when operating on young infants with a unilateral cataract who are <7 months of age was recommended by the authors of a prospective study published1 while the study was ongoing. Hence, an amendment was made to the original protocol to allow the inclusion of children wearing contact lenses to correct aphakia post surgery. Exclusion criteria included: active uveitis, neoplasia, or any active or suspected viral, bacterial, or fungal disease in the study eye; use of any topical medication in the study eye within 7 days before surgery (except those required for ocular examination or preoperative preparation); systemic use of steroids or non-steroidal anti-inflammatory drugs; a history of steroid-induced increases in intraocular pressure (IOP); current use of medication for ocular hypertension or glaucoma in the study eye; post-traumatic cataract; suspected permanent low vision or blindness in the non-study eye; human immunodeficiency virus, acquired immunodeficiency syndrome, or diabetes.\n\nInterventions\nAll patients completed a screening visit within the 14 days preceding or on the day of surgery (day 0). Study treatment began on day 0 with one drop of the randomized medication instilled into the operated eye immediately following surgery. Following surgery, the parent or legal guardian of each patient was instructed to instil one drop of the randomized study medication into the affected eye four times daily, beginning on day 1, for 14 days after surgery, followed by tapering for 14 days. The treatment regimen during tapering depended on the investigator's assessment of the response to treatment. The treatment regimen used in the present study in both treatment arms (one drop four times daily) was based upon current dosing recommendations for patients following cataract surgery.13\n\nStudy visits\nPatients were evaluated for safety and efficacy on days 0, 1, 8 (±1 day), and 15 (±2 days), and at the end of study drug treatment (day 29 ±2 days). Additional safety visits occurred 1 week (+2 days) and 3 months (+1 week) after the last dose of study drug, the last visit occurring at the earliest on day 92, and at the latest on day 99.\n\nSafety evaluations\nSafety was evaluated throughout the study by recording adverse events (AEs) as coded according to the Medical Dictionary for Regulatory Activities. Recorded AE data included incidence, seriousness, relationship to treatment, association with study discontinuation, and individual characteristics (eg, severity, onset, duration). Mean and change from baseline in visual acuity and IOP were also evaluated. Change from baseline in fundoscopic parameters (vitreous (⩾1 unit increase in grade from baseline), retina/macula/choroid (an increase to a score of grade 2, if not present at baseline), and optic nerve (⩾1 unit increase in grade from baseline), evidence of postoperative bacterial or fungal infection, and change from baseline (⩾1 unit increase) in ocular sign parameters (lids, cornea, iris, sclera, conjunctiva, lid margins, and lens) were also recorded. Ocular signs were included in the safety analysis.\n\nEfficacy evaluations\nThe primary efficacy end point was the number and percentage of patients with an anterior cell grade of 0 (ie, no cells) at the end of the 14-day treatment period (day 15±2 days). Secondary efficacy end points were assessed at all study visits and included a 3-point global assessment of inflammation scores (0 (clear), 1 (improving satisfactorily), and 2 (not improving or worsening, or withdrawal from study indicated to allow institution of appropriate alternative therapy), and the individual components that informed the global assessment score. The individual components comprised: anterior chamber cell grade, anterior chamber flare grade, corneal clarity, wound integrity, conjunctival injection, ciliary/limbal injection, chemosis, hypopyon, vitritis, lens reproliferation (described), and symptoms (photophobia and lacrimation). With the exception of anterior chamber cell grade, which was reported using a 5-point scale ranging from 0 (0 cells) to 4 (⩾50 cells), the individual components were reported using a 4-point scale: 0, absent; 1, mild; 2, moderate; and 3, severe.\n\nStatistical analyses\nTo allow for at least a 95% chance of detecting an AE with a 10% incidence rate, a minimum sample size of 30 patients per group (difluprednate 0.05% or prednisolone acetate 1%) was required. No inferential statistical analysis was planned, and data were summarized using descriptive statistics only. Assessment of efficacy was based primarily on the number and percentage of patients in each treatment group with an anterior chamber cell grade of 0 at day 15 and, secondarily, on the global assessment score of postoperative inflammation and the individual components of the global assessment score (number and percentage of patients in each treatment group in each score category at each visit). All statistical analyses were performed using Statistical Analysis System (SAS) software. The intent-to-treat data set included all patients who received study medication, and had at least one scheduled on-therapy study visit. Primary efficacy assessments were based upon the intent-to-treat data set.\n\nResults\nPatient disposition and demographics\nA total of 80 children were enrolled (difluprednate 0.05%, n=40; prednisolone acetate 1%, n=40; Supplementary Figure 1). One child randomized to difluprednate 0.05% had consent withdrawn before receiving study medication and was excluded from the intent-to-treat (n=79), and safety (n=79) populations. Eligible children's ages ranged from 10 days to a maximum of 47 months, although the majority of children were aged between 28 days and 23 months in all analysis data sets. Children in the category of 28 days to 23 months included all children of at least 28 days of age who had not reached their second birthday. Those in the 2–3-year category included all children who had reached their second birthdays even if they had reached their third birthday. There were no clinically relevant differences between the patient groups in terms of age, sex, ethnicity, race, or iris colour (Table 1).\n\nSafety\nAdverse events\nIn all, 2 (5.1%) children in the difluprednate 0.05% group and 2 (5.0%) children in the prednisolone acetate 1% group experienced at least one AE related to treatment. Of those, children experienced AEs involving IOP increases (difluprednate 0.05%, n=2, 5.1% prednisolone acetate 1%, n=1, 2.5%), and 1 child (prednisolone acetate 1%, n=1, 2.5%) experienced a Medical Dictionary for Regulatory Activities–coded AE of ocular hypertension (defined as IOP >21 mm Hg). An additional AE of increased IOP occurred in the difluprednate 0.05% group, but was reported by the investigator as unrelated to treatment. The third treatment-related AE report was of corneal oedema (Table 2) that occurred in the same patient from the difluprednate 0.05% group experiencing an AE of increased IOP.\n\nNonfatal serious adverse events (SAEs) were reported for 8 (20.5%) children in the difluprednate 0.05% group, and 11 (27.5%) children in the prednisolone acetate 1% group. The SAEs included ‘medical observation' (difluprednate 0.05%, n=6, 15.4% prednisolone acetate 1%, n=11, 27.5%), cortical cataract that was resolved by vitrectomy surgery (difluprednate 0.05%, n=1, 2.6% prednisolone acetate 1%, n=0), a metabolic and nutrition disorder that was Medical Dictionary for Regulatory Activities–coded as ‘failure to thrive' (difluprednate 0.05%, n=0; prednisolone acetate 1%, n=1, 2.5%), and increased IOP (difluprednate 0.05%, n=1, 2.6% prednisolone acetate 1%, n=0). The high incidence of ‘medical observation' as an SAE in this study occurred because overnight hospitalization is the standard of care for neonatal patients after surgery/anesthesia, and hospitalization automatically triggers recording of an SAE. None of the SAEs resulted in discontinuation of treatment.\n\nIntraocular pressure\nOn days 8, 15, and 29, mean IOP values were 2–3 mm Hg higher in children treated with difluprednate 0.05% than in those who received prednisolone acetate 1%, but mean values in the two groups were similar by the first week after treatment cessation and remained similar at 3 months after treatment (Figure 1). Two children (one from each treatment group) reported an IOP ⩾40 mm Hg at unscheduled visits between study days 15 and 29 (child in difluprednate 0.05% group, IOP=41 mm Hg) and between study days 1 and 8 (child in prednisolone acetate 1% group, IOP=43 mm Hg).\n\nOther safety variables\nThere were no clinical differences in visual acuity data between treatment groups. A higher proportion of children receiving prednisolone acetate 1% reported changes from baseline in optic nerve (increase in grade of ⩾1 unit from baseline: difluprednate 0.05%, n=0; prednisolone acetate 1%, n=1, 3.4%) and retina/macula/choroid (Grade 2; difluprednate 0.05%, n=0; prednisolone acetate 1%, n=2, 6.7%). Changes in vitreous (increase in grade from baseline of ⩾1 unit) were similar in the difluprednate 0.05% and prednisolone acetate 1% groups (n=2, 7.1% and n=1, 3.2%, respectively). There were no postoperative bacterial or fungal infections reported. For each ocular sign parameter (lids, lid margins, conjunctiva, cornea, sclera, iris/anterior chamber), more children treated with prednisolone acetate 1% had increases from baseline of ⩾1 unit at any visit than patients treated with difluprednate 0.05%.\n\nEfficacy\nPrimary efficacy end point\nThe two groups showed similar results for the primary efficacy end point: complete clearing of anterior chamber cells (anterior cell grade 0) on day 15 was recorded in 30 patients (78.9%) in the difluprednate 0.05% group and in 31 patients (77.5%) in the prednisolone acetate 1% group.\n\nSecondary efficacy end points\nA higher proportion of difluprednate-treated children had a global inflammation assessment score of 0 (no evidence of postoperative inflammation) on days 1 and 8 when compared with patients treated with prednisolone acetate (Table 3; day 1, 12 (30.8%) vs 7 (17.5%) children, respectively; day 8, 19 (48.7%) vs 10 (25.0%) children, respectively). The proportions of children who had a global inflammation assessment score of 0 on day 15 were comparable between the two groups (difluprednate 0.05%, n=22, 56.4% prednisolone acetate 1%, n=20, 50.0%).\n\nOn day 15, similar efficacy was reported between the two treatment groups for the individual components that informed the global inflammation assessment, including conjunctival injection, cillary/limbal injection, chemosis, and hypopyon (Table 4). Furthermore, by day 15, a similar proportion of patients in both groups had an anterior chamber flare grade of 0 (difluprednate 0.05%: n=29, 74.4% prednisolone acetate 1%: n=28 70.0%); 38 patients in both groups (difluprednate 0.05%, 97.4% prednisolone acetate 1%, 95.0%) were completely clear of inflammation, as indicated by absence of photophobia; 39 patients in both groups (difluprednate 0.05%, 100.0% prednisolone acetate 1%, 97.5%) were completely clear of cells in the vitreous; and ⩾90% of patients in both groups had complete corneal clarity (Table 4). As stated in the primary efficacy end point, the percentage of children with an anterior chamber cell grade of 0 was similar in the two groups.\n\nDiscussion\nIn a population of children (aged 0–3 years) undergoing cataract surgery, the overall incidences of AE of topical difluprednate 0.05% and prednisolone acetate 1% four times daily were similar, with no AEs leading to discontinuation. Serious adverse events were reported in both treatment groups, although no new or unexpected safety concerns were observed. Hospitalization for medical observation, the most commonly reported SAE in the current study, was associated with hospital policies of admission for infants after general anaesthesia. As a result, the number of SAEs recorded in this study may be higher than in an adult patient study9 in which postoperative hospital admission would not be automatic. Excluding hospitalization SAEs, and considering expected outcomes based on the characteristics of this population following cataract surgery4, 17 and previous experience with topical ocular steroids,18 no unexpected safety concerns were detected in our study. In our study, the overall percentages of patients reporting difluprednate-related increased IOP as an AE (5.1%) were similar to those reported by Smith et al19 (6.2%).\n\nIn our study, a substantial elevation in IOP ⩾40 mm Hg was found in two children, one from each treatment group.20, 21 Elevated IOP is a known potential adverse reaction to steroid use,22 and is listed in the warnings section of the package insert for this drug class. Based upon previous experience with topical ocular steroids, class labelling, and the characteristics of the patient population in the current study, the incidence of increased IOP is not unexpected.\n\nThe balance between efficacy and risk of increased IOP is an important challenge in the management of all cataract surgery patients.23 In our study, on day 8, when mean IOP values were higher in children treated with difluprednate 0.05% than in those treated with prednisolone acetate 1%, a higher percentage of difluprednate-treated children were completely clear of postoperative inflammation than patients treated with prednisolone acetate (48.7% vs 25.0%, respectively). These data suggest that although mean IOP values were initially higher with difluprednate 0.05% treatment, this came with a more rapid control of inflammation than was achieved with prednisolone acetate 1%. This is similar to the findings of Sheppard et al,14 in an endogenous anterior uveitis study.14\n\nWhen comparing the safety and efficacy of difluprednate 0.05% with prednisolone acetate 1%, differences in drug delivery and formulations should be taken into consideration. Prednisolone acetate 1% is a suspension and must therefore be shaken before application; difluprednate 0.05% is an emulsion that does not require shaking. This difference in formulation may be significant because if the prednisolone acetate 1% suspension does not receive adequate shaking before application, an incorrect dose may be delivered to the eye.24 Correct dosage is of particular importance in young children because, compared with adults, complications after cataract surgery have a greater impact on long-term visual outcomes.8 Emulsions, such as difluprednate 0.05%, and gel formulations may therefore be preferred to suspensions because of the accuracy that they offer from dose to dose.24, 25\n\nInclusion in the current study of aphakic infants treated with a contact lens is important, as contact lens use is commonly used for correction of aphakia in infants.1 In this study, application of the study medication in the affected eye was possible while the contact lens remained in place. Analysis of AEs by age showed no clinically relevant differences among the individual AE characteristics between the overall safety population and patients in each age category for any treatment group. Thus, the inclusion of children (including those <7 months of age) with contact lenses resulted in no new or unexpected safety concerns that would alter the safety profile of difluprednate 0.05% in pediatric patients dosed four times daily for at least 14 days.\n\nThis study had a number of important limitations. Children aged 0–3 years are often difficult to examine; nonetheless, the surgeons in this study were all experienced at examining very young children. IOP readings were a priority as the primary purpose of the study was to evaluate safety. The investigators were each experienced in the measurement of IOP postoperatively in young children. Cell and flare were evaluated as precisely as possible given the age of the patients. A tabletop slit lamp was used when possible to make this assessment. In addition, a global inflammation assessment was added as this evaluation was deemed appropriate by the investigators for this age group. It included an assessment of conjunctival injection, cillary/limbal injection, chemosis, and hypopyon. It is acknowledged that although serious inflammatory complications would not have been overlooked, precise comparisons of the cell and flare response to surgery between groups may have been limited in this study of children aged 0–3 years. As a result of this, the efficacy comparison between the drugs studied is less precise than it would be in an adult study.\n\nIn conclusion, this study has demonstrated that the safety profile of topical difluprednate 0.05% is similar to that of topical prednisolone acetate 1%, both dosed four times daily, in the postoperative management of children up to 3 years of age who have undergone cataract surgery. This study supports the safety of difluprednate 0.05% for the management of inflammation in young children after cataract surgery.\n\n\n\nWhile each of the authors actively participated in the writing and editing of this manuscript and approved each edit before submission, we acknowledge that additional medical writing support, funded by Alcon Research, was provided by Judith Leavy of DJE Science. The study was sponsored and supported, in part, by a grant from Alcon Laboratories, Inc. (Fort Worth, TX, USA). Alcon Laboratories, Inc. participated in the design and conduct of the study, data collection, data management, data analysis, interpretation of the data, preparation, review, and approval of the manuscript.\n\nSupplementary Information accompanies this paper on Eye website (http://www.nature.com/eye)\n\nMeeting presentation: The data within this manuscript have been previously presented in part at the Annual Meeting of the American Academy of Ophthalmology, Chicago, USA, 18–21 October 2014.\n\nKM and KG are employees and own stocks/shares of Alcon Laboratories, Inc. The other authors declare no conflict of interest.\n\nSupplementary Material\nSupplementary Information Click here for additional data file.\n\n Figure 1 Change in mean IOP (mm Hg) following difluprednate and prednisolone treatment after cataract surgery. IOP, intraocular pressure.\n\nTable 1 Patient characteristics (safety population)\nCharacteristic, n (%)\tDifluprednate 0.05% (n=39)\tPrednisolone acetate 1% (n=40)\t\nAge\t\n 0–27 Days\t3 (7.7)\t3 (7.5)\t\n 28 Days–23 months\t28 (71.8)\t26 (65.0)\t\n 24 Months–47 monthsa\t8 (20.5)\t11 (27.5)\t\n \t \t \t\nSex\t\n Male\t17 (43.6)\t20 (50.0)\t\n Female\t22 (56.4)\t20 (50.0)\t\n \t \t \t\nEthnicity\t\n Hispanic, Latino, or Spanish\t9 (23.1)\t8 (20.0)\t\n Other\t30 (76.9)\t32 (80.0)\t\n \t \t \t\nRace\t\n White\t21 (53.8)\t24 (60.0)\t\n Black or African American\t9 (23.1)\t9 (22.5)\t\n Asian\t0 (0.0)\t1 (2.5)\t\n Multi-racial\t3 (7.7)\t2 (5.0)\t\n Other\t6 (15.4)\t4 (10.0)\t\n \t \t \t\nIris colour\t\n Brown\t22 (56.4)\t22 (55.0)\t\n Green\t0 (0.0)\t1 (2.5)\t\n Blue\t15 (38.5)\t16 (40.0)\t\n Grey\t1 (2.6)\t0 (0.0)\t\n Other\t1 (2.6)\t1 (2.5)\t\na The 24–47-month category included all patients who had reached their second birthdays even if they had reached their third birthday. Hence, some patients reached 47 months.\n\nTable 2 Summary of adverse events (safety population)\nAE category, n (%)\tDifluprednate 0.05% (n=39)\tPrednisolone acetate 1% (n=40)\t\nDeath\t0 (0.0)\t0 (0.0)\t\nSerious AE\t8 (20.5)\t11 (27.5)\t\nDiscontinuation due to AE\t0 (0.0)\t0 (0.0)\t\n⩾1 AE (related or not related to study medication)\t29 (74.4)\t30 (75.0)\t\n Conjunctivitis\t3 (7.7)\t0 (0.0)\t\n Posterior capsule opacification\t3 (7.7)\t0 (0.0)\t\n Eye inflammation\t0 (0.0)\t2 (5.0)\t\n Pyrexia\t0 (0.0)\t2 (5.0)\t\n Nasopharyngitis\t5 (12.8)\t2 (5.0)\t\n Ear infection\t3 (7.7)\t1 (2.5)\t\n Sinusitis\t2 (5.1)\t0 (0.0)\t\n Medical observation\t6 (15.4)\t10 (25.0)\t\n Intraocular pressure increased\t3 (7.7)\t1 (2.5)\t\n Hypotonia\t0 (0.0)\t2 (5.0)\t\n Rash\t1 (2.6)\t2 (5.0)\t\n Dermatitis diaper\t0 (0.0)\t2 (5.0)\t\n Cataract operation (non-study eye)\t3 (7.7)\t6 (15.0)\t\n⩾1 AE related to treatment (adverse drug reaction)\t3 (7.7)\t2 (5.0)\t\n Corneal oedema\t1 (2.6)\t0 (0.0)\t\n Ocular hypertension\t0 (0.0)\t1 (2.5)\t\n Intraocular pressure increased\t2 (5.1)\t1 (2.5)\t\nAbbreviation: AE, adverse event.\n\nTable 3 Global assessment of inflammation by visit (intent-to-treat population)\nVisit\tAssessment score, n (%)\tDifluprednate 0.05% (n=39)\tPrednisolone acetate 1% (n=40)\t\nDay 1\tTotal\t39\t40\t\n \tClear\t12 (30.8)\t7 (17.5)\t\n \tImproving satisfactorily\t27 (69.2)\t33 (82.5)\t\n \tNot improving or worsening\t0 (0.0)\t0 (0.0)\t\nDay 8\tTotal\t39\t40\t\n \tClear\t19 (48.7)\t10 (25.0)\t\n \tImproving satisfactorily\t19 (48.7)\t28 (70.0)\t\n \tNot improving or worsening\t1 (2.6)\t2 (5.0)\t\nDay 15\tTotal\t39\t40\t\n \tClear\t22 (56.4)\t20 (50.0)\t\n \tImproving satisfactorily\t17 (43.6)\t20 (50.0)\t\n \tNot improving or worsening\t0 (0.0)\t0 (0.0)\t\nDay 29\tTotal\t39\t40\t\n \tClear\t31 (79.5)\t29 (72.5)\t\n \tImproving satisfactorily\t8 (20.5)\t10 (25.0)\t\n \tNot improving or worsening\t0 (0.0)\t1 (2.5)\t\n1 Week after last dose\tTotal\t39\t40\t\n \tClear\t35 (89.7)\t36 (90.0)\t\n \tImproving satisfactorily\t3 (7.7)\t3 (7.5)\t\n \tNot improving or worsening\t1 (2.6)\t1 (2.5)\t\n3 Months after last dose\tTotal\t39\t40\t\n \tClear\t36 (92.3)\t37 (92.5)\t\n \tImproving satisfactorily\t2 (5.1)\t3 (7.5)\t\n \tNot improving or worsening\t1 (2.6)\t0 (0.0)\t\nTable 4 Individual components of the global assessment of inflammation at day 15 (intent-to-treat population)\nIndividual components of global assessment of inflammation\tPatients with grade 0, n (%)\t\n \tDifluprednate 0.05% (n=39)\tPrednisolone acetate 1% (n=40)\t\nAnterior chamber cell\t30 (78.9)\t31 (77.5)\t\nAnterior chamber flare\t29 (74.4)\t28 (70.0)\t\nCorneal clarity\t37 (94.9)\t36 (90.0)\t\nConjunctival injection\t35 (89.7)\t37 (92.5)\t\nCiliary/limbal injection\t39 (100.0)\t40 (100.0)\t\nChemosis\t39 (100.0)\t39 (97.5)\t\nHypopyon\t39 (100.0)\t40 (100.0)\t\nVitritis\t39 (100.0)\t39 (97.5)\t\nWound integrity\t39 (100.0)\t40 (100.0)\t\nPhotophobia\t38 (97.4)\t38 (95.0)\t\nLacrimation\t39 (100.0)\t38 (95.0)\n==== Refs\nInfant Aphakia Treatment Study GroupInfant Aphakia Treatment Study GroupLambert SR Infant Aphakia Treatment Study GroupLynn MJ Infant Aphakia Treatment Study GroupHartmann EE Infant Aphakia Treatment Study GroupDuBois L Infant Aphakia Treatment Study GroupDrews-Botsch C et al. Comparison of contact lens and intraocular lens correction of monocular aphakia during infancy: a randomized clinical trial of HOTV optotype acuity at age 4.5 years and clinical findings at age 5 years . JAMA Ophthalmol \n2014 ; 132 (6): 676 –682.24604348 \nHartmann EE, Stout AU, Lynn JL, Yen KG, Kruger SJ, Lambert SR et al. Stereopsis results at 4.5 years of age in the Infant Aphakia Treatment Study . Am J Ophthalmol \n2014 ; 159 (1): 64 –70.25261241 \nJancevski M, Foster CS. Cataracts and uveitis . Curr Opin Ophthalmol \n2010 ; 21 (1): 10 –14.19829114 \nShoss BL, Tsai LM. Postoperative care in cataract surgery . Curr Opin Ophthalmol \n2013 ; 24 (1): 66 –73.23197268 \nDevgan U Inflammation and pain control in cataract surgery. Topics in Ocular Antiflammatories. Continuing Medical Education: University of Florida, USA 2003 (2).\nApple DJ, Solomon KD, Tetz MR, Assia EI, Holland EY, Legler UF et al. Posterior capsule opacification . Surv Ophthalmol \n1992 ; 37 (2): 73 –116.1455302 \nGass JD, Norton EW. Cystoid macular edema and papilledema following cataract extraction. A fluorescein fundoscopic and angiographic study . Arch Ophthalmol \n1966 ; 76 (5): 646 –661.5955948 \nHosal BM, Biglan AW. Risk factors for secondary membrane formation after removal of pediatric cataract . J Cataract Refract Surg \n2002 ; 28 (2): 302 –309.11821214 \nKorenfeld MS, Silverstein SM, Cooke DL, Vogel R, Crockett RS, Difluprednate Ophthalmic Emulsion 0.05% Study Group. Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain . J Cataract Refract Surg \n2009 ; 35 (1): 26 –34.19101421 \nRajpal RK, Fong R, Comstock TL. Loteprednol etabonate ophthalmic gel 0.5% following cataract surgery: integrated analysis of two clinical studies . Adv Ther \n2013 ; 30 (10): 907 –923.24136301 \nLorenz K, Dick B, Jehkul A, Auffahrt GU. Inflammatory response after phacoemulsification treated with 0.5% prednisolone acetate or vehicle . Graefes Arch Clin Exp Ophthalmol \n2008 ; 246 (11): 1617 –1622.18726610 \nSheppard JD, Toyos MM, Kempen JH, Kaur P, Foster CS. Difluprednate 0.05% versus prednisolone acetate 1% for endogenous anterior uveitis: a phase III, multicenter, randomized study . Invest Ophthalmol Vis Sci \n2014 ; 55 (5): 2993 –3002.24677110 \nAlcon. DUREZOL® Product information. 2013.\nFoster CS, Davanzo R, Flynn TE, McLeod K, Vogel R, Crockett RS. Durezol (Difluprednate Ophthalmic Emulsion 0.05%) compared with Pred Forte 1% ophthalmic suspension in the treatment of endogenous anterior uveitis . J Ocul Pharmacol Ther \n2010 ; 26 (5): 475 –483.20809807 \nPlager DA, Lynn MJ, Buckley EG, Wilson ME, Lambert SR et alInfant Aphakia Treatment Study G. Complications in the first 5 years following cataract surgery in infants with and without intraocular lens implantation in the infant aphakia treatment study . Am J Ophthalmol \n2014 ; 158 (5): 892 –898 e2.25077835 \nFDA. Clinical pharmacology review: Difluprednate Ophthalmic Emulsion 0.05%. 2014 (May 2014). Available from http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM353857.pdf.\nJancevski M, Foster CS. Cataracts and uveitis . Discov Med \n2010 ; 9 (44): 51 –54.20102686 \nMeehan K, Vollmer L, Sowka J. Intraocular pressure elevation from topical difluprednate use . Optometry \n2010 ; 81 (12): 658 –662.21111374 \nSmith S, Lorenz D, Peace J, McLeod K, Crockett RS, Vogel R. Difluprednate ophthalmic emulsion 0.05% (Durezol) administered two times daily for managing ocular inflammation and pain following cataract surgery . Clin Ophthalmol \n2010 ; 4 : 983 –991.20856594 \nSlabaugh MA, Herlihy E, Ongchin S, van Gelder RN. Efficacy and potential complications of difluprednate use for pediatric uveitis . Am J Ophthalmol \n2012 ; 153 (5): 932 –938.22265149 \nJeng KW, Fine HF, Wheatley HM, Roth D, Connors DB, Prenner JL. Incidence of steroid-induced ocular hypertension after vitreoretinal surgery with difluprednate versus prednisolone acetate . Retina \n2014 ; 34 (10): 1990 –1996.25121927 \nKaur S, Dhiman I, Kaushik S, Raj S, Pandav SS. Outcome of ocular steroid hypertensive response in children . J Glaucoma \n2016 ; 25 (4): 343 –347.25651206 \nLane S Considerations in the treatment of ocular inflammation: II. Loteprednol Etabonate Technical Paper 2009 ; II.\nMarlowe ZT, Davio SR. Dose uniformity of loteprednol etabonate ophthalmic gel (0.5%) compared with branded and generic prednisolone acetate ophthalmic suspension (1%) . Clin Ophthalmol \n2014 ; 8 : 23 –29.24357925 \nStringer W, Bryant R. Dose uniformity of topical corticosteroid preparations: difluprednate ophthalmic emulsion 0.05% versus branded and generic prednisolone acetate ophthalmic suspension 1% . Clin Ophthalmol \n2010 ; 4 : 1119 –1124.20957058\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0950-222X",
"issue": "30(9)",
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
"mesh_terms": "D000287:Administration, Topical; D001036:Aphakia, Postcataract; D002386:Cataract; D002387:Cataract Extraction; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D005477:Fluprednisolone; D005938:Glucocorticoids; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation; D007429:Intraocular Pressure; D019654:Lens Implantation, Intraocular; D008297:Male; D009883:Ophthalmic Solutions; D011239:Prednisolone; D014606:Uveitis, Anterior",
"nlm_unique_id": "8703986",
"other_id": null,
"pages": "1187-94",
"pmc": null,
"pmid": "27367745",
"pubdate": "2016-09",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "20957058;23197268;19101421;25261241;22265149;25651206;21111374;24677110;11821214;25077835;18726610;20102686;5955948;20809807;24604348;1455302;25121927;19829114;24357925;20856594;24136301",
"title": "Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients: a randomized safety and efficacy study.",
"title_normalized": "difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients a randomized safety and efficacy study"
} | [
{
"companynumb": "ALCN2016US006794",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIFLUPREDNATE"
},
"drugadditional": "3",
"dr... |
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