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"abstract": "OBJECTIVE\nEndoscopist directed nurse administered propofol sedation (EDNAPS) is widely considered to be safe and efficient, but there are limited data from the Australian health-care setting, and Australian sedation guidelines do not support the practice. Thus, we report data from a prospective audit of EDNAPS over a 6.5-year period in an Australian referral hospital.\n\n\nMETHODS\nConsecutive endoscopic procedures performed between January 2013 and June 2019. Sedation protocol was an initial dose of midazolam 1-3 mg intravenously (i.v.) and propofol 10-50 mg i.v.. Further aliquots of propofol 10-30 mg i.v. were given as required. ProvationMD® endoscopic reporting system was used to prospectively record patient demographics, medication and dose, American Society of Anesthesiologist's (ASA) class, and sedation-related complications.\n\n\nRESULTS\nDuring the 78-month period, 28 051 eligible procedures were performed; 3093 procedures performed with anesthetic support or without EDNAPS were excluded. In total, 24 958 procedures with EDNAPS were analyzed including 7563 gastroscopies, 12 941 colonoscopies, 2932 gastroscopy and colonoscopy, 1440 flexible sigmoidoscopies, and 82 combined gastroscopy and flexible sigmoidoscopy. Of these, 9539 were ASA 1 (38.2%), 13 680 were ASA 2 (54.8%), 1733 were ASA 3 (6.9%), and 4 were ASA 4 (0.02%). Sedation-related complications occurred in 66 patients (0.26%), predominantly transient hypoxic episodes. No patient required intubation for an airway emergency, and there was no sedation-related mortality. Sedation-related complications increased with ASA class and were significantly more common with gastroscopy.\n\n\nCONCLUSIONS\nEndoscopist directed nurse administered propofol sedation is a safe way of performing endoscopic sedation in low-risk patients in the hospital setting.",
"affiliations": "Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia.;Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia.;Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia.;Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia.;Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia.;Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia.;Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia.;Department of Gastroenterology and Hepatology, Cairns Hospital, Cairns, Queensland, Australia.",
"authors": "Gururatsakul|Montri|M|https://orcid.org/0000-0003-3878-240X;Lee|Richard|R|https://orcid.org/0000-0002-0876-8722;Ponnuswamy|Sureshkumar Kallippatti|SK|https://orcid.org/0000-0002-8318-4110;Gilhotra|Rajit|R|https://orcid.org/0000-0001-8055-6524;McGowan|Cathal|C|https://orcid.org/0000-0002-9619-2937;Whittaker|Debra|D|https://orcid.org/0000-0001-9464-0727;Ombiga|John|J|https://orcid.org/0000-0002-0101-5680;Boyd|Peter|P|https://orcid.org/0000-0003-3363-7406",
"chemical_list": "D006993:Hypnotics and Sedatives; D008874:Midazolam; D015742:Propofol",
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.15204",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0815-9319",
"issue": "36(2)",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "Endoscopy; Propofol; Sedation",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D001315:Australia; D016292:Conscious Sedation; D016099:Endoscopy, Gastrointestinal; D005260:Female; D000072102:Gastroenterologists; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008485:Medical Audit; D008874:Midazolam; D009726:Nurses; D015742:Propofol; D011446:Prospective Studies; D012017:Referral and Consultation; D012449:Safety",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "490-497",
"pmc": null,
"pmid": "33448489",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prospective audit of the safety of endoscopist-directed nurse-administered propofol sedation in an Australian referral hospital.",
"title_normalized": "prospective audit of the safety of endoscopist directed nurse administered propofol sedation in an australian referral hospital"
} | [
{
"companynumb": "AU-BAXTER-2021BAX017956",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MIDAZOLAM HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "Histoplasma capsulatum var. capsulatum is a dimorphic fungus endemic to America and subtropical regions. Several cases of this opportunist mycosis have been reported in immunocompromised patients. We report the case of a patient treated with methotrexate and corticosteroid therapy for rheumatoid arthritis and who presented with disseminated histoplasmosis that partially mimicked a dermatomyositis.",
"affiliations": "Service de Médecine Interne et Rhumatologie, Centre Hospitalier du Pays d'Aix, Aix en Provence, France.;Service de Réanimation, Hôpital Européen, Marseille, France.;Service de Médecine Interne et Rhumatologie, Centre Hospitalier du Pays d'Aix, Aix en Provence, France.;Service de Médecine Interne et Rhumatologie, Centre Hospitalier du Pays d'Aix, Aix en Provence, France.;Service de Parasitologie et Mycologie, Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France.;Service de Médecine Interne et Rhumatologie, Centre Hospitalier du Pays d'Aix, Aix en Provence, France.",
"authors": "Dussouil|A S|AS|;Allardet-Servent|J|J|;Dunogeant|L|L|;Grauer|J L|JL|;Ranque|S|S|;Nasser|V|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjd.13876",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "173(3)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D003882:Dermatomyositis; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006660:Histoplasmosis; D006801:Humans",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "797-800",
"pmc": null,
"pmid": "26197989",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated histoplasmosis partially mimicking a dermatomyositis in a patient with rheumatoid arthritis.",
"title_normalized": "disseminated histoplasmosis partially mimicking a dermatomyositis in a patient with rheumatoid arthritis"
} | [
{
"companynumb": "FR-TEVA-605588ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"... |
{
"abstract": "Of 84 renal transplants performed in our center since 1986, six recipients (7.1%) developed posttransplant lymphoproliferative disorder (PTLD). All received quadruple immunosuppression with Minnesota anti-lymphoblastic globulin or anti-thymocyte globulin, methylprednisolone, cyclosporine, and azathioprine or mycophenolate mofetil. Five were seronegative for Epstein-Barr virus (EBV) when they received their renal transplant. All patients received prophylactic acyclovir treatment postrenal transplant and none developed a cytomegalovirus (CMV) infection. All patients were positive for EBV by serology and polymerase chain reaction at the time of diagnosis of PTLD. Clinical features at presentation included fever (6/6), adenopathy (4/6), hypertrophied adenoids (4/6), liver involvement (2/6), and allograft involvement (2/6), 2-78 months (4/6<6 months) postrenal transplant. Histopathology of PTLD tissue revealed T cell rich/ Hodgkin disease-like B cell PTLD in one patient, polymorphic PTLD in four, and monomorphic (large B cell lymphoma) PTLD in one. Immunophenotyping of the PTLD biopsy specimen revealed predominant T cells in three, mixed B and T cells in two patients, and B cell in one. No aneuploid populations were identified by flow cytometric DNA ploidy assay. DNA from the PTLD tissue revealed weak to moderate IgH gene rearrangement in four of six patients but no T cell receptor beta-chain or c-myc gene rearrangement on Southern blot analysis. The child with monomorphic (large B cell lymphoma) PTLD was clonal with lambda light chain restriction on immunophenotyping. Treatment consisted of reduced immunosuppression and ganciclovir/ acyclovir in all patients. CMV hyperimmune globulin was used as an adjunctive therapy in two patients. Chemotherapy was needed in only one patient. A single rejection episode occurred in two children following reduction in immunosuppression, which reversed following intravenous methylprednisolone therapy. PTLD resolved in all patients and at present all patients are alive with functional grafts 2-54 months post diagnosis. Our experience suggests that reduced immunosuppression and anti-viral treatment is adequate in most cases of PTLD, but chemotherapy and hyperimmune globulin therapy may be beneficial in cases resistant to first-line therapy. Since all but one of our patients were EBV seronegative at the time of transplant, vigilance is especially important for early detection of PTLD in this group of the pediatric renal transplant population.",
"affiliations": "Section of Pediatric Nephrology, The Children's Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108, USA. tsrivastava@cmh.edu",
"authors": "Srivastava|T|T|;Zwick|D L|DL|;Rothberg|P G|PG|;Warady|B A|BA|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s004670050692",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "13(9)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": null,
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D002648:Child; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections; D005500:Follow-Up Studies; D015774:Ganciclovir; D006801:Humans; D007223:Infant; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D011183:Postoperative Complications; D013997:Time Factors",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "748-54",
"pmc": null,
"pmid": "10603113",
"pubdate": "1999-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Posttransplant lymphoproliferative disorder in pediatric renal transplantation.",
"title_normalized": "posttransplant lymphoproliferative disorder in pediatric renal transplantation"
} | [
{
"companynumb": "NVSC2020US143560",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Lamotrigine [LTG] is primarily an anti-epileptic drug used to treat seizure disorders, depression, and bipolar disease. It is generally well tolerated with limited side effects reported during routine use. Adverse events after overdose include neurotoxicity in the form of sedation and seizure activity, as well as cardiopulmonary toxicity in the form of sodium-channel blockade and cardiovascular collapse. There is no consensus regarding the role of hemodialysis (HD) in management of lamotrigine toxicity. Based on pharmacological properties, LTG is a candidate for extracorporeal removal, however, the successful use of HD for the treatment of this poisoning is not well described. We report the case of a 44 year-old female after a LTG overdose that experienced prolonged sedation that was ultimately treated with HD with an excellent response.",
"affiliations": "Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, New York, USA. Electronic address: aagrawal1@northwell.edu.;Division of Medical Toxicology, Department of Emergency Medicine, Zucker School of Medicine at Hofstra/Northwell, New York, USA.;Division of Pulmonary, Critical Care & Sleep Medicine, Department of Medicine, Zucker School of Medicine at Hofstra/Northwell, New York, USA.",
"authors": "Agrawal|Abhinav|A|;Nogar|Joshua N|JN|;Koenig|Seth|S|",
"chemical_list": "D000927:Anticonvulsants; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.05.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "37(8)",
"journal": "The American journal of emergency medicine",
"keywords": "Hemodialysis; Lamotrigine; Overdose; Respiratory depression; Seizure",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001714:Bipolar Disorder; D062787:Drug Overdose; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D006435:Renal Dialysis",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1603.e1-1603.e2",
"pmc": null,
"pmid": "31109780",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of lamotrigine overdose using hemodialysis.",
"title_normalized": "management of lamotrigine overdose using hemodialysis"
} | [
{
"companynumb": "US-CIPLA LTD.-2019US04363",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nA previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings.\n\n\nMETHODS\nRecords of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution.\n\n\nRESULTS\nTotally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3-5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8-2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48-0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥ 3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444).\n\n\nCONCLUSIONS\nIn real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities.\n\n\nBACKGROUND\nRetrospectively registered.",
"affiliations": "Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. ykuboki@east.ncc.go.jp.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.;Department of Medical Oncology, Graduated School of Medicine, Kagawa University, Takamatsu, Japan.;Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.",
"authors": "Kotani|Daisuke|D|;Kuboki|Yasutoshi|Y|;Horasawa|Satoshi|S|;Kaneko|Asumi|A|;Nakamura|Yoshiaki|Y|;Kawazoe|Akihito|A|;Bando|Hideaki|H|;Taniguchi|Hiroya|H|;Shitara|Kohei|K|;Kojima|Takashi|T|;Tsuji|Akihito|A|;Yoshino|Takayuki|T|",
"chemical_list": "D004338:Drug Combinations; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D000068258:Bevacizumab; D014498:Uracil; D013941:Thymine; D014271:Trifluridine",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-019-6475-6",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 647510.1186/s12885-019-6475-6Research ArticleRetrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer Kotani Daisuke 1Kuboki Yasutoshi ykuboki@east.ncc.go.jp 12Horasawa Satoshi 13Kaneko Asumi 4Nakamura Yoshiaki 13Kawazoe Akihito 1Bando Hideaki 15Taniguchi Hiroya 13Shitara Kohei 1Kojima Takashi 1Tsuji Akihito 6Yoshino Takayuki 11 0000 0001 2168 5385grid.272242.3Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan 2 grid.497282.2Department of Experimental Therapeutics, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 Japan 3 0000 0001 2168 5385grid.272242.3Translational Research Support Section, Translational Research Management Division, Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan 4 0000 0001 2168 5385grid.272242.3Department of Pharmacy, National Cancer Center Hospital East, Kashiwa, Japan 5 0000 0001 0722 8444grid.410800.dDepartment of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan 6 0000 0000 8662 309Xgrid.258331.eDepartment of Medical Oncology, Graduated School of Medicine, Kagawa University, Takamatsu, Japan 27 12 2019 27 12 2019 2019 19 125324 8 2019 17 12 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nA previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings.\n\nMethods\nRecords of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution.\n\nResults\nTotally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3–5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8–2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48–0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥ 3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444).\n\nConclusions\nIn real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities.\n\nTrial registration\nRetrospectively registered.\n\nKeywords\nTrifluridine/tipiracil plus bevacizumabTAS-102mCRCLonsurfissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nColorectal cancer (CRC) is the second leading cause of cancer-related death worldwide [1]. The development of combination chemotherapy regimens comprising cytotoxic agents (e.g., fluoropyrimidine, oxaliplatin, and irinotecan) and molecular targeted therapies (e.g., bevacizumab, ramucirumab, ziv-aflibercept, cetuximab, panitumumab, and regorafenib) have increased the survival of patients with metastatic CRC (mCRC) by approximately 30 months [2–7].\n\nTrifluridine/tipiracil (TAS-102) is a novel, oral combination comprising the thymidine-based nucleoside analog trifluridine and tipiracil hydrochloride at a molar ratio of 1:0.5. Trifluridine is incorporated into DNA after phosphorylation by thymidine kinase 1 (TK1). We previously reported results from a randomized phase 2 study of trifluridine/tipiracil (J003–10040030), and this therapy was first approved in Japan in 2014 [8]. More recently, the international phase 3 RECOURSE trial has demonstrated a more significant overall survival (OS) benefit of trifluridine/tipiracil compared with placebo, with acceptable toxicity, in patients with refractory mCRC [7]. In addition, the Asian phase 3 TERRA trial has reported the survival benefit and safety of trifluridine/tipiracil in Asian population [9]. Based on these findings, trifluridine/tipiracil has been approved by many countries and regions including the US Food and Drug Administration and European Medicines Agency.\n\nThe combination of trifluridine/tipiracil plus bevacizumab has been demonstrated to have synergistic activity in a xenograft model of human CRC [10]. We have reported results from the phase 1/2 C-TASK FORCE showing a promising activity of the aforementioned combination in patients with pretreated mCRC. The primary endpoint of 16-week progression-free survival (PFS) was 42.9% [80% confidence interval (CI), 27.8–59.0]. The most common grade ≥ 3 adverse events were neutropenia (72%), leucopenia (44%), anemia (16%), febrile neutropenia (16%), and thrombocytopenia (12%) [11]. Managing the higher incidence of hematological toxicities is crucial to reduce the risks of serious treatment-related adverse events and maximize the efficacy of trifluridine/tipiracil plus bevacizumab treatment. Furthermore, the non-comparative phase 2 TASCO1 study evaluated the efficacy and safety of trifluridine/tipiracil plus bevacizumab and capecitabine plus bevacizumab and provided evidence demonstrating the efficacy of trifluridine/tipiracil plus bevacizumab in patients with untreated mCRC who were not eligible for standard first-line intensive therapy. The primary endpoint of PFS was 9.2 months in the trifluridine/tipiracil plus bevacizumab group and 7.8 months in the capecitabine plus bevacizumab group [12].\n\nAlthough trifluridine/tipiracil plus bevacizumab is a promising regimen for mCRC patients, little is known about the survival benefit and safety profile of the combination compared with trifluridine/tipiracil monotherapy. Therefore, the aim of this study was to investigate efficacy and safety of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in the clinical practice.\n\nMethods\nStudy design and patients\nClinical data of patients with mCRC who received trifluridine/tipiracil plus bevacizumab or trifluridine/tipiracil monotherapy at the National Cancer Center Hospital East was retrospectively collected. Study protocol was approved by the institutional review board. Informed consent requirement was waived due to the study’s observational retrospective design, with an opt-out opportunity provided at the institution’s website. Patient follow-up was performed until December 2018.\n\nEligibility criteria were as follows: histologically confirmed colorectal adenocarcinoma; no prior treatment with regorafenib; refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan, regardless of angiogenesis inhibitors or anti-EGFR antibody (if RAS wild-type); Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2; adequate organ function; concurrent treatment with trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015.\n\nStudy procedures\nTrifluridine/tipiracil plus bevacizumab regimen consisted of trifluridine/tipiracil 35 mg/m2 of body surface area, given orally twice a day on days 1–5 and 8–12 in a 28-day cycle, and bevacizumab 5 mg/kg of bodyweight, administered by intravenous infusion every 2 weeks. Trifluridine/tipiracil monotherapy consisted of trifluridine/tipiracil 35 mg/m2 of body surface area, given orally twice a day on days 1–5 and 8–12 in a 28-day cycle.\n\nThe following baseline characteristics were collected for each patient: age, gender, ECOG PS, primary tumor location, history of primary resection, number of metastatic organs, time from first-line chemotherapy start, time from prior bevacizumab, prior chemotherapy agents, RAS status (KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4), BRAF V600E mutation status, and microsatellite instability (MSI) status, if available.\n\nOutcomes\nEfficacy endpoints included PFS, defined as time from study treatment initiation to disease progression or death due to any cause; OS, defined as time from study treatment start to death from any cause; overall response rate (ORR), defined as proportion of patients with a complete or partial response to study treatment; disease control rate (DCR), defined as proportion of patients with a complete or partial response plus stable disease lasting more than 6 weeks from study treatment start. Tumor response was assessed by investigators using the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.03.\n\nStatistical analysis\nPFS and OS were compared between treatment groups using log-rank test with a two-sided significance level of p = 0.05. Hazard ratio (HR) and corresponding 95% CI were determined using a Cox proportional hazard model. Survival curves were generated using Kaplan-Meier estimates. Univariate and multivariate analyses were performed to evaluate the impact of trifluridine/tipiracil plus bevacizumab or trifluridine/tipiracil monotherapy treatments. Regression analysis covariates included treatment group, age, gender, ECOG PS, primary tumor location, RAS status, time from first-line chemotherapy start, and time from prior bevacizumab. Multivariate Cox analysis was employed using forward stepwise regression. Enter and remove limits were p = 0.05 and p = 0.20, respectively. Confounding variables considered in multivariate analysis included age (< 65 years old vs. ≥65 years old), gender (male vs. female), ECOG PS (0 vs. ≥1), primary tumor location (right vs. left), RAS status (wild-type vs. mutant), time from first-line chemotherapy start (≥18 months vs. < 18 months), and time from prior bevacizumab (≤1 month vs. > 1 month or no prior bevacizumab). ORR, DCR, and safety analyses between treatment groups were performed using Fisher’s exact test. Follow-up time was defined as time from study treatment start until the last follow-up date for censored cases. Statistical analyses were performed using IBM SPSS statistics version 22.0 (IBM Corp, Armonk, NY), and two-sided p < 0.05 was considered statistically significant.\n\nResults\nPatients\nSixty patients received trifluridine/tipiracil plus bevacizumab and 66 patients received trifluridine/tipiracil monotherapy. Patient demographics and baseline characteristics are shown in Table 1. All patients had previously received fluoropyrimidine, oxaliplatin, and irinotecan. Most of the patients in each group had a history of treatment with angiogenesis inhibitors, including bevacizumab, ramucirumab, or ziv-aflibercept. Approximately half of patients had RAS wild-type tumors, and no patient had MSI-high tumor. BRAF V600E mutation was detected in one patient (1.7%) in the trifluridine/tipiracil plus bevacizumab group and in four patients (6.1%) in the trifluridine/tipiracil monotherapy group. Patients with left-sided primary tumors were dominant in both groups and comprised 81.7% of the trifluridine/tipiracil plus bevacizumab group and 84.8% of the trifluridine/tipiracil monotherapy group. Median interval from study treatment start to first computed tomography evaluation was 1.8 months in both groups. Median follow-up was 7.1 months in the trifluridine/tipiracil plus bevacizumab groups and 7.2 months in the trifluridine/tipiracil monotherapy group. After study treatment discontinuation, 41.7% of patients in the trifluridine/tipiracil plus bevacizumab groups and 48.5% of patients in the trifluridine/tipiracil monotherapy group received subsequent antitumor therapy including regorafenib (31.7 vs. 39.4%), clinical trial therapy (6.7 vs. 4.5%), and cytotoxic chemotherapy (3.3 vs. 6.0%).\nTable 1 Patient characteristics\n\n\t\tTrifluridine/tipiracil plus bevacizumab group\tTrifluridine/tipiracil monotherapy group\t\nN = 60\t%\tN = 66\t%\t\nAge\tMedian (range)\t60 (23–79)\t\t65 (30–80)\t\t\n≥65 years old\t19\t31.7\t34\t51.5\t\nGender\tMale\t35\t58.3\t42\t63.6\t\nECOG PS\t0\t35\t58.3\t42\t63.6\t\n1\t24\t40.0\t21\t31.8\t\n2\t1\t1.7\t3\t4.5\t\nPrimary location\tRight\t11\t18.3\t10\t15.2\t\nLeft\t49\t81.7\t56\t84.8\t\nNumber of metastatic organs\t1\t6\t10.0\t13\t19.7\t\n2\t26\t43.3\t39\t59.1\t\n≥3\t28\t46.7\t14\t21.2\t\nTime from start of first-line chemotherapy\t< 18 months\t22\t36.7\t23\t34.8\t\n≥18 months\t38\t63.3\t43\t65.2\t\nTime from prior bevacizumab\t≤1 month\t34\t56.7\t33\t50.0\t\n> 1 month or no prior bevacizumab\t26\t43.3\t33\t50.0\t\nNumber of prior regimens\t1\t4\t6.7\t2\t3.0\t\n2\t29\t48.3\t33\t50.0\t\n3\t15\t25.0\t16\t24.2\t\n≥4\t12\t20.0\t15\t22.7\t\nPrior chemotherapy agents\tFluoropyrimidine\t60\t100\t66\t100\t\nIrinotecan\t60\t100\t66\t100\t\nOxaliplatin\t60\t100\t66\t100\t\nAngiogenesis inhibitors\t58\t96.7\t61\t92.4\t\nAnti-EGFR antibodies\t27\t45.0\t27\t40.9\t\nRAS status\tWild-type\t28\t46.7\t30\t45.5\t\nMutant\t32\t53.3\t36\t54.5\t\nBRAF status\tWild-type\t52\t86.7\t52\t78.8\t\nV600E mutant\t1\t1.7\t4\t6.1\t\nNon-V600E mutant\t2\t3.3\t0\t0\t\nUnknown\t5\t8.3\t10\t15.2\t\nMSI status\tMSS\t53\t88.3\t51\t77.3\t\nUnknown\t7\t11.7\t15\t22.7\t\nECOG PS Eastern Cooperative Oncology Group performance status, EGFR epidermal growth factor receptor, MSS microsatellite stable\n\n\n\nEfficacy\nPatients in the trifluridine/tipiracil plus bevacizumab group had significantly longer PFS compared with those in the trifluridine/tipiracil monotherapy group (HR 0.69; 95% CI 0.48–0.99; log-rank p = 0.037). Median PFS was 3.7 months (95% CI 2.3–5.1 months) in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI 1.8–2.6 months) in the trifluridine/tipiracil monotherapy group (Fig. 1a). PFS rate at 16 weeks was 46.6 and 33.9%, respectively. In multivariate analysis, similar PFS was observed between groups (adjusted HR 0.62; 95% CI 0.42–0.90, p = 0.01). Subgroup analyses also showed a PFS benefit for trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy for all parameters except ECOG PS (Table 2).\nFig. 1 a Kaplan–Meier plots for PFS. b Kaplan–Meier plots for OS\n\n\nTable 2 PFS and OS subgroup analyses\n\n\t\tPFS\tOS\t\nN\tHR\t95% CI\tInteraction p\tHR\t95% CI\tInteraction p\t\nAll patients\t126\t0.69\t0.48–0.99\t\t0.74\t0.48–1.14\t\t\n Age\t< 65 years old\t73\t0.53\t0.31–0.88\t0.542\t0.85\t0.48–1.50\t0.300\t\n≥65 years old\t53\t0.74\t0.41–1.32\t0.49\t0.23–1.08\t\n Gender\tMale\t77\t0.72\t0.45–1.15\t0.560\t0.98\t0.57–1.70\t0.162\t\nFemale\t49\t0.61\t0.34–1.09\t0.51\t0.25–1.04\t\n ECOG PS\t0\t77\t0.50\t0.31–0.80\t0.009\t0.54\t0.30–0.99\t0.033\t\n≥1\t49\t1.42\t0.79–2.55\t1.46\t0.76–2.82\t\n Primary location\tLeft\t105\t0.65\t0.44–0.98\t0.758\t0.72\t0.44–1.16\t0.986\t\nRight\t21\t0.64\t0.26–1.59\t0.62\t0.21–1.80\t\n Time from start of first-line chemotherapy\t≥18 months\t81\t0.71\t0.45–1.11\t0.359\t0.66\t0.38–1.16\t0.635\t\n< 18 months\t45\t0.67\t0.36–1.25\t0.78\t0.39–1.55\t\n Time from prior bevacizumab\t≤1 month\t67\t0.48\t0.28–0.82\t0.165\t0.64\t0.37–1.12\t0.975\t\n> 1 month or no prior bevacizumab\t59\t0.77\t0.45–1.33\t0.73\t0.36–1.45\t\n RAS status\tWild-type\t58\t0.87\t0.50–1.49\t0.147\t0.67\t0.35–1.28\t0.580\t\nMutant\t68\t0.52\t0.31–0.87\t0.79\t0.44–1.41\t\n History of bevacizumab\tyes\t118\t0.75\t0.51–1.09\t0.47\t0.70\t0.45–1.09\t0.88\t\n\tno\t8\t0.50\t0.09–2.67\t3.30\t0.29–37.7\t\nCI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, HR hazard ratio, OS overall survival, PFS progression-free survival\n\n\n\nMedian OS was 8.6 months (95% CI 6.9–10.3 months) for trifluridine/tipiracil plus bevacizumab and 8.0 months (95% CI 6.6–9.4 months) for trifluridine/tipiracil monotherapy (Fig. 1b). In multivariate analysis, an OS benefit was also observed for trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy, but without statistical significance (HR 0.74; 95% CI 0.48–1.14; log-rank p = 0.164). Similarly to PFS, longer OS was observed for all subgroups, except ECOG PS.\n\nThree patients in the trifluridine/tipiracil plus bevacizumab group and one patient in the trifluridine/tipiracil monotherapy group had partial response, resulting in a 5.0 and 1.5% ORR for each group, respectively (p = 0.35). Disease control was achieved in 32 patients (53.3%) in the trifluridine/tipiracil plus bevacizumab group and in 30 patients (45.5%) in the trifluridine/tipiracil monotherapy group (p = 0.48) (Table 3). Additionally, proportion of patients with 6 months or longer of disease control were significantly higher in the trifluridine/tipiracil plus bevacizumab group than the trifluridine/tipiracil monotherapy group (26.7% vs. 12.1%, p = 0.04).\nTable 3 Overall response\n\nBest response\tTrifluridine/tipiracil plus bevacizumab group\tTrifluridine/tipiracil monotherapy group\tP\t\nN = 60\t%\tN = 66\t%\t\nPR\t3\t5.0\t1\t1.5\t\t\nSD\t29\t48.3\t29\t43.9\t\nPD\t25\t41.7\t34\t51.5\t\nNE\t3\t5.0\t2\t3.0\t\nORR\t3\t5.0\t1\t1.5\t0.346\t\nDCR\t32\t53.3\t30\t45.5\t0.476\t\nDCR disease control rate, NE not evaluated, ORR overall response rate, PD progressive disease, PR partial response, SD stable disease\n\n\n\nSafety\nAll patients initially received full-dose trifluridine/tipiracil and bevacizumab or trifluridine/tipiracil monotherapy. Any cycle delay for ≥4 days was registered in 37 (61.7%) and 27 (40.9%) patients in the trifluridine/tipiracil plus bevacizumab group and trifluridine/tipiracil monotherapy groups (p = 0.02), and trifluridine/tipiracil dose reductions were required in 10 (16.7%) and 15 (22.7%) patients (p = 0.50), respectively.\n\nAdverse events are summarized in Table 4. Overall, grade ≥ 3 adverse events were more frequent in the trifluridine/tipiracil plus bevacizumab than in the trifluridine/tipiracil monotherapy group (n = 41, 68.3% vs. n = 36, 54.5%; p = 0.14). Incidence of grade ≥ 3 neutropenia was slightly higher in the trifluridine/tipiracil plus bevacizumab group than in the trifluridine/tipiracil monotherapy group, although this difference was not statistically significant (50.0% vs. 40.9%; p = 0.37). In contrast, no increased incidence of febrile neutropenia was observed in the trifluridine/tipiracil plus bevacizumab compared with the trifluridine/tipiracil monotherapy group (3.3% vs. 7.8%; p = 0.444). Ten patients (16.7%) in the trifluridine/tipiracil plus bevacizumab group and four patients (6.1%) in the trifluridine/tipiracil monotherapy group received granulocyte colony-stimulating factor (G-CSF), with no G-CSF prophylaxis use in the both groups. Any grade proteinuria (41.7% vs. 13.6%; p < 0.01) and hypertension (38.3% vs. 16.7%; p < 0.01), potentially associated with bevacizumab, were more common in the trifluridine/tipiracil plus bevacizumab group. Emergency hospital admission was required for 15 (25.0%) and 19 (28.8%) patients in the trifluridine/tipiracil plus bevacizumab and trifluridine/tipiracil monotherapy groups, respectively. No treatment-related deaths occurred in the both groups.\nTable 4 Adverse events\n\n\tTrifluridine/tipiracil plus bevacizumab group (N = 60)\tTrifluridine/tipiracil monotherapy group (N = 66)\t\nAny grade (%)\tGrade 3 (%)\tGrade 4 (%)\tAny grade (%)\tGrade 3 (%)\tGrade 4 (%)\t\nHematological\t\n Neutropenia\t41 (68.3)\t25 (41.7)\t5 (8.3)\t47 (71.2)\t19 (28.8)\t8 (12.1)\t\n Leucopenia\t49 (81.7)\t23 (38.3)\t0 (0)\t47 (71.2)\t17 (25.8)\t2 (3.0)\t\n Anemia\t52 (86.7)\t8 (13.3)\t1 (1.7)\t60 (90.9)\t12 (18.2)\t2 (3.0)\t\n Thrombocytopenia\t26 (43.3)\t1 (1.7)\t1 (1.7)\t24 (36.4)\t2 (3.0)\t0 (0)\t\nNon-hematological\t\n Proteinuria\t25 (41.7)\t4 (6.7)\t0 (0)\t9 (13.6)\t1 (1.5)\t0 (0)\t\n Hypertension\t23 (38.3)\t4 (6.7)\t0 (0)\t11 (16.7)\t0 (0)\t0 (0)\t\n Febrile neutropenia\t2 (3.3)\t2 (3.3)\t0 (0)\t5 (7.8)\t5 (7.8)\t0 (0)\t\n Gastrointestinal perforation\t2 (3.3)\t2 (2.9)\t0 (0)\t1 (1.5)\t1 (1.5)\t0 (0)\t\n Fatigue\t30 (50.0)\t0 (0)\t0 (0)\t25 (37.9)\t0 (0)\t0 (0)\t\n Anorexia\t25 (41.7)\t0 (0)\t0 (0)\t27 (40.9)\t1 (1.5)\t0 (0)\t\n Nausea\t10 (16.7)\t0 (0)\t0 (0)\t15 (22.7)\t0 (0)\t0 (0)\t\n Diarrhea\t5 (8.3)\t0 (0)\t0 (0)\t8 (12.1)\t0 (0)\t0 (0)\t\n Vomiting\t2 (3.3)\t0 (0)\t0 (0)\t4 (6.1)\t0 (0)\t0 (0)\t\n\n\nDiscussion\nAlthough the clinical evidence for trifluridine/tipiracil plus bevacizumab in pretreated mCRC patients only comes from a phase 1/2 C-TASK FORCE trial with a single-arm design, the present study showed clinical benefit with manageable toxicities for this combination in the real-world setting.\n\nThe PFS improvement associated with trifluridine/tipiracil plus bevacizumab can be regarded as clinically meaningful in this patient population. Considering the median PFS difference between trifluridine/tipiracil and placebo of 0.3 and 0.2 months reported in RECOURSE and TERRA trials, respectively, the absolute 1.5-month median PFS improvement observed in this study is clinically meaningful in salvage setting. Of note, a higher 16-week PFS rate was observed with trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy (46.6 vs. 33.9%), consistent with the primary endpoint of the C-TASK FORCE trial. Furthermore, although limited efficacy was reported in the C-TASK FORCE trial for trifluridine/tipiracil plus bevacizumab in patients with mutant RAS, a consistent benefit of the combination was observed in subgroup analyses in this study, irrespectively of RAS status. Although not statistically significant, a 0.74 HR for OS was observed in favor of trifluridine/tipiracil plus bevacizumab in this study. Fewer OS events in the trifluridine/tipiracil plus bevacizumab group due to limited follow-up may have failed to show statistical difference between both groups. In subgroup analyses, patients with ECOG PS 0 especially benefited from trifluridine/tipiracil plus bevacizumab in both PFS and OS. Although no clear benefit of trifluridine/tipiracil plus bevacizumab were observed in patients with ≥ ECOG PS 1, it is not sufficient reason to refrain from using trifluridine/tipiracil plus bevacizumab in those patients, considering retrospective nature of this study.\n\nTrifluridine/tipiracil plus bevacizumab toxicities were well tolerated in the clinical practice setting. Frequency of grade ≥ 3 neutropenia in the trifluridine/tipiracil plus bevacizumab group in this study was lower than in the C-TASK FORCE trial (50.0 vs. 72%). Along with a relatively lower frequency of grade ≥ 3 neutropenia, G-CSF was used in 16.8% of patients in the trifluridine/tipiracil plus bevacizumab group in this study compared with 28% of patients in the C-TASK FORCE trial. However, considering the common occurrence of grade ≥ 3 neutropenia, the higher proportion of cycle initiation delay in the trifluridine/tipiracil plus bevacizumab group, and the patient population in salvage setting, appropriate supportive intervention with G-CSF or temporary dose interruptions were still important for safety management with trifluridine/tipiracil plus bevacizumab. As bevacizumab – related toxicities, incidence of any grade proteinuria and hypertension were significantly higher in the trifluridine/tipiracil plus bevacizumab group. In the salvage line setting, since almost all patients have received one or more prior angiogenesis inhibitor including bevacizumab, these bevacizumab – related toxicities should be monitored carefully. Notably, such safety management was not associated with an increase in emergency hospital admissions with trifluridine/tipiracil plus bevacizumab, and the incidence of serious adverse events in this study was similar to the observed in RECOURSE and C-TASK FORCE trials and in clinical practice, as previously reported from our institution [13].\n\nEfficacy and safety of trifluridine/tipiracil plus bevacizumab is also being investigated in prospective clinical trials. The phase 2 JFMC51–1702-C7 study (UMIN000030077) will validate the use of trifluridine/tipiracil plus bevacizumab in pretreated mCRC patients. Furthermore, this combination is an effective (ORR 40.5% and DCR 86.5%) and well-tolerated first-line treatment regimen for elderly patients (KSCC1602; UMIN000025241) [14]. More recently, a randomized Danish study of 80 patients with heavily pretreated mCRC reported a PFS extension with trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy [15]. Based on the above-mentioned findings, several phase 2 or 3 studies are in place, including studies investigating this regimen as post-induction chemotherapy maintenance (ALEXANDRIA; NCT02654639) and as second-line treatment for mCRC patients who failed first-line oxaliplatin-based chemotherapy versus FOLFIRI (or S-1 plus irinotecan) plus bevacizumab (TRUSTY; JapicCTI-173,618) [16].\n\nThis study has several limitations. Firstly, as previously noted, it was a non-randomized retrospective study in a single institution with a limited sample size. Secondly, no patients received prior regorafenib. However, the C-TASK FORCE trial also did not allow prior regorafenib and the study population was very similar to the Japanese subset of the RECOURSE trial. Finally, all patients enrolled in this study were Japanese. The absence of ethnic differences in the RECOURSE and TERRA trials could enable results to be applied to all patients, regardless of race.\n\nConclusions\nIn conclusion, in the present study trifluridine/tipiracil plus bevacizumab was shown to have superior clinical activity compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC. Additionally, similarly to trifluridine/tipiracil monotherapy, toxicities observed with the combination were manageable in the real-world setting.\n\nAbbreviations\nCIConfidence interval\n\nCRCColorectal cancer\n\nDCRDisease control rate\n\nECOG PSEastern Cooperative Oncology Group performance status\n\nG-CSFGranulocyte colony-stimulating factor\n\nHRHazards ratio\n\nmCRCMetastatic colorectal cancer\n\nMSIMicrosatellite instability\n\nORROverall response rate\n\nOSOverall survival\n\nPFSProgression-free survival\n\nTK1Thymidine kinase 1\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nDK initiated the study, participated in its design and data collection, performed statistical analyses, and drafted the manuscript. YK was responsible for study conception and helped manuscript writing. SH and AK1 participated in data collection. YN, AK2, HB, HT, KS, TK, AT edited manuscript. TY helped manuscript writing and participated in manuscript editing. All authors read and approved the final manuscript.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nStudy protocol was approved by the institutional review board (National Cancer Center IRB, ref. 2017–279). Informed consent requirement was waived due to the study’s observational retrospective design, with an opt-out opportunity provided at the institution’s website.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nDK reports receiving honoraria from Takeda, Chugai, Lilly, and Merck Serono. YK reports receiving honoraria from Taiho, research funding from Taiho, Takeda, Ono, AstraZeneca, INC research, Daiichi-Sankyo, and Boehringer Ingelheim. YN reports research funding from Ono and Taiho. AK2 reports receiving research funding from Ono, Sumitomo Dainippon and Taiho. HB reports receiving lecturer fee from Taiho and Lilly; research expenses from Taiho, AstraZeneca, and Sysmex. HT reports receiving honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly, Yakult, and Sanofi. KS reports paid consulting or advisory roles for Astellas, Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono and MSD; honoraria from Novartis, AbbVie, and Yakult; and research funding from Astellas, Lilly, Ono, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD and Medi Science. TK reports receiving research funding from Shionogi, MSD, Ono Pharmaceutical, Chugai, Oncolys BioPharma, Astellas Amgen BioPharma, and Parexel. AT reports receiving honoraria from Daiichi-Sankyo, Taiho, Chugai, Merck Serono, Takeda, and Bristol-Myers Squibb; speaker’s bureau from Chugai, Taiho, Takeda, and Merck Serono. YK reports receiving honoraria Takeda, Chugai, Bristol-Myers Squibb, Ono, Merck Biopharma, Taiho, Bayer, Lilly, Yakult Honsha, Sanofi, Nipro, Moroo, Asahi Kasei, Mitsubishi Tanabe, Otsuka, Medical Review, and Shiseido; research funding from MSD, Daiichi Sankyo, NanoCarrier, Eisai, Sysmex, Shionogi, IQVIA, Parexel International, Astellas, Mediscience, Sumitomo Dainippon, A2 Healthcare, Ono, Taiho, Bayer, Yakult Honsha, and Sanofi. TS reports receiving honoraria from Chugai, Merck Serono, Bristol-Myers Squibb, Takeda, Yakult Honsha, Lilly, Bayer Yakuhin, Ono, Merck, Astellas Pharma, Taiho, and Nihonkayaku; consulting or advisory role from Bayer, Lilly, Ono, Takara Bio, Merck Serono, and Nihonkayaku; research funding from Yakult Honsha, Chugai, Ono, Sanofi, Lilly, Daiichi Sankyo, Merck Serono, Gilead Sciences, and Dainippon Sumitomo. TE reports receiving honoraria from Lilly, Taiho, Bristol-Myers Squibb Japan, Eisai, Daiichi Sankyo, Merck Serono, Chugai, Ono, Takeda, Bayer, and Sanofi; research funding from Daiichi Sankyo, Merck Serono, MSD, Novartis, Dainippon Sumitomo, Ono, Astellas Pharma, Lilly, Bayer, Nihonkayaku, Pfizer, and Bristol-Myers Squibb Japan. SN reports receiving honoraria from Taiho and Astrazeneca. AS reports receiving research funding from MSD, Eisai, Ono, Taiho, Takeda, and Bayer. AO reports receiving honoraria from Ono, BMS, Chugai, Taiho, Eisai, and Amgen; research funding from Bristol-Myers Squibb; immediate family member of Atsushi Ohtsu have been employed by Celgene. TY reports receiving research funding from Novartus, MSD, Sumitomo Dainippon, Chugai, Sanofi, Daiichi-Sankyo, Parexel, Ono, GlaxoSmithKline, and Boehringer Ingelheim.\n==== Refs\nReferences\n1. 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Grothey A Van Cutsem E Sobrero A Siena S Falcone A Ychou M Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicenter, randomized, placebo-controlled, phase 3 trial Lancet 2013 318 303 312 10.1016/S0140-6736(12)61900-X \n7. Mayer RJ Van Cutsem E Falcone A Yoshino T Garcia-Carbonero R Mizunuma N Randomized trial of TAS-102 for refractory metastatic colorectal cancer N Engl J Med 2015 372 1909 1919 10.1056/NEJMoa1414325 25970050 \n8. Yoshino T Mizunuma N Yamazaki K Nishina T Komatsu Y Baba H TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomized, placebo-controlled phase 3 trial Lancet Oncol 2012 13 993 1001 10.1016/S1470-2045(12)70345-5 22951287 \n9. Xu J Kim TW Shen L Sriuranpong V Pan H Xu R Results of a randomized, double-blind, placebo-controlled, phase III trial of trifluridine/tipiracil (TAS-102) monotherapy in Asian patients with previously treated metastatic colorectal cancer: the TERRA study J Clin Oncol 2017 36 350 358 10.1200/JCO.2017.74.3245 29215955 \n10. Tsukihara H Nakagawa F Sakamoto K Ishida K Tanaka N Okabe H Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts Oncol Rep 2015 33 2135 2142 25812794 \n11. Kuboki Y Nishina T Shinozaki E Yamazaki K Shitara K Okamoto W TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicenter, phase 1/2 study Lancet Oncol 2017 18 1172 1181 10.1016/S1470-2045(17)30425-4 28760399 \n12. Lesniewski-Kmak K Moiseenko V Saunders M Wasan H Argiles G Borg C Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are non-eligible for intensive therapy (TASCO1): results of the primary analysis Ann Oncol 2018 29 mdy149.021 10.1093/annonc/mdy149.021 \n13. Kotani D Shitara K Kawazoe A Fukuoka S Kuboki Y Bando H Safety and efficacy of trifluridine/tipiracil monotherapy in clinical practice for patients with metastatic colorectal cancer: experience at a single institution Clin Colorectal Cancer 2016 15 e109 e115 10.1016/j.clcc.2015.11.005 26723516 \n14. Oki E Makiyama A Miyamoto Y Kotaka M Kawanaka H Miwa K Trifluridine/tipiracil plus bevacizumab in elderly patients with previously untreated metastatic colorectal cancer (KSCC1602): A multicenter, phase II clinical trial J Clin Oncol 2019 37 suppl abstr 3548 10.1200/JCO.2019.37.15_suppl.3548 \n15. Yoshino T Oki E Nozawa H Eguchi-Nakajima T Taniguchi H Morita S Rationale and design of the TRUSTY study: a randomized, multicenter, open-label phase II/III study of trifluridine/tipiracil plus bevacizumab versus irinotecan, fluoropyrimidine plus bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during following first-line oxaliplatin-based chemotherapy ESMO Open 2018 3 e000411 10.1136/esmoopen-2018-000411 30167332 \n16. Pfeiffer P Yilmaz M Möller S Maltha L Krogh M Zitnjak D Randomized study evaluating trifluridine/tipiracil (TAS-102) versus + trifluridine/tipiracil + bevacizumab as last-line therapy in patients with chemorefractory unresectable metastatic colorectal cancer (mCRC) J Clin Oncol 2019 37 637 10.1200/JCO.2019.37.4_suppl.637\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "19(1)",
"journal": "BMC cancer",
"keywords": "Lonsurf; TAS-102; Trifluridine/tipiracil plus bevacizumab; mCRC",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011759:Pyrrolidines; D012189:Retrospective Studies; D013941:Thymine; D014271:Trifluridine; D014498:Uracil; D055815:Young Adult",
"nlm_unique_id": "100967800",
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"pages": "1253",
"pmc": null,
"pmid": "31881856",
"pubdate": "2019-12-27",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article",
"references": "30167332;28632865;22951287;29215955;25088940;23177514;25877855;22949147;28760399;26723516;25812794;25970050",
"title": "Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer.",
"title_normalized": "retrospective cohort study of trifluridine tipiracil tas 102 plus bevacizumab versus trifluridine tipiracil monotherapy for metastatic colorectal cancer"
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"abstract": "Background: Parathyroid carcinoma is rare, representing <1% of primary hyperparathyroidism cases. Methods: Retrospective data of patients referred for evaluation of parathyroid disease between 2001 and 2018 were reviewed. The goal was to describe the clinical presentation, histopathologic characteristics, and treatment outcomes of parathyroid carcinoma. Results: We identified 8 cases of parathyroid carcinoma from the outpatient practice of a quaternary care Endocrine Oncology practice in Toronto, Canada. The clinical presentation was as follows: 5/8 cases (62.5%) of symptomatic hypercalcemia and 3/8 cases (37.5%) of a suspicious thyroid nodule. Hypercalcemia was evident in all 7 cases with pre-operative calcium measurements. Histopathologic features included: vascular invasion in 7/8 cases (87.5%) and immunohistochemical loss of either parafibromin, retinoblastoma, or p27 in all 8 cases. Additional treatment included: external beam radiotherapy in 5/8 cases (62.5%), chemotherapy for 2/8 patients (25%), and additional surgery for 3/8 patients (37.5%). Only 2 patients (25%) had long-term remission following surgical treatment, and the others had either persistent (3 patients) or recurrent disease (3 patients). Five patients developed metastatic disease, all involving lung. In one of two patients treated with Sorafenib there was evidence of regression of lung metastases. One patient died of disease progression. Conclusion: In this series of patients with parathyroid carcinoma largely presenting with symptomatic hypercalcemia and angioinvasive disease, only a minority achieved a durable remission. Lung was the most common site of distant metastasis. Surgery led to remission in two cases, but none of the six patients with persistent or recurrent disease ultimately achieved disease remission.",
"affiliations": "Department of Endocrine Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.;Department of Pathology, University Health Network, University of Toronto, Toronto, ON, Canada.;Department of Endocrine Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.;Department of Pathology, University Health Network, University of Toronto, Toronto, ON, Canada.;Division of Endocrinology, University Health Network and University of Toronto, Toronto, ON, Canada.;Department of Medicine, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.;Department of Endocrine Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.",
"authors": "Akirov|Amit|A|;Asa|Sylvia L|SL|;Larouche|Vincent|V|;Mete|Ozgur|O|;Sawka|Anna M|AM|;Jang|Raymond|R|;Ezzat|Shereen|S|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3389/fendo.2019.00731",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)Front Endocrinol (Lausanne)Front. Endocrinol.Frontiers in Endocrinology1664-2392Frontiers Media S.A. 10.3389/fendo.2019.00731EndocrinologyOriginal ResearchThe Clinicopathological Spectrum of Parathyroid Carcinoma Akirov Amit 123*Asa Sylvia L. 4Larouche Vincent 15Mete Ozgur 4Sawka Anna M. 6Jang Raymond 7Ezzat Shereen 11Department of Endocrine Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada2Institute of Endocrinology, Beilinson Hospital, Petach Tikva, Israel3Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel4Department of Pathology, University Health Network, University of Toronto, Toronto, ON, Canada5Division of Endocrinology and Metabolism, Department of Medicine, Jewish General Hospital, McGill University, Montreal, QC, Canada6Division of Endocrinology, University Health Network and University of Toronto, Toronto, ON, Canada7Department of Medicine, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, CanadaEdited by: Maria Chiara Zatelli, University of Ferrara, Italy\n\nReviewed by: Rosaria Maddalena Ruggeri, University of Messina, Italy; Jean-Yves Scoazec, Institut Gustave Roussy, France\n\n*Correspondence: Amit Akirov amit.akirov@gmail.comThis article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology\n\n23 10 2019 2019 10 73127 7 2019 10 10 2019 Copyright © 2019 Akirov, Asa, Larouche, Mete, Sawka, Jang and Ezzat.2019Akirov, Asa, Larouche, Mete, Sawka, Jang and EzzatThis 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.Background: Parathyroid carcinoma is rare, representing <1% of primary hyperparathyroidism cases.\n\nMethods: Retrospective data of patients referred for evaluation of parathyroid disease between 2001 and 2018 were reviewed. The goal was to describe the clinical presentation, histopathologic characteristics, and treatment outcomes of parathyroid carcinoma.\n\nResults: We identified 8 cases of parathyroid carcinoma from the outpatient practice of a quaternary care Endocrine Oncology practice in Toronto, Canada. The clinical presentation was as follows: 5/8 cases (62.5%) of symptomatic hypercalcemia and 3/8 cases (37.5%) of a suspicious thyroid nodule. Hypercalcemia was evident in all 7 cases with pre-operative calcium measurements. Histopathologic features included: vascular invasion in 7/8 cases (87.5%) and immunohistochemical loss of either parafibromin, retinoblastoma, or p27 in all 8 cases. Additional treatment included: external beam radiotherapy in 5/8 cases (62.5%), chemotherapy for 2/8 patients (25%), and additional surgery for 3/8 patients (37.5%). Only 2 patients (25%) had long-term remission following surgical treatment, and the others had either persistent (3 patients) or recurrent disease (3 patients). Five patients developed metastatic disease, all involving lung. In one of two patients treated with Sorafenib there was evidence of regression of lung metastases. One patient died of disease progression.\n\nConclusion: In this series of patients with parathyroid carcinoma largely presenting with symptomatic hypercalcemia and angioinvasive disease, only a minority achieved a durable remission. Lung was the most common site of distant metastasis. Surgery led to remission in two cases, but none of the six patients with persistent or recurrent disease ultimately achieved disease remission.\n\nhyperparathyroidismparathyroid carcinomathyroid noduleparathyroidectomyparathyroid diseaseEndocrine Oncology\n==== Body\nIntroduction\nThe diagnosis of parathyroid carcinoma is usually determined at pathology examination following surgery for a suspected parathyroid neoplasm or for another indication, as there are no reliable preoperative tests to confirm this diagnosis (1). While most patients with parathyroid cancer present with functioning lesions and hyperparathyroidism, some may have normal parathyroid hormone (PTH) levels (2, 3). As this is a very rare disease, accounting for <1% of all cases of primary hyperparathyroidism, data regarding the diagnosis, treatment modalities and outcomes are limited (1, 4, 5).\n\nThe diagnosis of parathyroid carcinoma must be made by the pathologist on the surgically resected tumor and is, therefore, typically post-operative. Occasionally there can be preoperative documentation of distant or lymph node metastasis or gross local invasion into adjacent organs, but these are more often identified by the pathologist; the diagnosis may also be confirmed in the absence of gross invasion or metastasis when there is unequivocal perineural, lymphatic, and/or vascular invasion identified on histopathology. The findings of fibrosis, necrosis and increased mitotic activity are worrisome histological findings but not do not necessarily warrant the diagnosis of malignancy, as they can be seen in parathyroid hyperplasia or adenomas that have been physically manipulated (6–9).\n\nThe American Joint Committee on Cancer (AJCC) eighth edition of cancer staging has recently proposed a classification of these tumors. Staging of the primary tumor (T) is as follows: localized to the parathyroid gland with limited extension to soft tissue (T1); direct invasion into the thyroid gland (T2); direct invasion into recurrent laryngeal nerve, esophagus, trachea, skeletal muscle, adjacent lymph nodes, or thymus (T3); or direct invasion into major blood vessel or spine (T4). Staging of regional lymph nodes (N) includes: no regional lymph node metastasis (N0); metastasis to regional lymph nodes (N1), including metastasis to level VI or VII (N1a) or to levels I, II, III, IV, V, or retropharyngeal nodes (N1b). Staging of distant metastasis (M) is, as for other tumors: no distant metastasis (N0) or with evidence of distant metastasis (M1). However, as the available data on tumor characteristics and prognosis are limited, no prognostic stage groups were suggested (10).\n\nPrevious studies have shown that surgical intervention has the best chance of disease control and long-term remission (4, 5). Sandelin et al. reported a median time from initial surgery to first recurrence of 33 months (range 1–228 months), with median survival time from the first recurrence to death of 28 months (range 0–129 months). The 5 year and the 10 year overall survival in their study was 85 and 70%, respectively. A review from the National Cancer Database reported a 5-year survival rate of 86% and 10-year survival rate of 49% (11).\n\nThere is some uncertainty regarding the benefit of external beam radiotherapy (EBRT) for prevention of recurrent disease. The American Association of Endocrine Surgeons published guidelines for definitive management of primary hyperparathyroidism stating that adjuvant EBRT should not be routinely performed after surgical resection of parathyroid cancer, suggesting that radiation should be reserved as a palliative option (12). There are very limited data in the medical literature regarding other treatment modalities specifically targeted against this rare endocrine carcinoma. Limited guidelines are available for medical treatment of parathyroid cancer, and the aforementioned guidelines by the American Association of Endocrine Surgeons did not include specific recommendations for drug treatment.\n\nThe aim of this study was to describe the clinical presentation, histopathologic characteristics, and treatment outcomes of patients with surgically-treated parathyroid carcinoma.\n\nMethods\nIn this retrospective chart review, we reviewed the records of all patients referred for evaluation and management of parathyroid disease at the Endocrine Oncology Clinic of one of the authors (SE) at the Princess Margaret Cancer Centre, Toronto, Ontario, between 2001 and 2018. Cases were identified using clinical scheduling records which were linked to billing diagnostic codes, and screening of the electronic and paper medical records of those with relevant billing codes.\n\nThe data from the electronic or paper health records was abstracted and entered into an electronic spreadsheet (Excel, Microsoft) by a study investigator (AA) and checked for accuracy by the treating physician (SE). The diagnosis of parathyroid cancer was based on the presence of invasive histopathologic features (e.g., vascular invasion, lymphatic invasion, perineural invasion or local gross malignant invasion into surrounding structures) of the primary tumor or the presence of biopsy-proven distant and/or nodal metastatic disease.\n\nThe study was restricted to surgically treated cases, where review of the surgical pathology was performed by the same two experienced endocrine pathologists (SLA; OM) to ensure consistency of detailed histopathologic features. All the pathology samples were reviewed and their reports in the electronic medical record detailed the status of vascular invasion (defined by tumor cells invading through a vessel wall and/or intravascular tumor cells admixed with thrombus), lymphatic invasion, perineural invasion, invasion of other tissues, surgical margin involvement, immunohistochemical reactivity of p27, parafibromin, and Rb, as well as the Ki67 labeling index. Both pathologists agreed in advance on the criteria for the diagnosis of vascular invasion (13). All patients were followed by a single Endocrine Oncologist (SE). The typical post-operative follow-up protocol included clinical, biochemical, and radiological follow-up. Remission was defined by the presence of low or appropriate PTH and calcium levels and no evidence of structural disease on cross-sectional imaging.\n\nWe summarized the data descriptively, including numbers and percentages for categorical data and mean or median and standard deviation (SD) or range for continuous data. The study was approved by the institutional research ethics board of University Health Network. Informed consent was not required for this retrospective chart review.\n\nResults\nWe reviewed 219 patients referred for parathyroid disease; 175 patients were found to have hyperparathyroidism, 14 patients were managed for hypoparathyroidism, and 30 patients were found to have normal parathyroid function. Of the 175 patients with hyperparathyroidism, 149 individuals had primary hyperparathyroidism, including 9 patients with parathyroid carcinoma; 22 cases were secondary hyperparathyroidism; 3 were tertiary hyperparathyroidism; one patient had familial hypocalciuric hypercalcemia. Of the parathyroid cancer cases, one was excluded as the pathology sample from another institution was not available for review. We ultimately included 8 patients (5 women, 3 men) with parathyroid carcinoma meeting our study eligibility criteria (with mean age ± SD at diagnosis of 53.5 ± 10.4 years, Table 1). The mean ± SD follow-up was 6.2 ± 3.8 years. The family history was negative for parathyroid carcinoma in all cases.\n\nTable 1 Clinical data and therapeutic approaches for eight patients with parathyroid carcinoma.\n\nPatient number\tFollow-up (years)\tStage\tSurgical intervention\tRadiation (Gy)\tChemotherapy\tMetastasis at baseline\tMetastasis during FU\tOutcome\tExitus\t\n#1\t3.5\tT3N0M1\tTotal Thyroidectomy\t56\t–\tLung, hip\tLung, hip liver\tPersistent disease\t–\t\n#2\t6.4\tT1NxM0\tRt. Hemithyroidecomy\t–\t–\t–\t–\tRemission\t–\t\n#3\t3.6\tT2N1M0\tTotal Thyroidectomy\t60\t–\t–\tlung\tPersistent disease\t+ (Parathyroid cancer)\t\n#4\t4.6\tT1N0M0\tRight Subtotal Thyroidectomy + Right Parathyroidectomy + Mediastinal Dissection + Right neck dissection\t–\t–\t–\t–\tRemission\t–\t\n#5\t6.7\tT1NxM0\tThree Surgeries – Resection of right superior PTA >> Right subtotal thyroidectomy + removal of multiple small nodules in the infero-lateral aspect of the gland and sternomastoid muscle >> Right central neck dissection\t66\t–\t–\t–\tInitial remission, followed by recurrent disease.\t–\t\n#6\t13.9\tT2NxM0\tTwo Surgeries – Right Hemithyroidectomy + Right Inferior Parathyroidectomy >> Right neck dissection\t50\t–\t–\tlung\tInitial remission, followed by recurrent disease.\t+ (Colon adenocarcinoma)\t\n#7\t2\tT2N1M0\tTotal Thyroidectomy + Central and Left neck dissection\t–\tSORAFENIB\t–\tlung\tPersistent disease\t–\t\n#8\t8.8\tT1NxM0\tLt. Parathyroidectomy + Small margin of the thyroid >> Thoracotomy with neck dissection, resection of mediastinal mass, part of the manubrium and clavicular head, sternum, first rib\t66\tCAP-TEM >> Etoposide-Cisplatin >> investigational therapy >> Sorafenib >> Everolimus\t–\tliver, skeletal, lung, peritoneum, lymph nodes.\tInitial remission, followed by recurrent disease\t–\t\nClinical Presentation\nThe diagnosis of parathyroid carcinoma was made at the time of histopathologic examination after surgical resection in all cases. Calcium levels were elevated in all seven patients who had these measured preoperatively (mean ± SD before surgery 3.7 ± 0.8 mmol/L; mean PTH ± SD levels before surgery 64.9 ± 63.3 pmol/L). Pre-operative management was not standardized, as some of these patients were referred only after the histopathologic diagnosis of parathyroid carcinoma was made after surgery.\n\nInvestigation of a neck mass led to diagnosis of a thyroid nodule in three patients (patients #1–3) who were referred for thyroidectomy; the pathology report following surgery revealed parathyroid carcinoma. One of these patients (patient #3), had been investigated for weight loss and constipation, leading to the diagnosis of hyperparathyroidism, and a neck ultrasound revealed a 3.5 cm hypoechoic nodule in the lower pole of the right thyroid that was suspicious for differentiated thyroid cancer on fine-needle aspiration biopsy. The patient underwent total thyroidectomy and the pathology was consistent with angioinvasive and widely invasive parathyroid carcinoma arising from the right parathyroid gland and involving the thyroid and the painted resection margins. In five other patients (patients #4–8), surgery was indicated for primary hyperparathyroidism identified during investigation of symptomatic hypercalcemia, including one case of kidney stones (patient #6), hypercalcemia-induced pancreatitis (patient #5), and other symptoms associated with high calcium levels such as bony aches, polyuria, polydipsia, and constipation (patients #4, #7, and #8). One of these patients (patient #4) presented to the emergency room with severe life-threatening hypercalcemia (calcium 5.0 mmol/L, PTH 27.8 pmol/L) and mental changes, was hospitalized in the intensive care unit and an ultrasound examination revealed a 6 cm mass in the right paratracheal area, as well as a mass in her right ipsilateral thyroid. This patient had an emergent right subtotal thyroidectomy with right parathyroidectomy, mediastinal dissection and right zone 6 neck dissection. The pathology revealed parathyroid carcinoma, as well as follicular variant papillary thyroid carcinoma.\n\nIn this case series, the parathyroid tumor was found mainly on the right side (6/8 patients, 75%). Only one patient was diagnosed with distant metastases immediately following the diagnosis of parathyroid carcinoma (patient #1), and these included metastases to the lungs, bone (hip) and liver. Four other patients (patient #3, #6, #7, and #8) had no evidence of metastasis at baseline, but developed metastases during follow-up, with evidence of lung metastases in all of them. Germline DNA testing for CDC73/HRPT2 was performed based on the documentation of loss of parafibromin by immunohistochemistry staining in three patients (patients #1, #7, #8); germline pathogenic mutations were not found in these patients.\n\nAll patients had a history of kidney stones, which were symptomatic in all but one patient (patient #4). There was no history of bony fractures in any of the patients, and preoperative bone mineral density results were not available. One patient (patient #8) had prior surgeries on his right humerus and left hip, all performed at another institution; these were possibly brown tumors.\n\nHistopathologic Findings\nThe pathology characteristics are summarized in Table 2. The mean tumor size was 49.0 ± 26.5 mm in the 6 patients for whom preoperative imaging results were available, as the remaining 2 patients were initially treated elsewhere. Vascular invasion was evident in 7 patients, and indeterminate in one patient (patient #1). Lymph node involvement was reported in two patients (patient #3 and #7); positive margins were evident in six patients (patients #1–4, #6, and #8). The adjacent thyroid was invaded in all of these patients; local gross invasion to other adjacent tissues was identified in one patient (patient #1) and perineural invasion was documented in one case (patient #7).\n\nTable 2 Pathology features of 8 parathyroid carcinomas.\n\nPatient number\tAge at diagnosis\tGender\tSize (mm)\tVascular invasion\tLymph Node involvement\tPositive margins\tInvasion to adjacent tissue\tChromogranin\tp27 Loss\tParafibromin loss\tRb loss\tNecrosis\tMIB1%\t\n#1\t54\tF\t37\tIndeterminate\t0/5\t+\tThyroid, Esophageal Margin\t+\t+\t+\t+\t–\t\t\n#2\t53\tF\t34\t+\t\t+\t–\t+\t+\t−\t+\t–\t5%\t\n#3\t73\tM\t35\t+\t5-Jan\t+\tThyroid\t+\t+\tminimal loss\t+\t+\t>20%\t\n#4\t51\tF\t65\t+\t0/2\t+\t–\t\t+\t–\t–\t\t5%\t\n#5\t41\tF\tNA\t+\t0\tNA\t–\t+\t+\t+\t+\t\t4%\t\n#6\t54\tF\tNA\t+\t\t+\tThyroid\t–\t+\t–\t+\t+\tNA\t\n#7\t61\tM\t27\t+\tJan-38\t−\tThyroid\t+\t+\t+\t–\t+\t19.60%\t\n#8\t41\tM\t96\t+\t\t+\t–\t\t\t+\t+\t\t14.98%\t\nIn addition to immunohistochemical biomarkers of parathyroid differentiation including chromogranin-A and parathyroid hormone and GATA3, the expression profile of biomarkers that may represent potential markers of malignancy or targets for novel therapies was also examined in these cases. Loss of p27 was found in six cases (patients #1, #2, #4, #5–7), while in 4 cases there was parafibromin loss (patients #1, #5, #7, and #8). Loss of Rb was reported in six patients (patients #1–3, #5, #6, and #8). Staining for p53 was done in 7 of 8 cases and showed no evidence of misexpression in all seven (i.e., no complete loss and no diffuse positivity). In two cases examined for further ancillary testing, galectin-3 was positive in both cases (patients #4 and #7), while BCL2 staining was retained in one (patient #4) and reduced in the other (patient #7). The Ki67 labeling index was available for 6 of 8 tumors; in three patients it was approximately 5% (patients #2, #4, #5), while in three others it was ≥15% (patients #3, #7, and #8). Of note, there were five patients who developed metastases during follow-up; the Ki67 labeling index was available for three of these patients, and in all three it was ≥15% in the primary tumor. The Ki67 data of the other two patients with metastatic disease was not available.\n\nThe TNM staging of the cancer is shown in Table 1. One patient had metastatic disease (M1) on presentation, two patients had evidence of regional lymph node metastasis (N1), while in 4 patients the nodal status was unknown (Nx). Half of the patients had tumor localized to the parathyroid gland with limited extension to soft tissue (T1) (Table 1).\n\nPre-operative FNA was performed in two of the three patients (patients #1–3) who were referred for surgical intervention due to suspected thyroid nodules; these resulted in an indeterminate result in one (patient #2) and a diagnosis of “suspicious for papillary thyroid cancer” in the other (patient #3). All these patients were found to harbor parathyroid carcinoma, with no evidence of thyroid malignancy. However, in four of six patients with primary hyperparathyroidism (patients #4, #5, #7, and #8), who were referred for surgical intervention for parathyroid disease, there was an incidental finding of papillary thyroid cancer, with three cases of microcarcinoma (patients #5, #7, and #8), and one case (patient #4) diagnosed with a 1.8 cm oncocytic follicular variant papillary thyroid carcinoma.\n\nTreatment\nAs shown in Table 1, five patients underwent only one surgical intervention. Two patients had total thyroidectomy (patients #1 and #3), one patient (patient #2) had right hemithyroidecomy for a suspicious nodule. Two patients (patients #6 and #8) had two surgeries (patient #6: right hemithyroidectomy with right inferior parathyroidectomy followed by neck dissection; patient #8: subtotal thyroidectomy with left inferior parathyroidectomy, followed by thoracotomy with neck dissection, resection of mediastinal mass, part of the manubrium and clavicular head, sternum, and first rib), while another patient (patient #5) had three surgeries, including initial resection of the right superior parathyroid gland, followed by right subtotal thyroidectomy with removal of multiple small nodules in the infero-lateral aspect of the gland and sternomastoid muscle, and eventually a right central neck dissection.\n\nRegarding the two patients without a diagnosis of hyperparathyroidism prior to the surgery (patients #1 and #2), one of them (patient #1) did not have PTH levels measured before surgery, however during post-operative follow up she was diagnosed with hyperparathyroidism and hypercalcemia. The other patient (patient #2) developed hypocalcemia with hungry bone syndrome after surgery, although she only had right hemithyroidectomy, as the indication for surgery was a suspected thyroid lesion. These findings, along with the fact that all patients had a history of kidney stones, suggest that all the patients in this cohort had functional hyperparathyroidism likely attributable to their disease.\n\nExternal beam radiation treatment (EBRT) to the neck was administered to five patients (patients #1, #3, #5, #6, and #8), at doses ranging between 50 and 66 Gy. This line of treatment was chosen due to persistent disease following surgery in 4 of 5 patients (patients #1, #3, #5, and #8). Right recurrent laryngeal palsy before the surgery and uncontrolled hypercalcemia following the parathyroid surgery was the indication for EBRT in the remaining patient (patient #6). Three patients went into remission following surgical and radiation treatment (patients #5, #6, and #8), but two of them (patients #6, and #8) were later diagnosed with recurrent local and distant disease. In the other two patients (patients #1, and #3) there was evidence of residual disease, both local and distant, and one (patient #3) passed away from his parathyroid cancer during the follow-up period.\n\nAdditional systemic therapies were used to control hypercalcemia; cinacalcet was used in one patient (patient #6), zoledronate was used in two patients (patients #7 and #8) but later was switched to denosumab 120 mg, which was also used in another patient (patient #3) with good response.\n\nSorafenib was used in two patients (patient #7 and #8) with evidence of metastatic disease following parathyroid surgery. Patient #7 received initially denosumab 120 mg every month for hypercalcemia, but as he developed lung metastasis, treatment with sorafenib 400 mg, twice daily, was initiated and imaging after 3 months revealed regression of the lung nodules. Patient #8 began treatment with sorafenib following disease progression with previous treatments, including combination of capecitabine and temozolomide, cisplatin and etoposide, zoledronate, denosumab, and an investigational drug. Due to disease progression the patient was then placed on everolimus.\n\nOutcomes\nRemission\nRemission was defined by the presence of low or appropriate PTH and calcium levels and no evidence of structural disease on cross-sectional imaging.\n\nFollowing the first surgical intervention, five patients went into remission (patients #2, #4, #5, #6, and #8); including one patient (patient #6) that shortly after right hemithyroidectomy and right inferior parathyroidectomy had EBRT.\n\nTwo of the patients (patients #2 and #4) remained in remission at the end of follow-up, with no further treatment and without evidence of recurrent biochemical or structural disease. Both of them developed hypocalcemia after the surgery requiring treatment with calcium and calcitriol, although in both cases, the surgical intervention did not include removal of all parathyroid glands or total thyroidectomy. In both patients with sustained remission, pathology did not reveal lymph node involvement, and Ki67 was 5% in both cases.\n\nIn both patients that went into long-term remission at the end of follow-up after parathyroid surgery, the initial tumor was localized to the parathyroid gland with limited extension to soft tissue (T1), with no clear evidence of regional lymph node metastasis (N0 or Nx).\n\nRecurrent Disease\nThree patients achieved remission after the first surgery, but later developed recurrent disease (patients #5, #6, and #8). The time interval between the first surgery and the recurrence was 22, 36, and 58 months, respectively.\n\nIn all the patients with evidence of recurrent disease, pathology indicated vascular invasion, and Rb loss. Loss of parafibromin and p27 loss were evident in 2/3 patients. Two of the patients with recurrent disease developed distant metastasis during follow-up (patients #6 and #8). All three patients had another surgery for their recurrent disease, and while one patient (patient #6) had already received EBRT post-operatively, the other two patients were treated with EBRT for their recurrent disease. However, EBRT treatment did not lead to remission, and all three patients were left with residual disease.\n\nPatient #5 was in remission for 22 months following parathyroidectomy, but reappearance of symptomatic hypercalcemia and elevated PTH levels led to the detection of recurrent disease. She was referred for neck exploration and right subtotal thyroidectomy with removal of multiple small nodules in the infero-lateral aspect of the gland and sternomastoid muscle. Surgical pathology revealed recurrent parathyroid carcinoma, as well as a focus of papillary thyroid microcarcinoma. Following this second surgery, her PTH levels did not normalize and she still had hypercalcemia. Imaging studies showed paratracheal nodules on the right and 1 year later she was referred for right central neck dissection, where pathology once again confirmed parathyroid carcinoma. The combination of this surgical intervention with postoperative EBRT normalized her PTH levels and at last follow-up there was no evidence of structural disease on imaging of the head and neck, other than two tiny non-specific nodules in the right thyroid bed.\n\nPatient #6 was diagnosed with recurrent parathyroid carcinoma <3 years following her initial surgery. She had recurrent structural and biochemical disease, with evidence of hypercalcemia and elevated PTH levels, as well as right recurrent laryngeal nerve palsy and lung metastasis. The patient was started on Cinacalcet for hypercalcemia and underwent a right neck dissection; pathology confirmed recurrent parathyroid carcinoma. The patient was later diagnosed with colon adenocarcinoma that was treated with surgery and chemotherapy but ultimately led to her demise.\n\nPatient #8 did not receive EBRT following his first surgery, and he was well and free of disease for almost 4 years. Prior to his recurrent parathyroid carcinoma, he was found to have a large liver mass which was biopsied and reported to be hepatocellular carcinoma. Three years later, he developed a growing neck mass, involving the mediastinum and left neck, which on core biopsy was found to be parathyroid carcinoma. The patient had extensive surgery, including thoracotomy with neck dissection, resection of mediastinal mass, part of the manubrium and clavicular head, sternum, and the first rib. Unfortunately, the tumor was adherent to the thoracic inlet, and although it was dissected off the trachea and lateral wall of the esophagus, disease was left in situ. Pathology again revealed angioinvasive parathyroid carcinoma and the patient completed post-operative EBRT. His PTH levels normalized and he did not require treatment for hypercalcemia, however, several months later, a new liver lesion was found, and this time a core biopsy revealed metastatic parathyroid carcinoma, which was not amenable to surgical excision. For that reason, he was started on a neuroendocrine tumor (NET)-type of chemotherapy regimen in the form of capecitabine and temozolomide. After 2 cycles there was progression of his liver disease that continued despite an additional two cycles of chemotherapy. The patient was switched to combination of cisplatin and etoposide, and given that the disease outside of his liver was relatively modest in burden, he also underwent bland liver embolization. Following this combination treatment, imaging studies showed widespread skeletal metastases, that were treated with EBRT to the focal bone lesions, in addition to zoledronate, which was later replaced by monthly denosumab 120 mg. Due to further disease progression, with evidence of metastases in the liver, skeleton, and lung, the patient was enrolled in a phase 1 trial to which he did not respond, as he manifested progression in the form of new peritoneal metastases. He was referred for peptide receptor radiotherapy (PRRT) but was found to be ineligible due to minimal uptake on Ga68-dotatate PET imaging. The patient was subsequently started on sorafenib but continued to progress and recently was switched to everolimus.\n\nIn all three patients with initial remission that were later found to have recurrent disease, the initial tumor was either localized to the parathyroid gland with limited extension to soft tissue (T1, patients #5 and #8) or with direct invasion into the thyroid gland (patient #6), and the lymph node status was unknown (Nx). However all three exhibited angioinvasion.\n\nPersistent Disease\nThree patients (patients #1, #3, and #7) had residual biochemical and structural disease following their first surgical intervention that persisted to the end of follow-up. In all three patients there was evidence of metastases, either at diagnosis (patient #1), or during follow-up (patients #3 and #7). In all these patients, pathology indicated invasion to adjacent tissue, which involved the thyroid gland in all cases, but only patient #1 had esophageal involvement. Loss of p27 was evident in all three, The Ki67 labeling index was available for two of the patients (patient #3 and #7) and was high (>20%, and 19.60%, respectively).\n\nThree other patients (patient #5, #6, and #8) had recurrent disease, that was treated (as described above) but all of them were left with persistent disease following their recurrence.\n\nPatient #1 was referred for total thyroidectomy for a suspicious thyroid nodule, which turned out to be parathyroid carcinoma. This was followed shortly after total thyroidectomy by EBRT with a reduction of PTH levels from nine- to five-fold the upper limit of normal and normal calcium levels. At diagnosis, he had evidence of metastasis in the lungs, hip, and liver. He had radiation treatment directed to his hip, followed by prosthesis insertion.\n\nPatient #3 was suspected to have thyroid cancer and primary hyperparathyroidism and underwent total thyroidectomy; pathology identified an angioinvasive and widely invasive parathyroid carcinoma. Following surgery, his PTH remained elevated, but calcium levels were in the normal range. He had EBRT to his neck. Although there was no evidence of metastasis at baseline, the patient developed lung metastasis during follow-up as well as recurrent hypercalcemia. Zoledronic acid failed to control hypercalcemia, followed by monthly denosumab 120 mg with good biochemical control. The patient had slowly progressing, low-volume disease, with enlarging pulmonary metastases, then manifested progression in the neck with a paraesophageal mass invading the esophageal wall. He was started on everolimus but could not tolerate the treatment at a dosage of 10 mg daily, which was subsequently reduced to 5 mg but this was discontinued as it proved ineffective. He was later started on sorafenib 400 mg daily, but this was discontinued after a few months due to severe walking difficulties and drop foot. The patient died of this disease 6 years after his parathyroid carcinoma diagnosis.\n\nPatient #7 was diagnosed with primary hyperparathyroidism, as previously reported (14), following investigation of symptomatic hypercalcemia, with diffuse bony aches, constipation, polyuria, polydipsia, and weight loss of more than 25 pounds. Imaging identified a left thyroid nodule and a left neck mass; biopsy of the left neck mass was suspicious for a neuroendocrine neoplasm. The patient had total thyroidectomy with central and left neck dissection. Pathology revealed an intrathyroidal 2.7 cm parathyroid carcinoma and metastatic carcinoma in 2 left neck lymph nodes, PTH decreased after the surgery but remained elevated, with hypercalcemia and hypophosphatemia. Imaging did not reveal any residual neck disease, but there were multiple pulmonary nodules, consistent with metastatic disease. The patient was started on denosumab 120 mg every month for his hypercalcemia. Later, the patient started treatment with sorafenib and imaging after 3 months showed regression of the lung nodules.\n\nIn all three patients with residual disease, the initial staging indicated evidence of distant metastasis (M1, patient #1), or regional lymph node involvement (N1, patients #3 and #7). In all three cases, the tumor was either invading the thyroid gland (T2, patients #3 and #7), or more extensively (T3, patient #1).\n\nDiscussion\nThis case series confirms the finding in previous studies that the diagnosis of parathyroid carcinoma is typically established only by pathology examination after surgery (1). As expected, primary hyperparathyroidism was the most common indication for surgery (15); thyroid nodule was another important reason for further investigation and intervention, which eventually led to diagnosis of parathyroid cancer. Another interesting finding is that all patients had a history of kidney stones, including those without a pre-operative diagnosis of hyperparathyroidism, suggesting previous undiagnosed hyperparathyroidism. This claim is supported by the fact that the patients without a pre-surgical diagnosis of hyperparathyroidism developed either hypercalcemic hyperparathyroidism, or hungry bone syndrome after surgery, even if the procedure was only a hemithyroidectomy.\n\nParathyroid carcinoma is often difficult to diagnose preoperatively, thus potentially limiting the scope of surgical intervention. As long-term survival is largely dependent on the extent of the primary surgical resection, it is of great importance to consider parathyroid carcinoma in the differential diagnosis of hyperparathyroidism. While our series included patients with symptoms related to hyperparathyroidism and hypercalcemia, there is significant variability in clinical patterns of the disease, and others have described asymptomatic patients with parathyroid carcinoma without clinical or biochemical clues to the diagnosis (16).\n\nThe histopathology diagnosis of parathyroid carcinoma in all our patients was made on the basis of vascular invasion or invasion of adjacent structures such as esophagus in one case, as well as loss of parafibromin, Rb, or p27 expression (13). These biomarkers have been proposed to support a diagnosis of malignancy in borderline cases without clear-cut angioinvasion or documented metastases at presentation. Erovic et al. investigated the expression profile of potential immunohistochemical biomarkers of parathyroid cancer, and completed staining for 34 proteins involved in angiogenesis, inflammation, cell adhesion, cell cycle, and apoptosis. They reported that a panel that includes BCL-2a, parafibromin, Rb, and p27 may be helpful in the assessment of parathyroid neoplasms, but there are additional possible biomarkers that may be helpful, though the data are preliminary. Parafibromin, Rb, and p27 are involved in cell cycle, while BCL-2a is involved in apoptosis. A panel that includes BCL-2a, parafibromin, Rb, and p27 was shown to be very helpful in the assessment of atypical parathyroid neoplasms, when there was no evidence of angioinvasion, perineural invasion, or gross local invasion into adjacent organs or metastasis (13). These data supported previous studies focusing on the biomarkers for parathyroid carcinoma (17–19). Recently, reports described novel mutations in genes that mediate chromosome organization, DNA repair, and cell cycle, and occasional mutations in MAPK signaling and immune response (including PTEN, NF1, KDR, PIK3CA, and TSC2). Additionally, epigenetic studies have described changes in DNA methylation, histone modifications, microRNA dysregulation, and unusual circular RNAs (20–22). Kutahyalioglu et al. evaluated tumor-specific genetic changes using next-generation sequencing (NGS) panels in 11 patients with parathyroid carcinoma, reporting mutations identified in the PI3K (4/11 patients) and TP53 (3/11 patients) pathways. In addition, mutations were identified in genes that were not previously reported in parathyroid carcinoma, including SDHA, TERT promoter, and DICER1. Actionable mutations were found in more than half of the patients (23). While no longer routinely used, silver-stained nucleolar organizer region (AgNOR) analysis may serve as an additional tool for the histological evaluation of parathyroid lesions to distinguish adenomatous from cancerous ones, as higher AgNORs per nucleus (NORA) scores were noted in malignant cases (24).\n\nOf note, invasion into the thyroid gland should not be considered a feature of malignancy, as parathyroid glands are frequently located within or immediately adjacent to thyroid tissue and benign parathyroid lesions can occur within the thyroid gland (25). This is a weakness in the new proposed AJCC staging system that identifies this feature as a criterion for upstaging a parathyroid carcinoma.\n\nAs stated previously, the first and foremost treatment for parathyroid carcinoma was surgical intervention (12). In two cases, the surgery that was performed for a different indication was the only treatment required for the parathyroid carcinoma, as the patients remained in remission at the end of follow-up. However, while the recommended treatment is en bloc resection (12), in one of the two patients in long-term remission, surgery was limited to hemithyroidectomy/parathyroidectomy, with no neck dissection.\n\nEBRT was administered to five patients; all these patients had recurrent or persistent disease and there was evidence of distant metastasis in four of them, with lung involvement in all cases. Our results confirm previous reports that could not show prominent response to radiotherapy and thus did not recommend this as a routine treatment for parathyroid cancer (12, 26, 27). Erovic et al. reported 11 of 16 patients who underwent postoperative radiotherapy, and this was one of the largest series with respect to the use of adjuvant radiotherapy. Of these 11 patients, 7 developed recurrent disease, including 3 of 4 patients who had positive surgical margins (27). Lee et al. reported that <10% of their 224 patients with parathyroid cancer received radiation therapy, and this treatment was not associated with an improved survival rate (26).\n\nBoth patients in long-term remission went into remission immediately after their first surgery, and did not require any additional treatment until the end of follow-up, which was at least 4 years in these patients. The pathology examination of these patients revealed that none of these three patients had lymph node metastasis or loss of parafibromin expression, and Ki67 was in the low range (~5%).\n\nA novel finding in our series is the high number of patients with additional other malignancies. In our cohort, four patients had thyroid cancer (diagnosed concurrently with the parathyroid cancer at thyroid surgery), one patient had colorectal cancer, and another had hepatocellular carcinoma. The diagnosis of incidental thyroid cancer is not surprising, given that it largely consisted of low risk subclinical disease. Campenni et al. completed a systematic literature search exploring the association between parathyroid cancer and thyroid disease, reporting 21 cases of parathyroid cancer with thyroid disease, including 10 cases of concomitant parathyroid carcinoma and thyroid cancer, mainly papillary thyroid carcinoma (28). In that series, the parathyroid cancer mean diameter was higher in those with both malignancies, and there was a slight predominance for the left side (28). Similarly, in our cohort, thyroid carcinoma was evident in 2 of 2 patients with parathyroid carcinoma on the left side, compared to 2 of 7 patients with parathyroid malignancy on the right side.\n\nIn the three patients with recurrent disease and those with persistent disease, further intervention, whether in the form of another surgery, EBRT, or chemotherapy, did not lead to clinical remission. Five of the six patients with persistent or recurrent disease developed metastases during the follow-up. As EBRT did not have a profound effect on tumor progression, chemotherapy was used in two patients. The lack of response to EBRT in these cases is in line with the recommendation by the American Association of Endocrine Surgeons that discourage the use of EBRT, other than for palliative reasons (12).One patient was treated with the tyrosine kinase inhibitor (TKI) sorafenib; imaging studies after several months showed regression of the lung metastases, but the second patient did not respond to several lines of chemotherapy, including sorafenib. The data in the literature indicate variable response to a wide range of chemotherapeutic regimens, including Dacarbazine, Cyclophosphamide, or Capecitabine, alone or in combination (4, 29). The response of one of our patients to Sorafenib, with regression of his pulmonary nodules, was reported previously in a case report (7). The response to Sorafenib, a multi-kinase inhibitor that blocks cell proliferation and angiogenesis, may stem from its effect against vascular endothelial growth factor-receptor and platelet-derived growth factor receptor, which may be highly expressed in parathyroid cancers (7, 15).\n\nThe recently defined AJCC staging based on the tumor characteristic at the time of initial presentation may aid in predicting the prognosis of these patients (10). In our case series, all patients with evidence of regional lymph node metastasis (N1) or distant metastasis (M1) had residual disease following parathyroid surgery and required additional treatment. On the other hand, all four patients with a tumor localized to the parathyroid gland with limited extension to soft tissue (T1) went into remission following the surgery, although two of them later developed recurrent disease and required further treatment.\n\nThe limitations of this study include the retrospective nature, small number of cases, and lack of a standardized pre-operative management, as some of these patients were referred only after the histopathologic diagnosis of parathyroid carcinoma was made after surgery and none of them had a clear preoperative suspicion of malignancy. In addition, as this study was performed at a single outpatient practice of a quaternary care Endocrine Oncology specialist practice, there is a potential for referral and selection bias. However, as parathyroid cancer is a very rare entity, with limited data available in the medical literature, this study may add important insights to the body of evidence. In addition, the long-term follow-up, treatment in a specialized center with involvement of a highly experienced team and various available treatment options, are among the strengths of this study.\n\nIn accordance with the guidelines for management of primary hyperparathyroidism by the American Association of Endocrine Surgeons, the diagnosis of parathyroid carcinoma should be considered in cases of primary hyperparathyroidism with marked elevation of PTH levels and severe hypercalcemia (12). Complete resection, which occasionally requires en bloc resection of adherent tissues is recommended as first line therapy. Genetic testing should be considered in patients with parathyroid carcinoma including those with parafibromin loss by immunohistochemistry even in the absence of family history or HPJT-related manifestations (30, 31). Adjuvant treatment, including repeat surgery, radiotherapy or medical treatment, should be considered on an individualized basis especially when remission is not achieved following surgery. Regular surveillance is recommended, including biochemical monitoring of PTH and calcium homeostasis, as well as imaging of the neck with neck ultrasound, parathyroid scan and/or head and neck computed tomography or magnetic resonance imaging, Initially, biochemical and radiographic monitoring is recommended every 3–6 months, depending on the aggressiveness of disease and the response to treatment. In case of long-term remission, the interval can be increased to once yearly.\n\nIn conclusion, our findings suggest that parathyroid cancer is usually identified only post-operatively, during the pathology examination, pointing to the importance of an experienced pathology team. While long-term remission is possible with surgery, in patients with evidence of residual disease after the intervention and in those with recurrent disease during follow-up, chances of cure are very low. Targeted therapies may prove to be an important treatment option for those patients with distant metastatic disease.\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by University Health Network. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor's Note\nAA had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data available on request from the authors.\n\nAuthor Contributions\nAA, SA, VL, AS, and SE: substantial contributions to conception and design, acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, final approval of the version to be published. OM: acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, final approval of the version to be published. RJ: drafting the article or revising it critically for important intellectual content, final approval of the version to be published.\n\nConflict of Interest\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==== Refs\nReferences\n1. Dotzenrath C Goretzki PE Sarbia M Cupisti K Feldkamp J Röher HD . 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"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "10()",
"journal": "Frontiers in endocrinology",
"keywords": "Endocrine Oncology; hyperparathyroidism; parathyroid carcinoma; parathyroid disease; parathyroidectomy; thyroid nodule",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "731",
"pmc": null,
"pmid": "31708875",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "30455668;28061891;28458892;1413841;30788456;11417985;27532368;29324469;10687728;7906387;18847176;29040582;17372919;23001705;31213128;21861982;28881068;8077300;19350316;8200932;10430265;11491274;11037351;27744598;26177319;31309300;22908071;22290780",
"title": "The Clinicopathological Spectrum of Parathyroid Carcinoma.",
"title_normalized": "the clinicopathological spectrum of parathyroid carcinoma"
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"abstract": "BACKGROUND\nSystemic lupus erythematosus (SLE) is known to cause inappropriate sinus tachycardia (IST). However, there is limited evidence available with regard to the treatment of IST in this setting. In this article, we report a case of drug refractory IST in a patient with SLE treated with radiofrequency catheter ablation (RFCA) using a non-contact mapping system.\n\n\nMETHODS\nA 33-year-old woman had been diagnosed with SLE in 2001. She presented with complaints of persistent palpitations for 1 month and persistent sinus tachycardia. She underwent RFCA using a non-contact mapping system for drug refractory IST. The voltage and activation maps did not show obvious differences in the earliest activation site at heart rates (HRs) 90-150 b.p.m. In contrast, the areas of breakout sites were clearly distinguished between those from the normal P-wave zones at HR <140 b.p.m. and those from higher rate sites at HR >140 b.p.m. Radiofrequency catheter ablation was performed in those areas as the target for ablation. Thereafter, the symptoms steadily disappeared and the maximum HR-using 24-h Holter monitoring-decreased from 156 to 120 b.p.m.\n\n\nCONCLUSIONS\nRadiofrequency catheter ablation using a non-contact mapping system was applied to the treatment of drug refractory IST in a patient with SLE. Of note, IST in such patients may be left untreated. This approach may be considered as a first-line therapy option for drug refractory IST in patients with SLE.",
"affiliations": "Division of Cardiology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Japan.;Division of Cardiology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Japan.;Division of Cardiology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Japan.;Division of Cardiology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Japan.",
"authors": "Yoshizawa|Reisuke|R|;Komatsu|Takashi|T|;Kojima|Kaori|K|;Owada|Shingen|S|",
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"fulltext": "\n==== Front\nEur Heart J Case RepEur Heart J Case RepehjcrEuropean Heart Journal: Case Reports2514-2119Oxford University Press 10.1093/ehjcr/ytz102ytz102Case ReportsRadiofrequency catheter ablation for inappropriate sinus tachycardia in a patient with systemic lupus erythematosus: a case report http://orcid.org/0000-0001-8790-9169Yoshizawa Reisuke Komatsu Takashi Kojima Kaori Owada Shingen \nDivision of Cardiology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, Japan Khan Habib Handling EditorKornej Jelen EditorKhan Habib EditorAkhtar Mohammed Majiid EditorThomson Ross Editor Corresponding author. Tel: +81 19 651 5111(8715), Fax: +81 19 651 0401, Email: yoshizawareisuke@gmail.com9 2019 13 7 2019 13 7 2019 3 3 ytz10202 2 2019 17 6 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nSystemic lupus erythematosus (SLE) is known to cause inappropriate sinus tachycardia (IST). However, there is limited evidence available with regard to the treatment of IST in this setting. In this article, we report a case of drug refractory IST in a patient with SLE treated with radiofrequency catheter ablation (RFCA) using a non-contact mapping system.\n\nCase summary\nA 33-year-old woman had been diagnosed with SLE in 2001. She presented with complaints of persistent palpitations for 1 month and persistent sinus tachycardia. She underwent RFCA using a non-contact mapping system for drug refractory IST. The voltage and activation maps did not show obvious differences in the earliest activation site at heart rates (HRs) 90–150 b.p.m. In contrast, the areas of breakout sites were clearly distinguished between those from the normal P-wave zones at HR <140 b.p.m. and those from higher rate sites at HR >140 b.p.m. Radiofrequency catheter ablation was performed in those areas as the target for ablation. Thereafter, the symptoms steadily disappeared and the maximum HR—using 24-h Holter monitoring—decreased from 156 to 120 b.p.m.\n\nDiscussion\nRadiofrequency catheter ablation using a non-contact mapping system was applied to the treatment of drug refractory IST in a patient with SLE. Of note, IST in such patients may be left untreated. This approach may be considered as a first-line therapy option for drug refractory IST in patients with SLE.\n\nInappropriate sinus tachycardiaSystemic lupus erythematosusNon-contact mapping system Radiofrequency catheter ablationCase report\n==== Body\nLearning points\n\nRadiofrequency catheter ablation was used for the treatment of drug refractory inappropriate sinus tachycardia (IST) in a patient with systemic lupus erythematosus.\n\nRadiofrequency catheter ablation using non-contact mapping system for the treatment of IST permits successful ablation, while reducing the risk of sinus node injury.\n\n\n\n\n\n\n\nIntroduction\nInappropriate sinus tachycardia (IST) is defined as: (i) a P-wave axis and morphology during the tachycardia similar to that of the sinus rhythm; (ii) a sinus heart rate (HR) >100 b.p.m. at rest; and (iii) a mean HR >90 b.p.m. via 24-h Holter monitoring.1\n\nThe autonomic dysfunction and abnormal automaticity of the sinus node involved in IST remain poorly understood.2–7 Although systemic lupus erythematosus (SLE) is known to cause IST,8 therapeutic strategies are not well-documented.\n\nRadiofrequency catheter ablation (RFCA) is an acceptable therapy for drug refractory IST.9–11 Herein, we describe the first application of RFCA using a non-contact mapping system for the treatment of drug refractory IST in a patient with SLE.\n\nTimeline\nDates\tEvents\t\n2001\tDiagnosis of systemic lupus erythematosus.\t\nOctober 2017\tAwareness of persistent palpitations.\t\n29 November 2017\t24-h electrocardiography (ECG) monitoring of the sinus rhythm. The minimum, maximum, and mean heart rates (HRs) were 71, 156, and 103 b.p.m., respectively. Total heart beats (THB)/day: 144 721. Echocardiography did not show structural pathology. Laboratory investigations were unremarkable. Diagnosis of inappropriate sinus tachycardia. Administration of a β-blocker or calcium channel blocker was initiated.\t\n10 September 2018\tHospitalization.\t\n11 September 2018\tRadiofrequency catheter ablation.\t\n13 September 2018\tDischarge without complications.\t\n9 October 2018\tPost-operation follow-up (1 month). 24-h ECG monitoring of the sinus rhythm. The minimum, maximum, and mean HR were 60, 129, and 82 b.p.m., respectively. THB/day: 115 245.\t\n13 November 2018\tPost-operation follow-up (2 months). 24-h ECG monitoring of the sinus rhythm. The minimum, maximum, and mean HR were 50, 120, and 77 b.p.m., respectively. THB/day: 107 063.\t\n25 March 2019\tPost-operation follow-up (6 months). 24-h ECG monitoring of the sinus rhythm. The minimum, maximum, and mean HR were 46, 130, and 78 b.p.m., respectively. THB/day: 107 664.\t\nCase presentation\nA 33-year-old woman was diagnosed with SLE in 2001. The patient was treated with prednisolone (initial and maintenance dose: 50 and 15 mg/day, respectively). Polyarthritis pain, Raynaud’s sign, and photosensitivity were recognized early in the onset of SLE. After initiation of prednisolone, the SLE symptoms improved. The patient complained of persistent palpitations for 1 month.\n\nExamination showed that she was haemodynamically stable. Surface electrocardiography (ECG) revealed narrow QRS tachycardia with a P-wave of 139 b.p.m. The P-wave axis during tachycardia was similar to that observed during sinus rhythm (Figure 1A). Of note, 24-h ECG monitoring showed a minimum, maximum, and mean HR of 71, 156, and 103 b.p.m., respectively. In addition, tachycardia was persistent at rest (Figure 1B). Laboratory investigations revealed proteinuria (2.3 g/day) and positivity for anti-DNA antibody. In contrast, there was no evidence of secondary pathological sinus tachycardia (e.g. anaemia, hyperthyroidism, or neurohormonal disease). Physical examination, chest X-ray, and echocardiography did not yield evidence of clinically overt structural and/or organic heart disease. We diagnosed IST on the basis of diagnostic criteria.1–3 Moreover, bisoprolol (2.5 mg/day), carvedilol (5.0 mg/day), and verapamil (240 mg/day) were administered. However, IST was refractory, and the administration of these agents was discontinued due to the development of adverse effects (i.e. general fatigue, headache, and dizziness).\n\n\nFigure 1 Surface electrocardiography pattern of sinus tachycardia (A). Heart rate trend during 24-h electrocardiography monitoring (B).\n\nAn electrophysiological evaluation was performed to verify the mechanism of arrhythmia and exclude the presence of other arrhythmias. A multielectrode array catheter (EnSite™ Array, St. Jude Medical, St. Paul, MN, USA) was placed in the right atrium (RA), approximately at the level of the superior vena cava and right atrial junction (Figure 2). A 7-Fr quadripolar ablation catheter with a 4-mm-tip electrode (Therapy™, St. Jude Medical, St. Paul, MN, USA) was percutaneously introduced into the RA, while the baseline geometry of the RA was determined.\n\n\nFigure 2 A multielectrode array catheter was placed in the right atrium.\n\nSurface ECG at rest prior to ablation showed a sinus rhythm of HR 100 b.p.m. (Figure 3A). Prior to RFCA, the HR was controlled (90–155 b.p.m.) through the intravenous administration of a β1 antagonist and agonist (Figure 3B and C). Moreover, voltage and activation mapping were performed at each HR 90–155 b.p.m. Activation mapping did not show differences in the earliest activation sites (EAS) at HR 90–150 b.p.m. during the intravenous administration of a β1 antagonist and agonist (Figure 4A and B). In contrast, the shift to the posteroseptal of breakout sites (BOS) was clearly distinguished between those from the normal P-wave zones at HR <140 b.p.m. and those from higher-rate sites at HR >140 b.p.m. (Figure 4A). This finding was in accordance with the appearance of tall P-waves (Figure 3C). Radiofrequency catheter ablation for 30–60 s under a pre-set temperature of 50°C and power limit of 30 W was delivered to the target areas of shifted BOS (Figure 4C). The ablation catheter potential prior to ablation was not a complete QS pattern, indicating that it was not the EAS (Figure 4D). Thereafter, the maximum HR decreased to 120 b.p.m. regardless of the intravenous administration of a β1 agonist (Figure 3D). After RFCA, the palpitations were markedly improved. The patient exhibited an uneventful course without evidence of recurrence for ≥6 months.\n\n\nFigure 3 Surface electrocardiography at rest (heart rate = 100 b.p.m.) (A). Under intravenous administration of a β1 antagonist (heart rate = 90 b.p.m.) (B). Under intravenous administration of a β1 agonist (heart rate = 155 b.p.m.) (C). After delivery of radiofrequency energy (heart rate = 120 b.p.m.) (D).\n\nFigure 4 Right anterior oblique view of the EnSite™ activation (A) and voltage (B) maps showing the right atrium. Green tag with the red circle: the earliest activation site. Yellow circle: target site for ablation (B). Red tag: ablation site (C). Local electrograms from the ablation catheter in the successful ablation point (D). Abl D, ablation catheter distal potential; Abl P, ablation catheter proximal potential; Abl Uni, ablation catheter unipolar potential; HR, heart rate.\n\nDiscussion\nThis is the first reported application of RFCA for the treatment of IST in a patient with SLE.\n\nFirstly, RFCA was effective in this setting. Currently, the mechanism of IST in SLE remains poorly understood.12,13 The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score is useful for assessing the relationship between the inflammatory activity of SLE and chronic tachycardia (i.e. IST).13 In this case, the SLEDAI score was 6, indicating that sustained SLE activity may induce IST.\n\nFurthermore, the IST was refractory to pharmacological therapy; thus, we performed RFCA. Informed consent was provided by the patient prior to the procedure. Following RFCA, the clinical status of the patient improved.\n\nSecondly, RFCA using a non-contact mapping system was effective against IST. The non-contact mapping system assists in the rapid, simple, and detailed assessment of sinus node activation, as expressed by the EAS and BOS activation routes per heartbeat.14 Therefore, it may be more effective against arrhythmias with fluctuating HR (i.e. IST) vs. contact mapping system. This approach clearly determined the BOS at different HR. At HR < 140 b.p.m., the BOS was conducted all around, whereas at HR ≥ 140 b.p.m. it shifted to the posteroseptal site. Consequently, it became possible to perform successful ablation without the risk of injury to the sinus nodal function. In this case, the ablation success site was distant from the EAS. This result was consistent with those of a previous study highlighting that a successful RFCA in IST patients may not take place at the earliest site, but at a distant one (mean: 7 mm) from the EAS.10 These findings suggest that the aetiology of IST involves the degeneration of the compact node (plus its paranodal areas) and sinoatrial conduction system.\n\nMoreover, autonomic nervous disorder may be involved in the development of IST. Regulation of the autonomic tone induces a shift in the activation site of the sinus node.9 In this case, RFCA using the Ensite™ mapping system effectively and safely separated the areas of the EAS and BOS (target site of RFCA).\n\nConclusion \nIn conclusion, RFCA using a non-contact mapping system was effective for the treatment of drug refractory IST in a patient with SLE. Further studies are warranted to clarify the mechanism of IST and develop therapeutic strategies involving mapping technology for patients with IST.\n\nLead author biography\nReisuke Yoshizawa is a graduate of the Teikyo University School of Medicine in 2008. Currently, he is an interventional cardiac electrophysiologist, and Assistant Professor in Division of Cardiology, Department of Internal Medicine, Iwate Medical University, Japan. \n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: none declared.\n\nSupplementary Material\nytz102_Supplementary_Slide_Set Click here for additional data file.\n==== Refs\nReferences\n1 \nSheldon RS , Grubb BP , Olshansky B , Shen W-K , Calkins H , Brignole M , Raj SR , Krahn AD , Morillo CA , Stewart JM , Sutton R , Sandroni P , Friday KJ , Hachul DT , Cohen MI , Lau DH , Mayuga KA , Moak JP , Sandhu RK , Kanjwal K. \n2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope . Heart Rhythm 2015 ;12 :e41 –e63 .25980576 \n2 \nOlshansky B , Sullivan RM. \nInappropriate sinus tachycardia . J Am Coll Cardiol 2013 ;61 :793 –801 .23265330 \n3 \nShen WK. \nHow to manage patients with inappropriate sinus tachycardia . Heart Rhythm 2005 ;2 :1015 –1019 .16171763 \n4 \nBauernfeind RA , Amat-Y-Leon F , Dhingra RC , Kehoe R , Wyndham C , Rosen KM. \nChronic nonparoxysmal sinus tachycardia in otherwise healthy persons . Ann Intern Med 1979 ;91 :702 –710 .496102 \n5 \nMorillo CA , Klein GJ , Thakur RK , Li H , Zardini M , Yee R. \nMechanism of ‘inappropriate’ sinus tachycardia. Role of sympathovagal balance . Circulation 1994 ;90 :873 –877 .7913886 \n6 \nZhou J , Scherlag BJ , Niu G , Hou Y , Lu Z , Zhang Y , Ding Y , Lazzara R , Jackman WM , Po SS. \nAnatomy and physiology of the right interganglionic nerve: implications for the pathophysiology of inappropriate sinus tachycardia . J Cardiovasc Electrophysiol 2008 ;19 :971 –976 .18373665 \n7 \nScherlag BJ , Yamanashi WS , Amin R , Lazzara R , Jackman WM. \nExperimental model of inappropriate sinus tachycardia: initiation and ablation . J Interv Card Electrophysiol 2005 ;13 :21 –29 .15976974 \n8 \nHejtmancik MR , Wright JC , Quint R , Jennings FL. \nThe cardiovascular manifestations of systemic lupus erythematosus . Am Heart J 1964 ;68 :119 –130 .14193537 \n9 \nMarrouche NF , Beheiry S , Tomassoni G , Cole C , Bash D , Dresing T , Saliba W , Abdul-Karim A , Tchou P , Schweikert R , Leonelli F , Natale A. \nThree-dimensional nonfluoroscopic mapping and ablation of inappropriate sinus tachycardia. Procedural strategies and long-term outcome . J Am Coll Cardiol 2002 ;39 :1046 –1054 .11897449 \n10 \nMan KC , Knight B , Tse H-F , Pelosi F , Michaud GF , Flemming M , Strickberger SA , Morady F. \nRadiofrequency catheter ablation of inappropriate sinus tachycardia guided by activation mapping . J Am Coll Cardiol 2000 ;35 :451 –457 .10676693 \n11 \nLee RJ , Kalman JM , Fitzpatrick AP , Epstein LM , Fisher WG , Olgin JE , Lesh MD , Scheinman MM. \nRadiofrequency catheter modification of the sinus node for “inappropriate” sinus tachycardia . Circulation 1995 ;92 :2919 –2928 .7586260 \n12 \nMaule S , Quadri R , Mirante D , Pellerito RA , Marucco E , Marinone C , Vergani D , Chiandussi L , Zanone MM. \nAutonomic nervous dysfunction in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA): possible pathogenic role of autoantibodies to autonomic nervous structures . Clin Exp Immunol 1997 ;110 :423 –427 .9409646 \n13 \nUtset TO , Ward AB , Thompson TL , Green SL. \nSignificance of chronic tachycardia in systemic lupus erythematosus . Arthritis Care Res 2013 ;65 :827 –831 .\n14 \nBonhomme CE , Deger FT , Schultz J , Hsu SS. \nRadiofrequency catheter ablation using non-contact mapping for inappropriate sinus tachycardia . J Interv Card Electrophysiol 2004 ;10 :159 –163 .15014217\n\n",
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"keywords": "Case report; Inappropriate sinus tachycardia; Non-contact mapping system ; Radiofrequency catheter ablation; Systemic lupus erythematosus",
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"title": "Radiofrequency catheter ablation for inappropriate sinus tachycardia in a patient with systemic lupus erythematosus: a case report.",
"title_normalized": "radiofrequency catheter ablation for inappropriate sinus tachycardia in a patient with systemic lupus erythematosus a case report"
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"abstract": "BACKGROUND\nWhile surgery and perioperative smoking cessation interventions may motivate patients to quit smoking in the short term, it is unknown how often this translates into permanent cessation. In this study, we sought to determine the rates of long-term smoking cessation after a perioperative smoking cessation intervention and predictors of successful cessation at 1 year.\n\n\nMETHODS\nWe previously reported short-term results from a perioperative randomized controlled trial comparing usual care with an intervention involving (1) brief counseling by the preadmission nurse, (2) smoking cessation brochures, (3) referral to a telephone quitline, and (4) a free 6-week supply of transdermal nicotine replacement. We now report our 1-year follow-up outcomes.\n\n\nRESULTS\nBetween October 2010 and April 2012, 168 patients were randomized. At 1 year, 127 patients (76%) were available for follow-up telephone interview. Smoking cessation occurred in 8% of control patients compared with 25% of patients in the intervention group (relative risk, 3.0; 95% confidence interval [CI], 1.2-7.8; P = 0.018). The number needed-to-treat to achieve smoking cessation for 1 patient at 1 year postoperatively was 5.9 (95% CI, 3.4-25.9). Multivariable logistic regression modeling found that the intervention (P = 0.020) and lower nicotine dependency at baseline (P < 0.001) were predictive of success at smoking cessation at 1 year. Poisson regression showed that adjusted for nicotine dependency, those randomized to the intervention group were 2.7 times (95% CI, 1.1-6.7; P = 0.028) more likely to achieve long-term cessation than those in the control group. Adjusted for randomization group, a low level of nicotine dependency resulted in a relative risk of quitting of 5.1 (95% CI, 2.0-12.8; P = 0.001).\n\n\nCONCLUSIONS\nThis study demonstrates that an intervention designed for a busy preadmission clinic results in decreased smoking rates not only around the time of surgery but also continued benefit in smoking cessation at 1 year. Perioperative care providers have a unique opportunity to assist patients in smoking cessation and achieve long-lasting results.",
"affiliations": "From the Department of Anesthesia & Perioperative Medicine, Department of Epidemiology & Biostatistics, University of Western Ontario, London, Ontario, Canada; and Pharmacy, St. Joseph's Health Care, London, Ontario, Canada.",
"authors": "Lee|Susan M|SM|;Landry|Jennifer|J|;Jones|Philip M|PM|;Buhrmann|Ozzie|O|;Morley-Forster|Patricia|P|",
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"title": "Long-term quit rates after a perioperative smoking cessation randomized controlled trial.",
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"abstract": "Prosthetic arthritis due to Candida species is uncommon, with only 15 cases reported in the literature. We recently cared for a human immunodeficiency virus-infected patient who developed Candida parapsilosis prosthetic arthritis unresponsive to resection arthroplasty, intravenous amphotericin B, and suppressive ketoconazole therapy. Treatment with fluconazole led to mycologic cure and symptom improvement, although he subsequently underwent above-the-knee amputation due to continued joint instability. Fluconazole may be useful follow-up therapy after a course of amphotericin B combined with resection arthroplasty or when removal of the prosthesis cannot be accomplished.",
"affiliations": "Division of Infectious Diseases, Medical College of Pennsylvania, Philadelphia 19129.",
"authors": "Tunkel|A R|AR|;Thomas|C Y|CY|;Wispelwey|B|B|",
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"mesh_terms": "D000328:Adult; D001170:Arthritis, Infectious; D002177:Candidiasis; D015725:Fluconazole; D015658:HIV Infections; D006801:Humans; D007720:Knee Prosthesis; D008297:Male; D016459:Prosthesis-Related Infections",
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"title": "Candida prosthetic arthritis: report of a case treated with fluconazole and review of the literature.",
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"abstract": "BACKGROUND\nTrastuzumab, one important treatment option for HER2-positive metastatic breast cancer (MBC) is limited by its cardiotoxic potential. Lapatinib and pegylated liposomal doxorubicin (PLD) represent a cardiosparing alternative that can cross the blood brain barrier. This is important, because one third of breast cancer patients develop brain metastases.\n\n\nMETHODS\nWe included 24 patients with HER2-positive MBC progressing under trastuzumab. They received 1,250 mg lapatinib daily until progression plus PLD (40 mg/m(2)) every 4 weeks for maximal 6 cycles. The primary end-point was the overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), 1-year PFS and 1-year OS rates.\n\n\nRESULTS\nORR was 54%. Median PFS was 5.8 and median OS 23.3 months. The one-year PFS rate was 27% and 1-year OS rate 76%.\n\n\nCONCLUSIONS\nLapatinib-plus-PLD is active and safe in HER2-positive MBC, especially suitable for patients with cardiological risk or brain metastases.",
"affiliations": "3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Centre, Salzburg Cancer Research Institute (SCRI) with the Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR) and the Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria.;3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Centre, Salzburg Cancer Research Institute (SCRI) with the Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR) and the Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria.;3rd Medical Department with Haematology and Medical Oncology, General Hospital Linz, Linz, Austria.;Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna)-LB-CTO and ACR-ITR VIEnna, Vienna, Austria.;Medical Department E with Oncology, General Hospital Rankweil, Rankweil, Austria.;Department of Gynaecology, Medical University Graz, Graz, Austria.;Ist Medical Department, General Hospital Elisabethinen Linz, Linz, Austria.;4th Medical Department, Hospital Wels-Grieskirchen, Grieskirchen, Austria.;3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Centre, Salzburg Cancer Research Institute (SCRI) with the Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR) and the Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria.;3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Centre, Salzburg Cancer Research Institute (SCRI) with the Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR) and the Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria.;3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Centre, Salzburg Cancer Research Institute (SCRI) with the Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR) and the Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria.;3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Centre, Salzburg Cancer Research Institute (SCRI) with the Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR) and the Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria.;Department of Medical Statistics and Informatics Medical University Innsbruck, Innsbruck, Austria.;3rd Medical Department with Haematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Centre, Salzburg Cancer Research Institute (SCRI) with the Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR) and the Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria r.greil@salk.at.",
"authors": "Pircher|Magdalena|M|;Mlineritsch|Brigitte|B|;Fridrik|Michael A|MA|;Dittrich|Christian|C|;Lang|Alois|A|;Petru|Edgar|E|;Weltermann|Ansgar|A|;Thaler|Josef|J|;Hufnagl|Clemens|C|;Gampenrieder|Simon Peter|SP|;Rinnerthaler|Gabriel|G|;Ressler|Sigrun|S|;Ulmer|Hanno|H|;Greil|Richard|R|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; C506643:liposomal doxorubicin; D000077341:Lapatinib; D011092:Polyethylene Glycols; D004317:Doxorubicin; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "35(1)",
"journal": "Anticancer research",
"keywords": "Her2-positive; Metastatic breast cancer; lapatinib; pegylated liposomal doxorubicin",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008875:Middle Aged; D011092:Polyethylene Glycols; D011799:Quinazolines; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "517-21",
"pmc": null,
"pmid": "25550597",
"pubdate": "2015-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Lapatinib-plus-pegylated liposomal doxorubicin in advanced HER2-positive breast cancer following trastuzumab: a phase II trial.",
"title_normalized": "lapatinib plus pegylated liposomal doxorubicin in advanced her2 positive breast cancer following trastuzumab a phase ii trial"
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"abstract": "Combination lithium, a mood stabilizer, and risperidone, an atypical antipsychotic drug, is widely used for treatment of psychotic disorders. Rare reports concern severe adverse drug reaction in multiple organic systems with their combined use. We report two episodes of neurotoxicity and nephrotoxicity in a patient following the combined use of lithium and risperidone.\n\n\n\nA 55-year-old male had a diagnosis of schizoaffective disorder at the age of 51. He was initially treated with a combination of lithium and olanzapine 5 to 15 mg/day for 2 years. He was admitted to psychiatric ward at the age of 53 due to manic episode with psychotic feature. Because of poor blood sugar control, we switched olanzapine 20 mg/day to risperidone 4.5 mg/day with combination of lithium 900mg/day. The patient presented neurotoxicity, neuroleptic-malignant-syndrome like symptoms, and nephrotoxicity, elevation of blood creatinine and decreased urine output few days later. These signs were fully recovered within 2 days after we discontinued all medications and gave normal saline hydration. Then we re-administered decreased dosage of lithium 600 mg/day and risperidone 3 mg/day, and the similar episode occurred again 3 days later. All drugs were discontinued again, then his delirium resolved and abnormal data returned to normal 1 day later. Finally, the patient was treated with risperidone 2 mg/day as monotherapy, and no episode of neurotoxicity and nephrotoxicity appeared in the following 2 years.\n\n\n\nThe case exemplifies neurotoxicity and nephrotoxicity after combined use of lithium and risperidone. These adverse effects resolved soon after discontinuing these medications and adequate hydration. Clinicians should be cautious about neurological and renal adverse effects.",
"affiliations": "Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. py1029@adm.cgmh.org.tw.",
"authors": "Hsu|Chih-Wei|CW|;Lee|Yu|Y|;Lee|Chun-Yi|CY|;Lin|Pao-Yen|PY|",
"chemical_list": "D014150:Antipsychotic Agents; D008094:Lithium; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": "10.1186/s40360-016-0101-x",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 10110.1186/s40360-016-0101-xCase ReportNeurotoxicity and nephrotoxicity caused by combined use of lithium and risperidone: a case report and literature review Hsu Chih-Wei 1Lee Yu 1Lee Chun-Yi 1Lin Pao-Yen 886-7-7317123py1029@adm.cgmh.org.tw 121 Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, 123, Dapi Road, Niaosong District, Kaohsiung City 833, Taiwan 14 12 2016 14 12 2016 2016 17 595 8 2016 27 10 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCombination lithium, a mood stabilizer, and risperidone, an atypical antipsychotic drug, is widely used for treatment of psychotic disorders. Rare reports concern severe adverse drug reaction in multiple organic systems with their combined use. We report two episodes of neurotoxicity and nephrotoxicity in a patient following the combined use of lithium and risperidone.\n\nCase presentation\nA 55-year-old male had a diagnosis of schizoaffective disorder at the age of 51. He was initially treated with a combination of lithium and olanzapine 5 to 15 mg/day for 2 years. He was admitted to psychiatric ward at the age of 53 due to manic episode with psychotic feature. Because of poor blood sugar control, we switched olanzapine 20 mg/day to risperidone 4.5 mg/day with combination of lithium 900mg/day. The patient presented neurotoxicity, neuroleptic-malignant-syndrome like symptoms, and nephrotoxicity, elevation of blood creatinine and decreased urine output few days later. These signs were fully recovered within 2 days after we discontinued all medications and gave normal saline hydration. Then we re-administered decreased dosage of lithium 600 mg/day and risperidone 3 mg/day, and the similar episode occurred again 3 days later. All drugs were discontinued again, then his delirium resolved and abnormal data returned to normal 1 day later. Finally, the patient was treated with risperidone 2 mg/day as monotherapy, and no episode of neurotoxicity and nephrotoxicity appeared in the following 2 years.\n\nConclusions\nThe case exemplifies neurotoxicity and nephrotoxicity after combined use of lithium and risperidone. These adverse effects resolved soon after discontinuing these medications and adequate hydration. Clinicians should be cautious about neurological and renal adverse effects.\n\nKeywords\nRisperidoneLithiumNeurotoxicityAcute kidney injuryDrug-drug interactionissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nLithium is a mood stabilizer for treatment of bipolar disorders [1]. Risperidone, an atypical antipsychotic drug with both dopamine D2 antagonistic and serotonin 5-HT2A antagonistic properties, is widely used for treatment of psychotic disorders. Combination of lithium and risperidone is commonly used for bipolar disorder or schizoaffective disorder [2]. There are rare reports concerning severe adverse drug reaction, neurotoxicity, with their combined use (Table 1) [3–9]. We report a patient who presented not only neurotoxicity but also nephrotoxicity following the combined use of lithium and risperidone.Table 1 Seven previous reports and 2 episodes of neurotoxicity and nephrotoxicity in our patient caused by combined use of lithium and risperidone\n\nR.N.\tAge\tSex\tDiagnosis\tRisperidone dose (mg)\tLithium dose (mg)\tTime to onseta\n\tClinical presentation\tLaboratory values and Image\t\n[3]\t69\tF\tBD\t6\t450\t3 weeks\tDelirium\tCr: NA; Li: 1.36\t\n[4]\t30\tM\tBD\tNA\t900\t1 week\tNMS\tCr: 1.6; Li: 0.6; CPK: 1428\t\n[5]\t46\tM\tNA\t3\t900\t2 years\tNMS, DKA\tBUN: 66\t\n[6]\t54\tF\tBD\t3\t1500\t2 months\tNMS\tCr: NA; Li: 0.7; CPK: 791\t\n[7]\t60\tF\tSD\t6\tNA\t3 weeks\tDelirium\tEEG: Abnormal; CK: 953\t\n[8]\t75\tM\tBD\t2\t900\t4 days\tLethargy\tEEG: Abnormal; Cr: NA; Li: 1.47\t\n[9]\t60\tF\tSD\t6\tNA\t6 days\tNMS\tEEG: Abnormal; CPK: 953\t\nIb\n\t56\tM\tSD\t4.5c\n\t900\t12 days\tDelirium\tBUN/Cr: 24/1.33; Li: 1.42; CK: 975\t\nIIb\n\t3\t600\t3 days\tDelirium\tBUN/Cr: 29/1.36; Li: 1.54; CK: 90\t\n\naTime is calculated from beginning the combination of lithium and risperidone to the occurrence of adverse events\n\n\nbI and II are serial numbers of the 2 episodes of our patient during hospitalization\n\n\ncIM Risperidone 25 mg/vial was prescribed 7 days before oral risperidone\n\n\n\n\nCase presentation\nA 55-year-old male had a diagnosis of schizoaffective disorder at the age of 51. He was initially diagnosed with bipolar I disorder at the age of 30, and mainly treated with a combination of lithium and valproic acid from age 30 to 51. At the age of 51, he was observed to have a manic episode concurrent with persecutory delusions and auditory hallucination. These psychotic symptoms persisted for more than 3 weeks after his manic symptoms had subsided. Later, a combination of lithium and olanzapine 5 to 15 mg/day were given as the main treatment. In addition, he had history of type 2 diabetes mellitus and hyperlipidemia for more than 10 years. He did not have any substance use or neurological disorder before. This time, after poor drug adherence for 4 months, he was admitted to our ward at the age of 53, due to symptoms including elevated mood, increased goal-directed activity, talkativeness, decreased need for sleep, and grandiose delusion lasting for 1 week.\n\nLithium 600 mg/day and olanzapine 10 mg/day were initially prescribed, and the dosages were titrated to 900 mg/day and 20 mg/day, respectively, over 1 week. His lithium serum level was reported to be 0.60 mEq/L (day 4) and 0.58 mEq/L (day 14). Because of poor blood sugar control, intramuscular injection of risperidone 25 mg was prescribed for switching antipsychotic agent on day 15. Olanzapine was discontinued and risperidone 4.5 mg/day was started on days 22 to 24. However, on day 27, the patient presented slurred speech, muscle rigidity, delirium (confused consciousness, inattention, and disorientation), and decreased urine output. At the same time, he did not present fever, focal neurological signs, or gastrointestinal symptoms. Laboratory data showed: blood urea nitrogen (BUN; 24 mg/dL), creatinine (1.33 mg/dL), serum lithium (1.42 mEq/L) on day 28, and creatine kinase (975 U/L) on day 29, compared with BUN (8 mg/dL) and creatinine (0.8 mg/dL) on admission. All medications were discontinued and he was treated with normal saline hydration. The delirium and abnormal laboratory data were fully recovered within 2 days, as follows: BUN (12 mg/dL), creatinine (0.82 mg/dL), and serum lithium (0.82 mEq/L). Lithium 600 mg/day and risperidone 3 mg/day were re-administered on day 32. But symptoms of delirium and elevated BUN (29 mg/dL), creatinine (1.36 mg/dL), serum lithium (1.54 mEq/L), and creatine kinase (90 U/L) were noted on day 35. All drugs were discontinued again and fluid hydration was given. One day later, the delirium resolved and abnormal data returned to normal: BUN (16 mg/dL), creatinine (0.88 mg/dL), and serum lithium (1.06 mEq/L). Finally, risperidone 2 mg/day monotherapy was given on day 38. The patient was discharged in a stable condition on day 42. He was kept regular treatment with risperidone 2 to 3 mg/day, and no episode of neurotoxicity and nephrotoxicity appeared in the following 2 years.\n\nConclusions\nOur patient had 2 episodes of neurotoxicity and nephrotoxicity during this hospitalization. He presented delirium, acute kidney injury (AKI) with increased level of serum creatinine [10], and lithium intoxication, which had developed soon after combined administration of lithium and risperidone, and subsided after discontinuing these medications. There were no other obvious medical causes that could better account for the development of above symptoms in this patient. The switching of antipsychotics was suitable for our patient with history of type 2 diabetes mellitus and hyperlipidemia [11]. His clinical features were considered to be side effects of lithium-risperidone interaction. The rating on the Naranjo Adverse Drug Reaction Probability Scale was 10, considered a “definite” adverse effect [12].\n\nWe searched PubMed from inception to June 2016 for literature review of neurotoxicity and nephrotoxicity due to combined use of lithium and risperidone. Google Scholar and pharmacovigilance databases of UK, Dutch, Australian, and Canadian were also searched for additional relevant articles. The search terms were: “lithium” and “risperidone” and (neuroto* or nms or neuroleptic malignant syndrome or delirium) as Search 1; lithium and risperidone and (nephroto* or renal failure or kidney injury) as Search 2. Articles without the direct concomitant use of lithium and risperidone or with toxicity highly related to other physical problem or obscure support were excluded. The Search 1 and 2 finally yielded 7 articles (twenty results from PubMed, then 14 articles were excluded and 1 report were included from Google Scholar) and showed in Table 1 [3–9]. These cases showed the mean age of 56.3 years, and no gender difference (4 females). The doses of lithium and risperidone ranged from 450 to 1500 mg/day and 2 to 6 mg/day, respectively, which are within normal therapeutic range. Side effects were noted within 3 weeks (5 of 7 cases) after the initial combination of lithium and risperidone, and varied from 4 days to 2 years. All cases developed neurotoxicity with symptoms of lethargy, delirium, and even neuroleptic malignant syndrome (NMS) (4 of 7 cases). NMS is characterized by delirium, muscular rigidity, fever, and autonomic nervous system dysregulation with typically high levels of creatine phosphokinase but not necessary in elevation of creatinine [13, 14]. Furthermore, our report specially showed the change of renal function in detail compared to previous reports.\n\nThere are two hypotheses of neurotoxicity from drug-drug interaction between lithium and risperidone. One is pure lithium intoxication-induced neurotoxicity without a relationship with risperidone [8]. The other one is that both lithium and risperidone increase the dopamine receptor blockade. Lithium inhibits pre-synaptic dopamine release, and risperidone blocks dopamine receptors [9]. As for nephrotoxicity, there are inconsistent results. One study including 13 patients indicates that switching a combination of lithium plus a conventional antipsychotic to a combination of lithium plus risperidone within 9 days is generally well tolerated and no statistically significant differences in the pharmacokinetics of serum lithium [15]. The other studies support lithium and risperidone may each induce it. Lithium may impair tubular function and next result in several renal complications, including AKI [16, 17]. Risperidone was also described as increasing the risk of AKI in a population-based cohort study [18]. Our case is an indicator to prove the nephrotoxicity by the concomitant use of these pharmaceuticals. He did not have a history of AKI while being treated with lithium or risperidone alone. We assume his AKI have a “2-pronged” effect of nephrotoxicity, which causes functional impairment of nephrons.\n\nBased on the literature review and our report, close observation of neurological signs for at least 3 weeks is necessary when lithium and risperidone are used at the same time. Once neurotoxicity occurs, further monitoring of renal function for nephrotoxicity survey is also required. Discontinuance of these agents will lead to remission of the aforementioned adverse effects.\n\nAbbreviation\nBDBipolar disorder\n\nBUNBlood urea nitrogen\n\nCPKCreatine phosphokinase\n\nCrCreatinine\n\nDKADiabetic ketoacidosis\n\nEEGElectroencephalography\n\nLiLithium\n\nNANot available\n\nNMSNeuroleptic malignant syndrome\n\nR.N.Reference number\n\nSDSchizoaffective disorder\n\nAcknowledgements\nAuthors thanks the patient to agree for publication of this report.\n\nFunding\nThis report received no research funding.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ Contributions\nDr. Hsu CW wrote the first draft. Drs. Lee Y and Lee CY helped with discussion. Drs. Hsu CW, Lee Y, Lee CY, and Lin PY gave critical comments on revision. Drs. Hsu CW and Lin PY finalized the manuscript. All the authors read and approved the final manuscript.\n\nAuthors’ Information\nChih-Wei Hsu, M.D., Yu Lee, M.D., M.M.S., Chun-Yi Lee, M.D., M.S., Pao-Yen Lin, M.D., Ph.D.*\n\nConsent for publication\nThe case described in this report has signed the informed consent for publication.\n\nCompeting interests\nThere is no competing conflict of interests regarding publication of this paper.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Oruch R Elderbi MA Khattab HA Pryme IF Lund A Lithium: a review of pharmacology, clinical uses, and toxicity Eur J Pharmacol 2014 740 464 73 10.1016/j.ejphar.2014.06.042 24991789 \n2. Mensink GJ Slooff CJ Novel antipsychotics in bipolar and schizoaffective mania Acta Psychiatr Scand 2004 109 6 405 19 10.1111/j.1600-0047.2004.00295.x 15117285 \n3. Chen B Cardasis W Delirium induced by lithium and risperidone combination Am J Psychiatry 1996 153 9 1233 4 10.1176/ajp.153.9.1233 8780436 \n4. Bourgeois JA Kahn DR Neuroleptic malignant syndrome following administration of risperidone and lithium J Clin Psychopharmacol 2003 23 3 315 7 10.1097/00004714-200306000-00015 12826996 \n5. Ananth J Johnson KM Levander EM Harry JL Diabetic ketoacidosis, neuroleptic malignant syndrome, and myocardial infarction in a patient taking risperidone and lithium carbonate J Clin Psychiatry 2004 65 5 724 10.4088/JCP.v65n0520d 15163265 \n6. Boker H Brandenberger M Schopper C [Neurotoxicity related to lithium-risperidon combination treatment in a patient with schizoaffective disorder] Psychiatrische Praxis 2007 34 1 38 41 10.1055/s-2005-915352 17106843 \n7. Kosehasanogullari SG Akdede B Akvardar Y Akan M Tunca Z Neuroleptic malignant syndrome caused by combination of risperidone and lithium in a patient with multiple medical comorbidities Prog Neuro-Psychopharmacol Biol Psychiatry 2007 31 5 1147 8 10.1016/j.pnpbp.2007.04.012 \n8. Boora K Xu J Hyatt J Encephalopathy with combined lithium-risperidone administration Acta Psychiatr Scand 2008 117 5 394 5 10.1111/j.1600-0447.2008.01165.x 18331580 \n9. Boeker H Seidl A Schopper C Neurotoxicity related to combined treatment with lithium, antidepressants and atypical antipsychotics Schweizer Archiv Fur Neurologie Und Psychiatrie 2011 162 72 6 \n10. Khwaja A KDIGO clinical practice guidelines for acute kidney injury Nephron Clin Pract 2012 120 4 c179 84 10.1159/000339789 22890468 \n11. Grande I Bernardo M Bobes J Saiz-Ruiz J Alamo C Vieta E Antipsychotic switching in bipolar disorders: a systematic review Int J Neuropsychopharmacol 2014 17 3 497 507 10.1017/S1461145713001168 24139622 \n12. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA Janecek E Domecq C Greenblatt DJ A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 45 10.1038/clpt.1981.154 7249508 \n13. Tse L Barr AM Scarapicchia V Vila-Rodriguez F Neuroleptic malignant syndrome: a review from a clinically oriented perspective Curr Neuropharmacol 2015 13 3 395 406 10.2174/1570159X13999150424113345 26411967 \n14. Baeza-Trinidad R Brea-Hernando A Morera-Rodriguez S Brito-Diaz Y Sanchez-Hernandez S El Bikri L Ramalle-Gomara E Garcia-Alvarez JL Creatinine as predictor value of mortality and acute kidney injury in rhabdomyolysis Intern Med J 2015 45 11 1173 8 10.1111/imj.12815 26010490 \n15. Demling J Huang ML Remmerie B Mannaert E Sperling W Pharmacokinetics and Safety of Combination Therapy with Lithium and Risperidone Pharmacopsychiatry 2006 39 6 230 1 10.1055/s-2006-950394 17124646 \n16. Oliveira JL Silva Junior GB Abreu KL Rocha Nde A Franco LF Araujo SM Daher Ede F Lithium nephrotoxicity Rev Assoc Med Bras 2010 56 5 600 6 10.1590/S0104-42302010000500025 21152836 \n17. Rej S Shulman K Herrmann N Harel Z Fischer HD Fung K Gruneir A Prevalence and correlates of renal disease in older lithium users: a population-based study Am J Geriatr Psychiatry 2014 22 11 1075 82 10.1016/j.jagp.2014.01.015 24566239 \n18. Hwang YJ Dixon SN Reiss JP Wald R Parikh CR Gandhi S Shariff SZ Pannu N Nash DM Rehman F Atypical antipsychotic drugs and the risk for acute kidney injury and other adverse outcomes in older adults: a population-based cohort study Ann Intern Med 2014 161 4 242 8 10.7326/M13-2796 25133360\n\n",
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"issue": "17(1)",
"journal": "BMC pharmacology & toxicology",
"keywords": "Acute kidney injury; Drug-drug interaction; Lithium; Neurotoxicity; Risperidone",
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"mesh_terms": "D058186:Acute Kidney Injury; D014150:Antipsychotic Agents; D003693:Delirium; D004359:Drug Therapy, Combination; D006801:Humans; D008094:Lithium; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders; D018967:Risperidone",
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"title": "Neurotoxicity and nephrotoxicity caused by combined use of lithium and risperidone: a case report and literature review.",
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"abstract": "OBJECTIVE\nTransplantation-mediated alloimmune thrombocytopenia (TMAT) occurs when leukocytes transferred in a donor organ from a patient with immune thrombocytopenia (ITP), mount a response against recipient platelets. We present the first fatal case of TMAT following liver transplantation and review its aetiology and treatment.\n\n\nMETHODS\nThe liver donor had ITP and died from an intracranial haemorrhage. The recipient platelet count fell to 2 × 109/l on post-operative day 2. Treatment refractory thrombocytopenia resulted in pulmonary haemorrhage and death. TMAT did not occur in a kidney recipient from the same ITP donor.\n\n\nMETHODS\nExtramedullary haematopoiesis was identified in the donor liver biopsy. Antibodies against platelet GPIb/IX were demonstrated in both donor and recipient. The thrombocytopenia was refractory to platelet transfusions, intravenous immunoglobulin, methylprednisolone, rituximab, romiplostim, plasmapheresis, vincristine and splenic artery embolization. On review of the literature, severe thrombocytopenia (<10 × 109/l) has started within 3 days of transplantation in all reported TMAT cases. Serious non-fatal bleeding was observed in 3/5 previously reported cases. The optimal treatment is unclear. TMAT should resolve as donor lymphocytes are eliminated but re-transplantation may be required in severe refractory cases. TMAT has been reported in recipients of a liver but not kidney or heart transplant from ITP donors, probably because of the greater burden of co-transplanted lymphoid tissue.\n\n\nCONCLUSIONS\nBefore using the liver of an ITP donor, the recipient's fully informed consent is required. However, the risk of TMAT from an ITP donor is currently unknown and systematic review of donor registries is needed.",
"affiliations": "a Department of Haematology , St James's University Hospital , Leeds , UK.;b Department of Hepatology , St James's University Hospital , Leeds , UK.;c Department of Anaesthesia & Intensive Care Medicine , St James's University Hospital , Leeds , UK.;d HMDS Laboratory and Department of Haematology , St James's University Hospital , Leeds , UK.;e Department of Transplant and Hepatobiliary Surgery , St James's University Hospital , Leeds , UK.;f Histocompatibility & Immunogenetics Laboratory , NHS Blood and Transplant , North Bristol Park, Bristol , UK.;b Department of Hepatology , St James's University Hospital , Leeds , UK.",
"authors": "Hill|Q A|QA|;Harrison|L C|LC|;Padmakumar|A D|AD|;Owen|R G|RG|;Prasad|K R|KR|;Lucas|G F|GF|;Tachtatzis|P|P|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D007518:Isoantibodies",
"country": "England",
"delete": false,
"doi": "10.1080/10245332.2016.1240392",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-5332",
"issue": "22(3)",
"journal": "Hematology (Amsterdam, Netherlands)",
"keywords": "GPIb/IX; Immune thrombocytopenia; TMAT; haemorrhage; liver transplantation; passenger lymphocyte syndrome; transplantation-mediated alloimmune thrombocytopenia",
"medline_ta": "Hematology",
"mesh_terms": "D000368:Aged; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D001792:Blood Platelets; D017809:Fatal Outcome; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D013916:Thrombelastography",
"nlm_unique_id": "9708388",
"other_id": null,
"pages": "162-167",
"pmc": null,
"pmid": "27764999",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A fatal case of transplantation-mediated alloimmune thrombocytopenia following liver transplantation.",
"title_normalized": "a fatal case of transplantation mediated alloimmune thrombocytopenia following liver transplantation"
} | [
{
"companynumb": "GB-ROCHE-1860525",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe liberal administration of hydroxychloroquine-sulphate (HCQ) to COVID-19 patients has raised concern regarding the risk of QTc prolongation and cardiac arrhythmias, particularly when prescribed with azithromycin. We evaluated the incidence of QTc prolongation among moderately and severely ill COVID-19 patients treated with HCQ and of the existence of concomitant alternative causes.\n\n\nMETHODS\nAll COVID-19 patients treated with HCQ (between Mar 1 and Apr 14, 2020) in a tertiary medical centre were included. Clinical characteristics and relevant risk factors were collected from the electronic medical records. Individual patient QTc intervals were determined before and after treatment with HCQ. The primary outcome measure sought was a composite end point comprised of either an increase ≥60 milliseconds (ms) in the QTc interval compared with pre-treatment QTc, and/or a maximal QTc interval >500 ms RESULTS: Ninety patients were included. Median age was 65 years (IQR 55-75) and 57 (63%) were male. Thirty-nine patients (43%) were severely or critically ill. Hypertension and obesity were common (n = 23 each, 26%). QTc prolongation evolved in 14 patients (16%). Age >65 years, congestive heart failure, severity of disease, C-reactive protein level, hypokalaemia and furosemide treatment, were all associated with QTc prolongation. Adjusted analysis showed that QTc prolongation was five times more likely with hypokalaemia [OR 5, (95% CI, 1.3-20)], and three times more likely with furosemide treatment [OR 3 (95% CI, 1.01-13.7)].\n\n\nCONCLUSIONS\nIn patients treated with HCQ, QTc prolongation was associated with the presence of traditional risk factors such as hypokalaemia and furosemide treatment.",
"affiliations": "Internal Medicine Department, Shaare Zedek Medical Center, School of Medicine, Hebrew University, Jerusalem, Israel.;Internal Medicine Department, Shaare Zedek Medical Center, School of Medicine, Hebrew University, Jerusalem, Israel.;Internal Medicine Department, Shaare Zedek Medical Center, School of Medicine, Hebrew University, Jerusalem, Israel.;Internal Medicine Department, Shaare Zedek Medical Center, School of Medicine, Hebrew University, Jerusalem, Israel.;Internal Medicine Department, Shaare Zedek Medical Center, School of Medicine, Hebrew University, Jerusalem, Israel.;The Adult Nephrology institute, Shaare Zedek Medical Center, School of Medicine, Hebrew University, Jerusalem, Israel.;Faculty of Medicine, Hebrew University, Jerusalem, Israel.;Faculty of Medicine, Hebrew University, Jerusalem, Israel.;Faculty of Medicine, Hebrew University, Jerusalem, Israel.",
"authors": "Fteiha|Bashar|B|https://orcid.org/0000-0001-7676-9447;Karameh|Hani|H|;Kurd|Ramzi|R|;Ziff-Werman|Batsheva|B|;Feldman|Itamar|I|;Bnaya|Alon|A|;Einav|Sharon|S|;Orlev|Amir|A|;Ben-Chetrit|Eli|E|",
"chemical_list": "D006886:Hydroxychloroquine; D017963:Azithromycin",
"country": "England",
"delete": false,
"doi": "10.1111/ijcp.13767",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1368-5031",
"issue": "75(3)",
"journal": "International journal of clinical practice",
"keywords": null,
"medline_ta": "Int J Clin Pract",
"mesh_terms": "D000368:Aged; D017963:Azithromycin; D000086382:COVID-19; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008133:Long QT Syndrome; D008297:Male; D000086402:SARS-CoV-2",
"nlm_unique_id": "9712381",
"other_id": null,
"pages": "e13767",
"pmc": null,
"pmid": "33063447",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "QTc prolongation among hydroxychloroquine sulphate-treated COVID-19 patients: An observational study.",
"title_normalized": "qtc prolongation among hydroxychloroquine sulphate treated covid 19 patients an observational study"
} | [
{
"companynumb": "IL-TEVA-2021-IL-1944462",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": "3",
... |
{
"abstract": "We present a rare case of taxane-pretreated metastatic gastric cancer with an excellent response to nab-paclitaxel. A 66- year-old woman was diagnosed with Stage Ⅳ gastric adenocarcinoma (T4aN3M1[LYM, OTH]P1CY1). She failed to respond to multiple chemotherapeutic regimens including S-1, capecitabine, cisplatin, L-OHP, paclitaxel, docetaxel, and CPT- 11. Finally, 6th line chemotherapy with nab-paclitaxel was tried. After 4 courses of nab-paclitaxel, a CT scan revealed decreasing ascites and a reduction in the size of the ovary metastasis. She experienced a clinical response for about 4 months. The adverse events were only Grade 1 peripheral sensory neuropathy and joint pain, and her performance status improved during the treatment period.",
"affiliations": "Dept. of Surgery, Osaka Rosai Hospital.",
"authors": "Kawabata|Ryohei|R|;Kimura|Yutaka|Y|;Kawase|Tomono|T|;Yoshikawa|Masato|M|;Kameda|Chizu|C|;Matsumura|Tae|T|;Koga|Chikato|C|;Murakami|Masahiro|M|;Hirota|Masaki|M|;Noura|Shingo|S|;Ikenaga|Masakazu|M|;Shimizu|Junzo|J|;Hasegawa|Junichi|J|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D013274:Stomach Neoplasms; D043823:Taxoids",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2088-90",
"pmc": null,
"pmid": "26805273",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Taxane-Pretreated Metastatic Gastric Cancer with Excellent Response to Nab-Paclitaxel.",
"title_normalized": "a case of taxane pretreated metastatic gastric cancer with excellent response to nab paclitaxel"
} | [
{
"companynumb": "JP-ACTAVIS-2016-08534",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein-Barr virus (EBV) infection (p = .00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.",
"affiliations": "a Department of Hematology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.;a Department of Hematology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.;c Department of Rheumatology and Clinical Immunology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.;b Division of Rheumatology, Department of Medicine , Keio University School of Medicine , Tokyo , Japan.;d Department of Pathology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.;d Department of Pathology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.;e Division of Hematology, Department of Medicine , Keio University School of Medicine , Tokyo , Japan.;e Division of Hematology, Department of Medicine , Keio University School of Medicine , Tokyo , Japan.;a Department of Hematology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.;c Department of Rheumatology and Clinical Immunology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.;e Division of Hematology, Department of Medicine , Keio University School of Medicine , Tokyo , Japan.;b Division of Rheumatology, Department of Medicine , Keio University School of Medicine , Tokyo , Japan.;d Department of Pathology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.;a Department of Hematology , Saitama Medical Center, Saitama Medical University , Kawagoe Saitama , Japan.",
"authors": "Tokuhira|Michihide|M|;Saito|Shuntaro|S|;Okuyama|Ayumi|A|;Suzuki|Katsuya|K|;Higashi|Morihiro|M|;Momose|Shuji|S|;Shimizu|Takayuki|T|;Mori|Takehiko|T|;Anan-Nemoto|Tomoe|T|;Amano|Koichi|K|;Okamoto|Shinichiro|S|;Takeuchi|Tsutomu|T|;Tamaru|Jun-Ichi|JI|;Kizaki|Masahiro|M|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2017.1369073",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "59(5)",
"journal": "Leukemia & lymphoma",
"keywords": "Methotrexate; autoimmune diseases; lymphoproliferative disorders; regression; rheumatoid arthritis",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D020031:Epstein-Barr Virus Infections; D005260:Female; D005500:Follow-Up Studies; D004854:Herpesvirus 4, Human; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011379:Prognosis; D012074:Remission Induction; D015996:Survival Rate",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1143-1152",
"pmc": null,
"pmid": "28877615",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with a focus on regression.",
"title_normalized": "clinicopathologic investigation of methotrexate induced lymphoproliferative disorders with a focus on regression"
} | [
{
"companynumb": "JP-PFIZER INC-2017417790",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "Diphenhydramine (DPH)-related deaths in adults are extremely rare, and detailed autopsy studies are rarer still. Toxicologic and anatomic findings in 4 cases of suicidal DPH overdose are described and compared with findings in a database of cocaine- and heroin-related deaths. Blood DPH levels were many times higher than those considered therapeutic (5000-35,000 ng/ml versus 50-100 ng/ml). Marked pulmonary edema with visceral congestion was a constant finding. Mean lung-body weight ratios for DPH, cocaine, heroin, and trauma controls were 0.015, 0.015, 0.019, and 0.013, respectively. When normalized for body weight in this fashion, edema in DPH-related deaths was comparable to that in cocaine-related deaths. Cardiac enlargement was apparent in 3 of the 4 DPH cases, 1 with marked myocardial fibrosis. The finding of increased heart size suggests that preexisting heart disease may provide the necessary substrate for lethal cases of DPH toxicity. Pulmonary edema in these cases remains unexplained, with edema in cases of heroin-related toxicity significantly worse than that produced by cocaine or DPH (p < .0001). Because DPH and cocaine can exert similar effects on the heart, a common mechanism may produce pulmonary edema in both. A different mechanism may account for heroin-related edema.",
"affiliations": "Office of the Assistant Medical Examiner, City and County of San Francisco, California 94103, USA.",
"authors": "Karch|S B|SB|",
"chemical_list": "D003932:Heroin; D004155:Diphenhydramine; D003042:Cocaine",
"country": "United States",
"delete": false,
"doi": "10.1097/00000433-199806000-00008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "19(2)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated; D003042:Cocaine; D004155:Diphenhydramine; D062787:Drug Overdose; D017809:Fatal Outcome; D005260:Female; D005355:Fibrosis; D003932:Heroin; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D009929:Organ Size; D011654:Pulmonary Edema; D013405:Suicide",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "143-7",
"pmc": null,
"pmid": "9662109",
"pubdate": "1998-06",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Diphenhydramine toxicity: comparisons of postmortem findings in diphenhydramine-, cocaine-, and heroin-related deaths.",
"title_normalized": "diphenhydramine toxicity comparisons of postmortem findings in diphenhydramine cocaine and heroin related deaths"
} | [
{
"companynumb": "US-SA-2020SA361705",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMalignant melanoma is a rare disease in the pediatric population and there are no recommendations regarding its management in children, while the current standard of care in metastatic or unresectable melanoma in adult patients includes immunotherapy (anti-CTLA-4 and anti-PD-1 antibodies). Advances in the management of adults with melanoma offer the prospect of promising therapeutic options for children.\n\n\nMETHODS\nWe describe a case of a 7-year-old patient with recurrent metastatic melanoma, for whom pembrolizumab was used as an adjuvant therapy on compassionate use basis.\n\n\nCONCLUSIONS\nDue to adverse events, the treatment was discontinued after 5 months of pembrolizumab, but with 12-months of follow-up, patient remains in complete remission.",
"affiliations": "Department of Pediatric Hematology and Oncology, Nicolaus Copernicus University Torun, Jurasz University Hospital, Collegium Medicum, Bydgoszcz, Poland agata.marjanska@wp.pl.;Department of General and Oncological Surgery for Children and Adolescents, Nicolaus Copernicus University Torun, Jurasz University Hospital, Collegium Medicum, Bydgoszcz, Poland.;Clinical Oncology Department, Oncology Center, Bydgoszcz, Poland.;Department of Pediatric Hematology and Oncology, Nicolaus Copernicus University Torun, Jurasz University Hospital, Collegium Medicum, Bydgoszcz, Poland.;Department of Pediatric Hematology and Oncology, Nicolaus Copernicus University Torun, Jurasz University Hospital, Collegium Medicum, Bydgoszcz, Poland.",
"authors": "Marjanska|Agata|A|;Galazka|Przemyslaw|P|;Marjanski|Michal|M|;Wysocki|Mariusz|M|;Styczynski|Jan|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D018501:Antirheumatic Agents; D013256:Steroids; C582435:pembrolizumab; D008727:Methotrexate",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13547",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "39(7)",
"journal": "Anticancer research",
"keywords": "Pembrolizumab; immunotherapy; malignant melanoma",
"medline_ta": "Anticancer Res",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D018501:Antirheumatic Agents; D001171:Arthritis, Juvenile; D002648:Child; D005260:Female; D006801:Humans; D008545:Melanoma; D008727:Methotrexate; D009364:Neoplasm Recurrence, Local; D012983:Soft Tissue Neoplasms; D013256:Steroids; D016896:Treatment Outcome; D014605:Uveitis",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "3945-3947",
"pmc": null,
"pmid": "31262925",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Efficacy and Toxicity of Pembrolizumab in Pediatric Metastatic Recurrent Melanoma.",
"title_normalized": "efficacy and toxicity of pembrolizumab in pediatric metastatic recurrent melanoma"
} | [
{
"companynumb": "PL-009507513-1907POL011488",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Encapsulating peritoneal sclerosis is a rare, recurring complication in peritoneal dialysis (PD) patients. With a mortality rate of 51%, it continues to be a therapeutic enigma among clinicians. However, the incidence after kidney transplantation (KT) has rarely been reported. We report a unique case of encapsulating peritoneal sclerosis (EPS), occurring years after failed initial living KT, and diagnosed after second deceased donor kidney transplantation. A 35-year-old male, on prior PD for 4 years, followed by failed KT of 8 years, was presented with abdominal pain, weight loss, and vomiting, 7 months after his second deceased donor KT. An abdominal computed tomography showed intra-abdominal loculated fluid collection, but no obstruction. Exploratory laparotomy revealed extensive peritoneal thickening and blocked intestinal loops. Histopathology was indicative of EPS with fibrous adhesions and sclerotic tissues. Besides restarting his immunosuppressive medications, tamoxifen therapy was initiated as definitive medical management. Currently, he is in clinical remission, follows at transplant clinic, and still experiences episodes of small bowel obstruction. Though the incidence of EPS after KT has been observed sporadically worldwide, none has been reported in the USA. Despite its prevalence in PD patients, therapeutic interventions attempted so far, are not definitive.",
"affiliations": "Division of Nephrology, University of Virginia, Charlottesville, Virginia, USA.;Division of Renal Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Internal Medicine, Frank H Netter MD School of Medicine, North Haven, Connecticut, USA.;Division of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.;Division of Renal Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.",
"authors": "Roy|Sasmit|S|;Alexander|Kyrstin|K|;Chowdhury|Monzurul Hasan|MH|;Vanguri|Vijay|V|;Bodziak|Kenneth|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000514062",
"fulltext": "\n==== Front\nCase Rep Nephrol Dial\nCase Rep Nephrol Dial\nCND\nCase Reports in Nephrology and Dialysis\n2296-9705\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000514062\ncnd-0011-0204\nSingle Case\nEncapsulating Peritoneal Sclerosis Presenting after Two Donor Kidney Transplantations: A Case Report and Literature Review\nRoy Sasmit a*\nAlexander Kyrstin b\nChowdhury Monzurul Hasan c\nVanguri Vijay d\nBodziak Kenneth b\naDivision of Nephrology, University of Virginia, Charlottesville, Virginia, USA\nbDivision of Renal Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA\ncInternal Medicine, Frank H Netter MD School of Medicine, North Haven, Connecticut, USA\ndDivision of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA\n*Sasmit Roy, docsasmit@gmail.com\nMay-Aug 2021\n16 7 2021\n16 7 2021\n11 2 204209\n16 9 2020\n23 12 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nEncapsulating peritoneal sclerosis is a rare, recurring complication in peritoneal dialysis (PD) patients. With a mortality rate of 51%, it continues to be a therapeutic enigma among clinicians. However, the incidence after kidney transplantation (KT) has rarely been reported. We report a unique case of encapsulating peritoneal sclerosis (EPS), occurring years after failed initial living KT, and diagnosed after second deceased donor kidney transplantation. A 35-year-old male, on prior PD for 4 years, followed by failed KT of 8 years, was presented with abdominal pain, weight loss, and vomiting, 7 months after his second deceased donor KT. An abdominal computed tomography showed intra-abdominal loculated fluid collection, but no obstruction. Exploratory laparotomy revealed extensive peritoneal thickening and blocked intestinal loops. Histopathology was indicative of EPS with fibrous adhesions and sclerotic tissues. Besides restarting his immunosuppressive medications, tamoxifen therapy was initiated as definitive medical management. Currently, he is in clinical remission, follows at transplant clinic, and still experiences episodes of small bowel obstruction. Though the incidence of EPS after KT has been observed sporadically worldwide, none has been reported in the USA. Despite its prevalence in PD patients, therapeutic interventions attempted so far, are not definitive.\n\nKeywords\n\nEncapsulating peritoneal sclerosis\nKidney transplantation\nPeritoneal dialysis\nTamoxifen\nEnd-stage renal disease\n==== Body\nIntroduction\n\nEncapsulating peritoneal sclerosis (EPS) is a rare, dreadful, and recurrent complication in patients undertaking peritoneal dialysis (PD). Although prevalent since 1907, this disease is still a diagnostic and management challenge among practicing clinicians everywhere. It entails a mortality rate of 51%, in the initial year, and has an incidence of 0.7–3.3% [1], which might be up to 13.6 per 1,000 patient-years [2].\n\nThe 2 most commonly implicated triggers in PD patients include prior history of peritonitis and extended duration of PD. This is succeeded by a second insult like peritonitis, surgery, hemoperitoneum on the damaged peritoneum [3]. Only a few cases of EPS have been reported in kidney transplantation (KT) recipients [4, 5, 6], but none in North America. Our case highlights a unique presentation of EPS, diagnosed years after failed living KT, and presenting after his second deceased donor KT.\n\nCase Report\n\nA 35-year-old African-American male presented to the emergency department, with chief complaints of nausea, vomiting, and abdominal distension for 2 months. He had persistent odynophagia with loss of appetite and profound weight loss. His notable past medical history included end-stage renal disease, from biopsy-proven focal segmental glomerular sclerosis; prior living KT 10 years ago (from mother), which failed after 8 years due to medicine noncompliance and recurrent focal segmental glomerular sclerosis. He was on PD for 4 years before his initial KT. Post first KT failure, he was on hemodialysis for 2 years before he received his second KT from a deceased donor. During his second transplantation, the hospital course was associated with complications like delayed graft function recovery, deep vein thrombosis. His transplant induction medications were rabbit antithymocyte globulin and corticosteroids. His maintenance immunosuppressant regimen being tablets tacrolimus 4 mg twice daily, mycophenolate mofetil 250 mg twice daily and prednisone 5 mg daily.\n\nOn physical examination, his blood pressure was 140/84 mm Hg, pulse rate 89/min, saturating 99% on room air, and his temperature was normal. He was severely cachexia and had oral thrush. Gastrointestinal (GI) system examination findings included abdominal distension, with diffuse tenderness and diminished bowel sounds. The rest of the systemic findings including respiratory, cardiovascular, and neurological systems were unremarkable. Pertinent lab findings were serum creatinine 2 mg/dL ([reference 0.6–1.3 mg/dL], which was his baseline), blood urea nitrogen 54 mg/dL (reference 8–20 mg/dL). Admission hematocrit was 33%. On hospitalization day 2, he experienced left upper quadrant acute sharp abdominal pain, 8/10 in intensity, nonradiating, with drop-in hematocrit from 33 to 23%, his condition deteriorated with blood pressure dropping to 70/40 mm Hg and requiring vasopressor support. Computerized tomography of the abdomen demonstrated loculated intra-abdominal fluid collections, shown in Figure 1. Diagnostic paracentesis revealed no signs of infection. Stool guaiac returned negative. The patient was treated conservatively with the cessation of warfarin and packed red blood cell transfusion. A bone marrow biopsy was done for suspected post-transplant lymphoproliferative disorder which returned negative. He was started on total parental nutrition for his persistent cachectic state. Suspecting EPS, an exploratory laparotomy was undertaken. This revealed extensive peritoneal thickening with signs of chronic inflammation along with adhesions and blocked intestinal loops, as shown in Figure 2. His abdomen was thoroughly washed and adhesiolysis was done. He was thereafter started on oral calcineurin inhibitor, that is, tamoxifen therapy, 10 mg twice daily. He continues to be on the same dose at present. Histopathology results returned positive for EPS findings, with encapsulating fibrous adhesions over terminal ileum and sclerotic tissues over intestinal wall smooth muscles as shown in Figure 3. The patient was subsequently able to tolerate oral intake, and he was successfully weaned off total parental nutrition. He was gradually initiated back on his immunosuppressants and discharged in stable condition. Throughout this hospitalization, his serum creatinine stayed stable at around 2–2.2 mg/dL.\n\nHe follows with the renal transplant clinic and continues to be on oral tamoxifen 10 mg twice daily, and other oral immunosuppressants, namely tacrolimus 4 mg twice daily, mycophenolate mofetil 250 mg twice daily and prednisone 5 mg daily. It has been 3 years since he has been last operated and he has been doing fairly well with occasional episodes of relapses. His abdominal symptoms recur periodically with small bowel obstructions. He has refused any further surgeries. Written consent was obtained from the patient before writing this case report.\n\nDiscussion\n\nPD is a successful modality of dialysis for end-stage renal disease patients which gives flexibility to them in managing their treatment, without compromising their quality of life. Overall, it is a very safe modality of dialysis. However, one of its dreadful complications, which are becoming more prevalent with wider use of PD, is encapsulating peritoneal sclerosis (EPS). EPS was initially observed in 1907 when it was coined as “Peritonitis Chronica Fibrosa Encapsulate.” This encases a clinical and pathological entity with intestinal obstruction and microscopic sclerosing features. EPS is characterized by bowel loops getting encased from extensive intraperitoneal fibrosis [7].\n\nEPS has an early inflammatory stage, succeeded by the sclerosing stage developing into an encapsulating cocoon, and thereby causing GI symptoms. EPS clinical features stem from underlying inflammation, peritoneal adhesions, and/or gut ileus. Initially, EPS mostly has benign symptoms like nausea, vomiting, progressive loss of appetite, weakness with intermittent periods of quiescence. It is typically associated with progressive ultrafiltration loss, causing edema and fluid retention. EPS is a gradual, insidious, nonacute clinical entity. Subsequent stages present as an abdominal mass, abdominal pain, ascites, and constipation [3]. These subtle symptoms and intermittent progression of EPS separate it from other GI disorders frequently encountered, for example, gut perforation, bowel obstruction, etc. [4].\n\nOverall, the cause of EPS is believed to be multifactorial and no specific pathology has been identified. Most studies have agreed on prolonged PD duration as a risk factor [7, 8, 9].\n\nVarious other parameters implicated in worldwide studies are − young individuals, higher dialysate glucose concentration, peritonitis (prolonged/severe), using conventional PD solutions (unlike the newer biocompatible PD solutions), icodextrin use, abdominal operative procedures, β-blockers use, KT (as our case), ultrafiltration failure, and higher peritoneal solute transport rate. However, these data are scattered and not completely implicit [10]. Calcineurin inhibitors, for example, cyclosporine, tacrolimus, which potentiates the transforming growth factor β expression, thereby leading to progressive peritoneal fibrosis, can be a possible reason in KT recipients [11].\n\nThe preferred diagnostic imaging modality is an abdominal computerized tomography scan. Standalone imaging features of EPS are bowel thickening, peritoneal calcification, bowel dilatation, and bowel tethering [3]. Occasionally, laparotomy and/or laparoscopic diagnostic confirmation is necessary. The inherent surgical features include peritoneal thickening enclosing intestinal contents [12].\n\nHistologically, EPS is identified by significant peritoneal membrane thickening with dense layers of fibro-connective tissue, and loss of mesothelium; exudates, ossification, increase in fibrin, calcification, and interstitial fibrosis are other notable features [3].\n\nAlthough not fruitful always, the management consensus of EPS has historically included the cessation of PD with the transition to hemodialysis, bowel rest with parenteral nutrition, and therapeutic interventions like immunosuppressive medications and/or surgery [10].\n\nSuccessful therapeutic medical interventions reported in EPS literature include tamoxifen [13], corticosteroids [14], and immunosuppression [15]. Most of these treatment modalities are in individual case series or small studies. Previously, the prognosis with surgical therapy was extremely poor. More recent studies done in Japan, UK, and Germany have shown encouraging surgical results [10]. Surgical treatment is highly complex because the pathology of EPS includes adhesive processes throughout the small intestine, and the end goal of the procedure is to release these adhesions from the intestine.\n\nTransplantation is prophesied to cause a survival benefit among EPS individuals. Few retrospective studies have predicted better survival among them when they undergo KT [13].\n\nOur case tries to highlight the rare risk factor of KT culminating into this scarce, recurring complication of EPS in PD patients. While studies have suggested KT may benefit EPS, we try to highlight that KT may increase the likelihood of this serious complication. Though few cases have been reported in post-KT recipients [4, 5, 6] − to our knowledge, this could be the first case reported from North America, where EPS has been diagnosed after second KT.\n\nConclusion\n\nEPS is a rare but dreadful complication of PD which can happen in individuals on the extended duration of PD. While only a few cases have been reported, the incidence of EPS following KT, that too after second transplantation, is extremely rare. Our case could be the first reported case of EPS in North America, in an individual who presented after 2 successive KTs. Also, tamoxifen therapy is a fairly well-tested option with limited efficacy. Clinicians should be mindful of this rare condition presenting as a diagnostic and management challenge to the medical fraternity. The fact that it can occur as a complication of KT even after suspending PD for many years should be a teaching point for every nephrologist. More research needs to be done to help treat these hapless patients better.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflicts of Interest Statement\n\nThe authors of this manuscript have no conflicts of interest to declare.\n\nFunding Sources\n\nThe authors did not receive any funding.\n\nAuthor Contributions\n\nSasmit Roy: case writing, corresponding author, and direct patient care; Kyrstin Alexander; Monzurul Hasan Chowdhury; Kenneth Bodziak: literature search, case writing, and direct patient care; and Vijay Vanguri: pathology interpretation and pathology slides.\n\nFig. 1 Computed tomogram abdomen showing loculated intra-abdominal fluid collections.\n\nFig. 2 Intraoperative findings of extensive peritoneal thickening with signs of chronic inflammation.\n\nFig. 3 Portion of encapsulating fibrous adhesions over terminal ileum. Smooth muscle from the intestinal wall (bottom) is covered by sclerotic tissue (*) with overlying fibrin deposition (top).\n==== Refs\nReferences\n\n1 Brown MC Simpson K Kerssens JJ Mactier RA Scottish Renal Registry Encapsulating peritoneal sclerosis in the new millennium: a national cohort study Clin J Am Soc Nephrol 2009 4 (7) 1222 9 19541815\n2 Burkart JM Post T Encapsulating peritoneal sclerosis in peritoneal dialysis patients UpToDate 2020 Waltham, MA UpToDate Available from: www.uptodate.com Accessed 2020 May 14.\n3 de Sousa E del Peso-Gilsanz G Bajo-Rubio MA Ossorio-González M Selgas-Gutiérrez R Encapsulating peritoneal sclerosis in peritoneal dialysis. A review and European initiative for approaching a serious and rare disease Nefrologia 2012 32 (32) 707 14 23169353\n4 Nakamoto H Encapsulating peritoneal sclerosis: a clinician's approach to diagnosis and medical treatment Perit Dial Int 2005 25 (Suppl) S30 8 16300270\n5 Korte MR Sampimon DE Betjes MG Krediet RT Encapsulating peritoneal sclerosis: the state of affairs Nat Rev Nephrol 2011 7 (7) 528 38 21808281\n6 Caicedo L Delgado A Caicedo LA Bravo JC Sclerosing encapsulated peritonitis: a devastating and infrequent disease complicating kidney transplantation, case report and literature review Int J Surg Case Rep 2017 33 135 28315818\n7 Brown EA Van Biesen W Finkelstein FO Hurst H Johnson DW Kawanishi H Length of time on peritoneal dialysis and encapsulating peritoneal sclerosis: position paper for ISPD Perit Dial Int 2009 29 (6) 595 600 19910558\n8 Nakayama M Miyazaki M Honda K Kasai K Tomo T Nakamoto H Encapsulating peritoneal sclerosis in the era of a multi-disciplinary approach based on biocompatible solutions: the NEXT-PD study Perit Dial Int 2014 34 (7) 766 74 24497585\n9 Vizzardi V Sandrini M Zecchini S Ravera S Manili L Cancarini G Encapsulating peritoneal sclerosis in an Italian center: thirty year experience J Nephrol 2016 29 (29) 259 67 26521254\n10 Brown EA Bargman J Van Biesen W Chang MY Finkelstein FO Hurst H Length of time on peritoneal dialysis and encapsulating peritoneal sclerosis: position paper for ISPD: 2017 update Perit Dial Int 2017 37 (4) 362 74 28676507\n11 Khanna A Plummer M Bromberek C Bresnahan B Hariharan S Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity Kidney Int 2002 62 (6) 2257 63 12427154\n12 Kawanishi H Moriishi M Tsuchiya S Experience of 100 surgical cases of encapsulating peritoneal sclerosis: investigation of recurrent cases after surgery Adv Perit Dial 2006 22 (22) 60 16983941\n13 Mohamed AO Kamar N Nogier MB Esposito L Duffas JP Rostaing L Tamoxifen therapy in kidney-transplant patients presenting with severe encapsulating peritoneal sclerosis after treatment for acute humoral rejection Exp Clin Transplant 2009 7 (3) 164 19715526\n14 Kawanishi H Kawaguchi Y Fukui H Hara S Imada A Kubo H Encapsulating peritoneal sclerosis in Japan: a prospective, controlled, multicenter study Am J Kidney Dis 2004 44 (44) 729 37 15384025\n15 Lafrance JP Létourneau I Ouimet D Bonnardeaux A Leblanc M Mathieu N Successful treatment of encapsulating peritoneal sclerosis with immunosuppressive therapy Am J Kidney Dis 2008 51 (51) e7 10 18215692\n\n",
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"title": "Encapsulating Peritoneal Sclerosis Presenting after Two Donor Kidney Transplantations: A Case Report and Literature Review.",
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"abstract": "Calcific uremic arteriolopathy (CUA), widely known as calciphylaxis, is a rare and lethal disease that usually affects patients with end-stage renal disease. It is characterised by widespread vascular calcification leading to tissue ischaemia and necrosis and formation of characteristic skin lesions with black eschar. Treatment options include sodium thiosulfate, cinacalcet, phosphate binders and in resistant cases, parathyroidectomy. We report a case of recurrent, treatment-resistant CUA successfully treated with parathyroidectomy. Her postoperative course was complicated by hungry bone syndrome and worsening of her wounds before they completely healed. We then discuss the morbidity of CUA, including the controversy around the use of parathyroidectomy and risk of aggressive management of hungry bone syndrome.",
"affiliations": "Department of Internal Medicine, Michigan State University College of Human Medicine, East Lansing, Michigan, USA.;Department of Internal Medicine, Michigan State University College of Human Medicine, East Lansing, Michigan, USA.;Department of Internal Medicine, Michigan State University College of Human Medicine, East Lansing, Michigan, USA.;Department of Internal Medicine, Michigan State University College of Human Medicine, East Lansing, Michigan, USA.",
"authors": "Hassanein|Mohamed|M|http://orcid.org/0000-0002-8247-5936;Laird-Fick|Heather|H|;Tikaria|Richa|R|;Aldasouqi|Saleh|S|",
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"mesh_terms": "D000328:Adult; D001847:Bone Diseases; D002115:Calciphylaxis; D005260:Female; D006801:Humans; D006996:Hypocalcemia; D016105:Parathyroidectomy; D011183:Postoperative Complications; D013577:Syndrome",
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"title": "Removing the problem: parathyroidectomy for calciphylaxis.",
"title_normalized": "removing the problem parathyroidectomy for calciphylaxis"
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"abstract": "Two men (66 and 73 Years) with a cardiovascular history were hospitalized for rapid onset encephalopathy associated with myoclonia and an extrapyramidal syndrome. On the basis of the French Pharmacovigilance system, this symptomatology has been attributed to the coadministration of a proton pump inhibitor, lansoprazole (15mg/day) with levodopa. Lansoprazole withdrawal led to a normalisation of the situation.",
"affiliations": "Service de Neurologie, Centre Hospitalier, Bourg en Bresse.",
"authors": "Boulliat|J|J|;Polard|E|E|;Colin|F|F|;Bentué-Ferrer|D|D|;Allain|H|H|",
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"title": "Myoclonic encephalopathy associated with proton pump inhibitors.",
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"abstract": "Therapeutic options in recurrent or metastasized vulvar squamous cell cancer (VSCC) not amenable to radiotherapy or radical surgery are limited. Evidence for the use of targeted therapies is sparse. All patients with VSCC treated at the Gynecological Cancer Center Hamburg-Eppendorf 20132019 were retrospectively evaluated for targeted therapeutic approaches. Furthermore, a MEDLINE, EMBASE, Web of Science, Scopus, and OVID database search was performed using the terms: vulvar cancer AND targeted therapy, erlotinib, EGFR, bevacizumab, VEGF, pembrolizumab, or immunotherapy. Twelve of 291 patients (4.1%) with VSCC received at least one targeted therapy at our institution. Previously, one or more platinum-based chemotherapy was applied to all patients [median 3.5 previous lines (range 25)]. In the erlotinib subgroup, two of five patients (40%) achieved stable disease (SD), while two patients (2/5, 40%) experienced partial response (PR). Treatment was given as monotherapy in second/third line for a median of 3.4 months (range 26 months). Bevacizumab (n=9) was given as maintenance therapy after platinum-based first-line chemotherapy (9/9); best response was complete response (CR) (n=2/9 22.2%). Median duration of treatment was 7 months (range 413 months) with two patients still under ongoing treatment. Best response in the pembrolizumab (n=3) subset was SD (n=1/3 33%). Treatment was given as monotherapy in second/third line for a median of 3.3 months (range 34 months). Nine of 12 patients (75%) experienced treatment-related adverse events (TRAEs), most commonly grade 1/2. Rapidly evolving antibody treatments have proven clinical benefit especially in HPV-driven tumor entities; however, clinical investigations in VSCC are still limited. These reported cases provide evidence for the clinical utility and feasibility while ensuring an acceptable safety profile.",
"affiliations": "Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany.;Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany.;Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany.;Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany.;Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany.;Department of Pathology, University Medical Center Hamburg-EppendorfHamburgGermany.;Center for Oncology, University Medical Center Hamburg-EppendorfHamburgGermany.;Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany.;Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany.;Department of Gynecology, University Medical Center Hamburg-EppendorfHamburgGermany.",
"authors": "Woelber|Linn|L|;Mathey|Sabrina|S|;Prieske|Katharina|K|;Kuerti|Sascha|S|;Hillen|Christoph|C|;Burandt|Eike|E|;Coym|Anja|A|;Mueller|Volkmar|V|;Schmalfeldt|Barbara|B|;Jaeger|Anna|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; C582435:pembrolizumab; D066246:ErbB Receptors",
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"fulltext": "\n==== Front\nOncol Res\nOncol Res\nOR\nOncology Research\n0965-0407\n1555-3906\nCognizant Communication Corporation Elmsford, NY\n\n33308371\nOR1448\n10.3727/096504020X16076861118243\nArticle\nTargeted Therapeutic Approaches in Vulvar Squamous Cell Cancer (VSCC): Case Series and Review of the Literature\nTARGETED THERAPEUTIC APPROACHES IN VULVAR CANCER\nWOELBER ET AL.\nWoelber Linn * 1\nMathey Sabrina * 1\nPrieske Katharina *†\nKuerti Sascha *\nHillen Christoph *\nBurandt Eike ‡\nCoym Anja §\nMueller Volkmar *\nSchmalfeldt Barbara *\nJaeger Anna *\n*Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany\n†Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany\n‡Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany\n§Center for Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany\n1These authors provided equal contribution to this work.\n\nAddress correspondence to Prof. Dr. med. Linn Woelber, Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. E-mail: lwoelber@uke.de\n2021\n16 3 2021\n28 6 645659\nCopyright © 2021 Cognizant, LLC.\n2021\nThis article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.\nTherapeutic options in recurrent or metastasized vulvar squamous cell cancer (VSCC) not amenable to radiotherapy or radical surgery are limited. Evidence for the use of targeted therapies is sparse. All patients with VSCC treated at the Gynecological Cancer Center Hamburg-Eppendorf 2013–2019 were retrospectively evaluated for targeted therapeutic approaches. Furthermore, a MEDLINE, EMBASE, Web of Science, Scopus, and OVID database search was performed using the terms: “vulvar cancer” AND “targeted therapy,” “erlotinib,” “EGFR,” “bevacizumab,” “VEGF,” “pembrolizumab,” or “immunotherapy.” Twelve of 291 patients (4.1%) with VSCC received at least one targeted therapy at our institution. Previously, one or more platinum-based chemotherapy was applied to all patients [median 3.5 previous lines (range 2–5)]. In the erlotinib subgroup, two of five patients (40%) achieved stable disease (SD), while two patients (2/5, 40%) experienced partial response (PR). Treatment was given as monotherapy in second/third line for a median of 3.4 months (range 2–6 months). Bevacizumab (n = 9) was given as maintenance therapy after platinum-based first-line chemotherapy (9/9); best response was complete response (CR) (n = 2/9 22.2%). Median duration of treatment was 7 months (range 4–13 months) with two patients still under ongoing treatment. Best response in the pembrolizumab (n = 3) subset was SD (n = 1/3 33%). Treatment was given as monotherapy in second/third line for a median of 3.3 months (range 3–4 months). Nine of 12 patients (75%) experienced treatment-related adverse events (TRAEs), most commonly grade 1/2. Rapidly evolving antibody treatments have proven clinical benefit especially in HPV-driven tumor entities; however, clinical investigations in VSCC are still limited. These reported cases provide evidence for the clinical utility and feasibility while ensuring an acceptable safety profile.\n\nKey words\n\nVulvar cancer (VC)\nTargeted therapy\nEGFR targeting\nVEGF signaling pathway\nImmuno-oncology\n==== Body\nINTRODUCTION\n\nDespite still being a rare disease of mostly elderly patients (median age of 70 years at diagnosis), the incidence of vulvar cancer (VC) is constantly on the rise to currently 3–5/100,000/year in Europe, whereas the age of onset is decreasing1–3. Almost 90% of VC are vulvar squamous cell cancer (VSCC); however, they remain clinically and pathologically heterogeneous. So far, two etiologies have been proposed, human papillomavirus (HPV)-associated and HPV-independent disease4. Approximately 40% of VSCC are related to high-risk HPV infections characterized by p16 overexpression, mostly arising in younger women. The majority of VSCC evolves based on HPV-independent pathways, often harboring TP53 mutations, preferably affecting postmenopausal patients5. Furthermore, a third subtype (p16-/p53-) has just recently been suggested based on the AGO-CaRE-1 translational data6. Prognosis is mainly determined by the tumor stage at initial diagnosis7–11. Both overall survival (OS) and progression-free survival (PFS) are strongly dependent on nodal involvement (3-year PFS rate of 35.2% and OS rate of 56.2% in node-positive patients compared to 75.2% and 90.2% in node-negative patients)9,12,13. In case of recurrent or metastasized disease not amenable to radiotherapy or radical surgery, therapeutic options are extremely limited. Especially after first-line treatment with platin-based combination regimens, response rates to the often used monochemotherapies are poor and range 0–15%14,15. Determination of the best therapeutic regimen with the least toxicity is difficult as there are only very few studies with heterogeneous populations. Current recommendations therefore rely on scarce and often controversial evidence instead of randomized data.\n\nConsequently, no improvement in survival could be achieved in the last two decades for locally advanced, recurrent, or metastatic disease—as reflected in a 1-year survival rate of only 15–30%16. A targeted approach to treatment has become of high clinical and scientific interest in order to improve therapeutic options. However, only little is known regarding underlying genetic and molecular alterations in VC17,18. Current therapeutic targets of interest are therefore mainly adopted from other entities like head and neck cancer and cervical cancer and focus on the epidermal growth factor receptor (EGFR) signaling cascade, VEGF-/angiogenesis-related markers, as well as immune checkpoints4. However, with the exception of erlotinib, data on the efficacy of these therapies in VC is very limited. We therefore analyzed a small cohort of patients with advanced VC treated with targeted agents at our own institution and conducted a review of literature, summarizing the emerging data.\n\nMATERIALS AND METHODS\n\nPatients\n\nBetween 2013 and 2019, n = 291 patients with VSCC were treated at our gynecologic oncology center. A retrospective evaluation regarding the application of targeted therapy was performed. Targeted therapy was recommended to a total of 16 patients (5.5%) with recurrent or metastasized VSCC not amenable to radical surgery or definitive radiotherapy, and 12 patients (4.1%) finally received one or more of the of the following drugs: erlotinib, bevacizumab, or pembrolizumab (Table 1). The remaining four patients chose different therapeutic options due to deterioration, or their health insurance did not cover the cost of treatment. Before the treatment was applied, all patients had received one or more prior lines of platinum-based chemotherapy. Duration of response, treatment tolerance, time to progression, and time to death after the beginning of targeted treatment was evaluated. Therefore, medical charts and pathological reports were reviewed. Previously, informed consent had been obtained from all included patients according to our investigational review board and ethics committee guidelines (Ethics Committee of the Medical Board Hamburg reference number 190504). Drug-related side effects were evaluated according to the National Cancer Institute Common Terminology for adverse events, CTCAE version 4.0. The following methods have been applied to classify the expression of the different molecular targets. In order to predict the responsibility to PD-L1 antagonist pembrolizumab, the combined positivity score (CPS) was evaluated—a score that represents the number of PD-L1 staining cells divided by the total number of viable tumor cells, multiplied by 100. According to the FDA approval criteria for pembrolizumab, a combined positivity score (CPS) ≥1 is mandatory. EGFR mutational status was analyzed by PCR, and HPV status was classified by analyzation of proliferation markers such as p16. The prognostic role of the HPV status and the use of immunohistochemical p16 overexpression as surrogate marker of HPV-induced transformation in VSCC are discussed controversially19,20; however, a recent study revealed a significant correlation between detection of HPV DNA and p16 overexpression (p < 0.001) in patients with VSCC. Furthermore, a significant correlation between p16 status and tumor stage (p = 0.003) could be observed as well as the association between p16 overexpression and higher tumor stage (>T2)21. Accordingly, in other squamous cell carcinomas, especially in oropharyngeal and anal cancers, overexpression of p16 by immunohistochemical staining (IHC) has been shown to be associated significantly with HPV positivity by PCR or in situ hybridization22,23. Furthermore, p16 overexpression has been found to be of independent prognostic value for the response to radiation treatment24–26. In accordance with oropharyngeal squamous cell carcinomas, scoring criteria for p16 in our study were no expression (negative), weak expression (<30% positive cells), moderate expression (31–50% positive cells), and strong expression (>50% positive cells). Samples scored as moderate or higher were considered as positive for p1627.\n\nTable 1 Summary of All Patients Who Received One or More Targeted Therapeutic Agents\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\tPatient 7\tPatient 8\tPatient 9\tPatient 10\tPatient 11\tPatient 12\t\nAge at FD\t74\t42\t58\t46\t57\t37\t61\t26\t64\t58\t49\t52\t\nFirst-line therapy/prior treatment before targeted treatment\t1. Surgery, adj. RT;\n2. Adj. RCTX; 3. CTX\t1. Surgery, adj. RCTX; 2. Surgery, RCTX\t1. Surgery;\n2. RT; 3. CTX\t1. Surgery, adj. RT;\n2. Surgery; 3. CTX\t1. Surgery, adj. RT;\n2. Surgery, RCTX;\n3. CTX\t1. Surgery, RCTX;\n2. Surgery;\n3. Surgery; 4. CTX\t1. Surgery; 2. CTX\t1. Surgery, RCTX;\n2. Surgery; 3. CTX\t1. Surgery;\n2. Surgery;\n3. CTX\t1. Surgery; 2. RCTX;\n3. Surgery + CTX;\n4. Surgery; 5. RCTX\n6. CTX\t1. Surgery, adj. local ablative RT;\n2. RT; 3. stereotactic irradiation; 4. CTX\t1. Surgery;\n2. RCTX; 3. CTX\t\nTargeted therapeutic agents (in applied order)\t1. Bevacizumab\n2. Erlotinib\t1. Erlotinib\n2. Bevacizumab\tErlotinib\tErlotinib\tErlotinib\t1. Bevacizumab\n2. Pembrolizumab\t1. Bevacizumab\n2. Pembrolizumab\t1. Bevacizumab\n2. Pembrolizumab\tBevacizumab\tBevacizumab\tBevacizumab\tBevacizumab\t\nHPV status/EGFR Mut/PDL-1 status\tHPV unknown/EGFR unknown\tHPV unknown/EGFR wild type (PCR)\tHPV unknown EGFR wild type (PCR)\tHPV negative EGFR wild type (PCR)\tHPV negative (p16−)/EGFR wild type (PCR)\tHPV negative; PD-L1: CPS 1-5\tHPV unknown/PD-L1 CPS 60\tHPV negative/PD-L1 CPS unknown\tHPV negative\tHPV unknown\tHPV unknown\tHPV unknown\t\nBest response\tBevacizumab: PR\nErlotinib: SD\tErlotinib: PR; Bevacizumab: PD\tSD\tPD\tPR\tBevacizumab and pembrolizumab: PD\tBevacizumab: CR\nPembrolizumab: SD\tBevacizumab: PD\nPembrolizumab: PD\tSD\tCR\tSD\tSD\t\nSide effects\tBevacizumab: grade 3 CTCAE: high blood pressure\nErlotinib: grade 1\nCTCAE: exanthema\tBevacizumab: no\nErlotinib: grade 2 CTCAE: diarrhea, elevated liver enzymes, skin alterations (facial comedo)\tGrade 2 CTCAE: Skin problems, elevated liver enzymes\tGrade 3 CTCAE: diarrhea with C. difficile infection, elevated liver enzymes\nGrade 2 CTCAE: skin problems (cutaneous rhagades)\tNone\tBevacizumab: grade 2 CTCAE: high blood pressure\nPembrolizumab: grade 2 CTCAE: fatigue, lymphedema\tBevacizumab: pericardial effusion\nPembrolizumab: none\tBevacizumab: grade 3 CTCAE: deep vein thrombosis\nPembrolizumab: grade 2 CTCAE: lymphedema, hypothyroidism\t\t\t\t\t\nGrade 2 CTCAE: diarrhea, lymphedema, high blood pressure\tGrade 3 CTCAE: arterial bleeding right groin 2 months after end of bevacizumab\tNone\tNone\t\nDose reduction\tBevacizumab: yes, due to high blood pressure resistant to therapy;\nErlotinib: no\tErlotinib and Bevacizumab: no\tNo\tYes, from 150 to 100 mg due to elevated liver enzymes\tNo\tBevacizumab and pembrolizumab: no\tBevacizumab and pembrolizumab: no\tBevacizumab: yes, end of bevacizumab due to deep vein thrombosis\nPembrolizumab: no\tNo\tNo\tNo\tNo\t\nTime to progression (months)\tBevacizumab: 4\nErlotinib: 2\tErlotinib: 3; Bevacizumab: 4\t6\t2\t4\tBevacizumab and pembrolizumab: 4\tBevacizumab: 13\nPembrolizumab: 3\tBevacizumab: 6\nPembrolizumab: 3\tOngoing treatment\t12\tOngoing treatment\t6\t\nTime to death from FD (months)\tUnknown\t36\t19\t47\tUnknown\tUnknown\tUnknown\t40\tNA\t48\tNA\tUnknown\t\nCause of death\tUnknown\tTumor progression\tTumor progression\tKidney failure, tumor progression\tUnknown\tUnknown\tUnknown\tTumor progression\tNA\tTumor progression\tNA\tUnknown\t\nadj., adjuvant; CPS, combined positive score; CTCAE, Common Terminology Criteria for Adverse Events; EGFR, epidermal growth factor receptor; HPV, human papilloma virus; loc, local, dist, distant; rec, recurrence; PD, progressive disease; RD, recurrent disease; SD, stable disease; PR, partial response; FD, first diagnosis; CTX, chemotherapy; RT, radiotherapy; CRTX, chemoradiation.\n\nCASE SERIES AND REVIEW OF THE LITERATURE\n\nMedline (Pubmed), EMBASE, Web of Science, Scopus, and OVID were searched for articles on targeted therapy in VC independent of publication date. We selected only studies reporting on VSCC. Search terms were “vulvar cancer” AND “targeted therapy,” “bevacizumab,” “VEGF,” “erlotinib,” “EGFR,” “pembrolizumab,” “checkpoint inhibitor,” or “immunotherapy.” In addition, we paired the search term “vulvar cancer” with different molecular markers involved in cell cycle, apoptosis, and angiogenesis.\n\nEGFR Targeting: Erlotinib\n\nThe EGFR is expressed on the surface of both normal and cancer cells and represents a key member of the family of receptor tyrosine kinases (TK), involved in cellular proliferation, migration, and differentiation. Being an EGFR inhibitor, erlotinib reversibly and selectively blocks EGFR-TK activity, leading to inhibition of intracellular phosphorylation and prevention of further downstream signaling. As a result, cell death is induced, while dissemination of tumor cells is reduced. The most commonly reported drug-related adverse reactions (>20%) are rash, fatigue, dyspnea, cough, nausea, and diarrhea. Erlotinib is applied orally, and recommendations regarding the dosage vary between 100 and 150 mg/day28.\n\nIncreased expression of EGFR has been detected in 40–67% of all VC29, and EGFR copy number increase was observed in 39.9%30. Moreover, amplification of EGFR is suggested to be associated with advanced tumor stages (p < 0.001), lymph node metastases (p = 0.02), and HPV negativity (p = 0.04) in VSCC30. In a prospective phase II trial with erlotinib, Horowitz et al. enrolled a total of 41 patients with VC either suitable for surgery or chemoradiation31. No information regarding the tumors’ mutational status or FISH results for amplification of EGFR were made available in the publication. Patients received erlotinib 150 mg orally per day; 28 days of treatment were considered to be one cycle. A remarkable clinical benefit rate of 67.5% was observed including 27.5% partial response (PR) and 40% stable disease (SD). Besides these promising results, a relatively short response duration with a median of 3 months was revealed, while toxicity with n = 10 grades 3 and 4 adverse events including renal failure (n = 2) was serious. However, the authors concluded that given the poor prognosis and the lack of treatment options in recurrent or metastasized VSCC, blocking the EGFR-signaling pathway by erlotinib may serve as one of the most promising therapeutic approaches available in this indication31.\n\nIn addition, encouraging results regarding the effect of erlotinib have been described in a few selected cases. Olawaiye et al. enrolled two elderly patients with locally advanced VC who were treated with oral erlotinib 150 mg/day; both patients experienced substantial clinical benefit with one CR and one PR32. More recently, another case of a 76-year-old patient with recurrent VSCC FIGO stage IIIA was published first showing a long-term response of 9 months under treatment with erlotinib33.\n\nIn our case series, five patients were treated with erlotinib (Table 2). All patients had received platin-based chemotherapy before and received erlotinib as second/third line treatment. Median age at treatment was 56 years (range 42–74). In 4/5 of patients (80%), EGFR mutational status analyzed by PCR were negative. Best responses were partial response (PR) in 2/5 of patients (40%) and stable disease (SD) in 2/5 of patients (40%). Median time to progression was 3.4 months (range 2–6). During the treatment with erlotinib, the patients experienced diarrhea, grade 2 (n = 1) and grade 3 including one Clostridium difficile infection. Further clinically relevant side effects were skin problems: facial comedo (n = 1), cutaneous rhagades (n = 1), or exanthema (n = 2), and elevated liver enzymes (n = 3)—in this context, dose reduction from 150 to 100 mg was necessary in one patient.\n\nTable 2 Erlotinib\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\t\nAge at FD\t74\t42\t58\t46\t57\t\nFirst diagnosis (MM/YY)\t11/17\t07/12\t01/13\t05/09\t10/15\t\nHistory of disease/time to recurrence (months)\t1. surgery, adj. RT/6; 2. loc rec > surgery R0/2; 3. loc rec -> surgery, R0, adj RCTX; 3. loc rec under ongoing RT -> CTX carboplatin/paclitaxel/bevacizumab/4; 4. dist rec -> erlotinib\t1. surgery, adj. RCTX/8; 2. local and dist rec(parallel) -> surgery, RCTX/4; 3. loc PD -> erlotinib/3; 4. Loc dist. PD -> CTX/4 (carboplatin/paclitaxel/bevacizumab)\t1. surgery -> R0/9; 2. loc rec -> surgery, RT/6; 3. distant rec -> CTX carboplatin/paclitaxel/5; 4. dist rec -> erlotinib/6; 5. dist PD -> best supp care\t1. surgery, adj RT/12; 2. loc rec -> surgery R0/10; 3. dist rec -> CTX cisplatin/topotecan/6; 4. dist PD - > CTX paclitaxel/4; 5. dist PD -> erlotinib/2; 6. dist rec -> best supp care\t1. surgery, adj. RT/10; 2. local and dist rec -> surgery, RCTX (cisplatin)/4; 3. dist PD -> CTX paclitaxel/3; 4. loc PD -> erlotinib/4; 5. loc PD -> electrochemotherapy + erlotinib\t\nDisease at indication (tumor load)\tLocal PD (left groin)\tLocal PD (right groin)\tDistant metastasis (bone)\tDistant metastasis (liver, bone)\tLocal PD (left groin)\t\nHPV status/EGFR Mut (HPV+/p16)\tHPV unknown/EGFR unknown\tHPV unknown/EGFR wild type (PCR)\tHPV unknown/EGFR wild type (PCR)\tHPV negative/EGFR wild type (PCR)\tHPV negative (p16−)/EGFR wild type (PCR)\t\nBest response\tSD\tPR\tSD\tPD\tPR\t\nSide effects\tGrade 1 CTCAE: exanthema\tGrade 2 CTCAE: diarrhea, elevated liver enzymes, skin alterations (facial comedo)\tGrade 2 CTCAE: Skin problems, elevated liver enzymes\tGrade 3 CTCAE: diarrhea with C. difficile infection, elevated liver enzymes grade 2 CTCAE: skin problems (cutaneous rhagades)\tNone\t\nDose reduction\tNo\tNo\tNo\tYes, from 150 to 100 mg due to elevated liver enzymes\tNo\t\nTime to progression\t2 months (8 weeks)\t3 months (12 weeks)\t6 months (24 weeks)\t2 months (8 weeks)\t4 months (16 weeks)\t\nTime to death from FD\tUnknown\t36 months\t19 months\t47 month\tUnknown\t\nCause of death\tUnknown\tTumor progression\tTumor progression\tKidney failure, tumor progression\tUnknown\t\nadj., adjuvant; CTCAE, Common Terminology Criteria for Adverse Events; EGFR, epidermal growth factor receptor; HPV, human papilloma virus; loc, local; dist, distant; rec, recurrence; MM/YY FD, month/year of first diagnosis; PD, progressive disease; RD, recurrent disease; SD, stable disease; PR, partial response; FD, first diagnosis; CTX, chemotherapy; RT, radiotherapy; CRTX, chemoradiation; R0, tumor free margins; R1, microscopic tumor residual.\n\nVEGF-Signaling Pathway: Bevacizumab\n\nThe rationale using antiangiogenetic treatment in cancer is supposed to depend on the presence of hypoxia in cancer tissue; the reduction of oxygen induces the transcription of the vascular endothelial growth factor receptor (VEGF-R). Subsequently, binding of VEGF to its receptors induces angiogenesis in the form of endothelial cell proliferation and new blood vessels. The inhibition of microvascular growth is therefore supposed to reduce the growth of all tissues, including metastatic tissue. Hence, the VEGF signaling pathway serves as an important mediator of tumor angiogenesis, an event directly correlating with the extent of disease and inversely correlating with survival.\n\nThe most commonly reported adverse reactions (>10%) caused by bevacizumab are epistaxis, headache, hypertension, proteinuria, and dry skin. Recent warnings furthermore include gastrointestinal perforations and fistula, wound healing complications, as well as arterial and venous thromboembolic events. Bevacizumab is administered as an intravenous infusion preferably every 3 weeks, and the recommended dosage usually ranges 10–15 mg/kg34.\n\nAngiogenesis inhibitors like bevacizumab have been approved by the FDA for treatment in various cancer types (e.g., colorectal cancer, non-small cell lung cancer, and glioblastoma). Regarding gynecologic malignancies, bevacizumab has shown promising results especially in cervical and also in ovarian cancer. The approval of bevacizumab for women with recurrent and metastatic cervical cancer was granted in 2014 based on the second interim analysis of the phase III Gynecologic Oncology Group (GOG) 240 trial35. Herein, the addition of bevacizumab to combination chemotherapy consisting of cisplatin and paclitaxel extended median OS by 3.7 months (17.0 vs. 13.3 months; HR: 0.71; 98% CI 0.54–0.95, p = 0.004) and resulted in higher response rates (48% vs. 36%, p = 0,008). More recently, in June 2017, the final OS analysis of GOG-240 was published by Tewari et al. and showed continued benefit of the addition of bevacizumab to chemotherapy in patients with metastatic, persistent, or recurrent cervical carcinoma (median OS of 16.8 months vs 13.3 months, HR = 0.77, p = 0.007)36. To date, antiangiogenic treatment has not been investigated in VC. However, there are a few analyses examining the role of the VEGF pathway in this rare disease. According to the data from previous studies, VEGF is supposed to be prognostically relevant in VC as serum concentration of VEGF protein is associated with tumor stage37 and patients with increased VEGF expression were reported to have significantly worse OS rates38.\n\nBased on the data mentioned above, we recommended bevacizumab to nine of our patients (Table 3). All of these patients received bevacizumab concomitantly to, and as maintenance approach after, platinum-based combination therapy. Therefore, isolated response to bevacizumab cannot be reported. Median age at treatment was 51.4 years (range 26–74). Median time to progression was 28 weeks (range 16–52 weeks), while two patients are still under ongoing treatment and are doing well. Best response was CR in 2/9 of cases (22.2%) followed by PR in 1/9 of cases (11.1%), and SD in 3/9 of cases (33.3%). In 2/9 of cases (22.2%), treatment with bevacizumab had to be stopped due to thromboembolic event and elevated blood pressure resistant to therapy.\n\nTable 3 Bevacizumab\n\n\tPatient 6\tPatient 7\tPatient 8\tPatient 9\tPatient 1\tPatient 2\tPatient 10\tPatient 11\tPatient 12\t\nAge at FD\t37\t61\t26\t64\t74\t42\t58\t49\t52\t\nMM/YY FD\t11/17\t03/16\t04/15\t11/17\t11/17\t07/12\t03/16\t01/16\t01/18\t\nHistory of disease/time to recurrence (months)\t1. surgery, RCTX/5;\n2. loc rec -> surgery/2;\n3. loc rec -> surgery/3;\n4. loc rec -> CTX (carboplatin/paclitaxel/bevacizumab)/4;\n5. loc and dist rec-> ctx with mitomycin/capecitabine/3;\n6. loc PD: pembrolizumab/4;\n7. loc and dist PD: best supp care\t1. surgery, RT/11;\n2. dist rec -> CTX (cisplatin/topotecan)/9;\n3. loc PD -> CTX (paclitaxel/bevacizumab)/13;\n4. dist rec -> pembrolizumab/3; 5. dist PD -> best supp care\t1. surgery, RTX/10;\n2. loc rec -> surgery R0/3; 3. dist rec -> CTX (carboplatin/paclitaxel/bevacizumab)/6; DVT: end of bevacizumab, start pembrolizumab/3;\n4. dist. rec -> CTX vinorelbine\t1. surgery/11;\n2. loc rec -> surgery (R1) -> RT/10; 3. loc and dist rec -> CTX (carboplatin/paclitaxel/bevacizumab)\t1. surgery, adj. RT/6;\n2. loc rec -> surgery R0/2;\n3. loc rec -> surgery, R0, adj RCTX;\n4. loc rec under ongoing RT -> CTX carboplatin/paclitaxel/bevacizumab/4;\n5. dist rec -> erlotinib\t1. surgery, adj. RCTX/8;\n2. local and dist rec/4 (parallel) -> surgery, RCTX;\n3. loc PD -> erlotinib/3; 4. Loc dist. PD -> CTX (carboplatin/paclitaxel/bevacizumab)/4\t1. surgery/10;\n2. loc rec -> RCTX/6;\n3. loc rec -> surgery (R0) + CTX (cisplatin, paclitaxel)/10;\n4. loc rec -> surgery (R1) -> RCTX/7;\n5. loc PD -> CTX (carboplatin/paclitaxel/bevacizumab)/12;\n6. loc PD -> CTX (paclitaxel mono)\t1. surgery, adj. local ablative RT/8;\n2. dist rec -> RT/7;\n3. dist rec -> stereotactic irradiation/9;\n4. dist PD -> CTX cisplatin/paclitaxel/bevacizumab\t1. surgery -> RCTX/7;\n2. loc rec -> CTX (carboplatin/paclitaxel/bevacizumab)/6 carboplatin/paclitaxel intolerance, bevacizumab maintenance;\n3. loc rec -> olaparib (known BRCA mutation)\t\nDisease at indication (tumor load)\tLocal PD (Vulva)\tLocal PD (Vulva)\tDistant metastasis (bone)\tLocal and distant PD (right groin, liver)\tLocal PD (vulva)\tLocal and distant PD (right groin, skin)\tLocal PD (right groin)\tDistant metastasis (lung, liver)\tLocal PD (left groin)\t\nHPV status\tUnknown\tUnknown\tUnknown\tNegative (p16−)\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t\nBest response\tPD\tCR\tPD\tSD\tPR\tPD\tCR\tSD\tSD\t\nSide effects\tGrade 2 CTCAE: high blood pressure\tGrade 2 CTCAE: pericardial effusion\tGrade 3 CTCAE: DVT\tGrade 2 CTCAE: diarrhea, lymphedema, high blood pressure\tGrade 3 CTCAE: high blood pressure\tNone\tGrade 3 CTCAE: arterial bleeding right groin 2 months after end of bevacizumab\tNone\tNone\t\nDose reduction\tNo\tNo\tYes, end of bevacizumab (DVT)\tNo\tYes, end of bevacizumab (high blood pressure resistant to therapy)\tNo\tNo\tNo\tNo\t\nTime to progression\t4 months\t13 months\t6 months\tOngoing treatment\t4 months\t4 months\t12 months\tOngoing treatment\t6 months\t\nTime to death from FD\tUnknown\tUnknown\t40 months\tUnknown\tUnknown\t36 months\t48\tNA\tUnknown\t\nCause of death\tUnknown\tUnknown\tTumor progression\tUnknown\tUnknown\tTumor progression\tTumor progression\tNA\tUnknown\t\nadj., adjuvant; CTCAE, Common Terminology Criteria for Adverse Events; HPV, human papilloma virus; loc, local; dist, distant; rec, recurrence; MM/YY FD, month/year of first diagnosis; PD, progressive disease; RD, recurrent disease; SD, stable disease; CR, complete response; PR, partial response; FD, first diagnosis; CTX, chemotherapy; RT, radiotherapy; CRTX, chemoradiation; R0, tumor-free margins; R1, microscopic tumor residual; DVT, deep vein thrombosis.\n\nCheckpoint Inhibition: Pembrolizumab\n\nPembrolizumab is a monoclonal, programmed cell death 1 (PD-1) binding antibody on the surface of activated T cells specifically blocking the interaction between PD-1 and programmed death ligand 1 (PD-L1), predominantly found on tumor cells of several cancer types. Thereby, T-cell proliferation is enhanced and PD-1 pathway-mediated inhibition of the adaptive immune response is released. Overexpression of PD-L1 as well as high microsatellite instability (MSI-H) seem to be predictive factors regarding the response to targeted PD-1/PD-L1 inhibitors in a variety of tumor types39–41; however, in other studies, no positive association between PD-L1 expression and response to immune checkpoint inhibitors or OS could be observed42. In VC, PD-L1 expression has been found in 12/103 of patients with VC (11.65%), and association with HPV negativity as well as with poor prognosis was observed (recurrence-free survival HR: 3.029 CI 1.228–8.471, p = 0.0018)43. However, more recently published data showed a statistically significant correlation between PD-L1 expression and low tumor stage, but association with the HPV status or OS in patients with VC could not be confirmed44,45.\n\nThe most frequent pembrolizumab-related side effects (reported in ≥20% of patients) are fatigue, musculoskeletal pain, and pruritus in case it is applied as a single agent; when given in combination with chemotherapy, nausea, constipation, diarrhea, rash, cough, and peripheral neuropathy are reported to have arisen the most. In addition, one should also be aware of immune-mediated complications such as pneumonitis, colitis, hepatitis, as well as endocrinopathies when treating patients with PD-1/PD-L1 antagonists. Pembrolizumab is administered as an intravenous infusion over 30 min46, and the recommended dosage varies between 200 and 300 mg q3w (every 3 weeks).\n\nGiven the similarities especially in HPV-associated tumorigenesis, the recent approval of pembrolizumab in cervical as well as head and neck cancer (HNSCC) might be seen as a predictor for efficacy in VC. Efficacy results in patients with recurrent or metastatic cervical cancer in the KEYNOTE-158 study revealed an ORR of 14.3% in PD-L1-positive disease (95% CI: 7.4%, 24.1%) with complete and partial response rates of 2.6% and 11.7%, respectively47. According to the FDA approval criteria for pembrolizumab, a combined positivity score (CPS) ≥1 is mandatory—a score that represents the number of PD-L1 staining cells divided by the total number of viable tumor cells, multiplied by 100. In June 2019, pembrolizumab was furthermore approved for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy based on the results of the phase III KEYNOTE-048 trial48. Herein, pembrolizumab/chemotherapy achieved superior OS in patients with PD-L1 CPS ≥1 disease and the total population with comparable safety; furthermore, pembrolizumab (alone) reached superior OS rates in the CPS ≥1 population, as well as noninferior OS in the total population with favorable safety.\n\nAs of today, only a few studies have been published evaluating the therapeutic impact of pembrolizumab in patients with advanced VC. Recently, Shields et al. reported a case of a 61-year-old patient with recurrent VC who was successfully treated with pembrolizumab for the first time49. In order to identify patients with potentially higher likelihood of response to anti-PD-L1 therapies, the KEYNOTE-028 trial most recently evaluated 471 patients with over 20 solid cancer types regarding PD-L1 expression, T-cell-flamed gene expression (GEP), and tumor mutational burden (TMB)50. Eighteen patients with advanced VC and PD-L1+ tumors were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was ORR, while the second end points included PFS, OS, and safety. For the cohort of heavily pretreated VC patients, the ORR was 6% with a median PFS of 3.1 months and relatively short median duration of OS with 3.8 months. PD-L1 expression by CPS was available for eight VC patients, and statistical testing revealed significant correlation between PD-L1 CPS and both ORR (p = 0.018) and PFS (p = 0.005).\n\nIn our case series, three patients with median age of 41 years (range 26–61) received pembrolizumab (Table 4). All were heavily pretreated; 2/3 patients (66.6%) had HPV negative and PD-L1 positive (CPS 1 and CPS 60, respectively) tumors. Median time to progression was 3.3 months (range 3–4), and the best response rate was SD in one patient (33.3%), while the remaining two patients experienced progressive disease (66.6%). However, tolerance was fairly good as only one patient suffered from moderate hypothyroidism induced by pembrolizumab.\n\nTable 4 Pembrolizumab\n\n\tPatient 6\tPatient 7\tPatient 8\t\nAge at FD\t37\t61\t26\t\nMM/YY FD\t11/17\t03/16\t04/15\t\nHistory of disease/time to recurrence (months)\t1. surgery, RCTX/5;\n2. loc rec -> surgery/2;\n3. loc rec -> surgery/3;\n4. loc rec -> palliative CTX (carboplatin/paclitaxel/bevacizumab)/4;\n5. loc and dist rec-> ctx with mitomycin/capecitabine/3;\n6. loc PD: pembrolizumab/4;\n7. loc and dist PD: best supp care\t1. surgery, RT/11;\n2. dist rec -> CTX (cisplatin/topotecan)/9;\n3. loc PD -> CTX (paclitaxel/bevacizumab)/13;\n4. loc rec -> pembrolizumab/3;\n5. dist PD -> best supp care/erlotinib;\t1. surgery, RTX/10;\n2. loc rec -> surgery (R0)/3;\n3. dist rec -> CTX (carboplatin/paclitaxel/bevacizumab)/6, DVT: end of bevacizumab, start pembrolizumab/3;\n4. dist rec -> ctx vinorelbine; 5. erlotinib\t\nDisease at indication (tumor load)\tLocal PD (left groin, vulva)\tLocal PD (left groin)\tDistant metastasis (bone)\t\nHPV status/PD-L1 status\tHPV negative/PD-L1: CPS 1-5\tHPV unknown/PD-L1 CPS 60\tHPV negative/PD-L1 CPS unknown\t\nBest response\tPD\tSD\tPD\t\nSide effects\tGrade 2 CTCAE: fatigue, lymphedema\tNone\tGrade 2 CTCAE: lymphedema, hypothyroidism\t\nDose reduction\tNo\tNo\tNo\t\nTime to progression\t4 months\t3 months\t3 months\t\nTime to death from FD\tUnknown\tUnknown\t40 month\t\nCause of death\tUnknown\tUnknown\tTumor progression\t\nadj., adjuvant; CPS, combined positive score; CTCAE, Common Terminology Criteria for Adverse Events; HPV, human papilloma virus; loc, local; dist, distant; rec, recurrence; MM/YY FD, month/year of first diagnosis; PD1-L1, programmed cell death ligand; PD, progressive disease; RD, recurrent disease; SD, stable disease; CR, complete response; PR, partial response; FD, first diagnosis; CTX, chemotherapy; RT, radiotherapy; CRTX, chemoradiation; R0, tumor-free margins; R1, microscopic tumor residual; DVT, deep vein thrombosis; CPS, combined positive score.\n\nDISCUSSION\n\nAlthough considerable improvement in the surgical management of VC was obtained within the last two decades, these achievements could not have been mirrored in the treatment for patients with advanced or metastasized VC. As mentioned in the National Comprehensive Cancer Network (NCCN) guidelines, treatment in recurrent settings strongly depends on the localization of the recurrence as well as on previous treatment51. Subsequent surgery and (chemo)radiation can be considered in case of local recurrence. However, mutilating results due to radical surgeries and higher cutaneous toxicity as well as elevated complication rates for surgery following (chemo)radiation eventually lead to increased morbidity and reduced quality of life in these often already elderly patients52. In patients not amenable to surgery or radiotherapy, systemic approach to treatment should be taken into consideration. However, as of today, no standard chemotherapy regimens exist for recurrent or metastatic VC. The NCCN guidelines therefore preferably suggest treatments applied in other HPV-driven cancers, mainly cervical cancer, including cisplatin, paclitaxel, mitomycin-C, 5-fluorouracil, and vinorelbine. Paclitaxel weekly has shown only slight activity in a phase II trial of 31 VC patients represented in an RR of 14%, PFS of 2.6 months, and median OS of 6.8 months, indicating a lower effectiveness in single-agent treatment in comparison to a platinum-based combination therapy53. Furthermore, chemotherapy in a recurrent setting appeared to be less effective than in a neoadjuvant setting as patients are mostly pretreated, and recurrence in previously treated fields is common13,52,54,55. Moreover, chemotherapy has proven to be less effective in VC compared with other HPV-induced tumor entities53. Nevertheless, the treatment of choice in primary recurrence is more or less standardized in the form of platinum-based (combination) chemotherapy, whereas in second-line settings, standardized treatment recommendations are lacking. In this context, as second-line treatment option, targeted agents have become of increasing clinical and scientific interest.\n\nEspecially, EGFR has been studied extensively and seems to be one of the most promising targets for HPV-independent VC when EGFR gene amplifications is observed31. Whereas Johnson et al. demonstrated better survival in patients with low EGFR levels compared with patients with high EGFR levels (DFS of 25% in patients with EGFR levels >90% vs. DFS of 54% in patients with EGFR levels <90%)29, a study of EGFR expression in 197 patients showed an association between high EGFR protein expression and increased depth of invasion as well as the presence of lymph node metastases (OR 2.12, 95% CI 1.09–4.10)56. Besides confirming these data by pointing out the relationship between EGFR overexpression, high tumor stage, and the number of metastatic lymph nodes (p < 0.001, p = −0.02, respectively), an analysis of 183 patients furthermore revealed a statistical correlation between EGFR protein expression and EGFR gene copy numbers as well as significant association between EGFR overexpression and HPV negativity (p < 0.05, p = 0.04, respectively)30. Growdon et al. additionally determined that high levels of EGFR amplification are linked to poor OS in VC (p < −0.025)57, and results from a study published by Dong et al. underline these findings by showing a negative correlation between EGFR expression and p16 and a positive association between p53 and EGFR58. Given the increased expression of EGFR in VC (40–67%) and its potential association to faster progression of the disease, anti-EGFR-targeted therapies are of high therapeutic interest in a subset of advanced VC. However, all this information provides only limited use when it comes to anticipate the response to EGFR-targeted treatment as especially protein expression does not serve as a reliable marker in this setting31. As known from other entities (e.g., lung cancer and HNSCC), immunohistochemistry of EGFR is difficult and not suitable to predict response to treatment, which is usually performed by mutational analysis. Therefore, in VC, the detection of EGFR mutation status has increasingly become of clinical interest as a molecular predictor of response to treatment with significant impact on prognosis. In order to determine whether EGFR TKIs have different efficacies in patients with and without EGFR mutations, Liu et al. enrolled 30 patients with advanced VC, performed EGFR genetic testing, and evaluated the clinical efficacy in both patients with and without EGFR mutation59. Treatment consisted of oral gefitinib (250 mg once daily), another anti-EGFR-targeted agent; the mutation rate was 30% (9/30), and EGFR wild-type (wt) patients accounted for 70% (21/30). The results demonstrated statistically significant higher efficacy of gefitinib in patients with EGFR mutations compared with patients with wt-EGFR (ORR 44.5% vs 14.3%, p = 0.096; median PFS 108 vs. 49 days p = 0.42), suggesting that targeted therapy based on EGFR mutation status might improve the prognosis of patients with advanced VC59. In addition, antibodies against the EGF receptor like cetuximab have been reported to be associated with increased clinical benefit in patients with advanced VC when combined with cisplatin chemotherapy and radiotherapy (PR 5 months)60. These findings underline the potential utility of EGFR inhibitors as single agent treatment or in combination with chemotherapy as a promising therapeutic approach. Therefore, further investigations may also focus on the evaluation of combining anti-EGFR targets with chemoradiation, other targeted therapies (antiangiogenic or PI3K inhibitors), or cytotoxic agents in order to improve the outcome in a subset of patients with advanced VC.\n\nPD-L1 expression has been detected in up to 73% of tumors in VC, and moderate or strong expression was revealed in 27%61. As these data confirm PD-L1 overexpression in a substantial subset of patients with VC in all stages and independent of HPV, immune checkpoint inhibition (ICI) serves as another suitable therapeutic target. Currently, pembrolizumab has been one of the best investigated agents in this context50. As mentioned earlier, the KEYNOTE-028 recently evaluated PD-L1 expression, TMB, and T-Cell GEP in 471 patients treated with pembrolizumab across 20 advanced solid cancer entities presenting with PD-L1+ tumors. A closer look toward gynecologic malignancies revealed rather disappointing results in VC with an ORR of 6% and OS of 3.8 month. Other HPV-driven tumor entities like cervical and anal cancer achieved twice as high results regarding the ORR with 17% and 16%, respectively. Nivolumab is another PD-1 agent currently being under investigation in a phase I/II study in 24 patients with recurrent or metastatic cervical, vaginal, and VC62. While preliminary data demonstrated encouraging disease control rates of 70.8% in all three tumor entities, responses were exclusively observed in patients with cervical cancer (ORR 26.3%) regardless of PD-L1 or HPV status or number of prior therapies. As for the available data, nivolumab provided similar results as pembrolizumab in regard to safety and toxicity with 12.5% treatment-related adverse events grade 3 or 4. In the light of these results, the future of immune oncology in VC will not be monotherapy with anti PD-1/L1 antibodies but combined and preferable early treatment in advanced disease. In this context just recently, an interim analysis of the phase I/II Checkmate-358 study has been presented at the ESMO 2019; herein, the combination of nivolumab and ipilimumab (CTLA-4 antagonist) showed durable clinical activity in patients with recurrent or metastatic (R/M) cervical cancer, regardless of tumor PD-L1 expression63. Noteworthy, ORR was higher in patients without prior systemic therapies (PST) compared with patients without PST (45.8% vs. 31.6%). As a result, the combination of checkpoint inhibitors could also provide an effective treatment alternative in patients with other HPV-driven cancers at an early point of recurrent/metastastic disease.\n\nIn conclusion, the management of advanced VC continues to be challenging, and data from clinical trials regarding therapeutic options are scarce due to the low incidence of the disease. Furthermore, small number of studies, heterogenous patient cohorts, and diverse treatment regiments impede comparing the available data. While the current “state-of-the-art” treatment in primary recurrent settings without radiotherapeutic or surgical options is platin-containing combination chemotherapy, in second-line treatment targeted agents can be used to improve clinical outcome.\n\nTo date, erlotinib is the best investigated targeted agent in VC. As high rates of EGFR expression and increased EGFR copy numbers have been found in VC, consequent EGFR mutation testing should be performed to predict treatment response in advanced VC. Bevacizumab was the first targeted agent to improve OS in a gynecologic cancer as shown in the GOG-240 trial; herein, adding bevacizumab to chemotherapy prolonged OS by 3.4 months in patients with cervical cancer. Application of bevacizumab in VC analogous to cervical cancer is feasible, as shown by our case series. However, data confirming the activity in VC will probably never be available. The role of immunooncology for VC will have to be determined in the coming years. Pembrolizumab monotherapy showed only very modest antitumor activity with an ORR of 6% and median PFS duration of 3.1 month in patients with advanced VC and PD-L1+ tumors. Centralized clinical observations, translational research, and new study designs such as basket trials will be needed to individualize therapy by identifying effective molecular and biological markers for subtype characterization, prognosis, and predication of treatment response as well as to reduce the rates of recurrence and concurrently improve the survival.\n\nACKNOWLEDGMENTS\n\nThis study was funded by internal departmental sources. The authors declare the following conflicts of interest involved with the presented data. Prof. Dr. Linn Woelber: Congress fees and reimbursement of travel expenses as well as lecture fees from med update GmbH, medac oncology, promedicis GmbHRoche, Tesaro, TEVA, OmniaMed, and Pfizer. Study support (third-party funding) from Greiner, Roche Diagnostics, and medac oncology. Prof. Dr. Volkmar Mueller: VM received speaker honoraria from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics, and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro, and Nektar. Institutional research support from Novartis, Roche, Seattle Genetics, Genentech Travel grants: Roche, Pfizer, and Daiichi Sankyo. Prof. Dr. Barbara Schmalfeldt: Congress fees and reimbursement of travel expenses as well as lecture fees from Roche, Tesaro, Astra Zeneca, Clovis Oncology, med update GmbH, promedicis GmbH, TEVA, OmniaMed, Ethicon, and Olympus. Study support (third-party funding) from Roche, Astra Zeneca, MSD, Tesaro.\n\nDr. Sabrina Mathey, PD Dr. Katharina Prieske, Dr. Sascha Kuerti, Dr. Christoph Hillen, PD Dr. Eike Burandt, Dr. Anja Coym, and Dr. Anna Jaeger declare no conflict of interest.\n==== Refs\nREFERENCES\n\n1 Holleczek B , Sehouli J , Barinoff J . 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T-Cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37 (4 ):318–27.30557521\n51 NCCN Guidelines Version 03.2020 vulvar caner (squamous cell carcinoma). https://wwwnccnorg/professionals/physician_gls/pdf/vulvarpdf\n52 Mahner S , Prieske K , Grimm D , Trillsch F , Prieske S , von Amsberg G , Petersen C , Mueller V , Jaenicke F , Woelber L . Systemic treatment in vulvar cancer. Expert Rev Anticancer Ther. 2015;15 (6 ):629–37.25997120\n53 Witteveen PO , van der Velden J , Vergote I , Guerra C , Scarabeli C , Coens C , Demonty G , Reed N . Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: A study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer—Gynaecological Cancer Group). Ann Oncol. 2009;20 (9 ):1511–6.19487487\n54 Aragona AM , Cuneo N , Soderini AH , Alcoba E , Greco A , Reyes C , Lekmann S . Tailoring the treatment of locally advanced squamous cell carcinoma of the vulva: Neoadjuvant chemotherapy followed by radical surgery. Int J Gynecol Cancer. 2012;22 (7 ):1258–63.22864334\n55 Raspagliesi F , Zanaboni F , Martinelli F , Scasso S , Laufer J , Ditto A . Role of paclitaxel and cisplatin as the neoadjuvant treatment for locally advanced squamous cell carcinoma of the vulva. J Gynecol Oncol. 2014;25 (1 ):22–9.24459577\n56 Oonk MHM , de Bock GH , van der Veen DJ , ten Hoor KA , de Hullu JA , Hollema H , van der Zee AGJ . EGFR expression is associated with groin node metastases in vulvar cancer, but does not improve their prediction. Gynecol Oncol. 2007;104 (1 ):109–13.16963112\n57 Growdon WB , Boisvert SL , Akhavanfard S , Oliva E , Dias-Santagata DC , Kojiro S , Horowitz NS , Iafrate AJ , Borger DR , Rueda BR . Decreased survival in EGFR gene amplified vulvar carcinoma. Gynecol Oncol. 2008;111 (2 ):289–97.18768215\n58 Dong F , Kojiro S , al. BDe. Squamous cell carcinoma of the vulva: A subclassification of 97 cases by clinicopathologic, immunohistochemical, and molecular features (p16, p53 and EGFR). Am J Surg Pathol. 2015;39 (8 ):1045–53.26171917\n59 Liu K , Yang Y , Wang C , Wang Y , Zhu Y . EGFR mutation status and TKI therapy in patients with advanced vulvar cancer: Clinical observations. OALib. 2017 01/01;04 :1–10.\n60 Richard SD , Krivak TC , Beriwal S , Zorn KK . Recurrent metastatic vulvar carcinoma treated with cisplatin plus cetuximab. Int J of Gynecol Cancer 2008;18 (5 ):1132–5.18021214\n61 Choschzick M , Gut A , Fink D . PD-L1 receptor expression in vulvar carcinomas is HPV-independent. Virchows Arch. 2018;473 (4 ):513–6.29736798\n62 Hollebecque A , Meyer T , Moore KN , Machiels J-PH , Greve JD , López-Picazo JM , Oaknin A , Kerger JN , Boni V , Evans TRJ , Kristeleit RS , Rao S , Soumaoro I , Cao ZA , Topalian SL . An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers. J Clin Oncol. 2017;35 (15_suppl ):5504.\n63 Naumann R , Oaknin A , Meyer T , Lopez-Picazo J , Lao C , Bang YJ , Boni V , Sharfman W , Park J , Devriese L , Harano K , Chung C , Topalian S , Zaki K , Chen T , Gu J , Li B , Barrows A , Horvath A , Moore K . LBA62Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: Results from CheckMate 358. Ann Oncol. 2019;30 (Suppl 5 ):v851–934.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0965-0407",
"issue": "28(6)",
"journal": "Oncology research",
"keywords": null,
"medline_ta": "Oncol Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002294:Carcinoma, Squamous Cell; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014846:Vulvar Neoplasms",
"nlm_unique_id": "9208097",
"other_id": null,
"pages": "645-659",
"pmc": null,
"pmid": "33308371",
"pubdate": "2021-03-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "28799431;25104331;31912902;24296343;16963112;22552830;18021214;21601474;30755690;24821878;24459577;26171917;22864334;30557521;17561233;28756902;26028255;27411473;9190969;22266935;29190964;18768215;27637349;19305339;22750258;27718847;25618900;29736798;24552320;10537345;15823112;8910628;12598309;30067880;24371640;27329249;30943124;28040721;30972492;19487487;27401841;28528690;28734759;28536037;30016784;22128196;32335720;19832900;20186832;27031618;25997120;31572682",
"title": "Targeted Therapeutic Approaches in Vulvar Squamous Cell Cancer (VSCC): Case Series and Review of the Literature.",
"title_normalized": "targeted therapeutic approaches in vulvar squamous cell cancer vscc case series and review of the literature"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-316599",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"druga... |
{
"abstract": "Postoperative pain and analgesia present challenges in bariatric surgery patients. Multimodal analgesia may provide better efficacy, less complications and expedite fast-track bariatric surgical care. There are no studies of the broader topic of perioperative analgesia and the overall impact. This study highlights the impact of multimodal intraoperative analgesia on fast-track bariatric surgery.\n\n\n\nThis observational study examined the perioperative outcome data of 412 consecutive laparoscopic bariatric surgery patients over a 6-year period. Perioperative outcome and variables were analysed and compared between different intraoperative analgesia types.\n\n\n\nMean BMI was 49, mean age was 42 and male:female ratio was 1:4. About 82% of patients received multimodal intraoperative analgesia, comprising various combinations of bupivacaine infiltration and intravenous acetaminophen, morphine, tramadol, parecoxib or diclofenac. Morphine was administered in 83% of patients and tramadol in 17%. Multimodal intraoperative analgesia provided better postoperative analgesia, shorter postanaesthesia care unit (PACU) duration, lower postoperative opioid requirement, less postoperative vomiting, earlier postoperative oral intake, earlier ambulation and shorter hospital stay compared to unimodal intraoperative morphine analgesia (p = 0.0001). Multimodal analgesia comprising tramadol + acetaminophen + diclofenac provided better postoperative analgesia, shorter PACU duration, lower postoperative opioid requirement, earlier ambulation, shorter hospital stay and less postoperative hypopnoea compared to patients who received morphine (p = 0.0001).\n\n\n\nMultimodal intraoperative analgesia provides better postoperative analgesia, less complications and better perioperative outcomes and facilitates fast-track bariatric surgical care. Tramadol is suitable, efficacious and safe and associated with the best perioperative outcomes in bariatric surgery patients.",
"affiliations": "Department of Anaesthesia, University of British Columbia, Vancouver, BC, Canada. olu.bamgbade@gmail.com.;Department of Community Health and Epidemiology, University of Saskatchewan, Saskatoon, SK, Canada.;Department of Surgery, University of Manchester, Manchester, UK.",
"authors": "Bamgbade|Olumuyiwa A|OA|;Oluwole|Oluwafemi|O|;Khaw|Rong R|RR|",
"chemical_list": "D000700:Analgesics; D000779:Anesthetics, Local; D014147:Tramadol",
"country": "United States",
"delete": false,
"doi": "10.1007/s11695-017-2562-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8923",
"issue": "27(7)",
"journal": "Obesity surgery",
"keywords": "Enhanced recovery; Fast track; Laparoscopic bariatric surgery; Multimodal analgesia; Perioperative analgesia; Tramadol",
"medline_ta": "Obes Surg",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016058:Analgesia, Patient-Controlled; D000700:Analgesics; D000779:Anesthetics, Local; D002985:Clinical Protocols; D004359:Drug Therapy, Combination; D005260:Female; D015390:Gastric Bypass; D006801:Humans; D007430:Intraoperative Care; D010535:Laparoscopy; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid; D010147:Pain Measurement; D010149:Pain, Postoperative; D019990:Perioperative Care; D011446:Prospective Studies; D014147:Tramadol; D055815:Young Adult",
"nlm_unique_id": "9106714",
"other_id": null,
"pages": "1828-1834",
"pmc": null,
"pmid": "28120147",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "26084250;27177956;21191303;25614351;23700237;25521841;20563662;16925195;25680474;16608607;23499469;19357516;16957821;22488683;16925285;9190322;21516916;19142095;27418005;21735322;24993524",
"title": "Perioperative Analgesia for Fast-Track Laparoscopic Bariatric Surgery.",
"title_normalized": "perioperative analgesia for fast track laparoscopic bariatric surgery"
} | [
{
"companynumb": "CA-JNJFOC-20170716059",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPIVACAINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSentinel headache is a well-known warning sign preceding subarachnoid hemorrhage (SAH) caused by rupture of an intracranial aneurysm. New-onset seizure or \"sentinel seizure\" preceding aneurysmal SAH, however, is uncommon.\n\n\nMETHODS\nWe report a 51-year-old man with a new-onset seizure. Diagnostic workup revealed a giant middle cerebral artery aneurysm without evidence of subarachnoid or intracerebral hemorrhage. Antiepileptic therapy was initiated, elective diagnostic angiography and subsequent treatment was scheduled, and the patient was discharged home. Four days later, he suddenly lost consciousness and subsequently died of a massive aneurysmal SAH.\n\n\nCONCLUSIONS\nAs with sentinel headache, new-onset seizures in patients with unruptured intracranial aneurysms might prompt immediate treatment to prevent imminent SAH with its subsequent high morbidity and mortality.",
"affiliations": "Department of Neurosurgery, University of Bern, Inselspital, Bern, Switzerland; Department of Neurosurgery and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Neurosurgery, University of Bern, Inselspital, Bern, Switzerland. Electronic address: robert.andres@hin.ch.",
"authors": "Andereggen|Lukas|L|;Andres|Robert H|RH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2017.02.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "100()",
"journal": "World neurosurgery",
"keywords": "Aneurysm; Seizure; Sentinel headache; Subarachnoid hemorrhage",
"medline_ta": "World Neurosurg",
"mesh_terms": "D017542:Aneurysm, Ruptured; D002539:Cerebral Arterial Diseases; D017809:Fatal Outcome; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D020768:Middle Cerebral Artery; D012640:Seizures",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "709.e11-709.e13",
"pmc": null,
"pmid": "28216212",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Sentinel Seizure\" as a Warning Sign Preceding Fatal Rupture of a Giant Middle Cerebral Artery Aneurysm.",
"title_normalized": "sentinel seizure as a warning sign preceding fatal rupture of a giant middle cerebral artery aneurysm"
} | [
{
"companynumb": "CH-UCBSA-2017019060",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended.",
"affiliations": "Department of Internal Medicine, Division of Gastroenterology, University of Washington Medical Center, Seattle, 98195, USA. amlarson@u.washington.edu",
"authors": "Larson|Anne M|AM|;Polson|Julie|J|;Fontana|Robert J|RJ|;Davern|Timothy J|TJ|;Lalani|Ezmina|E|;Hynan|Linda S|LS|;Reisch|Joan S|JS|;Schiødt|Frank V|FV|;Ostapowicz|George|G|;Shakil|A Obaid|AO|;Lee|William M|WM|;|||",
"chemical_list": "D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1002/hep.20948",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "42(6)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D018806:APACHE; D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D000368:Aged; D000437:Alcoholism; D062787:Drug Overdose; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "1364-72",
"pmc": null,
"pmid": "16317692",
"pubdate": "2005-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.",
"title_normalized": "acetaminophen induced acute liver failure results of a united states multicenter prospective study"
} | [
{
"companynumb": "US-JNJFOC-20210849562",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Sixty-four patients underwent 66 remission induction courses with intermediate-dose cytosine-arabinoside (Ara-C) for treatment of acute myelogenous leukemia, acute lymphoblastic leukemia, or high-grade malignant non-Hodgkin's lymphoma. The Ara-C was administered in combination with amsacrine with or without VP16-213 and prednisone. After complete remission was achieved, 27 patients received 38 consolidation courses consisting of high-dose Ara-C either alone or in combination with amsacrine with or without VP16-213 and prednisone. Seven (11%) of 66 induction courses and eight (21%) of 38 consolidation courses were complicated by respiratory failure that was considered a pulmonary reaction to Ara-C therapy. The initial findings on chest radiographs in the 15 cases included a diffuse interstitial pattern (two), a mixed interstitial-alveolar pattern (eight), an alveolar pattern (three), and a normal pattern (two). In 11 cases, the abnormalities were diffuse throughout both lungs with a preference for the lower lobes in five. The changes were localized in two cases. A small pleural effusion was observed in two patients. In the majority of cases, the initial radiographic changes progressed to a predominantly alveolar pattern. Thirteen patients recovered clinically within 2-9 days, and two patients died of pulmonary complications. Radiologic recovery took 7-21 days. Rapid regression of alveolar consolidations within 3-7 days was the first sign of radiologic improvement. The interstitial pattern gradually regressed. We conclude that the spectrum of radiologic abnormalities in cases of pulmonary reaction to Ara-C therapy includes diffuse interstitial, mixed interstitial-alveolar, or alveolar pulmonary changes.",
"affiliations": null,
"authors": "Tham|R T|RT|;Peters|W G|WG|;de Bruïne|F T|FT|;Willemze|R|R|",
"chemical_list": "D000677:Amsacrine; D003561:Cytarabine; D005047:Etoposide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.2214/ajr.149.1.23",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-803X",
"issue": "149(1)",
"journal": "AJR. American journal of roentgenology",
"keywords": null,
"medline_ta": "AJR Am J Roentgenol",
"mesh_terms": "D000677:Amsacrine; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D005047:Etoposide; D006801:Humans; D007945:Leukemia, Lymphoid; D015470:Leukemia, Myeloid, Acute; D008168:Lung; D008228:Lymphoma, Non-Hodgkin; D011241:Prednisone; D011859:Radiography; D012074:Remission Induction; D012131:Respiratory Insufficiency",
"nlm_unique_id": "7708173",
"other_id": null,
"pages": "23-7",
"pmc": null,
"pmid": "3495987",
"pubdate": "1987-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pulmonary complications of cytosine-arabinoside therapy: radiographic findings.",
"title_normalized": "pulmonary complications of cytosine arabinoside therapy radiographic findings"
} | [
{
"companynumb": "NL-PFIZER INC-2021001923",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nLong-term benefits of combination therapy (combotherapy) with infliximab (IFX) and azathioprine (AZA) have been less studied in ulcerative colitis (UC) than in Crohn's disease. The aim of the present study was to determine UC disease activity in patients who received at least 6 months of combotherapy, and whether cotreatment for more than 6 months was useful in these patients.\n\n\nMETHODS\nA retrospective multicenter study was conducted in seven French academic centers from January 2010 to September 2012, including all UC patients having received at least 6 months of combotherapy in prolonged remission off steroids. During the follow-up period, which was divided into trimesters, scheduled IFX was continued as maintenance and AZA could be withdrawn. Assessment of UC activity by trimester was based on the following events: disease relapse defined by clinical relapse requiring a change of treatment, IFX failure, and colectomy.\n\n\nRESULTS\nEighty-two patients were included (mean age 38 years; male:female ratio 1:1) and followed up for a median of 22.3±14.0 months. Comparing 393 trimesters of combotherapy with 282 trimesters of IFX alone, fewer clinical relapses were observed with combotherapy (p = 0.049). Similar results were observed for IFX failure (p = 0.048). No difference was observed for colectomy. Duration of combotherapy longer than 9 months was inversely associated with clinical relapse (hazard ratio = 0.32 [95% confidence interval 0.15-0.70]).\n\n\nCONCLUSIONS\nUC patients treated with combotherapy should maintain IFX and AZA for at least 9 months. Further studies are required to determine the optimal duration of combotherapy before stopping AZA in this situation.",
"affiliations": "Gastroenterology, University Hospital of Nice, Nice, France.;Gastroenterology, University Hospital of Bordeaux, Bordeaux, France.;Gastroenterology, University Hospital of Dijon, Dijon, France.;Gastroenterology, University Hospital of Nantes, Nantes, France.;Gastroenterology, University Hospital of Rennes, Rennes, France.;Gastroenterology, University Hospital of Lyon Sud, Lyon, France.;Gastroenterology and Clinic Investigation Center, University Hospital of Saint Etienne, Saint Etienne, France.;Gastroenterology, University Hospital of Nice, Nice, France.;Gastroenterology, University Hospital of Nice, Nice, France.;Gastroenterology, University Hospital of Nice, Nice, France.;Gastroenterology and Clinic Investigation Center, University Hospital of Saint Etienne, Saint Etienne, France xavier.roblin@chu-st-etienne.fr.",
"authors": "Filippi|J|J|;Laharie|D|D|;Michiels|C|C|;Flamand|M|M|;Bouguen|G|G|;Nancey|S|S|;Presles|E|E|;Paul|S|S|;Schneider|S|S|;Hébuterne|X|X|;Roblin|X|X|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069285:Infliximab; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjv001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "9(3)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Azathioprine; combotherapy; infliximab; ulcerative colitis",
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D003093:Colitis, Ulcerative; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D007166:Immunosuppressive Agents; D060828:Induction Chemotherapy; D000069285:Infliximab; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012372:ROC Curve; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "252-8",
"pmc": null,
"pmid": "25588386",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Efficacy of sustained combination therapy for at least 6 months with thiopurines and infliximab in patients with ulcerative colitis in clinical remission: a retrospective multicenter French experience.",
"title_normalized": "efficacy of sustained combination therapy for at least 6 months with thiopurines and infliximab in patients with ulcerative colitis in clinical remission a retrospective multicenter french experience"
} | [
{
"companynumb": "FR-JNJFOC-20151015715",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Chlorpromazine is a low potency \"typical\" antipsychotic agent used to treat schizophrenia. It continues to be prescribed frequently in India owing to its lower cost. There have been previous reports of ocular adverse effects with prolonged use of chlorpromazine. We report three patients who developed corneal and lenticular opacities secondary to prolonged chlorpromazine use leading to visual impairment. Early detection of ocular deposits and switching over to risperidone from chlorpromazine helped in the reversal of chlorpromazine- induced ocular side effects in one of them. The case series further adds evidence to the causative relationship between chlorpromazine and ocular side effects.",
"affiliations": "Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India. Electronic address: drgsgowda@gmail.com.;Northwest Mental Health, Victoria, Australia.;Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India.;Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India.;Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India.",
"authors": "Gowda|Guru S|GS|;Hegde|Aditya|A|;Shanbhag|Vandita|V|;Narayanaswamy|Janardhanan C|JC|;Jaisoorya|T S|TS|",
"chemical_list": "D014150:Antipsychotic Agents; D002746:Chlorpromazine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ajp.2016.11.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-2018",
"issue": "25()",
"journal": "Asian journal of psychiatry",
"keywords": "Cataract; Chlorpromazine; Corneal deposits; Switch over; Visual impairment",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D002386:Cataract; D002746:Chlorpromazine; D003315:Cornea; D005260:Female; D006801:Humans; D007903:Lens Capsule, Crystalline; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia; D014786:Vision Disorders",
"nlm_unique_id": "101517820",
"other_id": null,
"pages": "188-190",
"pmc": null,
"pmid": "28262147",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Kerato-lenticular ocular deposits and visual impairment with prolonged chlorpromazine use: A case series.",
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"abstract": "Buprenorphine, a semisynthetic mixed agonist/antagonist opioid used primarily for the treatment of opioid use disorder, was reported in 194 driving under the influence of drugs (DUID) cases in Southwestern Virginia during the period of 2017 through 2019. Identifying and confirming buprenorphine in DUID cases is common in this region. Interpretation is complex due to the large range of concentrations of buprenorphine found in blood and frequent combinations with other therapeutic and abused drugs. Buprenorphine was identified by immunoassay and quantified by liquid chromatography-tandem mass spectrometry (LC-MS-MS). A sensitive method was necessary as one-third of concentrations of buprenorphine and/or norbuprenorphine were less than 1.0 µg/L. Concentrations of buprenorphine ranged from < 0.5 µg/L to 11 µg/L (mean 2.5 µg/L, median 1.8 µg/L) and concentrations of norbuprenorphine ranged from < 0.5 µg/L to > 20 µg/L (mean 3.3 µg/L, median 2.2 µg/L). Buprenorphine polysubstance use was common. Only 10% of cases examined did not contain other drugs confirmed in routine DUID screening tests. The most common drug groups confirmed were benzodiazepines, amphetamines and cannabinoids. The DUID case histories presented represent examples of buprenorphine abuse, buprenorphine with no other drug groups, buprenorphine combined with other drug groups, cases consistent with impairment and cases with minimal impairment. Central nervous system depressant and narcotic analgesic symptoms were commonly observed; however, some cases contained stimulant symptoms. Buprenorphine to norbuprenorphine ratios (B/NB) had a mean and median ratio of 1.1 and 0.8, respectively. B/NB ratios greater than 3.0 were found in 4.7% of cases. The finding of a higher B/NB ratio may indicate a more recent buprenorphine administration and a greater potential for impairment. No relationship between the concentration of buprenorphine and/or norbuprenorphine in blood and performance on Drug Recognition Expert (DRE) evaluation or Standardized Field Sobriety Tests (SFST) could be determined.",
"affiliations": "Virginia Department of Forensic Science, Western Laboratory, 6600 Northside High School Road, Roanoke, VA 24019 USA.;Virginia Department of Forensic Science, Western Laboratory, 6600 Northside High School Road, Roanoke, VA 24019 USA.;Virginia Department of Forensic Science, Western Laboratory, 6600 Northside High School Road, Roanoke, VA 24019 USA.",
"authors": "Kuhlman|James J|JJ|;Harris|Chad|C|;Wright|Trista|T|",
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"abstract": "Nocardiosis is an uncommon bacterial gram-positive infection caused by aerobic actinomycetes in the genus Nocardia. Nocardiosis is typically regarded as an opportunistic infection with approximately two-thirds of infected patients being immunocompromised. In this case report we describe a 45-year-old female who presented with a right thigh abscess. She had been taking high-dose prednisolone and ciclosporin for Cogan's syndrome. She presented with erythema and severe pain over her right thigh. Ultrasound showed a collection and Nocardia farcinica was isolated. This case report stresses the importance of considering atypical infections in immunocompromised patients, even with minor symptoms, to avoid delay in diagnosis and treatment.",
"affiliations": "The Ipswich Hospital NHS Trust , Ipswich , UK.;The Ipswich Hospital NHS Trust , Ipswich , UK.;The Ipswich Hospital NHS Trust , Ipswich , UK.;The Ipswich Hospital NHS Trust , Ipswich , UK.;The Ipswich Hospital NHS Trust , Ipswich , UK.",
"authors": "Merinopoulos|Dimos|D|;Khan|Haroon|H|;Ginwalla|Sara|S|;Lane|Suzanne|S|;Watts|Richard|R|",
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"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omu016omu0162300Case ReportsNocardia farcinica complicating Cogan's syndrome Merinopoulos Dimos *Khan Haroon Ginwalla Sara Lane Suzanne Watts Richard The Ipswich Hospital NHS Trust, Ipswich, UK* Correspondence address. The Ipswich Hospital NHS Trust, Heath Road, Ipswich IP4 5PD, UK. E-mail: dmerinopoulos@yahoo.com5 2014 28 5 2014 2014 2 36 38 5 3 2014 15 4 2014 18 4 2014 Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author 20142014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comNocardiosis is an uncommon bacterial gram-positive infection caused by aerobic actinomycetes in the genus Nocardia. Nocardiosis is typically regarded as an opportunistic infection with approximately two-thirds of infected patients being immunocompromised. In this case report we describe a 45-year-old female who presented with a right thigh abscess. She had been taking high-dose prednisolone and ciclosporin for Cogan's syndrome. She presented with erythema and severe pain over her right thigh. Ultrasound showed a collection and Nocardia farcinica was isolated. This case report stresses the importance of considering atypical infections in immunocompromised patients, even with minor symptoms, to avoid delay in diagnosis and treatment.\n==== Body\nINTRODUCTION\nNocardia species are parasitic bacteria, which grow and reproduce on organic material. Their main habitat is carbon-rich sources such as soil, vegetable matter and aquatic environment [1]. The main mode of infection in humans is aerogenic. The lung is most commonly affected, but Nocardia can disseminate haematogenously to the central nervous system (CNS) and also to bone, retina, heart, joints, kidneys and soft tissues. Cutaneous infection is the least common site of infection and presents mainly with abscesses [2, 3]. Cell-mediated immunity is critical in containing Nocardia infection and this makes immunocompromised patients with cell-mediated abnormalities, more susceptible to Nocardia infections [4, 5]. The most common causes are glucocorticoid therapy, malignancy, immunosuppressive therapy, organ transplantation and HIV infection. Although there are more than 80 species in the genus Nocardia, only 33 species cause disease in humans [4, 6]. Nocardia farcinica is among the most virulent species, since infection is more likely to result in disseminated disease. Nocardia can disseminate from a pulmonary or cutaneous focus to virtually any organ.\n\nCASE REPORT\nA 45-year-old Caucasian lady presented following a 3-week history of progressively worsening pain, swelling and erythema in her right thigh. She initially reported the symptoms in clinic when they were minimal with no external signs and an ultrasound was requested. She was taking ciclosporin (2 mg/kg/day) and prednisolone 15 mg/day for Cogan's syndrome. In 2009 she developed recurrent episodes of scleritis and audiovestibular disturbance, leading to a diagnosis of Cogan's syndrome in 2010. She had received prednisolone (60 mg/day), azathioprine, mycophenolate mofetil and cyclophosphamide for her Cogan's syndrome. Other past medical history included autoimmune hepatitis and monoclonal gammopathy of unknown significance. She had had a urine infection, treated with Trimethoprim, a few days before admission and also a recent dental work. She denied any history of trauma or insect bite to the thigh. On examination her right thigh was swollen, erythematous, tender and warm to touch. She was afebrile and systemically well. Her initial blood revealed a WCC 4.8 × 109/l, neutrophils 3.6 × 109/l, CRP 8 mg/l, ESR 61 mm/h. Ultrasonography of her right thigh revealed a 6-cm hypoechoic collection within the right vastus lateralis muscle (Figure 1). The collection was aspirated and she was started on empirical treatment with IV benzylpenicillin 1.2 g tds and IV flucloxacillin 2 g QDS. Ciclosporin was withheld and prednisolone increased to 20 mg/day. Cultures grew branched and beaded Gram-positive rods, suggestive of Nocardia species. The antibiotic regimen was therefore changed to IV meropenem 1 g tds and amikacin 7.5 mg/kg bd. Meropenem and amikacin were stopped after 2 days, as the patient described symptoms of cough, chest tightness and wheeze. She was commenced on co-trimoxazole 960 mg po tds. However, 4 days later Nocardia farcinica sensitive to co-amoxiclav, co-trimoxazole, minocycline, doxycycline and clarithromycin was confirmed and the antibiotic was changed to IV co-amoxiclav 1.2 tds. During her admission the patient remained generally well. A computed tomography (CT) abdomen and pelvis revealed ring-enhancing lesions within the left gluteus muscle. These lesions were attributed to a fall that the patient had in the ward; there were no signs of abscess. A CT head, performed after the patient complained of headache and nausea, was also normal. Both CT scans were undertaken to rule out disseminated Nocardial infection. After 7 days of IV co-amoxiclav the patient was discharged on minocycline 100 mg po bd for 6 months. She developed abnormal liver function and antibiotic therapy was changed to moxifloxacin (400 mg/day). She remained well for the past 6 months taking oral prednisolone.\nFigure 1: Six-centimetre hypoechoic collection (abscess) within the right vastus lateralis muscle.\n\n\n\nDISCUSSION\nNocardiosis is an uncommon infection, affecting mainly patients with cell-mediated immunodeficiency [4, 5]. In the USA, there are ∼500–1000 new cases each year [7].\n\nThe majority of patients with nocardiosis are immunocompromised. In a review of 1050 cases, it was found that 64% of patients with nocardial infections were immunocompromised [5]. The most important risk factors are glucocorticoid therapy, malignancy, organ and hematopoietic stem cell transplantation and HIV infection.\n\nThirty-three species of Nocardia have been shown to cause disease in humans. Members of the N. asteroides complex (N. asteroides sensu stricto, N. farcinica and N. nova) are most common worldwide [8]. Nocardia farcinica, the identified organism in our case, appears to be among the most virulent species of the N. asteroids complex as it is more likely to result in disseminated disease and usually shows high resistance to antibiotics [9]. Nocardia farcinica is the second most common species after N. nova [9]. The usual antibiotics of choice for Nocardia have been co-trimoxazole and amikacin; meropenem can also be used [9].\n\nIn our case, meropenem and amikacin, initially used for Nocardia, were stopped after the patient developed intolerance to them (unclear which one) and were switched to co-trimoxazole. The patient remained on co-trimoxazole until Nocardia farcinica sensitive to co-amoxiclav was identified. Due to the potential side effects of co-trimoxazole and the fact that our patient was systemically well, co-trimoxazole was switched to IV co-amoxiclav. The patient was discharged on minocycline for 6 months. Minocycline was preferred to co-amoxiclav, as the patient would require higher doses than the po 625 mg.\n\nThe best data on the sites of nocardial infection come from a 1994 literature review of 1050 cases of nocardiosis [5]. Systemic (>2 sites involved), 32%; pulmonary (only), 39%; CNS (only), 9%; cutaneous or lymphocutaneous, 8%; single site extrapulmonary (e.g. eyes, bone), 12%. Systemic disease due to nocardiosis, especially sepsis, is associated with a high mortality rate of 44–85% [10].\n\nOur patient presented with subcutaneous nocardiosis, progressively worsening pain and erythema over her right thigh. Cutaneous nocardiosis is clinically indistinguishable from lesions produced by common pyogenic bacteria such as Staphylococcus aureus and Group A streptococcus. It may present as ulcerations, pyoderma, cellulitis, nodules and subcutaneous abscesses [3]. This case report describes a rather subacute presentation of a Nocardia abscess without systemic involvement. The clinical challenge in nocardiosis is that there are no pathognomonic signs or symptoms for it. Therefore, the diagnosis lies on clinical suspicion, which must be high in immunocompromised patients. This case report stresses the importance of considering atypical infections in immunocompromised patients, even with minor symptoms, to avoid delay in diagnosis and treatment.\n==== Refs\nREFERENCES\n1 Goodfellow M Williams ST Ecology of actinomycetes Annu Rev Microbiol 1983 37 189 6357051 \n2 Ukai Y Fujimoto N Fujii N Shirai M Wakabayashi M Uenishi T J Dermatol 2012 39 466 69 doi:10.1111/j.1346-8138.2011.01393.x . 22011194 \n3 Shimizu T Furumoto H Asagami C Kanaya K Mikami Y Muto M Disseminated subcutaneous Nocardia farcinica abscesses in a nephrotic syndrome patient J Am Acad Dermatol 1998 38 874 9591807 \n4 Sorrell TC Mitchell DH Iredell JR Chen SC-A Mandell GL Bennett JE Dolin R Nocardia species Principles and Practice of Infectious Diseases, 7 2010 Philadelphia Churchill Livingstone Elsevier 3199 \n5 Beaman BL Beaman L Nocardia species: host–parasite relationships Clin Microbiol Rev 1994 7 213 8055469 \n6 Roth A Andrees S Kroppenstedt RM Harmsen D Mauch H Phylogeny of the genus Nocardia based on reassessed 16S rRNA gene sequences reveals underspeciation and division of strains classified as Nocardia asteroides into three established species and two unnamed taxons J Clin Microbiol 2003 41 851 12574299 \n7 Beaman BL Burnside J Edwards B Causey W Nocardial infections in the United States, 1972–1974 J Infect Dis 1976 134 286 789786 \n8 Conville PS Witebsky FG Murray PR Baron EJ Jorgensen JH Nocardia, Rhodococcus, Gordonia, Actinomadura, Streptomyces, and other aerobic actinomycetes Manual of Clinical Microbiology, 9 2007 Washington, DC ASM Press 515 \n9 Brown-Elliott BA Brown JM Conville PS Wallace RJ Jr. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy Clin Microbiol Rev 2006 19 259 82 16614249 \n10 Lerner PI Nocardiosis Clin Infect Dis 1996 22 891 903 8783685\n\n",
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"title": "Nocardia farcinica complicating Cogan's syndrome.",
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"abstract": "This is a case report of a 29-year-old man, who presented with progressive confusion, memory problems and personality changes during 1.5 months. Later, he developed bilateral hearing impairment but had no visual symptoms. A brain MRI showed numerous small hyperintensities in both hemispheres, a retinal fluorescence angiography revealed multiple hyperfluorescent arterial occlusions, and an audiogram showed bilateral hearing impairment. The patient was treated for Susac syndrome with high-dose corticosteroids initially, followed by intravenous immunoglobulin and cyclophosphamide.",
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"affiliations": "Infectious Diseases and Infection Control Research Group, Hospital Universitario de Sincelejo, Sincelejo, Sucre, Colombia; PhD Program in Tropical Medicine, Universidad de Cartagena, Cartagena, Universidad del Atlantico, Barranquilla, Colombia.;Infectious Diseases and Infection Control Research Group, Hospital Universitario de Sincelejo, Sincelejo, Sucre, Colombia.;Public Health and Infection Research Group, Faculty of Health Sciences, Universidad Tecnologica de Pereira, Pereira, Risaralda, Colombia; Medical School, Faculty of Health Sciences, UniFranz, Cochabamba, Bolivia.",
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"title_normalized": "visceral leishmaniasis in a patient with systemic lupus erythematosus from colombia latin america"
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"abstract": "Although radical nephrectomy alone is widely accepted as the standard of care in localized treatment for renal cell carcinoma (RCC), it is not sufficient for the treatment of metastatic RCC (mRCC), which invariably leads to an unfavorable outcome despite the use of multiple therapies. Currently, sequential targeted agents are recommended for the management of mRCC, but the optimal drug sequence is still debated. This case was a 57-year-old man with clear-cell mRCC who received multiple therapies following his first operation in 2003 and has survived for over 10 years with a satisfactory quality of life. The treatments given included several surgeries, immunotherapy, and sequentially administered sorafenib, sunitinib, and everolimus regimens. In the course of mRCC treatment, well-planned surgeries, effective sequential targeted therapies and close follow-up are all of great importance for optimal management and a satisfactory outcome.",
"affiliations": "Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.;Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.",
"authors": "Yuan|J L|JL|;Wang|F L|FL|;Yi|X M|XM|;Qin|W J|WJ|;Wu|G J|GJ|;Huan|Y|Y|;Yang|L J|LJ|;Zhang|G|G|;Yu|L|L|;Zhang|Y T|YT|;Qin|R L|RL|;Tian|C J|CJ|",
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"fulltext": "\n==== Front\nBraz J Med Biol ResBraz. J. Med. Biol. ResBrazilian Journal of Medical and Biological Research0100-879X1414-431XAssociação Brasileira de Divulgação Científica 2549338010.1590/1414-431X20144096Case ReportMore than 10 years survival with sequential therapy in a patient with\nadvanced renal cell carcinoma: a case report Yuan J.L. 1*Wang F.L. 1*Yi X.M. 1*Qin W.J. 1Wu G.J. 1Huan Y. 2Yang L.J. 1Zhang G. 1Yu L. 1Zhang Y.T. 1Qin R.L. 1Tian C.J. 11 Department of Urology, Xijing Hospital, Fourth Military Medical\nUniversity, Xi'an, Shaanxi, China2 Department of Radiology, Xijing Hospital, Fourth Military Medical\nUniversity, Xi'an, Shaanxi, ChinaCorrespondence: Jianlin Yuan, E-mail: <yuanjianlin317@126.com>* These authors contributed equally to this study.\n\n31 10 2014 1 2015 48 1 34 38 29 4 2014 22 9 2014 This is an Open Access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial License, which permits unrestricted\nnon-commercial use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited.Although radical nephrectomy alone is widely accepted as the standard of care in\nlocalized treatment for renal cell carcinoma (RCC), it is not sufficient for the\ntreatment of metastatic RCC (mRCC), which invariably leads to an unfavorable outcome\ndespite the use of multiple therapies. Currently, sequential targeted agents are\nrecommended for the management of mRCC, but the optimal drug sequence is still\ndebated. This case was a 57-year-old man with clear-cell mRCC who received multiple\ntherapies following his first operation in 2003 and has survived for over 10 years\nwith a satisfactory quality of life. The treatments given included several surgeries,\nimmunotherapy, and sequentially administered sorafenib, sunitinib, and everolimus\nregimens. In the course of mRCC treatment, well-planned surgeries, effective\nsequential targeted therapies and close follow-up are all of great importance for\noptimal management and a satisfactory outcome.\n\nMetastatic renal cell carcinomaSequential therapyTargeted anticancer agentsSorafenibSunitinibImmunotherapy\n==== Body\nIntroduction\nRenal cell carcinoma (RCC) is the sixth most common malignancy among men and the eighth\namong women in the USA, and the sixth leading cause of cancer-related deaths (1,2).\nCurrently, radical nephrectomy alone is widely accepted as the standard of care for\ntreatment of localized RCC, but it is not sufficient for the treatment of metastatic RCC\n(mRCC), which invariably leads to an unfavorable outcome despite the use of multiple\ntherapies. Metastases are found in approximately 30% of newly diagnosed RCC patients,\nresulting in a poor 5-year survival rate of less than 10% (3). However, the availability of several targeted agents [e.g.,\ntyrosine kinase inhibitors such as sorafenib, sunitinib, pazopanib, axitinib, tivozanib,\nmonoclonal antibodies such as bevacizumab (with interferon), and mammalian target of\nrapamycin (mTOR) inhibitors such as temsirolimus and everolimus] has dramatically\nchanged the treatment of mRCC (4,5). Extensive use of cytokines such as interferon-α\nand interleukin-2 in the past decade has evolved into controlled use of targeted\ntherapies.\n\nmRCC is one of the most treatment-resistant malignancies. Although targeted agents\nsignificantly prolong progression-free survival (PFS) compared with previously used\ntherapies, drug resistance is inevitable. Patients in whom treatment is initially\neffective almost always experience disease progression (6). As persistent complete remission of mRCC is rare with current therapeutic\nmodalities, more efficacious treatments with minimal adverse effects are urgently\nneeded. At present, sequential treatment is strongly recommended for the management of\nmRCC, but the optimal sequenced approach and the prognosis of these patients have not\nbeen defined (7,8).\n\nHere, we describe the case of a 57-year-old male patient with clear-cell mRCC who has\nsurvived for more than 10 years with a satisfactory quality of life since undergoing a\nradical nephrectomy in 2003. During that interval, the patient has benefitted from\nseveral advances in the management of mRCC. To the best of our knowledge, this is the\nfirst documented case of survival for more than 10 years following multiple therapies,\nincluding several surgical procedures, cytokine therapy, and sequentially administered\ntargeted agents with long switching intervals.\n\nCase description\nDisease history\nIn February 2003, a 57-year-old man (height, 168 cm; body weight, 77 kg) presented\nwith painless gross hematuria. Ultrasonography indicated a solid mass in the left\nkidney. He took Chinese herbal medicines for several months, but the hematuria\ncontinued. When he revisited our clinic in October 2003, a computed tomography (CT)\nscan showed a solid mass of about 8×7 cm in the lower pole of the left kidney (about\n14×11 cm) infiltrating the major psoas muscle, with a long embolus in the inferior\nvena cava (IVC) that reached the entrance of the hepatic vein (Figure 1A). He had a Karnofsky Performance Status (KPS) score of\n70%, and Eastern Cooperative Oncology Group (ECOG) performance status of 2. The\npatient had a history of chronic gastritis (diagnosed in 1998), hyperlipidemia\n(diagnosed in 2002), fatty liver disease (diagnosed in 2004), right carotid artery\natherosclerosis (diagnosed in 2005), benign prostatic hyperplasia (BPH, diagnosed in\n2005), and a left maxillary sinus cyst (diagnosed in 2006), but he is currently\ntaking no medications for these conditions.\n\nFigure 1 Computed tomography (CT) images of the patient with metastatic renal cell\ncarcinoma at different time points. A, CT image before radical\nnephrectomy of the left kidney (white arrow: embolus in the inferior vena cava\n(IVC); gray arrow: embolus in the left renal vein; black arrow: the renal tumor\nsite. November 2003). B, CT image before enucleation of two\nmetastases in the right kidney (black arrow: metastasis in the right kidney.\nJune 2006). C, a distinct metastasis in the left lower lung\n(black arrow, January 2007). D, CT image revealing the embolus\nin the IVC (white arrow) and the metastasis in the left adrenal gland (black\narrow, November 2011). E, a large metastasis in the right\nkidney (white arrow) and the embolus in the IVC (black arrow, January 2013).\nF, a round metastatic site was found in the liver (white\narrow, January 2013).\nIn November 2003, the patient underwent radical left nephrectomy and removal of the\ntumor embolus in the IVC. The tumor was stage IV according to the 2002 American Joint\nCommittee on Cancer (AJCC) staging system. Postoperative pathological examination\nconfirmed advanced clear-cell carcinoma (pT4N0M0 Fuhrman grade II). Forty days later,\nCT scans revealed no residue of tumor in the surgical site, but one small (about 0.6\ncm) nodule was discovered in the left lower lung. Fortunately, the patient was\nstratified as favorable according to Memorial Sloan-Kettering Cancer Center RCC\nnomogram. He was started on a combined immunotherapy regimen (interleukin-2 plus\ninterferon), an adjuvant protocol that followed the treatment guidelines for renal\ncancer recommended by the Chinese Urological Association, and which was adapted for\nChinese patients from National Comprehensive Cancer Network (NCCN) practice\nguidelines (9). The protocol included two\ncycles of recombinant human interleukin-2 (18 million IU, sc for 5\ndays in the first week, followed by 3 weeks of 18 million IU for 2 days and 9 million\nIU for 3 days) and recombinant human interferon-α2b (9 million IU,\nim, 3 times per week for 12 weeks). Close follow-up was\nmaintained, including disease history, physical examination, routine blood tests,\nkidney and liver function tests, and CT imaging every 3 months. In August 2005, a\ncystic change was noted in the right kidney. Urodynamic tests revealed increased\nresidual urine (70 mL), and ultrasonography suggested BPH.\n\nIn June 2006, two solid masses (1.0×1.0 cm and 1.5×1.5 cm in size) appearing to be\nmetastases were found, in the middle and upper pole of the right kidney (Figure 1B). The small nodule in the left lower\nlung had not changed significantly. The patient underwent a second surgical procedure\nvia the primary abdominal incision to enucleate the two masses in the right kidney.\nIntraoperative frozen sections confirmed metastatic clear-cell carcinoma. The patient\ncontinued the previous immunotherapy for two cycles after the surgery. Unfortunately,\nin November 2006, three lung nodules involving both lungs, each smaller than 1 cm,\nwere found.\n\nSorafenib as first-line targeted therapy\nSorafenib is recommended as a first-line targeted therapy for mRCC by the NCCN\nguidelines, and received marketing approval in China in November 2006. As the\npatient's mRCC diagnosis satisfied the 2002 AJCC criteria, he began sorafenib\ntherapy, 400 mg twice daily, in January 2007, when the largest of the 3 lung nodules\nbecame more apparent, growing to about 1.3×1.5 cm in size (Figure 1C).\n\nTreatment response was evaluated according to the response evaluation criteria in\nsolid tumors (RECIST) by an expert team that included both a radiologist and a\nurologist. The disappearance of all known lesions within 1 month was considered a\ncomplete response. A greater than 30% decrease in the total length of longest lesion\ndiameter was considered a partial response, and a greater than 20% increase in the\nsmallest sum as progressive disease. Changes between these limits were defined as\nstable disease. Adverse events were assessed by National Cancer Institute's Common\nTerminology Criteria for Adverse Events (CTCAE) 3.0. Grade 1, 2, 3 adverse events\nthat occurred in this patient were described as mild, moderate and severe,\nrespectively.\n\nOne week after starting sorafenib therapy, the patient experienced grade 1 hand-foot\nsyndrome, stomatitis, fatigue, and grade 2 diarrhea. These reactions were controlled\nby symptomatic treatment without the need for dose reduction or therapy interruption.\nTwo months after starting sorafenib therapy, a small embolus was found in the IVC,\nbut the size of the nodules in the lung had decreased. The RECIST evaluation\nindicated stable disease until January 2011, when CT images revealed a nodule, about\n2.9×3.0 cm in size, in the left adrenal gland, an oval, low-density lesion in the\ntail of the pancreas, and several small nodules in the left lower lung. The RECIST\nevaluation clearly confirmed progressive disease. A larger dose of sorafenib (600 mg\ntwice daily) was recommended. However, the patient could not tolerate the higher dose\nowing to uncontrolled severe diarrhea (grade 3), and so in February 2011 sunitinib\nwas carefully selected as a sequential targeted agent.\n\nSunitinib as second-line targeted therapy\nThe patient started sunitinib therapy at a dose of 50 mg/day in February 2011 and\nexperienced mild adverse effects, grade 1 diarrhea. In November 2011, metastases were\nconfirmed in the right kidney, left adrenal gland (Figure 1D), tail of the pancreas, and the liver, and the embolus in the\nIVC was enlarged. The nodules in both lungs had disappeared. One month later, the\nmetastases in the left adrenal gland and tail of the pancreas had shrunk, but the two\nmetastatic nodules in the liver and the embolus in the IVC were still present. As the\ncomprehensive evaluation at this time was stable disease, the patient continued\nsunitinib therapy.\n\nIn December 2012, the patient was hospitalized for acute urinary retention.\nUrodynamic tests revealed a maximum voiding flow rate of 1.7 mL/s and residual urine\nof 36 mL consistent with bladder outlet obstruction induced by BPH. He then underwent\na third operation, transurethral resection of the prostate as treatment of the BPH.\nPostoperative pathological examination confirmed the BPH diagnosis. The patient\nrecovered well and regained normal urination.\n\nBy January 2013, the metastasis in the right kidney had increased to 2.7×2.2 cm\n(Figure 1E), at which time the patient\nunderwent a fourth operation for cryoablation of metastases in both the right kidney\nand the right hepatic lobe (Figure 1F).\nSunitinib therapy was continued until disease progression was confirmed in July\n2013.\n\nEverolimus as third-line targeted therapy\nIn August 2013, the patient was started on everolimus at a dose of 10 mg/day. He\ntolerated this treatment well; the only adverse events were grade 2 fatigue and\nstomatitis. As of 10 February 2014, the patient continues on everolimus therapy with\nstable disease and ECOG and KPS score of 1 and 90%, respectively. His quality of\nlife, evaluated using the WHOQOL-100 questionnaire, is satisfactory. Close follow-up\nof the patient is ongoing.\n\nDiscussion\nA definitive curative treatment for mRCC is still lacking. Many factors, such as disease\nsubtype, prognostic factors, comorbidities, and treatment tolerance, may influence the\nPFS of patients in clinical practice (10).\nSeveral novel targeted agents for mRCC treatment have become available in recent years.\nTargeted agents such as the vascular endothelial growth factor receptor (VEGFR),\ntyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors\nhave been shown to prolong the PFS of mRCC patients (11). Sorafenib was the first multi-kinase inhibitor (Raf kinases, VEGFRs 1-3,\nPDGF-β, Flt-3, c-KIT) to become available (4).\nPatients who do not respond to immunotherapy may benefit from sorafenib therapy.\nSunitinib, a tyrosine kinase inhibitor of VEGFRs, is also effective in the treatment of\nmRCC (6). Based on the results of a phase III\nplacebo-controlled study, the mTOR inhibitor everolimus was approved for patients who\nhave failed sunitinib treatment (12). However,\nresistance to targeted therapy is unavoidable and most patients relapse within 1 year\n(6). The molecular complexity of the target\ncells is considered a key factor in the development of resistance to treatment (13).\n\nAdequate management of the drug sequence in the course of treatment is helpful in\novercoming drug resistance to targeted agents, and can provide a favorable outcome for\nmRCC patients even after progression of the disease (14). Sequential therapy with several targeted agents having different\nmechanisms of action provides sustainable clinical benefit and should be considered in\nall patients who can tolerate such treatment (15). Generally, targeted agents are changed according to RECIST criteria, but\nsometimes the choice of agent is relatively arbitrary in various clinical settings\n(16). Retrospective studies in Sweden found\nthat first-line treatment with sorafenib was a favorable choice (17), and a Swiss study reported that a sorafenib-sunitinib sequence\nhad a longer combined PFS than a sunitinib-sorafenib sequence (18). Based on the positive results of the phase III RECORD-1 trial,\ncurrent clinical practice guidelines uniformly recommend treatment with the mTOR\ninhibitor everolimus after initial failure with VEGFR-TKI (19).\n\nThis case report describes an mRCC patient who was treated sequentially with cytokines\nand targeted therapies including sorafenib, sunitinib, and everolimus. Sequential\ntherapy and cytoreductive surgery provided significant benefit for the patient and\ncontributed to his survival of over 10 years after a diagnosis of advanced RCC. After 38\nmonths of cytokine therapy, he received 49 months of sorafenib therapy, 30 months of\nsunitinib therapy, and more than 6 months of everolimus therapy. The treatment intervals\nfor each of the sequentially targeted therapies were significantly longer than those\nused in previous reports (18,20). The follow-up results also demonstrate the\nsafety of long-term administration of targeted agents.\n\nIt is noteworthy that mixed treatment responses, as evaluated by radiological\nexaminations, occurred in the course of combined therapies for this patient.\nSpecifically, new lesions were found in the liver, whereas the nodules in the lung\ngradually disappeared. This phenomenon appears more frequent with targeted therapy. We\npropose that the death of cancer cells sensitive to targeted agents might lead to the\ngrowth of a resistant population and the spread of resistant progeny to new metastatic\nsites. Therefore, more definitive criteria to describe this type of change would\ncomplement the RECIST criteria as a tool to evaluate treatment response.\n\nCytoreductive surgeries, including enucleation and cryoablation of tumors, were\nperformed repeatedly in this patient. In our opinion, large kidney tumors are relatively\ninsensitive and respond slowly to medications. Performing appropriate surgical\ninterventions in operable patients could improve their quality of life and result in\nlonger PFS and overall survival.\n\nMultiple therapies including well-planned surgical procedures, prudent decisions in\nmodifying the dosage of targeted agents, and in switching sequential therapy are of\ngreat importance in optimizing the clinical management of mRCC. Moreover, close\nfollow-up is indispensable for long-term survival. When disease progression occurs,\ncareful decision-making is essential. In our opinion, individualized therapy should be\nconsidered in all mRCC treatment courses. More importantly, with the availability of\nnewer targeted agents such as pazopanib, axitinib, and tivozanib, extensive studies are\nwarranted to determine the optimal choice of sequential therapy and to evaluate new\nmethods for the treatment of mRCC.\n\nAcknowledgments\nResearch supported by the Scientific Innovative Project of Shaanxi Province\n(#2012KTCL03-03).\n\nFirst published online.\n==== Refs\nReferences\n1 Kim SW Kim SJ Park SH Yang HG Kang MC Choi YW Complete regression of metastatic renal cell carcinoma\nby multiple injections of engineered mesenchymal stem cells expressing dodecameric\nTRAIL and HSV-TK Clin Cancer Res 2013 19 415 427 10.1158/1078-0432.CCR-12-1568 23204131 \n2 Danilin S Sourbier C Thomas L Lindner V Rothhut S Dormoy V Role of the RNA-binding protein HuR in human renal cell\ncarcinoma Carcinogenesis 2010 31 1018 1026 10.1093/carcin/bgq052 20219773 \n3 Norian LA Kresowik TP Rosevear HM James BR Rosean TR Lightfoot AJ Eradication of metastatic renal cell carcinoma after\nadenovirus-encoded TNF-related apoptosis-inducing ligand (TRAIL)/CpG\nimmunotherapy PLoS One 2012 7 10.1371/journal.pone.0031085 \n4 Strumberg D Sorafenib for the treatment of renal\ncancer Expert Opin Pharmacother 2012 13 407 419 10.1517/14656566.2012.654776 22263843 \n5 Procopio G Verzoni E Iacovelli R Guadalupi V Gelsomino F Buzzoni R Targeted therapies used sequentially in metastatic renal\ncell cancer: overall results from a large experience Expert Rev Anticancer Ther 2011 11 1631 1640 10.1586/era.11.154 22050012 \n6 Wang X Zhang L O'Neill A Bahamon B Alsop DC Mier JW Cox-2 inhibition enhances the activity of sunitinib in\nhuman renal cell carcinoma xenografts Br J Cancer 2013 108 319 326 10.1038/bjc.2012.591 23322198 \n7 Levy A Menard J Albiges L Loriot Y Di Palma M Fizazi K Second line treatment of metastatic renal cell\ncarcinoma: The Institut Gustave Roussy experience with targeted therapies in 251\nconsecutive patients Eur J Cancer 2013 49 1898 1904 10.1016/j.ejca.2013.02.003 23490648 \n8 Lombardi G Zustovich F Donach M Dalla Palma M Nicoletto O Pastorelli D An update on targeted therapy in metastatic renal cell\ncarcinoma Urol Oncol 2012 30 240 246 10.1016/j.urolonc.2009.12.018 20456985 \n9 Motzer RJ Agarwal N Beard C Bolger GB Boston B Carducci MA NCCN clinical practice guidelines in oncology: kidney\ncancer J Natl Compr Canc Netw 2009 7 618 630 19555584 \n10 Escudier B Szczylik C Porta C Gore M Treatment selection in metastatic renal cell carcinoma:\nexpert consensus Nat Rev Clin Oncol 2012 9 327 337 10.1038/nrclinonc.2012.59 22473096 \n11 Wada Y Takahashi W Kawano Y Eto M Current status of pharmacotherapy against metastatic\nrenal cell carcinoma in Japan Int J Urol 2012 19 284 295 10.1111/j.1442-2042.2012.02962.x 22452375 \n12 Porta C Tortora G Linassier C Papazisis K Awada A Berthold D Maximising the duration of disease control in metastatic\nrenal cell carcinoma with targeted agents: an expert agreement Med Oncol 2012 29 1896 1907 10.1007/s12032-011-0016-8 21735145 \n13 O'Mahony FC Nanda J Laird A Mullen P Caldwell H Overton IM The use of reverse phase protein arrays (RPPA) to\nexplore protein expression variation within individual renal cell\ncancers J Vis Exp 2013 10.3791/50221 \n14 Khattak M Larkin J Sequential therapy with targeted agents in metastatic\nrenal cell carcinoma: beyond second-line and overcoming drug\nresistance World J Urol 2014 32 19 29 10.1007/s00345-012-1013-z 23297098 \n15 Oudard S Elaidi RT Sequential therapy with targeted agents in patients with\nadvanced renal cell carcinoma: optimizing patient benefit Cancer Treat Rev 2012 38 981 987 10.1016/j.ctrv.2011.12.009 22289686 \n16 Shinohara N [Renal cell carcinoma-response criteria of molecular\ntargeted therapy and the timing of sequential drugs in patients with advanced\nrenal cell carcinoma] Gan To Kagaku Ryoho 2012 39 1462 1466 23064056 \n17 Ambring A Bjorholt I Lesen E Stierner U Oden A Treatment with sorafenib and sunitinib in renal cell\ncancer: a Swedish register-based study Med Oncol 2013 30 331 10.1007/s12032-012-0331-8 23254966 \n18 Stenner F Chastonay R Liewen H Haile SR Cathomas R Rothermundt C A pooled analysis of sequential therapies with sorafenib\nand sunitinib in metastatic renal cell carcinoma Oncology 2012 82 333 340 10.1159/000338001 22677881 \n19 Gonzalez Larriba JL Espinosa E Garcia Carbonero I Garcia-Donas J Lopez M Meana A Sequential therapy in metastatic renal cell carcinoma:\npre-clinical and clinical rationale for selecting a second- or subsequent-line\ntherapy with a different mechanism of action Cancer Metastasis Rev 2012 31 (Suppl 1) S11 S17 10.1007/s10555-012-9354-z 22674353 \n20 Oudard S More than 4 years of progression-free survival in a\npatient with metastatic renal cell carcinoma treated sequentially with sunitinib,\neverolimus, sorafenib, and temsirolimus Anticancer Res 2010 30 5223 5225 21187517\n\n",
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"journal": "Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas",
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"medline_ta": "Braz J Med Biol Res",
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"title": "More than 10 years survival with sequential therapy in a patient with advanced renal cell carcinoma: a case report.",
"title_normalized": "more than 10 years survival with sequential therapy in a patient with advanced renal cell carcinoma a case report"
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"abstract": "BACKGROUND\nRitonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin is one of the current recommended therapies for HCV genotype 1b monoinfected patients in compensated (Child-Pugh A) cirrhosis. Whether it is known that the worsening of liver function is a rare but possible complication of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir therapy, to our knowledge no description of treatment-related acute liver failure is available in the literature.\n\n\nMETHODS\nAn 84-year-old Caucasian man with chronic compensated HCV genotype 1b cirrhosis received Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy. After 13 days he developed grade 4 hyperbilirubinaemia and ascites. Even though treatment was promptly stopped, patient's clinical condition worsened, and he underwent hospitalization, several paracentheses, and developed sub-acute kidney injury. The bilirubinemia returned under three times the upper normal limit only after five months. Notably, he achieved sustained virological response despite the very short duration of therapy.\n\n\nCONCLUSIONS\nHepatic decompensation and acute liver failure are rare but severe complications of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy in patients with compensated cirrhosis. Close monitoring for signs or symptoms of worsening of liver disease is mandatory, and further research for stratifying risk factors are required.",
"affiliations": "Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. marco.masetti3@gmail.com.;Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.;Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy.",
"authors": "Masetti|Marco|M|;Magalotti|Donatella|D|;Martino|Elena|E|;Andreone|Pietro|P|;Scuteri|Alessandra|A|;Zoli|Marco|M|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
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"mesh_terms": "D015081:2-Naphthylamine; D000369:Aged, 80 and over; D000813:Anilides; D000998:Antiviral Agents; D001201:Ascites; D002219:Carbamates; D056486:Chemical and Drug Induced Liver Injury; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D006932:Hyperbilirubinemia; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis; D017114:Liver Failure, Acute; D008111:Liver Function Tests; D047028:Macrocyclic Compounds; D008297:Male; D011392:Proline; D019438:Ritonavir; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D013997:Time Factors; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "101272825",
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"pages": "559-561",
"pmc": null,
"pmid": "27981315",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Case of Acute Liver Failure during Ritonavir-Boosted Paritaprevir, Ombitasvir and Dasabuvir Therapy in a Patient with HCV Genotype 1b Cirrhosis.",
"title_normalized": "a case of acute liver failure during ritonavir boosted paritaprevir ombitasvir and dasabuvir therapy in a patient with hcv genotype 1b cirrhosis"
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"abstract": "Few groups of aggressive non-Hodgkin's lymphomas (NHL) that are refractory to standard chemotherapy are rarely reported. Primary CD20 negative diffuse large B cell lymphoma (DLBCL) without human immunodeficiency virus infection is an uncommon presentation and this case report is challenging in terms of diagnosis and treatment as well.",
"affiliations": "Department of Medical Oncology, Aga Khan University, Karachi, Pakistan.;Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan.;Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan.",
"authors": "Devi|Kanti|K|https://orcid.org/0000-0001-5347-219X;Ali|Natashi|N|;Ahmed|Arsalan|A|",
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"doi": "10.1093/omcr/omab114",
"fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855\nOxford University Press\n\n10.1093/omcr/omab114\nomab114\nCase Report\nAcademicSubjects/MED00010\nomcrep/1000\nomcrep/1500\nCase report of primary CD20 negative diffuse large B-cell lymphoma\nhttps://orcid.org/0000-0001-5347-219X\nDevi Kanti 1\nAli Natashi 2\nAhmed Arsalan 2\n1 Department of Medical Oncology, Aga Khan University, Karachi, Pakistan\n2 Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan\nCorrespondence address. Department of Medical Oncology, Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan. Tel: +92 21 3486 4290; E-mail: kanta.devi@aku.edu\n11 2021\n25 11 2021\n25 11 2021\n2021 11 omab1149 8 2021\n13 10 2021\n16 10 2021\n© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nABSTRACT\n\nFew groups of aggressive non-Hodgkin’s lymphomas (NHL) that are refractory to standard chemotherapy are rarely reported. Primary CD20 negative diffuse large B cell lymphoma (DLBCL) without human immunodeficiency virus infection is an uncommon presentation and this case report is challenging in terms of diagnosis and treatment as well.\n==== Body\npmcINTRODUCTION\n\nThe most common subtype of non-Hodgkin’s lymphoma (NHL) is diffuse large B-cell lymphoma (DLBCL) which constitutes around 30–40% of all cases [1]. B-cell activation is dependent on CD-20 antigen which is a membrane protein and pan B-cell marker due to its expression on neoplastic B lymphocytes [1]. Primary CD20 negative DLBCL has rarely been reported and accounts for 1–3% of cases [2]. There are few known subtypes of CD-20 negative DLBCL [1]. Primary CD20 negative DLBCL is not common and has comparably bad prognosis as CD-20 negative DLBCL is refractory to standard treatment and this subtype is usually associated with extra nodal disease, unusual morphology and aggressive behavior. [2, 3]. We report a case of de novo CD20 negative DLBCL that did not respond to first-line treatment and required salvage chemotherapy to achieve partial remission.\n\nCASE\n\nA 33-year-old male with no known comorbid presented with complaints of neck swelling which progressively increased in size for 3 months, associated with fever and difficulty in breathing. On examination he was vitally stable. General physical examination showed multiple skin lesions and bilateral cervical and axillary lymphadenopathy with the left cervical node measuring 4 × 6 cm in size. Systemic examination was unremarkable. His computed tomography (CT) scan of chest, abdomen and pelvis showed large infiltrative heterogeneously enhancing mass involving superior anterior and middle mediastinum involving root of aorta and other major vessels with extension of disease encasing trachea, superior vena cava, brachiocephalic veins, pulmonary trunk and veins (Fig. 1). Punch biopsy of the skin was done which showed mild irregular acanthosis and focal parakeratosis representing inflammatory hyperpigmentation which was managed with skin moisturizers. Excisional lymph node biopsy from left cervical area was sent for AFB smear culture, Gene-Xpert for tuberculosis (cartridge-based nucleic acid amplification test) and bacterial culture which were negative. Histopathology showed effaced architecture and infiltration with atypical lymphoid cells showing pleomorphic nuclei with prominent nucleoli. Immunohistochemistry (IHC) for leukocyte common antigen (LCA) was positive, while it was negative for CD-20 but positive for CD79a, PAX-5 which are other B cell markers (Fig. 2).\n\nConsidering diagnosis of CD20 negative DLBCL further work up including CD138 for possible plasmablastic variant, ALK protein, EBV, CD30 and HHV 8 was performed for other differential diagnosis, which were negative (Fig. 2). Human immunodeficiency virus (HIV) serology was also negative. Considering the diagnosis of primary CD20 negative DLBCL, which is a high-grade lymphoma, we started him on infusion chemotherapy regimen i.e. EPOCH (Etoposide, Prednisolone, Doxorubicin, vincristine along with bolus of cyclophosphamide). His follow-up interim scan done after four cycles of EPOCH did not show any change in the disease status (treatment failure). Subsequently he was started on second-line chemotherapy i.e. GCD (Gemcitabine, Cisplatin and Dexamethasone) and after two cycles his interim PET-CT scan showed partial remission. We are now planning for autologous stem cell transplantation (ASCT) once he achieved response on two more cycles of GCD.\n\nFigure 1 CT chest with contrast showing large heterogeneous mass.\n\nFigure 2 (A), (B) and (C) showing Lymph node biopsy HE at 20-X and 40-X show effaced architecture by group of atypical lymphocytes. (D) PAX-5, (E) and (F) CD 79a at 40X shows positive staining in neoplastic cells. (G) CD 20 negative. (H) CD 3 negative in neoplastic cells. (I) Ki-67 increased. (J) CD 30 negative. (K) MUM-1 and (L) C-MYC positive in neoplastic cell.\n\nDISCUSSION\n\nA rare entity like CD20 negative DLBCL is a heterogonous group of aggressive lymphomas [1]. They constitute 1–3% of all B-cell non-Hodgkin’s lymphomas [2]. CD20 is a pan B-cell marker and cells can still survive even after loss of CD20 expression in CD20 negative DLBCL [1]. Known subtypes include plasmablastic lymphomas (PBL), primary effusion lymphomas (PEL), anaplastic kinase positive large B-cell lymphomas (ALK+ve LBCL) and large B-cell lymphomas arising in human herpes virus 8 associated multicentric Castleman disease (HHV-8 MCD-LBCL) [2].\n\nThe most prevalent and well-known sub-type is PBL, which accounts for 75% of the reported cases [3]. Both HIV-positive and -negative patients have been found to have primary CD20 loss in DLBCL [1]. Pathologically, CD20 negative DLBCL is more closely associated with aggressive pathologic parameters with a high proliferation index and a higher proportion of non-GCB type [1]. Only a few cases of well-established sub-types of CD-20 negative DLBCL have been reported that could not be categorized as known variants of CD20 negative DLBCL [4]. This might broaden the spectrum of unclassifiable primary CD20 negative DLBCL which shows genetic and immunophenotypic aberrancy and results in diagnostic and therapeutic challenges [4]. Morphology and the results of immunohistochemistry and flowcytometry are used to identify DLBCL. Positivity of CD19, CD79, PAX5 are the major immunohistochemical biomarkers used to establish a diagnosis of CD20 negative B cell lymphomas, while flowcytometric analysis shows positivity for CD19, CD79a, CD5 and CD10 in cases of CD20 negative B cell lymphomas [5]. Molecular analysis using cytogenetic and fluorescence in situ hybridization (FISH) to detect rearrangement or translocation of BCL-2, BCL-6 and C-MYC is an important part of diagnosis and the most frequently found mutation is BCL-2 [6].\n\nPatients with CD20 negative DLBCL do not respond to standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), and still no standard of care for CD20 negative B-cell lymphomas has been identified. Considering poor prognosis, high-dose chemotherapy had been suggested i.e. either cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose cytarabine and methotrexate (hyperCVAD), EPOCH with modified dose, or cyclophosphamide, vincristine, doxorubicin, methotrexate alternating with ifosfamide, etoposide and cytarabine (CODOX M/IVAC) [7–9] as per previous literature review.\n\nOur patient did not respond to EPOCH chemotherapy regimen. He was therefore started on salvage chemotherapy and has been planned for autologous stem cell transplant considering poor prognosis of disease course [10].\n\nFOLLOW UP OF CASE\n\nPost 4 cycles of GDP he achieved partial response and went autologous stem cell transplant and is doing well with engraftment of all cell lines.\n\nACKNOWLEDGEMENT\n\nHematology team at the Aga Khan University who assisted in the management.\n\nCONFLICT OF INTEREST\n\nNothing to declare.\n\nFUNDING\n\nNot available.\n\nETHICAL APPROVAL\n\nN/A.\n\nCONSENT\n\nInformed written consent taken.\n\nGUARANTOR\n\nKanta Devi is the guarantor of this manuscript.\n==== Refs\nREFERENCES\n\n1. Li Y-J, Li Z-M, Rao H-L, Xia Y, Huang H-Q, Xia Z-J, et al. CD20-negative de novo diffuse large B-cell lymphoma in HIV-negative patients: a matched case-control analysis in a single institution. J Transl Med 2012;10 :1–11.22214470\n2. Li J, Zhao S, Wang J, Chen J, Wen W, Zhang Q. CD20-negative diffuse large B cell lymphoma: a comprehensive analysis of 695 cases. Tumor Biol 2016;37 :3619–37.\n3. Nakatsuka S-i, Yutani C, Kurashige M, Kohara M, Nagano T, Goto T, et al. An unusual case of Epstein-Barr virus-positive large B-cell lymphoma lacking various B-cell markers. Diagn Pathol 2017;12 :1–6.28049534\n4. Garg M, Lee BE, McGarry K, Mangray S, Castillo JJ. CD 20-negative diffuse large B-cell lymphoma presenting with lactic acidosis. Am J Hematol 2015;90 :E49–50.25417998\n5. Narurkar R, Alkayem M, Liu D. SOX11 is a biomarker for cyclin D1-negative mantle cell lymphoma. Biomarker research 2016;4 :1–3.26823978\n6. Cao Y, Yang G, Hunter ZR, Liu X, Xu L, Chen J, et al. The BCL2 antagonist ABT-199 triggers apoptosis, and augments ibrutinib and idelalisib mediated cytotoxicity in CXCR4 wild-type and CXCR4 WHIM mutated Waldenstrom macroglobulinaemia cells. Br J Haematol 2015;170 :134–8.25582069\n7. Davidson KL, Devaney MB, Tighe JE, Rogers SY, Dunlop DJ, Mackie MJ, et al. A pilot study of CODOX-M/IVAC in primary refractory or relapsed high-grade non-Hodgkin's lymphoma. A Scotland and Newcastle lymphoma group study. Haematologica 2003;88 :1366–71.14687989\n8. Purroy N, Bergua J, Gallur L, Prieto J, Lopez LA, Sancho JM, et al. Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA group. Br J Haematol 2015;169 :188–98.25521006\n9. Saste A, Arias-Stella J, Kuriakose P. Progression of a hepatosplenic gamma delta T-cell leukemia/lymphoma on hyper CVAD/MTX and ara-C: literature review and our institutional treatment approach. Clinical case reports 2016;4 :67.26783439\n10. Qunaj L, Castillo JJ, Olszewski AJ. Survival of patients with CD20-negative variants of large B-cell lymphoma: an analysis of the National Cancer Data Base. Leuk Lymphoma 2018;59 :1375–83.29019447\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "2021(11)",
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"title": "Case report of primary CD20 negative diffuse large B-cell lymphoma.",
"title_normalized": "case report of primary cd20 negative diffuse large b cell lymphoma"
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"abstract": "Cyclosporine (CsA) combined with short-course methotrexate is considered standard-of-care graft-versus-host disease (GVHD) prophylaxis for patients with severe aplastic anemia (AA) who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. However, there is no consensus on optimal post-transplant GVHD prophylaxis for patients undergoing matched related donor (MRD) transplantation using fludarabine (Flu)-based conditioning. We conducted a single-center retrospective analysis of patients with acquired AA (n = 106) undergoing MRD transplantation from July 2007 through January 2019. All patients received Flu-Cy-ATG conditioning and single-agent CsA as GVHD prophylaxis. Median age of the study cohort was 20 years (range, 3 to 52) and male to female ratio was 3.8:1. Median time from diagnosis to transplant was 11.5 months (range, 2.8 to 62). Graft source was bone marrow harvest in 71 (68%), combined bone marrow and peripheral blood stem cells in 34 (31%), and peripheral blood alone in 1 (1%) patient. Cumulative incidence of neutrophil engraftment at day 28 was 93.4% (95% confidence interval [CI], 87.3% to 97.1%) while that of platelet engraftment at day 100 was 90.5% (95% CI, 84% to 96%). Cumulative incidence of primary graft failure at day 28 was 6.6% (95% CI, 4% to 8%) while secondary graft failure occurred at a median of 190 days (range, 90 to 415) at a cumulative incidence of 3.7% (95% CI, 2% to 5%). Cumulative incidence of grade II to IV acute GVHD at day 100 was 3.8% (95% CI, 1.4% to 9.9%), while a 1-year probability of chronic GVHD was calculated as 7.5% (95% CI, 2.6% to 15%). Median follow-up post-transplant was 61 months (range, 6 to 144). Overall survival was 84.9%, disease-free survival was 80.2%, and GVHD-free relapse-free survival was 76.3%. This study indicates that single-agent cyclosporine is a feasible option for GVHD prophylaxis in MRD hematopoietic stem cell transplantation using Flu-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD.",
"affiliations": "Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan. Electronic address: drraheeliftikhar@gmail.com.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Molecular Hematology, National University of Medical Sciences, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan.;Baptist Medical Center South, Montgomery, Alabama.;Shifa International Hospital, Islamabad, Pakistan.;Department of Hematology, Medical Oncology, Tausig Cancer Center, Cleveland Clinic, Cleveland, Ohio.;Department of Hematology Oncology and Stem Cell Transplant, Quaid-e-Azam International Hospital, Islamabad, Pakistan.",
"authors": "Iftikhar|Raheel|R|;Chaudhry|Qamar Un Nisa|QUN|;Mahmood|Syed Kamran|SK|;Ghafoor|Tariq|T|;Satti|Humayun Shafique|HS|;Shahbaz|Nighat|N|;Khan|Mehreen Ali|MA|;Khattak|Tariq Azam|TA|;Shamshad|Ghassan Umair|GU|;Rehman|Jahanzeb|J|;Farhan|Muhammad|M|;Humayun|Saima|S|;Risalat|Amina|A|;Wahab|Ahsan|A|;Satti|Tariq Mehmood|TM|;Anwer|Faiz|F|;Ahmed|Parvez|P|",
"chemical_list": "D016572:Cyclosporine; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2020.07.026",
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"issue": "26(12)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Aplastic anemia; Cyclosporine; Fludarabine; Graft-versus-host disease",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D014740:Vidarabine; D055815:Young Adult",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "2245-2251",
"pmc": null,
"pmid": "32717437",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Single-Agent Cyclosporine for Graft-versus-Host Disease Prophylaxis in Patients with Acquired Aplastic Anemia Receiving Fludarabine-Based Conditioning.",
"title_normalized": "single agent cyclosporine for graft versus host disease prophylaxis in patients with acquired aplastic anemia receiving fludarabine based conditioning"
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"abstract": "A 60-year-old female underwent right upper lobectomy of the lung and lymph node dissection under a diagnosis of cancer in the upper lobe of the right lung. Pathological examination showed stage IIIA adenocarcinoma with mediastinal lymph node metastasis. One month after the operation, adjuvant chemotherapy with carboplatin (CBDCA) and paclitaxel (PTX) was initiated. Four days after the chemotherapy, hyponatremia progressed, and central nervous system disorder developed. A diagnosis of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was made. She recovered after fluid intake restriction and electrolyte correction. SIADH was considered to be due to the adverse effects of anticancer drugs. In postoperative adjuvant chemotherapy, attention should be paid to the serum Na level.",
"affiliations": "Division of General Thoracic Surgery, Tottori University Hospital, Yonago, Tottori, Japan. shinji-f-oka@med.tottori-u.ac.jp",
"authors": "Fujioka|S|S|;Nakamura|H|H|;Miwa|K|K|;Taniguchi|Y|Y|;Haruki|T|T|;Takagi|Y|Y|;Yurugi|Y|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014667:Vasopressins; D016190:Carboplatin; D017239:Paclitaxel",
"country": "Germany",
"delete": false,
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"issn_linking": "0031-7144",
"issue": "66(9)",
"journal": "Die Pharmazie",
"keywords": null,
"medline_ta": "Pharmazie",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D008168:Lung; D008175:Lung Neoplasms; D008207:Lymphatic Metastasis; D008875:Middle Aged; D017239:Paclitaxel; D014667:Vasopressins",
"nlm_unique_id": "9800766",
"other_id": null,
"pages": "729-30",
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"pubdate": "2011-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) following carboplatin-paclitaxel administration in a patient with lung cancer.",
"title_normalized": "syndrome of inappropriate secretion of antidiuretic hormone siadh following carboplatin paclitaxel administration in a patient with lung cancer"
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... |
{
"abstract": "BACKGROUND\nAnabolic steroids have been widely used in recent years. It could adversely affect the cardiovascular system. Non-traditional risk factors for coronary heart diseases (CHDs) have raised great concern.\n\n\nMETHODS\nA young bodybuilder was presented with crushing retrosternal chest pain, excessive diaphoresis, and vomiting. The symptoms began during wrestling. The patient did not have a history of traditional cardiovascular risk factors. He was using large quantities of nutritional and bodybuilding supplements with multiple intramuscular injections of dexamethasone during past 6 months. The electrocardiography (ECG) revealed ST-segment elevation in the precordial, I and aVL leads consistent with acute extensive myocardial infarction (MI). Lipid profile, cardiac troponin, and creatine phosphokinase-MB (CPK-MB) was abnormal. Transthoracic echocardiography (TTE) revealed mild left ventricular (LV) enlargement and reduced global systolic dysfunction with regional wall akinesia. The patient received thrombolytic therapy which was resulted in symptomatic relief and resolution in ST-T changes. Significant smoke was seen in LV cavity without clot formation on the discharge day. About 1 week later, large fresh clots were seen in the apex. He was admitted again, and the burden of clots was reduced significantly after initiation of oral warfarin. Other laboratory tests were as follows: High-sensitivity C-reactive protein (CRP): 25.9 mg/dl, homocysteine: 26.2 µmol/l. The patient was discharged with specific medication. Clots were disappeared after 6 weeks of warfarin therapy. Later, the patient was evaluated again, and there was not any symptom and LV clots.\n\n\nCONCLUSIONS\nHyperhomocysteinemia could be induced by steroid abuse and may cause atherosclerotic and thrombotic effects in healthy athletes. We suggest clinicians to take a careful history of young athletes presented with MI or thrombotic events and also pay special attention to their homocysteine levels in their follow-ups.",
"affiliations": "Cardiologist, Atherosclerosis Prevention Research Center AND Department of Cardiovascular, School of Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.;Student Research Committee, Sabzevar University of Medical Sciences, Sabzevar, Iran.;Cardiologist, Atherosclerosis Prevention Research Center AND Department of Cardiovascular, School of Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.;Cardiologist, Atherosclerosis Prevention Research Center AND Department of Cardiovascular, School of Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.",
"authors": "Poorzand|Hoorak|H|;Jafarzadeh Esfehani|Reza|R|;Hosseinzadeh|Peyman|P|;Vojdanparast|Mohammad|M|",
"chemical_list": null,
"country": "Iran",
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"fulltext": "\n==== Front\nARYA AtherosclerARYA AtherosclerARYAARYA Atherosclerosis1735-39552251-6638Isfahan Cardiovascular Research Center, Isfahan University of Medical Sciences ARYA-11-366Case ReportAcute myocardial infarction in a young male wrestler: A case report Poorzand Hoorak 1Jafarzadeh Esfehani Reza 2Hosseinzadeh Peyman 1Vojdanparast Mohammad 11 Cardiologist, Atherosclerosis Prevention Research Center AND Department of Cardiovascular, School of Medicine, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran2 Student Research Committee, Sabzevar University of Medical Sciences, Sabzevar, IranCorrespondence to: Mohammad Vojdanparast, Email: vejdanparast.m@gmail.com11 2015 11 6 366 369 30 6 2015 12 8 2015 © 2015 Isfahan Cardiovascular Research Center & Isfahan University of Medical Sciences2015This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.BACKGROUND\nAnabolic steroids have been widely used in recent years. It could adversely affect the cardiovascular system. Non-traditional risk factors for coronary heart diseases (CHDs) have raised great concern.\n\nCASE REPORT\nA young bodybuilder was presented with crushing retrosternal chest pain, excessive diaphoresis, and vomiting. The symptoms began during wrestling. The patient did not have a history of traditional cardiovascular risk factors. He was using large quantities of nutritional and bodybuilding supplements with multiple intramuscular injections of dexamethasone during past 6 months. The electrocardiography (ECG) revealed ST-segment elevation in the precordial, I and aVL leads consistent with acute extensive myocardial infarction (MI). Lipid profile, cardiac troponin, and creatine phosphokinase-MB (CPK-MB) was abnormal. Transthoracic echocardiography (TTE) revealed mild left ventricular (LV) enlargement and reduced global systolic dysfunction with regional wall akinesia. The patient received thrombolytic therapy which was resulted in symptomatic relief and resolution in ST-T changes. Significant smoke was seen in LV cavity without clot formation on the discharge day. About 1 week later, large fresh clots were seen in the apex. He was admitted again, and the burden of clots was reduced significantly after initiation of oral warfarin. Other laboratory tests were as follows: High-sensitivity C-reactive protein (CRP): 25.9 mg/dl, homocysteine: 26.2 µmol/l. The patient was discharged with specific medication. Clots were disappeared after 6 weeks of warfarin therapy. Later, the patient was evaluated again, and there was not any symptom and LV clots.\n\nCONCLUSION\nHyperhomocysteinemia could be induced by steroid abuse and may cause atherosclerotic and thrombotic effects in healthy athletes. We suggest clinicians to take a careful history of young athletes presented with MI or thrombotic events and also pay special attention to their homocysteine levels in their follow-ups.\n\nHyperhomocysteinemiaAnabolic AgentsThrombosis\n==== Body\nIntroduction\nAlthough the importance of conventional risk factors is well established, it is commonly suggested that more than 50% of patients with coronary heart disease (CHD) lack any of the conventional risk factors. This claim implies that other factors play a significant role in CHD and have led to considerable interest in non-traditional risk factors and genetic causes of CHD.1\n\nHyperhomocysteinemia has been proposed as a risk factor for increased tendency of vessel thrombosis and cardiac ischemia.2,3 Elevated levels of homocysteine can also affect coagulation cascade or even cause multivessel coronary artery disease.3,4 On the other hand, anabolic androgenic steroids can directly affect cardiovascular system by inducing left ventricular (LV) hypertrophy and dysfunction or even indirectly causing hyperhomocysteinemia.5 Here, we discuss a 23-year-old male wrestler with a 6 months history of excessive anabolic steroid use presenting with crushing retrosternal chest pain.\n\nCase Report\nThe 23-year-old man was referred to the emergency department with a 4 hours history of crushing retrosternal chest pain, excessive diaphoresis, and vomiting. The symptoms began during wrestling. The patient had a previous history of retrosternal chest discomfort ascribed to gastric upset which always relieved spontaneously. He did not have traditional cardiovascular risk factors (cigarette smoking, diabetes, and hypertension). The patient was a bodybuilder and wrestler, who was continually using large quantities of nutritional and bodybuilding supplements with multiple intramuscular injections of dexamethasone during past 6 months. The vital signs were as follows on admission: Blood pressure: 140/90 mmHg, pulse rate of 72/minutes, respiratory rate: 14/minutes. The third and fourth heart sounds were prominent. The electrocardiography (ECG) which was recorded in emergency room revealed ST-segment elevation in the precordial, I and aVL leads consistent with acute extensive myocardial infarction (MI) (Figure 1).\n\nIncreased serum level of cardiac troponin was detected. Lipid profile was abnormal [high-density lipoprotein (HDL): 20 mg/dl, low-density lipoprotein (LDL): 101 mg/dl, triglycerides (TG): 305 mg/dl, cholesterol: 317 mg/dl]. Transthoracic echocardiography (TTE) revealed mild LV enlargement and reduced global systolic function (ejection fraction: 35-40%) with akinesia of all apical segments and mid-anterior and anteroseptal regions. The door to needle-door to balloon time was estimated to be long lasting. Hence, thrombolytic (streptokinase) was prescribed which was resulted in symptomatic relief and resolution in ST-T changes. About 4 days later, coronary angiography was done, showing non-significant stenosis in mid portion of left anterior descending artery (Figure 2). In the last day of admission, significant smoke was seen in LV cavity without clot formation.\n\nThe patient was reassessed 1 week after discharge and TTE was done. LV ejection fraction was 40%, and large fresh clots were seen in the apex (Figure 3-A). He was admitted again for better cardiac monitoring and initiation of anticoagulation. The size of the clots was reduced significantly after initiation of oral warfarin (Figure 3-B). Other laboratory tests were as follow: High-sensitivity C-reactive protein (CRP): 25.9 mg/dl, homocysteine: 26.2 µmol/l. The patient was discharged on warfarin, folic acid, vitamin B12 in addition to carvedilol, atorvastatin, losartan, and low dose furosemide. In the follow-up visits, the patient underwent echocardiography. The clots were disappeared after 6 weeks of warfarin therapy (Figure 3-C).\n\nSix months later, the patient was evaluated again and there was not any symptom and the LV clots were disappeared. Serum level of homocysteine was within the normal limits. Vitamin B12 and folic acid drugs were discontinued. During 3 years follow-up, there was not any clot formation in LV cavity in TTE and the patient had occasionally non-angina chest pain, exertional dyspnea (New York Heart Association I/II) without worsening of global LV function or any thromboembolic events. Lipid profile was normal in repeated assessment. The patient is now taking carvedilol, captopril, aspirin, atorvastatin, spironolactone, and warfarin and involved regularly in cardiac rehabilitation programs.\n\nDiscussion\nIn this report, we presented a case of acute chest pain in a young wrestler who uses bodybuilding supplements and intramuscular dexamethasone. ECG, echocardiographic and laboratory data were considered to be a more compatible with MI. However, not every chest pain and rises in cardiac biomarkers are due to acute coronary syndromes. Chest pain with associated increase in cardiac biomarker could be found in acute pulmonary embolism. ECG and echocardiographic findings were not compatible with such diagnosis in this patient. Myocarditis should also be considered as a possible diagnosis in young patients with acute coronary syndrome presentation especially in the absence of atherosclerosis risk factors or with normal coronary angiogram. In one series of patients with chest pain and ECG abnormalities, 32% of the cases have myocarditis on myocardial biopsy.6 Wall motion abnormalities could also be seen in echocardiography in myocarditis, but it is more global rather than segmental. ECG abnormalities or segmental distribution of wall motion abnormalities extend beyond a single coronary artery territory in the typical cases.7 This was in contrary to the presented case in which the ECG changes and regional wall motion abnormalities were comparable and suggesting the involvement of anterior coronary circulation.\n\nAnabolic steroids have various effects on cardiovascular system. Atherosclerosis, systemic hypertension, impaired diastolic, and systolic ventricular function and disturbances in lipid metabolisms have all been reported with anabolic steroid abuse.8 Increased platelet activity is also observed in such patients, and might be responsible for MI or even stroke.8\n\nThere are many cases of androgenic anabolic steroid abuse in young athletes showing cardiovascular problems such as MI or thrombosis of different vessels such as renal artery.5\n\nLV dysfunction is the other effect of long-term androgenic anabolic steroid abuse and could increase the risk of sudden death in these patients.9 Pathologic studies in such patients revealed small arteriole wall thickening and intimal hyperplasia, which could be responsible for causing ischemic myocardial damage and subsequent ventricular dysfunction.10\n\nUse of anabolic steroid can induce acute hyper homocysteinemia and associated thrombotic events.2 A higher level of homocysteine could be seen with lower HDL concentration, higher plasma LDL, and triglycerides.5\n\nHomocysteine is a sulfhydryl amino acid, absent in human natural dietary sources.11 It can be toxic to endothelial cells leading to the smooth muscle proliferation in vessel wall and affecting the coagulation cascade.3 Multivessel coronary artery disease and acute MI have been reported in the setting of the high level of homocysteine.4 Anabolic steroids can affect the absorption of B6 and B12 vitamins and cause an elevation in homocysteine levels.12 This effect might be responsible for the elevation of homocysteine levels in our patient; causing potential stenosis and thrombosis.\n\nWhile administration of folate supplement is somehow controversial, normalizing plasma homocysteine levels with healthy diet containing vegetables and fresh fruits accompanied by moderate exercise is more favorable.11 Administration of high dose of vitamin B6 with folic acid after acute MI does not reduce the risk of death or recurrence of cardiovascular disease.13 On the other hands, it can adversely affect myocardial repair and increase morbidity and mortality among patients with cardiovascular disease.13\n\nUse of anabolic steroid in young athletes is an important issue for clinicians. These substances have various effects on the cardiovascular system as well as other organs. Hyperhomocysteinemia could be induced by steroid abuse and may have atherosclerotic and thrombotic effects in healthy athletes. However, if a patient has the previous hyperhomocysteinemia, the risk of catastrophic cardiovascular events might be higher. We suggest clinicians to take history of young athletes presented with MI or thrombotic events carefully and also pay special attention to the homocysteine levels in their follow-up visits.\n\nAcknowledgments\nNone.\n\n\nConflicts of Interest\n\n\nAuthors have no conflict of interests.\n\nFigure 1 Twelve-leads electrocardiogram revealed significant ST elevation in precordial (tombstone sign), I and aVL leads (compatible with acute extensive anterior myocardial infraction)\n\nFigure 2 (A, B and C) Coronary angiography showing just a non-significant lesion in mid portion of left anterior descending (arrow in B), Left circumflex and right coronary artery were normal\n\nFigure 3 Echocardiographic images in apical four chamber views, (A) Large fresh clots in the apex (1 week later), (B) arrows denting the residual but small clots and (C) no residual clots\n==== Refs\nREFERENCES\n1 Amoozgar H Soltani M Besharati A Cheriki S Undiagnosed anemia in pediatric patients with congenital heart diseases. Int Cardiovasc Res J 2011 5 2 70 1 \n2 Ebenbichler CF Kaser S Bodner J Gander R Lechleitner M Herold M Hyperhomocysteinemia in bodybuilders taking anabolic steroids. Eur J Intern Med 2001 12 1 43 7 11173010 \n3 Perna A Ingrosso D de Santo NG Homocysteine and oxidative stress. Amino Acids 2003 25 3 409 17 14661100 \n4 Eftychiou C Antoniades L Makri L Koumas L Costeas PA Kyriakou E Homocysteine levels and MTHFR polymorphisms in young patients with acute myocardial infarction: a case control study. Hellenic J Cardiol 2012 53 3 189 94 22653243 \n5 Nockels K Invalid citation [Online]. Available from: URL:http://community.thomsonreuters.com/t5/EndNote-General/INVALID-CITATION/td-p/33811 2012 \n6 Dec GW Waldman H Southern J Fallon JT Hutter AM Palacios I Viral myocarditis mimicking acute myocardial infarction. J Am Coll Cardiol 1992 20 1 85 9 1607543 \n7 Magnani JW Dec GW Myocarditis: current trends in diagnosis and treatment. Circulation 2006 113 6 876 90 16476862 \n8 Vanberg P Atar D Androgenic anabolic steroid abuse and the cardiovascular system. Handb Exp Pharmacol 2010 195 411 57 20020375 \n9 Baggis AL Weiner RB Kanayama G Hudson JI Picard MH Hutter AM Long term anabolic-androgenic steroid use is associated with left ventricular dysfunction. Circ Heart Fail 2010 3 472 6 20424234 \n10 di Paolo M Agozzino M Toni C Luciani AB Molendini L Scaglione M Sudden anabolic steroid abuse-related death in athletes. Int J Cardiol 2007 114 1 114 7 16364470 \n11 Eldibany MM Caprini JA Hyperhomocysteinemia and thrombosis: an overview. Arch Pathol Lab Med 2007 131 6 872 84 17550314 \n12 Hartgens F Kuipers H Effects of androgenic-anabolic steroids in athletes. Sports Med 2004 34 8 513 54 15248788 \n13 Bonaa KH Njolstad I Ueland PM Schirmer H Tverdal A Steigen T Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006 354 15 1578 88 16531614\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1735-3955",
"issue": "11(6)",
"journal": "ARYA atherosclerosis",
"keywords": "Anabolic Agents; Hyperhomocysteinemia; Thrombosis",
"medline_ta": "ARYA Atheroscler",
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"nlm_unique_id": "101487337",
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"title": "Acute myocardial infarction in a young male wrestler: A case report.",
"title_normalized": "acute myocardial infarction in a young male wrestler a case report"
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"abstract": "BACKGROUND\nVenlafaxine is an antidepressant and anxiolytic agent that functions by inhibiting central serotonin and norepinephrine reuptake, and it is a relatively recently introduced drug. In particular, overdose of venlafaxine has been reported to cause severe cardiac toxicity including ventricular tachycardia, prolongation of QT interval, and seizure or severe muscular injury. However, reports describing venlafaxine-induced rhabdomyolysis with neuropathy remain scarce. Accordingly, we report such a case involving a 49-year-old woman with bilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose.\nThe patient complained of severe pain and tenderness in both thighs, weakness in both ankle flexor and extensor muscles, and a tingling sensation in the toes of both feet.\nBilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose.\n\n\nMETHODS\nNeedle electromyography revealed fibrillation potentials and positive sharp waves, with absent recruitment in all the major muscles innervating the sciatic nerve bilaterally. Pelvic magnetic resonance imaging was performed after electromyography and revealed multifocal enhancement of signal intensity, suggesting muscle necrosis in the gluteus and thigh muscles, and swelling of both sciatic nerves on short tau inversion recovery (STIR) imaging sequences.\n\n\nRESULTS\nTwo months later, the patient's ankle dorsiflexion strength, measured with manual muscle test, was grade 0/0, and ankle plantar flexion was grade 0/0. The patient reported little sensation at the lateral and posterior aspects of her lower leg, and dorsum and sole of the foot. A follow-up electromyography study revealed improvement in the long head of the right biceps femoris; polyphasic motor unit action potentials with diminished recruitment were observed, but otherwise unchanged.\n\n\nCONCLUSIONS\nWhen encountering patients who have overdosed on venlafaxine, it is very important to detect and treat severe complications such as cardiac toxicity, seizure, and rhabdomyolysis, among others. However, if rhabdomyolysis has already materialized, it should not be forgotten that the secondary damage caused by it. Physicians should rapidly detect and be minimized to mitigate future complications.",
"affiliations": "Department of Rehabilitation Medicine, Chungbuk National University Hospital, Cheongju Department of Rehabilitation Medicine, Daegu Fatima Hospital, Daegu, Republic of Korea.",
"authors": "Ko|Jae Ung|JU|;Seo|Hyeunsuk|H|;Lee|Goo Joo|GJ|;Park|Donghwi|D|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30212953MD-D-18-0337410.1097/MD.0000000000012220122205300Research ArticleClinical Case ReportBilateral sciatic neuropathy with severe rhabdomyolysis following venlafaxine overdose A case reportKo Jae Ung MDaSeo Hyeunsuk MDaLee Goo Joo MDa∗Park Donghwi MDb∗NA. a Department of Rehabilitation Medicine, Chungbuk National University Hospital, Cheongjub Department of Rehabilitation Medicine, Daegu Fatima Hospital, Daegu, Republic of Korea.∗ Correspondence: Goo Joo Lee, Department of Rehabilitation Medicine, Chungbuk National University Hospital 776 1-Sunhwan-ro (Gaeshin-dong), Seowon-gu, Cheongju-si, Chungcheongbuk-do 35015, Republic of Korea (e-mail: gjlee1225@gmail.com); Donghwi Park, Department of Rehabilitation Medicine, Daegu Fatima Hospital, Ayangro 99, Dong gu, Daegu 41199, Republic of Korea (e-mail: bdome@hanmail.net).9 2018 14 9 2018 97 37 e1222013 5 2018 10 8 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nVenlafaxine is an antidepressant and anxiolytic agent that functions by inhibiting central serotonin and norepinephrine reuptake, and it is a relatively recently introduced drug. In particular, overdose of venlafaxine has been reported to cause severe cardiac toxicity including ventricular tachycardia, prolongation of QT interval, and seizure or severe muscular injury. However, reports describing venlafaxine-induced rhabdomyolysis with neuropathy remain scarce. Accordingly, we report such a case involving a 49-year-old woman with bilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose.\n\nPatient concerns:\nThe patient complained of severe pain and tenderness in both thighs, weakness in both ankle flexor and extensor muscles, and a tingling sensation in the toes of both feet.\n\nDiagnoses:\nBilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose.\n\nIntervention:\nNeedle electromyography revealed fibrillation potentials and positive sharp waves, with absent recruitment in all the major muscles innervating the sciatic nerve bilaterally. Pelvic magnetic resonance imaging was performed after electromyography and revealed multifocal enhancement of signal intensity, suggesting muscle necrosis in the gluteus and thigh muscles, and swelling of both sciatic nerves on short tau inversion recovery (STIR) imaging sequences.\n\nOutcomes:\nTwo months later, the patient's ankle dorsiflexion strength, measured with manual muscle test, was grade 0/0, and ankle plantar flexion was grade 0/0. The patient reported little sensation at the lateral and posterior aspects of her lower leg, and dorsum and sole of the foot. A follow-up electromyography study revealed improvement in the long head of the right biceps femoris; polyphasic motor unit action potentials with diminished recruitment were observed, but otherwise unchanged.\n\nLessons:\nWhen encountering patients who have overdosed on venlafaxine, it is very important to detect and treat severe complications such as cardiac toxicity, seizure, and rhabdomyolysis, among others. However, if rhabdomyolysis has already materialized, it should not be forgotten that the secondary damage caused by it. Physicians should rapidly detect and be minimized to mitigate future complications.\n\nKeywords\nrhabdomyolysissciatic neuropathyvenlafaxine hydrochlorideOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nVenlafaxine is a relatively new antidepressant and anxiolytic agent that functions by inhibiting central serotonin and norepinephrine reuptake.[1] There are a few side effects, including tachycardia, fatigue, headache, dizziness, sexual dysfunction, and dry mouth.[1,2] Notably, overdose of venlafaxine has been reported to cause severe cardiac toxicity, including ventricular tachycardia, prolongation of QT interval, and seizure or severe muscular injury.[3,4] Rhabdomyolysis, especially following overdose of venlafaxine, has been repeatedly reported. However, reports describing venlafaxine-induced rhabdomyolysis with neuropathy remain scarce. Accordingly, we report such a case involving a 49-year-old woman with bilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose.\n\n2 Case report\nA 49-year-old woman with depression, sleeplessness, and feelings of helplessness began taking venlafaxine (75 mg) daily 4 months prior to this encounter. She was admitted to hospital with stupor (Glasgow Coma Scale score = 8) 4 hours after ingestion of approximately 40 tablets (total of 3 g) without signs of trauma. She did not take any other medication in this attempted suicide.\n\nInitial vital signs were as follows: arterial blood pressure 101/77 mmHg; heart rate 64 beats/min, respiratory rate 22 breaths/min; and core temperature 34 °C. Electrocardiography revealed QRS duration of 105 ms and prolonged QT interval (0.51 second). Neurological and physical examination revealed reactive mydriasis (5 mm), generalized muscle weakness, and normal tones. Dark urine was revealed upon Foley catheter insertion.\n\nLaboratory findings revealed elevated levels of plasma creatine kinase (CK, 19,090 IU/L), alanine aminotransferase (ALT, 150 IU/L), aspartate aminotransferase (AST, 105 IU/L), a white blood cell count of 23,900/μL, serum calcium (7.0 mg/dL), serum creatinine (0.34 mg/dL), and urine myoglobin (1263 ng/mL). Initially, intravenous normal saline, infused at a rate of 150 mL/h, was started after 300 mL hydration, as was alkalization with bicarbonate infusion; a hot air fan was used to counteract low core temperature.\n\nSix hours later, the patient's mental status improved to lethargic (Glasgow Coma Scale score = 13) and core temperature improved to 36.2 °C. However, arterial blood pressure was low (90/60 mmHg), CK levels were elevated (34,540 IU/L), and oliguria was evident. She was admitted to the intensive care unit with a diagnosis of rhabdomyolysis and underwent continuous renal replacement therapy for 3 days. Subsequently, her mental status fully recovered. Laboratory data were as follows: plasma CK 16,238 IU/L; ALT 242 IU/L; AST 192 IU/L; white blood cell counts 21,960/μL; and urine myoglobin (407 ng/mL). A bone imaging study was conducted with Technetium-99m methylene (Fig. 1A). Three weeks later, all abnormal laboratory findings were normalized.\n\nFigure 1 (A) Diffuse increased muscle uptake in the back, both buttocks, both thighs, and calf area. (B) Axial sort tau inversion recovery image revealing hyperintensity in both hamstrings, adductor muscles, and quadriceps femoris.\n\nThe patient complained of severe pain and tenderness in both thighs, weakness in both ankle flexor and extensor muscles, and a tingling sensation in the toes of both feet. Although swelling was observed in both thighs and buttocks, it was not severe and there was no evidence of arterial insufficiency in both lower extremities in three-dimensional computed tomography angiography. Two weeks later, she was referred to the Department of Rehabilitation for lower leg weakness and gait disturbances. An electrodiagnostic study (Synergy 12.2, VIASYS Healthcare, Warwick, Warwickshire, UK) was performed and the patient was diagnosed with severe bilateral sciatic neuropathy. A nerve conduction study of the upper extremities was normal. The sural and superficial peroneal nerves were bilaterally inexcitable, and the saphenous nerves were unremarkable. Compound muscle action potential was not evoked in the bilateral common peroneal nerve at the tibialis anterior muscle and posterior tibial nerve at the gastrocnemius muscle. There was no response to somatosensory evoked potential in the posterior tibial nerve. Needle electromyography revealed fibrillation potentials and positive sharp waves, with absent recruitment in all the major muscles innervating the sciatic nerve bilaterally (Table 1). Pelvic magnetic resonance imaging was performed after electromyography and revealed multifocal enhancement of signal intensity, suggesting muscle necrosis in the gluteus and thigh muscles, and swelling of both sciatic nerves on short tau inversion recovery imaging sequences (Fig. 1B).\n\nTable 1 Electromyography—lower extremities.\n\nTwo months later, the patient's ankle dorsiflexion strength, measured with manual muscle test, was grade 0/0, long toe extension was grade 0/0, and ankle plantar flexion was grade 0/0. The patient reported little sensation at the lateral and posterior aspects of her lower leg, and dorsum and sole of the foot. A follow-up electromyography study revealed improvement in the long head of the right biceps femoris; polyphasic motor unit action potentials with diminished recruitment were observed, but otherwise unchanged. Informed consent was obtained from the patient for the purpose of publication.\n\n3 Discussion\nIn a case series study, patients with venlafaxine poisoning were divided into 2 groups based on the presence of seizures. Median and interquartile range were as follows: venlafaxine dose was 2800 (2006–4350) mg and the measured serum CK level was 317 (109–588) U/L in the seizure group. Venlafaxine dose was 1500 (900–2700) mg and the measured serum CK level was 91 (61–150) U/L in the non-seizure group.[4] Venlafaxine overdose directly caused skeletal muscle toxicity and severe rhabdomyolysis. In the case of severe rhabdomyolysis, a CK level of 52,600 U/L was measured after the ingestion of 4.5 g of venlafaxine.[5]\n\nIt is also known that muscle necrosis, compartment syndrome, acute renal failure, and peripheral nerve damage occur as major adverse effects of rhabdomyolysis.[6,7] The patient in the present case was not taking any other accompanying medication, was in a drowsy state for a few hours, sustained no direct trauma, and exhibited no evidence of vascular insufficiency in both lower extremity arteries in three-dimensional computed tomography angiography.\n\nAlthough pathogenesis in the present patient was unclear, the most likely diagnosis was compressive neuropathy due to increased tissue gluteal compartment pressure, with rhabdomyolysis and swelling of the gluteal muscles. In this patient, rhabdomyolysis occurred after taking venlafaxine, and it was assumed that additional muscular injury, including postural muscle compressions, may have occurred in the gluteal region while the patient was in an unconscious state and during her stay in the intensive care unit.[8] While the pressure of the gluteal compartment was not measured during the early days of hospitalization, this putative diagnosis was made with consideration of symptoms of pain, tenderness, and sensory depression of both thighs, as well as three-dimensional computed tomography and blood tests. The sciatic nerve does not pass through the fascial compartment, but is known to be vulnerable to swelling of the surrounding muscles as it passes under the gluteus maximus.[8,9]\n\nNevertheless, the possibility of hypoperfusion of the nerves and compromised circulation in the thighs due to increased tissue pressure cannot be completely excluded.[6] The possibility of direct nerve injury due to the drug is unlikely, considering the results of the nerve conduction studies on the upper extremities.\n\nIn this case, the diagnosis was compartment syndrome, and early diagnosis and proper decompression procedure, such as fasciotomy to lower tissue pressure, was performed; it was possible to lessen the severity of nerve injury and increase the probability of better neurological recovery.\n\nThere were some limitations in this case. First, the dose of venlafaxine was dependent on the patient's memory alone. We did not measure the serum concentration of venlafaxine; thus, it is difficult to determine the exact dose of venlafaxine. Nevertheless, it was determined that the patient ingested a sufficient dose to cause rhabdomyolysis. Secondly, a careful neurological examination was not performed at the time of admission to the emergency room. This was because medical treatment was prioritized, focusing on the patient's unconscious state and vital signs. Therefore, it is not known exactly when the patient's neurological symptoms began and how they progressed. Finally, because the pressure in the compartment was not measured, there was weak evidence for a putative diagnosis of compartment syndrome and therapeutic recommendations, including fasciotomy.\n\nWhen encountering patients who have overdosed on venlafaxine, it is very important to detect and treat severe complications, such as cardiac toxicity, seizure, and rhabdomyolysis. However, if rhabdomyolysis has materialized, the secondary damage caused by it should be acknowledged. Physicians should rapidly detect and mitigate future complications.\n\nAuthor contributions\nConceptualization: Goo Joo Lee.\n\nInvestigation: Hyeunsuk Seo.\n\nSupervision: Goo Joo Lee.\n\nWriting – original draft: Jae Ung Ko.\n\nWriting – review & editing: Goo Joo Lee, Donghwi Park.\n\nAbbreviations: ALT = alanine aminotransferase, Amp = amplitude, AST = aspartate aminotransferase, CK = creatine kinase, Dur = duration, Fibs = fibrillation potential, Ins = insertional activity, N = normal, Poly = polyphasic activity, PSW = positive sharp waves, Recr = recruitment, WBC = white blood cell.\n\nGJL and DP are co-corresponding authors.\n\nNo commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated.\n\nThe authors have no conflicts of interest.\n==== Refs\nReferences\n[1] Holliday SM Benfield P \nVenlafaxine. A review of its pharmacology and therapeutic potential in depression . Drugs \n1995 ;49 :280–94 .7729333 \n[2] Pacher P Kecskemeti V \nTrends in the development of new antidepressants. Is there a light at the end of the tunnel? \nCurr Med Chem \n2004 ;11 :925–43 .15078174 \n[3] Cooper JM Brown JA Cairns R \nDesvenlafaxine overdose and the occurrence of serotonin toxicity, seizures and cardiovascular effects . Clin Toxicol (Phila) \n2017 ;55 :18–24 .27622824 \n[4] Wilson AD Howell C Waring WS \nVenlafaxine ingestion is associated with rhabdomyolysis in adults: a case series . J Toxicol Sci \n2007 ;32 :97–101 .17327698 \n[5] Pascale P Oddo M Pacher P \nSevere rhabdomyolysis following venlafaxine overdose . Ther Drug Monit \n2005 ;27 :562–4 .16175126 \n[6] Akmal M Massry SG \nPeripheral nerve damage in patients with nontraumatic rhabdomyolysis . Arch Intern Med \n1983 ;143 :835–6 .6301396 \n[7] Cadnapaphornchai P Taher S McDonald FD \nAcute drug-associated rhabdomyolysis: an examination of its diverse renal manifestations and complications . Am J Med Sci \n1980 ;280 :66–72 .7435519 \n[8] Adrish M Duncalf R Diaz-Fuentes G \nOpioid overdose with gluteal compartment syndrome and acute peripheral neuropathy . Am J Case Rep \n2014 ;15 :22–6 .24459539 \n[9] David V Thambiah J Kagda FH \nBilateral gluteal compartment syndrome. A case report . J Bone Joint Surg Am \n2005 ;87 :2541–5 .16264132\n\n",
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"mesh_terms": "D018687:Antidepressive Agents, Second-Generation; D062787:Drug Overdose; D004576:Electromyography; D005260:Female; D006801:Humans; D008875:Middle Aged; D012206:Rhabdomyolysis; D020426:Sciatic Neuropathy; D012720:Severity of Illness Index; D000069470:Venlafaxine Hydrochloride",
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"title": "Bilateral sciatic neuropathy with severe rhabdomyolysis following venlafaxine overdose: A case report.",
"title_normalized": "bilateral sciatic neuropathy with severe rhabdomyolysis following venlafaxine overdose a case report"
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"abstract": "Adverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkin's lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkin's lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation.\n\n\n\nWe recruited female participants from the randomised phase 3 RATHL trial, aged 18-45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkin's lymphoma, stage IIB-IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0-3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327.\n\n\n\nBetween Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3-17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07-0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37-0·65; p<0·0001).\n\n\n\nReduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes.\n\n\n\nMedical Research Foundation and Cancer Research UK.",
"affiliations": "MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK. Electronic address: richard.anderson@ed.ac.uk.;Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UK.;Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UK.;Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UK.;Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UK.;Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UK.;Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UK.;Department of Haematology, Oxford University Hospitals, Oxford, UK.;Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre, Liverpool, UK.;Centre for Haematology and Stem Cell Transplantation, Heart of England NHS Foundation Trust, Birmingham, UK.;Department of Haematology, Beatson West of Scotland Cancer Centre, Glasgow, UK.;Department of Haematology, University Hospital of Wales, Cardiff, UK.;Department of Haematology, Western General Hospital, Edinburgh, UK.;Cancer Research UK Centre, Southampton General Hospital, University of Southampton, Southampton, UK.",
"authors": "Anderson|Richard A|RA|;Remedios|Rachel|R|;Kirkwood|Amy A|AA|;Patrick|Pip|P|;Stevens|Linsey|L|;Clifton-Hadley|Laura|L|;Roberts|Tom|T|;Hatton|Chris|C|;Kalakonda|Nagesh|N|;Milligan|Don W|DW|;McKay|Pam|P|;Rowntree|Clare|C|;Scott|Fiona M|FM|;Johnson|Peter W M|PWM|",
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"doi": "10.1016/S1470-2045(18)30500-X",
"fulltext": "\n==== Front\nLancet OncolLancet OncolThe Lancet. Oncology1470-20451474-5488Lancet Pub. Group S1470-2045(18)30500-X10.1016/S1470-2045(18)30500-XArticleDeterminants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial Anderson Richard A ProfMDrichard.anderson@ed.ac.uka*Remedios Rachel MScbKirkwood Amy A MScbPatrick Pip PhDbStevens Linsey bClifton-Hadley Laura PhDbRoberts Tom MScbHatton Chris MDcKalakonda Nagesh PhDdeMilligan Don W ProfMDfMcKay Pam MBChBgRowntree Clare PhDhScott Fiona M MDiJohnson Peter W M ProfMDja MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UKb Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UKc Department of Haematology, Oxford University Hospitals, Oxford, UKd Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UKe Clatterbridge Cancer Centre, Liverpool, UKf Centre for Haematology and Stem Cell Transplantation, Heart of England NHS Foundation Trust, Birmingham, UKg Department of Haematology, Beatson West of Scotland Cancer Centre, Glasgow, UKh Department of Haematology, University Hospital of Wales, Cardiff, UKi Department of Haematology, Western General Hospital, Edinburgh, UKj Cancer Research UK Centre, Southampton General Hospital, University of Southampton, Southampton, UK* Correspondence to: Prof Richard A Anderson, MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK richard.anderson@ed.ac.uk1 10 2018 10 2018 19 10 1328 1337 © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY-NC-ND 4.0 license2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Summary\nBackground\nAdverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkin's lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkin's lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation.\n\nMethods\nWe recruited female participants from the randomised phase 3 RATHL trial, aged 18–45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkin's lymphoma, stage IIB–IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0–3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327.\n\nFindings\nBetween Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3–17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07–0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37–0·65; p<0·0001).\n\nInterpretation\nReduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes.\n\nFunding\nMedical Research Foundation and Cancer Research UK.\n==== Body\nIntroduction\nHodgkin's lymphoma is predominantly a cancer of young adult life, occurring at a median age of 35 years. Systemic treatment for this condition has evolved from chemotherapy regimens based on alkylating agents, which had a high risk of infertility and premature ovarian insufficiency in women, to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which is the current treatment of choice for many adult patients with Hodgkin's lymphoma. ABVD results in a disease-free survival of 75%,1 and with less gonadotoxicity than previous treatments.2 Increasing evidence supports that treatment intensification could benefit patients who are at higher risk of relapse, and some clinicians advocate treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP) for patients with advanced stage or high-risk early stage disease. However, female gonadal toxicity is high with dose-escalated BEACOPP resulting in amenorrhoea (a surrogate marker of premature ovarian insufficiency) in about 95% of patients older than 30 years.3\n\nResearch in context\nEvidence before this study\n\nChemotherapy regimens are associated with toxic effects on human ovaries, manifesting as premature ovarian insufficiency, infertility, and reduced reproductive lifespan. Therefore, accurate assessment of the ovarian toxicity of widely used chemotherapy regimens is needed. We searched PubMed for articles published in English between inception and March 12, 2018, using the terms “ovary”, “ovarian reserve”, “chemotherapy”, and “cancer”. We found little data from prospective studies that used current biomarkers of ovarian function. Both age and ovarian reserves before treatment are predictive of ovarian recovery after chemotherapy with some regimens, but their importance is unknown for treatments for patients with Hodgkin's lymphoma.\n\nAdded value of this study\n\nWe found that changes in antimüllerian hormone concentration could distinguish between the effects of treatment on ovarian function with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD, and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP) in patients with advanced Hodgkin's lymphoma, particularly from 3 years of follow-up after chemotherapy. Treatment with ABVD or AVD was confirmed to have little gonadotoxcity in female patients with Hodgkin's lymphoma who were younger than 35 years at diagnosis; however, in older patients (≥35 years) recovery of ovarian function was affected by age. We found that among older women baseline concentrations of antimüllerian hormone did not affect recovery, so reduced hormone recovery in older women was not due to the age-related decline in ovarian reserve. Little recovery in ovarian function was seen after treatment with BEACOPP in women of all ages, although a similar number of pregnancies was observed in the two treatment groups. Due to the small size of the cohorts analysed, these results warrant further confirmation.\n\nImplication of all the available evidence\n\nThe absence of detectable ovarian damage after treatment with ABVD or AVD in younger women with Hodgkin's lymphoma is reassuring, although longer follow-up is needed in future studies for a full assessment of potential reproductive effects. Antimüllerian hormone is not a predictor of short-term fertility. The finding of reduced ovarian recovery in older women with Hodgkin's lymphoma treated with chemotherapy indicates that age-specific discussions and consideration of fertility preservation procedures should be considered before treatment. These considerations are of growing importance given the increasing age at which women are having children in developed countries.\n\n\n\nAnalysis of the effects of cancer therapies on the ovaries requires consideration of both the degree of loss of ovarian function during chemotherapy and changes in ovarian function thereafter. The degree of loss of the primordial follicle pool (the ovarian reserve) during chemotherapy is the most important effect since it determines the potential for any recovery of ovarian function and fertility, and subsequent age at menopause, although the degree of loss cannot be assessed in vivo. Additional effects of chemotherapy might be seen on the non-follicular components of the ovary, including the stroma and vasculature.4 Few prospective analyses have been done of ovarian function from the time of diagnosis and before chemotherapy.5, 6, 7, 8, 9 Most larger studies use amenorrhoea to indicate loss of ovarian function,3 and so are unable to differentiate between women who have largely intact remaining ovarian function and those who have lost most of their ovarian reserve and will soon become menopausal and infertile.2, 10 Although measurement of follicle-stimulating hormone concentration is central to the diagnosis of premature ovarian insufficiency, the hormone has substantial variation during the menstrual cycle, complicating its use to measure ovarian reserve in women with ovarian activity.11 Analysis of concentrations of serum antimüllerian hormone as an indirect biomarker of the ovarian reserve has become increasingly valuable for women with ovarian activity.12 Antimüllerian hormone concentrations decrease during chemotherapy in girls and women, with variable recovery after treatment reflecting the gonadotoxicity of each regimen.5, 6, 7, 8 In the past 5 years, refinements in assay methods have improved their sensitivity, and thus their ability to detect low circulating concentrations of antimüllerian hormone in women after chemotherapy, which were previously undetectable.13, 14 How the pretreatment ovarian reserve and the patient's age influence recovery of ovarian function after chemotherapy is unclear, with most data derived from women who have been treated for breast cancer.5, 9, 15, 16 In this study, we aimed to determine the effect of response-adapted chemotherapy regimens on ovarian function in adult women with Hodgkin's lymphoma, since they are both a younger population and often treated with less gonadotoxic drugs than women with breast cancer.\n\nMethods\nStudy design and participants\nIn this prospective cohort study, participants were recruited from the RATHL trial, which used PET-CT to guide response-adapted chemotherapy, for patients with advanced Hodgkin's lymphoma (appendix p 1).17 Recruitment for RATHL was open in hospitals across the UK, Italy, Norway, Sweden, Denmark, Australia, and New Zealand from Aug 29, 2008, to Dec 21, 2012. RATHL inclusion criteria were histologically confirmed classic Hodgkin's lymphoma according to the WHO classification; age 18 years or older; stage IIB–IV or IIA with adverse features (such as bulky disease or more than two sites of involvement); no previous treatment with chemotherapy, radiotherapy, or investigational treatments for Hodgkin's lymphoma; performance status 0–3 (according to WHO criteria); adequate bone marrow function; creatinine less than 150% of the upper limit of normal (ULN); bilirubin concentration less than two times ULN; aminotransferase concentration less than 2·5 times ULN; and life expectancy of more than 3 months. The full eligibility criteria for the RATHL trial are available in the protocol.\n\nFor this prospective cohort substudy, women and aged 18–45 years (ie, premenopausal) were actively recruited from RATHL sites in the UK (appendix pp 3–5). The protocol for the substudy is available online.\n\nThis cohort substudy received centralised ethical committee approval that covered all sites (National Research Ethics Service, Southampton and South West Hampshire) and all participants gave written informed consent.\n\nProcedures\nIn the RATHL study, after initial staging and a baseline PET-CT scan, participants were treated with two cycles of ABVD, intravenously, on days 1 and 15 of a 28 days cycle followed by an interim PET-CT scan (doses and schedule in the appendix [p 2]). Participants who had negative interim scans by central review (PET score of 1 to 3 per Lugano criteria) were randomly assigned (1:1) by the Cancer Research UK and University College London Cancer Trials Centre using minimisation, with stratification according to PET score (1, 2, or 3) and centre, to continue ABVD (intravenously, days 1 and 15) or to receive doxorubicin, vinblastine, and dacarbazine (AVD; intravenously, days 1 and 15) for four more cycles. Since randomisation was done centrally, concealment of assignment was not an issue. Participants with positive scans (PET score of 4 or 5) were escalated to either BEACOPP-14 for six cycles of 14 days or escalated BEACOPP for four cycles (doses and schedule in the appendix [p 2]). Neither patients nor study staff were masked to allocation.\n\nOvarian function was assessed by use of serum concentrations of antimüllerian hormone in participants enrolled into this substudy and follicle-stimulating hormone concentrations from all eligible participants (women and aged 18–45 years) from the RATHL trial. Luteinising hormone and oestradiol measurements were also taken. Oestradiol measurements are necessary for the identification of women with premature ovarian insufficiency.11\n\nDuring the RATHL trial, blood samples were taken before any treatment, after two cycles of initial ABVD treatment, at the end of chemotherapy, and at 1, 2, and 3 years after chemotherapy. Samples taken after participants showed disease progression and required additional treatment were excluded from both analyses reported here. Sampling was not timed by the participant's stage of menstrual cycle. Follicle-stimulating hormone measurements were done locally as part of the RATHL trial; additional samples from participants enrolled in this substudy were taken to measure antimüllerian hormone, follicle-stimulating hormone, luteinising hormone, and oestradiol concentrations by use of Roche Elecsys assays (automated cobas e 411 analyser, Roche, Burgess Hill, UK). The substudy samples were sent by post to a central laboratory (MRC Centre for Reproductive Health, Edinburgh), where the serum was stored at −20°C until analysis. The antimüllerian hormone assay has a limit of detection of 0·07 pmol/L, and for all assays the interassay and intra-assay coefficients of variation were below 5%. A follicle-stimulating hormone threshold of more than 25 IU/L indicated probable premature ovarian insufficiency.11\n\nAfter recovery from chemotherapy, antimüllerian hormone was additionally analysed in association with predictors from before treatment, specifically age and antimüllerian hormone concentration. Antimüllerian hormone recovery was calculated at 2 years after chemotherapy to allow full recovery of ovarian function but minimise any age-related changes. The study was not designed to assess fertility, and menstrual bleeding was not recorded since it does not help to distinguish between women with normal ovarian function and those with very depleted ovarian reserves.\n\nData on previous pregnancy or use of hormonal contraceptives were only collected from participants enrolled in the ovarian function substudy. Decisions regarding fertility preservation procedures were between the participant and the local centre, and were not recorded as part of the study.\n\nOutcomes\nThe primary outcome of this study, specified as an exploratory outcome in the RATHL trial, was assessment of gonadal function. The prespecified outcomes in this substudy were analysis of acute toxic effects of each treatment regimen on the ovaries, and ovarian function after treatment (including progression to ovarian failure and recovery of ovarian function). Other prespecified outcomes were the association between fertility after treatment and ovarian function before treatment, degree of acute ovarian toxic effects, which will be reported separately.\n\nStatistical analysis\nAs a secondary analysis of the RATHL trial, the prespecified exploratory analyses presented here are not powered; we aimed to recruit as many patients as possible while the RATHL trial was open. We hypothesised that antimüllerian hormone concentrations could show differences between the gonadotoxicity of the chemotherapy regimens in the RATHL trial, both during and after treatment, and that concentrations of antimüllerian hormone before treatment would be predictive of recovery of ovarian function after treatment. We analysed antimüllerian hormone and follicle-stimulating hormone concentrations in the ovarian subgroup after log transformation using ANOVA with Bonferroni's multiple comparisons test for changes during treatment and recovery. We calculated Pearson correlation coefficients and used multiple linear regression without transformation to analyse age and before treatment concentration of antimüllerian hormone against percentage hormone recovery (calculated as [concentration at 2 years÷concentration before treatment] x 100) and against concentration at 2 years. We used the Mann-Whitney U test to compare hormone concentrations between the treatment groups. We analysed proportions of participants using Fisher's exact test to determine the number of women who had a pregnancy after chemotherapy. We measured follicle-stimulating hormone recovery using Cox regression and Kaplan-Meier survival analysis. We measured time to recovery (follicle-stimulating hormone concentration of ≤25 IU/L) from the end of treatment until the first follicle-stimulating hormone measurement of 25 IU/L or less, or a reported pregnancy (whichever came first). Patients with follicle-stimulating hormone concentrations of more than 25 IU/L at baseline were excluded, and patients who had neither event were censored at the last reported follicle-stimulating hormone measurement. Any measurements recorded after disease progression were excluded from all analyses because patients would have been exposed to further treatment at this point. We tested the assumption of proportional hazards using Schoenfeld residuals, and when it did not hold we used restricted mean survival times with a 3 year cutoff. All p values are two-sided and a p value of less than 0·05 was considered statistically significant.\n\nData analyses were done in STATA (version 15.1) and Graphpad Prism 7. The RATHL trial is registered with ClinicalTrials.gov, number NCT00678327.\n\nRole of the funding source\nThe funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. RAA, AAK, and PWMJ had access to the raw data. The corresponding author had final responsibility for the decision to submit for publication.\n\nResults\nBetween Dec 13, 2010, and Dec 19, 2012, participants from the RATHL trial were recruited for this ovarian function substudy (figure 1; appendix p 3). 115 (9%) of 1214 participants in the RATHL trial were eligible for the substudy, of whom 74 (69%) registered. Seven (10%) of 74 registered participants were excluded from the substudy and the main trial, six for scan protocol deviations, and one for psychological reasons, leaving 391 (94%) of 415 eligible (18–45 years) female RATHL participants, of whom 321 (82%) were evaluable for follicle-stimulating hormone analyses, and 67 (91%) were evaluable for substudy analyses. Of the 67 evaluable participants for the substudy analyses, 24 (36%) had been treated with ABVD, 33 (49%) with AVD, four (6%) with BEACOPP-14, and six (9%) with escalated BEACOPP. No difference in baseline hormone concentrations were found between participants treated with ABVD versus AVD, or BEACOPP-14 versus escalated BEACOPP (table); thus these subgroups were combined as ABVD-AVD (n=57) and BEACOPP (n=10), respectively, for subsequent analyses. The baseline characteristics of the participants who had follicle-stimulating hormone measurements from the RATHL trial, and the combined ABVD-AVD and BEACOPP subgroups evaluated in this substudy are in the table.Figure 1 Study profile\n\nRATHL trial and ovarian function substudy participants who contributed to analysis. ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine. BEACOPP=bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone. FSH=follicile-stimulating hormone.\n\nTable Baseline characteristics\n\n\t\tOvarian function substudy cohorts\tRATHL trial cohorts\t\n\t\tABVD-AVD group (n=57)\tBEACOPP group (n=10)\tABVD group (n=165)\tAVD group (n=171)\tBEACOPP-14 group (n=27)\tEscalated BEACOPP group (n=28)\t\nAge, years\t26 (18–44)\t31 (19–43)\t27 (18–44)\t28 (18–44)\t24 (18–44)\t35 (18–43)\t\nInternational prognostic index of 3 or more\t4 (7%)\t4 (40%)\t33 (20%)\t24 (14%)\t9 (33%)\t7 (25%)\t\nWHO performance status\t\n\t0\t47 (82%)\t7 (70%)\t123 (75%)\t143 (84%)\t20 (74%)\t20 (74%)*\t\n\t1\t9 (16%)\t2 (20%)\t34 (21%)\t26 (15%)\t7 (26%)\t6 (22%)*\t\n\t2\t1 (2%)\t1 (10%)\t4 (2%)\t2 (1%)\t0\t1 (4%)\t\n\t3\t0\t0\t4 (2%)\t0\t0\t0\t\nStage\t\t\t4 (2%)\t\t\t\t\n\tII\t34 (60%)\t3 (30%)\t90 (55%)\t86 (50%)\t14 (52%)\t11 (39%)\t\n\tIII\t9 (16%)\t1 (10%)\t37 (22%)\t46 (27%)\t2 (7%)\t7 (25%)\t\n\tIV\t14 (25%)\t6 (60%)\t38 (23%)\t39 (23%)\t11 (41%)\t10 (36%)\t\nPrevious pregnancy\t16 (28%)\t7 (70%)\t..\t..\t..\t..\t\nHormonal contraception at baseline\t17 (30%)\t3 (30%)\t..\t..\t..\t..\t\nBaseline antimüllerian hormone, pmol/L\t9·8 (5·9–18·1)\t6·8 (2·2–12·8)\t..\t..\t..\t..\t\nBaseline follicle-stimulating hormone concertation, IU/L\t4·6 (0·3–12)\t5·7 (1·9–21·8)\t4·4 (0·1–48·7)\t4·7 (0·1–50·7)\t5·7 (0·3–26·5)\t3·6 (0·1–35·7)\t\nData are median (range) or n (%) unless otherwise stated. RATHL trial cohort data are for women younger than 45 years included in this study. ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine. BEACOPP= bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone.\n\n* One patient in this group had a missing performance status.\n\n\n\nFor nine participants in the substudy, data at post-baseline timepoints were not available because of disease progression and further treatment (six in the ABVD-AVD group, three in the BEACOPP group), and 13 blood samples were missing or taken at incorrect timepoints. Eight blood samples taken from eight women during pregnancy in the ovarian subgroup were excluded from analysis.\n\nAntimüllerian hormone concentrations decreased in all participants during chemotherapy treatment with reciprocal increases in follicle-stimulating hormone concentrations (figure 2). In the ABVD-AVD group, concentrations of antimüllerian hormone decreased from a median of 9·8 pmol/L (IQR 5·9–18·1) before treatment to 1·7 pmol/L (IQR 0·4–4·3) at the end of treatment (p<0·0001), with a small rise between cycle two of initial ABVD treatment and the end of treatment (p<0·0001). After chemotherapy in the ABVD-AVD group, concentrations of antimüllerian hormone increased to 10·5 pmol/L (IQR 4·3–17·3) at 1 year, similar to concentrations before treatment, with no change at later timepoints (figure 2). Antimüllerian hormone was undetectable in two (4%) of 56 participants at the end of treatment with follicle-stimulating hormone concentration higher than 25 IU/L and low oestradiol concentrations indicating premature ovarian insufficiency. For one of these participants, antimüllerian hormone became detectable during recovery, and for the other, antimüllerian hormone showed a transient recovery at 1 year after treatment, becoming undetectable thereafter.Figure 2 Ovarian function biomarkers at prespecified timepoints per treatment group\n\n(A) Concentrations of antimüllerian hormone and (B) follicle-stimulating hormone. All participants included in the substudy were analysed (ABVD-AVD group, n=57; BEACOPP group, n=10). Boxes are median and IQR, bars are ranges. Panel A is plotted on a log10 scale to clearly show the low concentrations seen in the BEACOPP group. ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine. BEACOPP=bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone.\n\n\n\nIn the BEACOPP group, concentrations of antimüllerian hormone decreased from a median of 6·8 pmol/L (IQR 2·2–12·8) before treatment to 0·08 pmol/L (0·07–0·24) at the end of treatment (p<0·0001; figure 2). After treatment, by contrast with participants in the ABVD-AVD group, concentrations of antimüllerian hormone showed very little recovery (median 0·11 pmol/L [IQR 0·07–0·20] at 1 year) and were undetectable in five (71%) of seven participants at 3 years (figure 2A).\n\nFollicle-stimulating hormone concentrations had generally reciprocal changes compared with concentrations of antimüllerian hormone and increased during treatment in both groups (figure 2B). Subsequently, in the ABVD-AVD group concentrations of follicle-stimulating hormone decreased to levels similar to before treatment at years 1 to 3 after treatment. However, in the BEACOPP group, follicle-stimulating hormone concentrations did not decrease in the follow-up period. Concentrations of luteinising hormone showed the same pattern of changes, increasing from before treatment to the end of treatment in both groups (both p<0·0001) and then recovering after treatment to before-treatment concentrations in the ABVD-AVD group, but remaining significantly increased after treatment in the BEACOPP group (data not shown).\n\nBoth antimüllerian hormone concentration 2 years after treatment and follicle-stimulating hormone recovery data provide evidence of the effect of age on ovarian recovery in women treated with ABVD or AVD (Figure 3, Figure 4). We saw a correlation between the concentration of antimüllerian hormone before treatment and at 2 years after treatment (r=0·89; p<0·0001) but not with antimüllerian hormone recovery (r=–0·30; p=0·051). However, significant and similar negative correlations were seen between age and antimüllerian hormone concentrations at 2 years (r=–0·40; p=0·0055) and with antimüllerian hormone recovery (r=–0·40; p=0·0080). This negative effect of age on recovery was supported by mean concentrations of antimüllerian hormone at recovery, with participants younger than 35 years showing complete recovery at 127% (SD 12; median 10·0 pmol/L [IQR 7·5–21·1] before treatment vs 13·4 pmol/L [7·1–22·3] at 2 years), whereas concentrations in those aged 35 years and older had incomplete recovery (37% [SD 10]; ≤35 years, median 5·7 pmol/L [IQR 2·1–9·7] before treatment vs 1·4 pmol/L [0·2–4·2]) at 2 years; for comparison of age groups p<0·0001). Analysis of antimüllerian hormone concentrations before treatment grouped by whether they were below or above the overall median value (9·77 pmol/L [IQR 5·9–18·1]) showed that recovery was similar between the two groups (below 123% [SD 21] vs above 103% [SD 9]; p=0·85). Multiple linear regression analysis also confirmed that age had a significant effect on antimüllerian hormone recovery (β=–0·43; p=0·004), but that antimüllerian hormone concentrations before treatment did not have an effect on hormone recovery (β=–0·15, p=0·30). Thus, although overall concentrations of antimüllerian hormone after treatment seem to recover to before treatment concentrations, the degree of recovery is restricted by increasing age.Figure 3 Correlations of antimüllerian hormone recovery and before treatment hormone concentrations or age for the ABVD-AVD group\n\nPanels show scatter plots of baseline hormone concentration versus concentration at 2 years (A) and versus percentage hormone recovery (B), and age versus hormone concentration at 2 years (C) and percentage hormone recovery (D). All patients in the ABVD-AVD group of the substudy included. Each dot shows antimüllerian hormone concentration or recovery; recovery was calculated for each participant as the concentration at 2 years after treatment as a proportion of the concentration before treatment. In the case of missing data, recovery could not be calculated. Dotted ine shows linear regression. ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine.\n\nFigure 4 Recovery of follicle-stimulating hormone concentrations after the end of treatment in evaluable patients from the RATHL trial\n\nKaplan-Meier curves shows recovery of follicle-stimulating hormone concentrations per treatment group (A) and by age group (B). Evaluable female participants (n=391) were divided by chemotherapy regimen received: ABVD or ABVD followed by AVD (ABVD-AVD group), and ABVD followed by BEACOPP-14 or escalated BEACOPP (BEACOPP group). ABVD=doxorubicin, bleomycin, vinblastine, and dacarbazine. AVD=doxorubicin, vinblastine, and dacarbazine. BEACOPP=bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. HR=hazard ratio.\n\n\n\nWe also assessed the degree and timecourse of recovery of ovarian function, as indicated by normalisation of follicle-stimulating hormone concentrations, in the evaluable participants from the RATHL trial (figure 4). Follicle-stimulating hormone measurements after treatment were available from 321 women in the RATHL trial, with a median follow-up (censoring at recovery) of 59·3 months (IQR 41·9–60·9). Follicle-stimulating hormone concentration recovery to 25 IU/L or lower was seen in 270 (96%) of 282 of participants treated with ABVD or AVD, compared with 26 (67%) of 39 treated with BEACOPP-14 or escalated BEACOPP (hazard ratio [HR] 0·37, 95% CI 0·25–0·56; p=0·0001). The assumption of proportional hazards did not hold for this comparison so a better estimate is given by the restricted mean survival (recovery) times (areas under the curves up to 3 years), which are 208·9 days for ABVD or AVD and 529·9 days for BEACOPP (p<0·0001)—ie, patients treated with ABVD or AVD have a mean recovery time of 321·0 days (95% CI 205·7–436·4) less than those treated with BEACOPP. Kaplan-Meier estimates for participants treated with ABVD or AVD were 75% (95% CI 70–80) 1 year after treatment and 93% (89–95) 2 years after treatment, whereas the estimates for those treated with BEACOPP were 33% (20–52) 1 year after treatment and 69% (52–84) 2 years after treatment. The relative difference in ovarian function (between ABVD or AVD and BEACOPP) did not differ when analysed by age (<35 years, HR 0·38, 95% CI 0·23–0·62; p=0·0001 vs ≥35 years, HR 0·40, 0·19–0·83; p=0·011). This pattern was also found when analysed by use of restricted mean survival (recovery) times (<35 years, 154·6 days for ABVD or AVD and 446·5 days for BEACOPP [difference: 291·9 days, 95% CI 163·4–420·4; p<0·0001] vs ≥35 years, 361·5 days for for ABVD or AVD and 663·4 days for BEACOPP [difference 301·9 days, 95% CI 94·1–509·7; p=0·005]). However, age seemed to affect time to recovery among these participants, with a smaller proportion of those aged 35 years or older showing recovery at both 1 year (41 [50%]) and 2 years (64 [79%]) after treatment than those younger than 35 years did (176 [79%] at 1 year and 211 [95%] at 2 years after treatment; HR 0·49, 95% CI 0·37–0·65; p<0·0001). Thus, the Kaplan-Meier estimates for follicle-stimulating hormone concentration recovery for those younger than 35 years treated with ABVD or AVD were 83% (95% CI 77–88) at 1 year and 96% (93–98) at 2 years compared with estimates for those aged 35 years and older of 54% (43–66) at 1 year and 83% (73–91) at 2 years. The proportions were similar between the age groups at 3 years (<35 years 98% [95–99] vs ≥35 years 93% [85–97]). We saw no difference in follicle-stimulating hormone recovery between participants treated with escalated BEACOPP or BEACOPP-14 for all ages (HR 0·72, 95% CI 0·33–1·56).\n\nIn the RATHL cohort, 64 (16%) of 391 participants were recorded as having 81 pregnancies. Median follow-up for the 91 patients was 52 months (IQR 42–64). 57 (17%) participants in the ABVD-AVD group had 71 pregnancies and seven (13%) participants in the BEACOPP group had ten pregnancies. These proportions were not substantially different. In the subgroup cohort, antimüllerian hormone measurements were available within the follow-up period for six women who became pregnant in the ABVD-AVD group and two in the BEACOPP group. At 1 year after chemotherapy, concentrations of antimüllerian hormone ranged from 0·74 pmol/L to 26·9 pmol/L in those who became pregnant in the ABVD-AVD group, and were 0·19 pmol/L and 0·20 pmol/L in those in the BEACOPP group. Two women, one in each treatment group, had undetectable antimüllerian hormone, high follicle-stimulating hormone, and low oestradiol concentrations after the recorded pregnancy, consistent with development of premature ovarian insufficiency within 3 years of chemotherapy treatment.\n\nAdverse event data were reported in detail previously,17 but they did not include any data on ovarian function or fertility. The main study17 found an excess of grade 3–4 toxic effects from BEACOPP regimens, specifically febrile neutropenia and thrombocytopenia.\n\nDiscussion\nIn this prospective cohort study, we have shown that antimüllerian hormone concentrations decrease in women with Hodgkin's lymphoma who are treated with ABVD, AVD, or BEACOPP (BEACOPP-14 or escalated BEACOPP), and although antimüllerian hormone concentrations recover to baseline concentrations after treatment with ABVD or AVD, little recovery is seen after treatment with BEACOPP. However, we found that recovery of ovarian function after treatment with ABVD or AVD is dependent on age, with full recovery of antimüllerian hormone seen in participants younger than 35 years, but not in women aged 35 years or older. We found that recovery of follicle-stimulating hormone after these two chemotherapy regimens also differed in both speed and extent. Follicle-stimulating hormone recovery after treatment with ABVD or AVD was slower in women aged 35 years or older than in those younger than 35 years, and the extent of recovery was much lower for those treated with either BEACOPP regimen, supporting the increased ovarian toxicity of this drug combination. The greater toxicity to other organ systems is also reflected in the higher incidence of febrile neutropenia and thrombocytopenia with BEACOPP.\n\nThe potential adverse effect of chemotherapy on ovarian function in women with Hodgkin's lymphoma is of major concern, affecting fertility, sexual and bone health, and cardiovascular risk. Potential loss of fertility is a key concern of young women treated for cancer18 and, when appropriate, options for fertility preservation have been established; thus, the accurate assessment of the effect of different chemotherapy regimens is of substantial importance. Assessment of ovarian function after treatment via menstrual function and traditional biomarkers such as follicle-stimulating hormone are not of value in detecting ovarian damage that has resulted in incomplete loss of ovarian function. Measurement of concentrations of antimüllerian hormone has emerged as a reliable biomarker to detect partial loss of ovarian function in women after cancer therapy, with the additional advantages of showing little variation across the menstrual cycle.12 Although most data are from women after treatment for breast cancer and childhood cancer,5, 7, 8 we have shown the merit of antimüllerian hormone measurements in the assessment of ovarian function in adult women with Hodgkin's lymphoma. Specifically, younger women treated with ABVD or AVD showed full initial recovery of antimüllerian hormone after chemotherapy, consistent with previous data2 that indicate that this regimen has little effect on age at menopause, but reduced recovery was seen in women aged 35 years or older at diagnosis. By contrast, treatment with BEACOPP resulted in noticeable and irreversible decreases in antimüllerian hormone concentrations, so low in many women that the hormone was undetectable after treatment even with the highly sensitive assay we used. However, the number of participants we analysed was small, which should inform interpretation of tests of significance. Participants received either escalated BEACOPP or BEACOPP-14, a dose-intense version that appears to be similarly gonadotoxic to baseline BEACOPP.3 Our data support this similarity, although the confidence intervals in our estimates were wide.\n\nAntimüllerian hormone concentrations decreased quickly during treatment with both regimens, consistent with both treatments resulting in loss of the growing follicles that are the source of antimüllerian hormone. After the initial decrease, a small partial recovery in antimüllerian hormone was seen after two cycles in women treated with ABVD or AVD during later treatment cycles. This finding is consistent with increased activation of early follicles during chemotherapy resulting from reduced inhibition of growth initiation, which is proposed to be part of the mechanism for chemotherapy-induced premature ovarian insufficiency. This mechanism has been shown for high toxicity, cyclophosphamide-based regimens,19 but has not previously been identified for low toxicity regimens such as ABVD or AVD.\n\nThe degree of recovery of antimüllerian hormone after treatment with ABVD or AVD in young women could indicate a low toxic effect on the non-growing primordial follicle pool, which constitutes the true ovarian reserve and is the basis for after treatment fertility and the duration of the female reproductive lifespan. Under physiological conditions, antimüllerian hormone concentrations reflect the size of the primordial follicle population, although this population size can be perturbed under circumstances such as a new diagnosis of lymphoma.20 However, the 3-year follow-up period in this study is likely to have been sufficient for full recovery of ovarian function and therefore restoration of physiological associations between antimüllerian hormone and the ovarian reserve. We saw a prominent effect of age on recovery, with substantially lower recovery in women aged 35 years or older than in those younger than 35 years, independent of their antimüllerian hormone concentration before treatment. This finding indicates an effect either of age alone or of age in addition to the effects of ABVD or AVD that result in a substantial decrease in the size of the growing follicle population, and by implication of the non-growing population, after treatment. Chemotherapy has been shown to affect both the stroma and vasculature of the human ovary, causing fibrosis and hyalinisation of small vessels with loss of primordial follicles within areas of damage.4 Changes in ovarian stromal function with age include fibrosis and other hallmarks of chronic inflammation, such as the presence of macrophages,21 and can impair follicle development.22 These changes could be reversed by gonadotropin suppression,22 indicating that the increases in concentrations of luteinising hormone and follicle-stimulating hormone during chemotherapy shown here could be of aetiological importance, and the pre-existing more fibrotic stroma in older women could be more susceptible to chemotherapy-induced changes than the stroma in younger women, even with so-called low gonadotoxicity regimens such as ABVD or AVD. These age-associated effects of chemotherapy could have therapeutic implications and be part of the mechanism of action of gonadotropin-releasing hormone agonists to reduce the risk of premature ovarian insufficiency after chemotherapy for breast cancer,23, 24 although this effect has not been confirmed for women treated for lymphoma.25\n\nThe effect of age on recovery of ovarian function after both regimens, and the different toxic effects of each regimen on the ovaries, is also supported by our analysis of follicle-stimulating hormone recovery in the whole RATHL study cohort. In this analysis, follicle-stimulating hormone was dichotomised at a value consistent with premature ovarian insufficiency.11 In addition to confirming the effect of age on recovery from treatment with ABVD or AVD, our analysis showed clear differences in both the speed and extent of recovery between regimens, supporting the antimüllerian hormone data. Follicle-stimulating hormone concentrations are affected to a much greater extent than antimüllerian hormone concentrations by changes across the menstrual cycle and use of hormonal contraception, but our analysis shows measurement of follicle-stimulating hormone concentrations is of value in large cohorts in which more detailed characterisation is difficult.\n\nPrevious analyses in women with breast cancer have shown that receiving treatment at a young age and high concentrations of antimüllerian hormone before treatment are predictive of recovery of ovarian function after chemotherapy, albeit with variable relative contributions.5, 9, 14, 15 Women with breast cancer are generally older (approximate mean age 40 years5, 9, 14, 15) than those with Hodgkin's lymphoma and treatment involves more gonadotoxic alkylating agent-based regimens, resulting in a high probability of premature loss of ovarian function, particularly in women older than 40 years. These differences emphasise the need for defined populations and treatment regimens to analyse the toxic effects of chemotherapeutic regimens on the ovaries and, particularly, recovery.\n\nThe data in this study support the paucity of the value of current ovarian reserve markers for the prediction of fertility in the short term, because very low concentrations of antimüllerian hormone did not preclude chances of pregnancy. The lack of predictive value of antimüllerian hormone measurements for short term fertility has been shown in prospective cohorts of women mostly in their twenties and thirties,26, 27 and in women after cancer treatment.28 This study was not designed to assess chances of pregnancy after treatment, and indeed current clinical advice is that women should not attempt to conceive after chemotherapy for around 1–2 years—ie, most of the duration of follow-up in this study. We do not know how many women in each group attempted to conceive, but a similar proportion of pregnancies were seen in women in the BEACOPP group as in the ABVD-AVD group within the substudy. Although these results show that a low concentrations of antimüllerian hormone do not preclude pregnancy in the short term, they probably do indicate a reduced interval to menopause and thus a shortened duration of opportunity to achieve pregnancy in the longer term.29 Thus, a low concentration of antimüllerian hormone after recovery from chemotherapy could identify women who should not unduly postpone pregnancy, and inform individualised discussion; longer follow-up studies are needed to assess this interpretation.\n\nOur study had several limitations. The study was not designed to assess fertility, which would require longer follow-up and a design that incorporates intention to conceive. The antimüllerian hormone analysis is restricted by the size of the dataset, reflecting the short period for which recruitment was open for the substudy. We also acknowledge the limitations of using follicle-stimulating hormone measurements in isolation without a more robust evidence of premature ovarian insufficiency, which was not possible in the main RATHL trial, and data on hormonal contraceptive use during and after treatment were not available.\n\nIn conclusion, the results of this secondary analysis of the RATHL trial indicate the value of antimüllerian hormone as a biomarker of toxic effects of chemotherapy on the ovaries during and after different chemotherapy regimens for advanced Hodgkin's lymphoma. We provide additional evidence that treatment with ABVD or AVD has no detectable effect on gonadal function in young women, although increasing age does restrict ovarian recovery; confirmation in larger studies is needed to confirm and define this interpretation more precisely, and determine its mechanism. By contrast, BEACOPP shows substantial gonadotoxicity in women of all ages, although some patients might have sufficient ovarian function after treatment to achieve pregnancy. Concentrations of antimüllerian hormone after treatment could be of use in advising women treated for Hodgkin's lymphoma of their probable reproductive lifespan after treatment.\n\nSupplementary Material\nSupplementary appendix\n \n\nAcknowledgments\nThe RATHL trial was funded by Cancer Research UK (reference CRUK/07/033), and the ovarian substudy by the Medical Research Foundation (reference 509909). Part of this work was done in the MRC Centre for Reproductive Health, University of Edinburgh, UK, which is funded by MRC Centre grant MR/N022556/1. We thank Roche Diagnostics for the supply of assay reagents, A Forbes Howie for hormone assays, and all investigators in RATHL for their contributions to patient recruitment and management.\n\nContributors\nRAA and PWMJ designed the study; collected, analysed, and interpreted data; contributed to manuscript writing; and approved the manuscript before submission. RR collected and analysed data and approved the manuscript before submission. AAK and LC-H collected, analysed, and interpreted data, contributed to manuscript writing, and approved the manuscript before submission. PP managed the study, collected data, gave constructive comments on the manuscript, and approved the manuscript before submission. LS and TR collected data, gave constructive comments on the manuscript, and approved the manuscript before submission. CH collected data via patient recruitment, and gave constructive comments on the manuscript. NK, DWM, PM, and FMS collected data, contributed to manuscript writing, and approved the manuscript before submission. CR recruited patients, collected data, contributed to manuscript writing, and approved the manuscript before submission.\n\nDeclaration of interests\nRAA reports non-financial support from Roche diagnostics, and a grant from the Medical Research Foundation. All other authors declare no competing interests.\n==== Refs\nReferences\n1 Hoskin PJ Lowry L Horwich A Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin's lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244 J Clin Oncol 27 2009 5390 5396 19738111 \n2 Swerdlow AJ Cooke R Bates A Risk of premature menopause after treatment for Hodgkin's lymphoma J Natl Cancer Inst 106 2014 dju207 25139687 \n3 Behringer K Breuer K Reineke T Secondary amenorrhea after Hodgkin's lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin's Lymphoma Study Group J Clin Oncol 23 2005 7555 7564 16234521 \n4 Meirow D Dor J Kaufman B Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury Hum Reprod 22 2007 1626 1633 17324957 \n5 Anderson RA Cameron DA Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer J Clin Endocrinol Metab 96 2011 1336 1343 21325458 \n6 Decanter C Morschhauser F Pigny P Lefebvre C Gallo C Dewailly D Anti-müllerian hormone follow-up in young women treated by chemotherapy for lymphoma: preliminary results Reprod Biomed Online 20 2010 280 285 20113967 \n7 van Beek RD van den Heuvel-Eibrink MM Laven JS Anti-müllerian hormone is a sensitive serum marker for gonadal function in women treated for Hodgkin's lymphoma during childhood J Clin Endocrinol Metab 92 2007 3869 3874 17726078 \n8 Brougham MF Crofton PM Johnson EJ Evans N Anderson RA Wallace WH Anti-müllerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study J Clin Endocrinol Metab 97 2012 2059 2067 22472563 \n9 Su HC Haunschild C Chung K Prechemotherapy antimüllerian hormone, age, and body size predict timing of return of ovarian function in young breast cancer patients Cancer 120 2014 3691 3698 25081546 \n10 Partridge AH Ruddy KJ Gelber S Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer Fertil Steril 94 2010 638 644 19409543 \n11 Eurpoean Society for Human Reproduction and Embryology Guideline Group on POI ESHRE guideline: management of women with premature ovarian insufficiency Hum Reprod 31 2016 926 937 27008889 \n12 Jayasinghe YL Wallace WHB Anderson RA Ovarian function, fertility and reproductive lifespan in cancer patients Expert Rev Endocrinol Metab 13 2018 125 136 30058903 \n13 Decanter C Peigne M Mailliez A Toward a better follow-up of ovarian recovery in young women after chemotherapy with a hypersensitive antimüllerian hormone assay Fertil Steril 102 2014 483 487 24951363 \n14 Anderson RA Mansi J Coleman RE Adamson DJA Leonard RCF The utility of anti-müllerian hormone in the diagnosis and prediction of loss of ovarian function following chemotherapy for early breast cancer Eur J Cancer 87 2017 58 64 29117576 \n15 Barnabei A Strigari L Marchetti P Predicting ovarian activity in women affected by early breast cancer: a meta-analysis-based nomogram Oncologist 20 2015 1111 1118 26341758 \n16 Dezellus A Barriere P Campone M Prospective evaluation of serum anti-müllerian hormone dynamics in 250 women of reproductive age treated with chemotherapy for breast cancer Eur J Cancer 79 2017 72 80 28463758 \n17 Johnson P Federico M Kirkwood A Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma N Engl J Med 374 2016 2419 2429 27332902 \n18 Peate M Meiser B Hickey M Friedlander M The fertility-related concerns, needs and preferences of younger women with breast cancer: a systematic review Breast Cancer Res Treat 116 2009 215 223 19390962 \n19 Kalich-Philosoph L Roness H Carmely A Cyclophosphamide triggers follicle activation and “burnout”; AS101 prevents follicle loss and preserves fertility Sci Transl Med 5 2013 185ra62 \n20 Lekovich J Lobel ALS Stewart JD Pereira N Kligman I Rosenwaks Z Female patients with lymphoma demonstrate diminished ovarian reserve even before initiation of chemotherapy when compared with healthy controls and patients with other malignancies J Assist Reprod Genet 33 2016 657 662 26943918 \n21 Briley SM Jasti S McCracken JM Reproductive age-associated fibrosis in the stroma of the mammalian ovary Reproduction 152 2016 245 260 27491879 \n22 Umehara T Kawai T Kawashima I The acceleration of reproductive aging in Nrg1flox/flox;Cyp19-Cre female mice Aging Cell 16 2017 1288 1299 28857490 \n23 Leonard RCF Adamson DJA Bertelli G GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial Ann Oncol 28 2017 1811 1816 28472240 \n24 Lambertini M Moore HCF Leonard RCF Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data J Clin Oncol 36 2018 1981 1990 29718793 \n25 Demeestere I Brice P Peccatori FA No evidence for the benefit of gonadotropin-releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy: final long-term report of a prospective randomized trial J Clin Oncol 34 2016 2568 2574 27217453 \n26 Hagen CP Vestergaard S Juul A Low concentration of circulating antimüllerian hormone is not predictive of reduced fecundability in young healthy women: a prospective cohort study Fertil Steril 98 2012 1602 1608 22959460 \n27 Steiner AZ Pritchard D Stanczyk FZ Association between biomarkers of ovarian reserve and infertility among older women of reproductive age JAMA 318 2017 1367 1376 29049585 \n28 Hamy AS Porcher R Eskenazi S Anti-müllerian hormone in breast cancer patients treated with chemotherapy: a retrospective evaluation of subsequent pregnancies Reprod Biomed Online 32 2016 299 307 26803206 \n29 Depmann M Broer SL van der Schouw YT Can we predict age at natural menopause using ovarian reserve tests or mother's age at menopause? A systematic literature review Menopause 23 2015 224 232\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1470-2045",
"issue": "19(10)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D054304:Anti-Mullerian Hormone; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D005260:Female; D059247:Fertility Preservation; D043373:Follicle Stimulating Hormone, Human; D006689:Hodgkin Disease; D006801:Humans; D007247:Infertility, Female; D008875:Middle Aged; D009367:Neoplasm Staging; D010053:Ovary; D000072078:Positron Emission Tomography Computed Tomography; D011446:Prospective Studies; D020127:Recovery of Function; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D055815:Young Adult",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1328-1337",
"pmc": null,
"pmid": "30220622",
"pubdate": "2018-10",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "22472563;28857490;30058903;17726078;24951363;19738111;29718793;23677591;29117576;28472240;27491879;29049585;16234521;19409543;17324957;19390962;22959460;20113967;26803206;25139687;27332902;27217453;26341758;27008889;26372034;26943918;21325458;28463758;25081546",
"title": "Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.",
"title_normalized": "determinants of ovarian function after response adapted therapy in patients with advanced hodgkin s lymphoma rathl a secondary analysis of a randomised phase 3 trial"
} | [
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"companynumb": "GB-PFIZER INC-2019079331",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN HYDROCHLORIDE"
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"drugadditional": ... |
{
"abstract": "BACKGROUND\nSeveral classes of drugs, such as antibiotics, may interact with warfarin to cause an increase in warfarins anticoagulant activity and the clinical relevance of warfarin-antibiotic interactions in older adults is not clear.\n\n\nOBJECTIVE\nThe aim of this study was to determine the effect of oral antibiotics, such as amoxicillin, azithromycin, cephalexin, ciprofloxacin, levofloxacin, and moxifloxacin, on the international normalized ratio (INR) in patients ≥65 years on stable warfarin therapy. The secondary objective was to compare the effect of warfarin-antibiotic interactions on outcomes of overanticoagulation.\n\n\nMETHODS\nData for this retrospective cohort study were collected through a medical record review of patients in an outpatient anticoagulation clinic of a Veterans Affairs medical center. Patients aged ≥65 years on stable warfarin therapy and with at least 1 prescription of an oral antibiotic of interest during the period from January 1, 2003 to March 1, 2011 were included. A mixed-effects repeated-measures ANOVA model was used to determine the effect of antibiotics on the mean change in patients' INR. The Fisher exact test was used to determine the association between the antibiotics and secondary outcomes of overanticoagulation, using cephalexin as the control. Statistical significance was defined as a P value <0.05.\n\n\nRESULTS\nA total of 205 patients had 364 prescriptions for warfarin and antibiotics concomitantly, and there was a significant interaction between antibiotic and time (F(15, 358) = 1.9; P = 0.0221). Antibiotics with a significant increase in INR were amoxicillin (P = 0.0019), azithromycin (P < 0.0001), ciprofloxacin (P = 0.002), levofloxacin (P < 0.0001) and moxifloxacin (P < 0.0001). There was a significant association between type of antibiotic and secondary outcomes of overanticoagulation.\n\n\nCONCLUSIONS\nIn older patients on stable warfarin therapy, antibiotics may lead to an increase in INR. However, this may not result in clinically significant outcomes of bleeding or hospitalization, suggesting that antibiotics may be prescribed for older adults taking warfarin as long as their INR is being routinely monitored.",
"affiliations": "Geriatric Pharmacotherapy Program, Department of Pharmacotherapy and Outcomes Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.",
"authors": "Ghaswalla|Parinaz K|PK|;Harpe|Spencer E|SE|;Tassone|Daniel|D|;Slattum|Patricia W|PW|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-7761",
"issue": "10(6)",
"journal": "The American journal of geriatric pharmacotherapy",
"keywords": null,
"medline_ta": "Am J Geriatr Pharmacother",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000553:Ambulatory Care; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents; D000925:Anticoagulants; D015331:Cohort Studies; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006470:Hemorrhage; D006760:Hospitalization; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D017063:Outcome Assessment, Health Care; D012189:Retrospective Studies; D013997:Time Factors; D014481:United States; D014493:United States Department of Veterans Affairs; D014859:Warfarin",
"nlm_unique_id": "101190325",
"other_id": null,
"pages": "352-60",
"pmc": null,
"pmid": "23089199",
"pubdate": "2012-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Warfarin-antibiotic interactions in older adults of an outpatient anticoagulation clinic.",
"title_normalized": "warfarin antibiotic interactions in older adults of an outpatient anticoagulation clinic"
} | [
{
"companynumb": "US-JNJFOC-20130103056",
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"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
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... |
{
"abstract": "Zolpidem is a widely prescribed anti-insomnia agent. Although most pediatric zolpidem ingestions are benign, large ingestions can cause significant central nervous system (CNS) depression. Flumazenil has been reported to reverse the CNS effects of zolpidem. We describe a case of a large pediatric zolpidem ingestion resulting in profound CNS depression that responded to flumazenil administration. Serial zolpidem serum levels confirmed the ingestion. A 10-year-old boy with trisomy 21 presented to the emergency department 1 hour after he was found sedate with several zolpidem 5-mg tablets in his mouth. Seventeen tables (85 mg) were unaccounted for from a prescription bottle. He became unarousable approximately 2 hours after his ingestion. Flumazenil 0.2 mg intravenously was given with rapid return to his baseline mental status. He became resedate 1 hour later but was arousable. Sixteen hours after his presentation, he was asymptomatic. Serial zolpidem serum levels were obtained, showed an initial level of 310 ng/mL, and demonstrated zero-order kinetics. Zolpidem is an imidazopyridine, which binds to the benzodiazepine receptor. It is rapidly absorbed and has a short-half life. Unintentional pediatric ingestions of zolpidem are typically well tolerated. However, this case demonstrates that large ingestions may cause significant and prolonged CNS depression. Flumazenil, a benzodiazepine receptor antagonist, has been described to reverse the effects of zolpidem in adult ingestions. There are few published reports describing flumazenil use in pediatric ingestion patients. This case suggests that flumazenil may be an effective treatment for zolpidem-induced CNS depression in the pediatric patient.",
"affiliations": "From the *Department of Emergency Medicine, University of Kansas Hospital, Kansas City, KS; and †Department of Emergency Medicine, University of California-San Diego; and ‡Department of Emergency Medicine, Naval Medical Center, San Diego, CA.",
"authors": "Thornton|Stephen L|SL|;Negus|Elezer|E|;Carstairs|Shaun D|SD|",
"chemical_list": "D000931:Antidotes; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D011725:Pyridines; D005442:Flumazenil; D000077334:Zolpidem",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0b013e3182aa139c",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "29(11)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000931:Antidotes; D002492:Central Nervous System Depressants; D002648:Child; D003128:Coma; D004314:Down Syndrome; D062787:Drug Overdose; D004630:Emergencies; D005442:Flumazenil; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D015394:Molecular Structure; D011041:Poisoning; D011725:Pyridines; D000077334:Zolpidem",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "1204-6",
"pmc": null,
"pmid": "24196090",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil.",
"title_normalized": "pediatric zolpidem ingestion demonstrating zero order kinetics treated with flumazenil"
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"companynumb": "PHHY2013US147566",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
"drugadditional": null... |
{
"abstract": "Small bowel adenocarcinoma (SBA) is a rare tumor of the gastrointestinal system with poor prognosis. Since these are rarely encountered tumors, there are limited numbers of studies investigating systemic treatment in advanced SBA. The purpose of this study was to evaluate the prognostic factors and systemic treatments in patients with advance SBA.\n\n\n\nSeventy-one patients from 18 Centers with advanced SBA were included in the study. Fifty-six patients received one of the four different chemotherapy regimens as first-line therapy and 15 patients were treated with best supportive care (BSC).\n\n\n\nOf the 71 patients, 42 (59%) were male and 29 (41%) female with a median age of 56 years. Median follow- up duration was 14.3 months. The median progression free survival (PFS) and overall survival (OS) were 7 and 13 months, respectively (N=71). In patients treated with FOLFOX (N=18), FOLFIRI (N=11), cisplatin-5-fluorouracil/ 5-FU (N=17) and gemcitabine alone (N=10), median PFS was 7, 8, 8 and 5 months, respectively, while median OS was 15, 16, 15 and 11 months, respectively. No significant differences between chemotherapy groups were noticed in terms of PFS and OS. Univariate analysis revealed that chemotherapy administration, de novo metastatic disease, ECOG PS 0 and 1, and overall response to therapy were significantly related to improved outcome. Only overall response to treatment was found to be significantly prognostic in multivariate analysis (p=0.001).\n\n\n\nIn this study, overall response to chemotherapy emerged as the single significant prognostic factor for advanced SBAs. Platin and irinotecan based regimens achieved similar survival outcomes in advanced SBA patients.",
"affiliations": "Department of Medical Oncology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey.",
"authors": "Aydin|Dincer|D|;Sendur|Mehmet Ali|MA|;Kefeli|Umut|U|;Umut Unal|Olcun|O|;Tastekin|Didem|D|;Akyol|Murat|M|;Tanrikulu|Eda|E|;Ciltas|Aydin|A|;Bala Ustaalioglu|Basak|B|;Sener Dede|Didem|D|;Esbag|Onur|O|;Inal|Ali|A|;Bilir|Cemil|C|;Bilici|Ahmet|A|;Harputlu|Hakan|H|;Berk|Veli|V|;Sevinc|Alper|A|;Yildirim Ozdemir|Nuriye|N|;Yildirim|Emre|E|;Sonkaya|Alper|A|;Ali Ustaoglu|Mehmet|M|;Gumus|Mahmut|M|",
"chemical_list": null,
"country": "Cyprus",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1107-0625",
"issue": "21(5)",
"journal": "Journal of B.U.ON. : official journal of the Balkan Union of Oncology",
"keywords": null,
"medline_ta": "J BUON",
"mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms; D007421:Intestine, Small; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010166:Palliative Care; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014421:Turkey",
"nlm_unique_id": "100883428",
"other_id": null,
"pages": "1242-1249",
"pmc": null,
"pmid": "27837629",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Evaluation of prognostic factors and treatment in advanced small bowel adenocarcinoma: report of a multi-institutional experience of Anatolian Society of Medical Oncology (ASMO).",
"title_normalized": "evaluation of prognostic factors and treatment in advanced small bowel adenocarcinoma report of a multi institutional experience of anatolian society of medical oncology asmo"
} | [
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"companynumb": "TR-FRESENIUS KABI-FK201702343",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstance": {
"activesubstancename": "OXALIPLATIN"
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"abstract": "Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib.\n\n\n\nEligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0-1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120-360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation.\n\n\n\nThe trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy.\n\n\n\nThe combination of topotecan and oral tivantinib was not tolerable in this patient population.",
"affiliations": "Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. stephen.v.liu@gunet.georgetown.edu.;University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.;University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.;City of Hope Comprehensive Cancer Center, Duarte, CA, USA.;Penn State Cancer Institute, Hershey, PA, USA.;City of Hope Comprehensive Cancer Center, Duarte, CA, USA.;University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.;University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.;City of Hope Comprehensive Cancer Center, Duarte, CA, USA.;University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.;University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.;University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.;University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.;City of Hope Comprehensive Cancer Center, Duarte, CA, USA.;University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.;City of Hope Comprehensive Cancer Center, Duarte, CA, USA.",
"authors": "Liu|Stephen V|SV|0000-0002-4852-3914;Groshen|Susan G|SG|;Kelly|Karen|K|;Reckamp|Karen L|KL|;Belani|Chandra|C|;Synold|Timothy W|TW|;Goldkorn|Amir|A|;Gitlitz|Barbara J|BJ|;Cristea|Mihaela C|MC|;Gong|I-Yeh|IY|;Semrad|Thomas J|TJ|;Xu|Yucheng|Y|;Xu|Tong|T|;Koczywas|Marianna|M|;Gandara|David R|DR|;Newman|Edward M|EM|",
"chemical_list": "C551661:ARQ 197; D000970:Antineoplastic Agents; D011760:Pyrrolidinones; D011804:Quinolines; D019772:Topotecan; D019859:Proto-Oncogene Proteins c-met",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-018-3672-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "82(4)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "ARQ-197; Circulating tumor cells; MET phosphorylation; Tivantinib; Topotecan",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms; D009503:Neutropenia; D019859:Proto-Oncogene Proteins c-met; D011760:Pyrrolidinones; D011804:Quinolines; D013921:Thrombocytopenia; D019772:Topotecan; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "723-732",
"pmc": null,
"pmid": "30128950",
"pubdate": "2018-10",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23417696;23287988;25711511;11908677;24737778;28004284;12488290;25226813;21976535;24337769;8955651;2790129;25971939;14685170;21768463;28373408;10388079;24327519;10659996;25294187;21383285;26891420;28865153;26123926;11750879",
"title": "A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors.",
"title_normalized": "a phase i trial of topotecan plus tivantinib in patients with advanced solid tumors"
} | [
{
"companynumb": "PHHY2018US081152",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS"
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{
"abstract": "Transplant-related liver complications are a potentially fatal condition of hematopoietic stem cell transplantation (HSCT) in pediatric patients, actually representing one of the main factors involved in transplant-related mortality (TRM). The search for a specific marker capable of predicting the development of this condition is a relevant clinical issue. We have observed a variable reduction in serum butyrylcholinesterase (BChE) activity after a cyclophosphamide-containing conditioning regimen. This study aims to determine the cutoff of BChE activity reduction that might be a specific prognostic marker for liver complications after HSCT. Our results show that the reduction of BChE values below 2000 U/L the day before the transplantation is an indicator strongly associated with the transplant-related liver complications (p < 0.0001). The incidence of overall survival at 1 year was significantly higher in the BChE > 2000 U/L group compared to the BChE < 2000 U/L group (84.7% versus 58.5%, p < 0.001), while the TRM rate was significantly lower (8.1% versus 23.1%, p < 0.05). None of the patients undergoing prophylaxis with defibrotide developed severe liver complications. Starting defibrotide treatment at the first signs of hepatic dysfunction in patients with particularly low BChE activity levels reduces severe liver transplant-related complications.",
"affiliations": "Bone Marrow Transplant Unit, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, via dell'Istria 65/1, 34137 Trieste, Italy. natalia.maximova@burlo.trieste.it.;Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy. g.caddeo88@gmail.com.;Pharmacy and Clinical Pharmacology Unit, Institute for Maternal and Child Health-IRCC Burlo Garofolo, via dell'Istria 65/1, 34137 Trieste, Italy. davide.zanon@burlo.trieste.it.;Pharmacy and Clinical Pharmacology Unit, Institute for Maternal and Child Health-IRCC Burlo Garofolo, via dell'Istria 65/1, 34137 Trieste, Italy. alessandra.maestro@burlo.trieste.it.;Department of Transfusion Medicine, ASUITS, Piazza dell'Ospitale 1, 34129 Trieste, Italy. roberto.simeone@asuits.sanita.fvg.it.",
"authors": "Maximova|Natalia|N|;Caddeo|Giulia|G|;Zanon|Davide|D|;Maestro|Alessandra|A|;Simeone|Roberto|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm8060825",
"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm8060825jcm-08-00825ArticleDrop of Butyrylcholinesterase Activity after Cyclophosphamide Conditioning as a Predictive Marker of Liver Transplant-Related Complications and Its Correlation with Transplant-Related Mortality in Pediatric Hematopoietic Stem Cell Recipients https://orcid.org/0000-0003-0934-1875Maximova Natalia 1*Caddeo Giulia 2Zanon Davide 3Maestro Alessandra 3Simeone Roberto 41 Bone Marrow Transplant Unit, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, via dell’Istria 65/1, 34137 Trieste, Italy2 Department of Medicine, Surgery and Health Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy; g.caddeo88@gmail.com3 Pharmacy and Clinical Pharmacology Unit, Institute for Maternal and Child Health-IRCC Burlo Garofolo, via dell’Istria 65/1, 34137 Trieste, Italy; davide.zanon@burlo.trieste.it (D.Z.); alessandra.maestro@burlo.trieste.it (A.M.)4 Department of Transfusion Medicine, ASUITS, Piazza dell’Ospitale 1, 34129 Trieste, Italy; roberto.simeone@asuits.sanita.fvg.it* Correspondence: natalia.maximova@burlo.trieste.it; Tel.: +39-040-3785276/565; Fax: +39-040-378549410 6 2019 6 2019 8 6 82515 5 2019 05 6 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Transplant-related liver complications are a potentially fatal condition of hematopoietic stem cell transplantation (HSCT) in pediatric patients, actually representing one of the main factors involved in transplant-related mortality (TRM). The search for a specific marker capable of predicting the development of this condition is a relevant clinical issue. We have observed a variable reduction in serum butyrylcholinesterase (BChE) activity after a cyclophosphamide-containing conditioning regimen. This study aims to determine the cutoff of BChE activity reduction that might be a specific prognostic marker for liver complications after HSCT. Our results show that the reduction of BChE values below 2000 U/L the day before the transplantation is an indicator strongly associated with the transplant-related liver complications (p < 0.0001). The incidence of overall survival at 1 year was significantly higher in the BChE > 2000 U/L group compared to the BChE < 2000 U/L group (84.7% versus 58.5%, p < 0.001), while the TRM rate was significantly lower (8.1% versus 23.1%, p < 0.05). None of the patients undergoing prophylaxis with defibrotide developed severe liver complications. Starting defibrotide treatment at the first signs of hepatic dysfunction in patients with particularly low BChE activity levels reduces severe liver transplant-related complications.\n\nserum butyrylcholinesterase activitycyclophosphamidepediatric transplant recipientsliver transplant-related complicationsdefibrotide\n==== Body\n1. Introduction\nHematopoietic stem cell transplantation (HSCT) has become a well-established treatment for various malignant and non-malignant disorders originating from the hematopoietic system [1].\n\nImprovements in transplantation techniques over the recent years have led to a significant reduction in treatment-related complications.\n\nDifferent areas of improvement have included changes in conditioning regimens, larger donor availability, better Human Leucocyte Antigens (HLA)—matching techniques and graft source manipulation, advanced techniques to detect minimal residual disease, posttransplant immunotherapy, progress in supportive care, graft-versus-host disease (GVHD) prophylaxis and therapy, detection and treatment of subsequent infections [2].\n\nDespite the reduction in overall transplant-related mortality (TRM) over time, it currently exceeds 10% in allogeneic settings [3]. Indeed, it depends above all on the relative stability in the incidence of liver-related complications, with approximately 70% of pediatric patients displaying abnormal levels of either aminotransferases or bilirubin [4]. Previous studies have shown how pretransplant liver dysfunction is related to higher risk of overall TRM. Factors involved in this dysfunction include chronic viral hepatitis, pretransplant chemotherapy-induced liver toxicity, and severe iron overload from multiple transfusions [5,6,7,8]. Clinically significant liver disease presenting early after HSCT, as in the case of sinusoidal obstruction syndrome (SOS) or acute GVHD, plays an important role in determining adverse outcomes, being usually associated with poor survival and often considered to be the primary cause of death [9].\n\nSOS, also known as veno-occlusive disease (VOD), is a potentially fatal complication of HSCT and a relevant challenge in the management of children undergoing a transplantation.\n\nIts incidence is quite variable depending on the composition and intensity of the conditioning regimen. In the pediatric setting, most of the conditioning regimes are myeloablative and includes the use of cyclophosphamide and total body irradiation (TBI).\n\nReported rates of SOS in patients receiving this conditioning regime often exceed 50% [10]. While mild or moderate SOS usually resolves within weeks in most patients, the severe form, which is estimated to involve 30–60% of affected children, is associated with multiorgan dysfunction and a mortality rate higher than 80% [11,12].\n\nThe transplant community aims to achieve a further reduction in TRM after allogeneic HSCT, bringing it down to 5%. Reducing TRM due to liver dysfunction is a way to achieve this goal.\n\nButyrylcholinesterase (BChE), also known as pseudocholinesterase, is a major detoxification enzyme capable of hydrolyzing many different choline-based esters. BChE is synthesized in the liver and, for this reason, it is commonly used in the clinical routine as a quick and cheap biomarker for liver function, reflecting hepatic synthetic capacity. Lower BChE activity levels correlate with a more extensive liver injury [13] and are associated with disease severity and mortality in critically ill patients [14,15,16], especially with respect to systemic inflammation and sepsis [17,18].\n\nIn our 15 years of experience with butyrylcholinesterase (BChE) activity monitoring, we have observed a reduction in the serum BChE activity levels in all patients given a pretransplant conditioning regime containing high-dose of cyclophosphamide. The decline in serum BChE activity values was variable in each patient, from a minimum of 20% to a maximum of more than 80%.\n\nThe primary objective of this study is to determine the association between the degree of BChE activity reduction after two days of cyclophosphamide treatment and the development of transplant-related liver complications after HSCT. The secondary aim is to define a cutoff of BChE activity decrease which allows identification of those patients who are at high risk for liver complications and to eventually tailor the therapeutic approach.\n\n2. Methods\nA retrospective single-center study was conducted at the pediatric transplant center of the Institute for Maternal and Child Health “IRCCS Burlo Garofolo” in Trieste, Italy. The study protocol was approved by the institutional review board of the institute (reference no. 10\\2018).\n\nAll patients have given written consent for collection and use of personal data.\n\n2.1. Patients\nMedical records of all patients who underwent allogeneic or autologous HSCT at our center between January 2003 and January 2018 were investigated.\n\nInclusion criteria in the study were: Age of recipient under 18 years at the time of transplantation, first transplant attempt, use of a myeloablative conditioning regime including high-dose cyclophosphamide, documented serum BChE activity levels during conditioning. All patients aged over 18 years at the time of transplantation were excluded. Disease risk was established considering the type of diagnosis and the disease stage [19]. Patients with genetic diseases, aplastic anemia, refractory cytopenia, and leukemia in first or second remission were included in the low disease risk group, while patients with solid tumors, relapsed leukemia (or leukemia in more than second remission), and refractory anemia with excess blasts were considered at high risk.\n\n2.2. HSCT Procedure\nAll patients were treated according to standard myeloablative protocols. In patients over 2 years of age with acute lymphoblastic leukemia (LLA), the myeloablative conditioning regime preceding allogeneic HSCT was based on total-body irradiation (TBI), while in the remaining cases, a busulfan-based conditioning regime was used. In both cases, conditioning also included high-dose cyclophosphamide (1800 mg/m2 for two consecutive days). In the case of matched unrelated donors, haploidentical or sibling donors and patients with hemoglobinopathy, rabbit anti-thymocyte globulin (ATG) was used. GVHD prophylaxis was performed with calcineurin-inhibitor alone or associated with mycophenolate mofetil and prednisone, as previously described [20].\n\nAll patients undergoing an autologous HSCT received busulfan orally (360 mg/m2) and cyclophosphamide (1800 mg/m2 for two consecutive days). In case of abnormal bilirubin values, during both autologous and allogeneic HSCT, the second dose of cyclophosphamide was slightly reduced.\n\n2.3. Liver Disease at Transplant Assessment\nBefore 2012, the level of liver siderosis was estimated by calculating the number of blood units transfused and determining the serum ferritin concentration [21]. Liver iron overload assessment by liver biopsy was performed in only 14% of the patients. Beginning in 2012, the liver iron concentration has been evaluated using magnetic resonance (MR) in all patients for whom HSCT is anticipated. The algorithm for quantification of iron concentration in the liver by MRI was previously described [22]. The diagnosis of all other pretransplant liver dysfunctions was histological.\n\n2.4. Prophylaxis of Transplant-Related Liver Complications\nBetween January 2010 and June 2014, all patients receiving an allogeneic transplantation underwent SOS prophylaxis with defibrotide, while beginning in July 2014, prophylaxis has been limited only to high-risk patients. Defibrotide was started on the first day of conditioning and lasted until 28 days after HSCT, at a dose of 25 mg/kg divided into four administrations per day. Moreover, all recipients, in both autologous and allogeneic transplants, received prophylaxis with ursodeoxycholic acid (UDCA), at a dose of 30 mg/kg/day for a minimum of two months after HSCT, regardless of their liver function. In addition, the patients with abnormal liver functional tests (LFTs) received N-acetylcysteine at a dose of 150 mg/kg in single daily administration.\n\n2.5. Criteria for the Diagnosis of Transplant-Related Liver Complications\nThe diagnosis of SOS was established according to the modified Seattle diagnostic criteria [23]. Posttransplant liver dysfunction was defined as SOS based on clinical symptoms including weight gain, hepatomegaly, ascites, and elevated bilirubin. All cases of mild, moderate, or late-onset SOS were histologically proven. Transplant-related liver damage was considered to have occurred only when histologically proven or in the presence of increased bilirubin and transaminases values with symptoms not fulfilling SOS diagnostic criteria. Liver damage was defined as mild in the case of bilirubin values between 2 and 3 mg/dL and transaminases levels not exceeding twice the normal range. Moderate damage was defined by the presence of bilirubin values from 3 to 5 mg/dL and transaminases values from 2 to 5 times higher than normal. Severe liver damage was defined by bilirubin values higher than 5 mg/dL, and transaminases values 5 times higher than normal. Clinical diagnosis and histological features of hepatic GVHD were based on the National Institute of Health (NIH) criteria [9,24]. In particular, histological features of acute liver GVHD were defined as the presence of dysmorphic or destroyed small bile ducts with or without cholestasis and lobular and/or portal inflammation.\n\n2.6. Statistical Analysis\nCollected data were analyzed using descriptive statistics to determine the distribution and frequency of the variables. Continuous variables were expressed as median and confidence interval (CI) between second and third quartiles (percentile 25 and percentile 75), while categorical variables were expressed as the frequency, and absolute or a percentage value. Box and whisker plots were generated for displaying the distribution of the numeric variable. The Mann–Whitney test was used to compare the different groups of patients as appropriate. The two-tailed Fisher exact test was performed to assess the association between categorical variables. We assessed the validity of biochemical parameters in predicting the transplant-related liver complications by evaluating the respective area under curve (AUC) and receiver operating characteristic (ROC) curves. The Youden index was used to establish the best cutoff for sensitivity and specificity of each variable. Kaplan–Meier plots were generated for a graphical explanation of clinical outcomes. p-values < 0.05 were considered as statistically significant. The Cox proportional-hazards regression model was used to investigate the association between the survival time of patients and a series of possible predictive variables. Statistical analyses were performed using WinStat (v.2012.1; In der Breite 30, 79189 Bad Krozingen, Germany) and MedCalc (Statistical Software version 18.9.1, Ostend, Belgium; http://www.medcalc.org; 2018).\n\n2.7. Analysis of Biochemical Parameters\nBiochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), BuChE, total bilirubin, and C reactive protein (CRP) concentrations were measured by AU Beckman Coulter reagents and autoanalyzer (Indianapolis, IN, USA).\n\n3. Results\n3.1. Demographic Features\nDuring the study period (from January 2003 to January 2018) 225 HSCTs in 214 patients were performed in our transplant center. The eligibility criteria was met by 176 pediatric patients, 110 boys and 66 girls, for whom this was their first HSCT. At the time of analysis, 75% of the patients were alive, while 25% had died. The minimum follow-up for survivors was 12 months. Median age at the time of transplantation was 9 years (range 0–17).\n\nTable 1 summarizes the baseline patient demographics. As shown, acute lymphoblastic leukemia was the most common underlying disease treated, followed by non-malignant disorders, acute myeloid leukemia, myelodysplastic syndromes, and malignant solid tumors. Non-malignant disorders consisted of hemoglobinopathy, primary immunodeficiencies, inherited metabolic diseases, and osteopetrosis. Solid tumor diagnoses included neuroblastomas, Ewing sarcomas, primitive neuroectodermal tumors, and rhabdomyosarcomas.\n\nThe majority of patients had a low disease risk at transplant (62% versus 38% in the high disease risk group). All 176 HSCTs, 92% allogeneic and 8% autologous, were preceded by a myeloablative conditioning regime. Chemotherapy-based conditioning was more frequently used compared to TBI-based conditioning (64% versus 36%). The mean total dose of cyclophosphamide received during conditioning was only slightly lower compared to the standard dose (3500 mg/m2 versus 3600 mg/m2).\n\nOne hundred fifty-three patients (87%) had liver disorders at transplant with a clear predominance of liver siderosis (72%).\n\n3.2. Analysis of the Suitability of the Prognostic Markers Chosen for the Study\nFirst of all, we evaluated a possible relationship between baseline serum BChE activity levels and subsequent severe transplant-related liver disorders (SOS and third-grade liver disease). As shown in the corresponding ROC curve (Figure 1A), baseline BChE activity values were very poor in predicting the onset of transplant-related liver damage (AUC = 0.507; 95% confidence interval (CI) = 0.49–0.64; p = 0.932). The maximum Youden index for absolute BChE activity values was 6820 U/L with a sensitivity of 55.2% and a specificity of 63.3%. In an analogous way, we evaluated the predictive performance of the absolute BChE activity values on day −1 (Figure 1B). We observed that a serum BChE activity value ≤ 1799 U/L performed best in predicting a severe posttransplant liver damage with AUC = 0.801 and 95% CI = 0.73–0.86 (p < 0.001), sensitivity 72.4% and specificity 80.8%.\n\nConsidering only the patients who underwent allogenic HSCT for hematologic malignancies, BChE activity value ≤ 1799 U/L maintained a good predictive performance for severe liver damage with AUC = 0.761 and 95% CI = 0.673–0.835 (p < 0.001), sensitivity 63.2% and specificity 84.7%.\n\nIn addition, we evaluated the performance of some other commonly used markers such as C-reactive protein (CRP), total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT) on day −1, obtaining the respective ROC curves. None of these variables showed acceptable predictive performance (Table 2).\n\nPreliminary analysis was performed in order to assess if the correlation between BChE activity and each of the other markers listed in Table 2 could improve the predictive performance but the test did not show significative results.\n\n3.3. Analysis of the Relationship between Patients’ Variables and the Reduction in the Serum BChE Activity Level\nIn all 176 patients, we detected a variable reduction in serum BChE activity values ranging from 13.9% to 92.1%. The most significant BChE activity drop was documented on day −1, after cessation of cyclophosphamide (Figure 2). We considered both the absolute and percentage value of BChE activity reduction on day −1 and we divided the study cohort into two groups, respectively. Percentage BChE activity loss was calculated by comparing the baseline values with those documented on day −1. The results are listed in Table 3 and Table 4, respectively.\n\nThe cutoff point was arbitrarily set at 2000 U/L in the case of absolute reduction, and at 70% in the case of percentage reduction. Cutoff of 2000 U/L, chosen due to sample size, is very close to maximum Youden index of 1799 U/L. The BChE activity basal values were significantly higher in the BChE > 2000 U/L group, compared with the BChE < 2000 U/l group (p < 0.05), and in the BChE drop > 70% group compare with the BChE drop < 70% group (p < 0.001).\n\nStatistical analysis showed that the degree in BChE activity level reduction was not associated with patient demographic features such as, gender, age at transplant, ferritin baseline level, presence of liver disease at transplant, etc. It was also independent of any liver toxicity prophylaxis.\n\nConsidering the primary disease, only an association between acute lymphoblastic leukemia and BChE drop > 70% (p < 0.001) was detected. The high disease risk had a close correlation with BChE activity loss (p < 0.0001) and this association was seen also for those patients treated with TBI conditioning (p < 0.05 Table 2; p < 0.001 Table 3).\n\nIn addition, severe iron overload was significantly related to BChE loss (p < 0.05), and abnormal baseline ferritin levels showed high predictive performance for the onset of transplant-related liver damage (AUC = 0.691; 95% CI = 0.62−0.76; p < 0.001). The maximum Youden index was 1028 μg/L for ferritin baseline level, with a corresponding sensitivity of 86.2% and specificity of 53.8%.\n\n3.4. Analysis of the Relationship between the Reduction in Serum BChE Activity Level and the Transplant Outcomes\nWe looked at the association between the decrease in the absolute serum BChE activity values and the onset of transplant-related liver complications (Table 5). The statistical analysis showed that BChE fall < 2000 U/L was associated with the onset of posttransplant liver dysfunction and SOS (p < 0.05). No statistically significant differences in the cumulative incidence of any grade of GVHD (in both the BChE > 2000 U/L and BChE < 2000 U/L groups) were observed. In a follow-up after 12 months, the incidence of overall survival (OS) was significantly higher in the BChE > 2000 U/L group compared with the BChE < 2000 U/L group (84.7% versus 58.5%, p < 0.001). In total, 44 patients (25%) died, 24 (13.4%) for transplant-related complications and 20 (11.4%) for the recurrence of the underlying disease. Transplant-related deaths occurred at a median of 91.7 ± 75.6 days, while disease recurrence deaths at a median of 211.3 ± 78.0 days. The cumulative mortality rate was significantly higher in the BChE < 2000 U/L group compared with the BChE > 2000 U/L group (41.5% versus 15.3%, respectively, p < 0.001), with the same trend observed both for TRM (23.1% versus 8.1%, p < 0.05) and disease recurrence mortality (18.5% versus 7.2%, p < 0.05). BChE activity drop < 2000 U/L was significantly associated with a higher probability of transplant-related death (Odds Ratio (OR) = 3.4; 95% CI = 1.39−8.3; p < 0.005). Two patients died due to VOD in the BChE > 2000 U/L group versus nine patients in the BChE < 2000 U/L; five and four patients, respectively, died due to infections; one and two patients, respectively, died due to acute GVHD; and one patient in the BChE > 2000 U/L group died due to diffuse alveolar hemorrhage.\n\nAnalyzing the association between the percentage reduction in BChE activity and the transplant outcomes (Table 6) we found that overall survival (OS), TRM, and disease recurrence related death were not associated with BChE percentage decrease >70%. Considering all liver dysfunctions, only SOS had a strong association with BChE percentage drop (p < 0.005).\n\nWe evaluated the predictive performance of both absolute and percentage BChE values on day −1 in the diagnosis of SOS, obtaining the respective ROC curves (Figure 3A,B), which showed how the absolute and percentage BChE values performed at similarly high performances (AUC = 0.76; 95% CI = 0.69–0.82; p < 0.001). In trying to identify a cutoff of absolute BChE value on day −1, we found the maximum Youden index was 1571 U/L with specificity of 82.9% and sensitivity of 62.5% for the diagnosis of SOS. Regarding the percentage value, a cutoff of 71.6% correlated to a specificity of 62.9%, although with a sensitivity of 87.5%.\n\nWe looked at the association between the absolute BChE values on day −1 and 1 year posttransplant follow-up outcomes such as, overall survival (OS) and TRM rate. One year OS in the BChE > 2000 U/L group was 84.7% versus 58.5% in the BChE < 2000 U/L group (p < 0.001), while TRM was 8.1% versus 23.1% (p < 0.05), respectively.\n\nKaplan–Meier curve analysis confirmed the statistically higher survival probability (p < 0.0001) (Figure 4A) and lower probability of TRM (p < 0.0001) in the BChE > 2000 U/L group (Figure 4B).\n\nThe apparent increase of mortality between days 0–70 and days 150–250 reflects the common trend of early and late TRM. Early forms are mainly caused by acute GVHD, infections, SOS, and other angiopathic diseases, while late forms by chronic GVHD, pulmonary fibrosis, secondary tumors, and hepatic or kidney insufficiency.\n\nAn analogue Kaplan–Meier analysis was performed to assess TRM considering only patients who underwent an allogenic HSCT for hematologic malignancies. The analysis showed a statistically lower TRM probability (p < 0.05) in the BChE > 2000 U/L group.\n\nFinally, using a Cox proportional-hazards regression model, we investigated the association between TRM and some other variables including type of diagnosis, disease risk, source of stem cells, year of transplantation, type of conditioning, preexisting liver siderosis, or other pretransplant hepatopathy. Both in the BChE > 2000 U/L and in the BChE < 2000 U/L groups, the only variable that turn out to be associated with TRM was disease risk (p < 0.0001).\n\n3.5. Analysis of Patient and Disease Variables Associated with the Risk of Severe Liver Damage Development\nWe studied the possible association between some patient and disease variables and the transplant-related severe liver damage development (Table 7). Of the 176 pediatric patients analyzed, 44 (25%) developed severe liver damage, while 132 (75%) developed no impairment or only a mild grade damage. The patients’ underlying disease and conditioning regimen were not correlated with the risk of liver damage.\n\nHowever, we found that patients with a low risk disease had a lower probability of developing severe liver damage during the follow-up period (27.3% versus 72.7%, p < 0.0001). Severe iron overload and higher serum ferritin levels proved to be related in a statistically significant way to the probability of developing severe liver damage (p < 0.0001 and <0.05, respectively). Among all patients who underwent SOS prophylaxis with defibrotide, we did not identify any case of severe liver damage (p < 0.0001). As a result, overall survival was significantly higher for patients in which liver damage was absent or mild compared with those who had severe liver damage (85.6% versus 43.2%, p < 0.0001).\n\n4. Discussion\nCyclophosphamide is a chemotherapeutic agent widely used in various combinations with other drugs for the treatment of a large number of different malignancies. It is also included in the vast majority of conditioning regimes before HSCT [25]. Hepatic microsomal enzymes convert cyclophosphamide into active cytotoxic metabolites. In particular, the mixed function oxidase system (cytochrome P450) converts cyclophosphamide in 4-hydroxy-cyclophosphamide and aldophosphamide [26]. These metabolites are then transported to the healthy and neoplastic tissues where aldophosphamide is converted to the alkylating phosphoramide mustard and acrolein, which produces reactive oxygen species (ROS) with subsequent oxidative tissue damage. Acrolein also induces cellular damage mediated by lipid peroxidation [27]. Oxidative stress created by cyclophosphamide metabolites and the direct toxicity of aldehydes are responsible for acute tissue toxicity, and in particular of hepatic toxicity [28]. The association between the administration of high-dose cyclophosphamide and a significative reduction in BChE levels has been previously described [29,30,31,32]. The underlying mechanism is not clear, but the rapidity of enzyme inhibition in vitro suggests a direct effect rather than an interference with BChE synthesis [33]. At the same cyclophosphamide dose, the suppression in BChE activity varies widely from patient to patient, and in some cases, can last for several days. Despite these findings, the possible association between the basal value of BChE activity or its reduction with therapy and the incidence of short-term transplant-related liver complications has been never investigated.\n\nIn our study, we analyzed the performance of various commonly used markers such as CRP, total bilirubin, ALT, AST, GGT, in predicting the probability of hepatic transplant-related complication development. Considering their baseline values obtained before starting the conditioning regime, none of these variables showed acceptable predictive performance. Regarding BChE activity level, we found that the baseline values had little predictive significance, while the same measurement obtained on day −1 had high sensitivity and high specificity in predicting hepatic transplant-related complications.\n\nOur analysis shows how the most relevant factors predisposing significant BChE activity reduction are a high disease risk, the use of TBI-based myeloablative conditioning and a severe preexistent iron liver overload. Some of these findings were predictable. Patients with an underlying high-risk disease correspond to those with an advanced stage of pathology which usually had already been subjected to different courses of therapy. In this group of patients, the complexity of the therapies leads to an expected increased drug-induced liver toxicity, as witnessed by the lower basal BChE activity values recorded. In an analogous way, TBI-based conditioning and preexisting iron overload are a well-known risk factor for SOS [34,35,36,37,38], so it is not surprising that BChE reduction is more marked in these groups. Looking at the percentage reduction in BChE activity values, we found that a more significant decrease was associated with the diagnosis of LLA. This data is predictable since TBI is the conditioning choice in this type of patient.\n\nIn terms of predictive performance, our data show the superiority of the absolute BChE activity values compared to the percentage ones. This is mainly due to the significantly higher basal BChE activity level of patients in whom a reduction >70% was detected compared with those included in the group who reached a value <2000 UI/L. In fact, in the first case, a substantial percentage reduction >70% led, in some patients, to absolute values within the limits of the standard range while, in the second, a lower percentage reduction led to very much lower BChE activity reflecting impaired hepatic synthesis.\n\nAnother relevant finding that emerged in our study is the association between BChE activity reduction and the development of hepatic non-immunologic complications due to direct drug-induced or radiotherapy-induced hepatic damage. In contrast, we have not found any association between BChE activity and the incidence or severity of hepatic GVHD.\n\nIt is well known that disease risk, iron overload, ferritin levels, and the presence of preexisting liver disease are all factors correlated with TRM [35,39,40]. In our analysis, the pretransplant liver disease did not prove to be associated with hepatic complications, but this finding is probably due to the low sample size.\n\nOur data confirmed the efficacy of defibrotide administration in the treatment of SOS, with a significant impact in reducing TRM and improving OS. Defibrotide is a complex mixture of polydeoxyribonucleotides with strong protective and anti-inflammatory activities on the vessel endothelium [41,42]. We used it in prevention for a few years in our transplant unit, zeroing SOS incidence in that period. This result is very encouraging considering that the incidence rate of SOS reported in the literature is around 10–15% in allogeneic HSCT recipients after a myeloablative conditioning regime, with the mortality rate in patients with severe SOS still exceeding 80% and 20% in patients with non-severe SOS [43,44]. Unexpectedly, our data showed the increased incidence of relapse in the group of patients treated with defibrotide. This phenomenon is probably due to a significant increase in OS in the defibrotide-treated group.\n\nSo far, SOS represents the main factor involved in TRM. The diagnosis is not always easy since signs and symptoms of SOS may be very insidious, particularly in pediatric patients, or may be confused with other conditions [11]. Early administration of defibrotide is the only effective treatment in the management of SOS, but currently, its use is formally indicated only in cases of severe SOS [45,46]. The prophylactic use of defibrotide is presently off-label. Moreover, its high cost represents a further limitation to its prescription in many centers.\n\nIdentification of markers with high sensitivity and specificity in predicting the risk of SOS is a relevant clinical issue. These selective markers would allow identification of those patients who can benefit from early treatment with defibrotide and to further improve their prognosis. In the past decades, numerous serum and plasma proteins have been investigated [47]. Plasminogen activator inhibitor-1 (PAI-1) is very sensitive, with a negative predictive value of around 100%, but nonspecific, since it does not discriminate between different causes of liver dysfunction [48]. Moreover, the measuring of PAI-1 is not feasible everywhere nor in a real time, and this strongly limits its use in clinical practice. Ultrasonography, computerized tomography, and magnetic resonance imaging may yield abnormal results in patients with SOS [49], but they are unlikely to be used as diagnostics in the early stage of the disease. Liver stiffness measurements with transient elastography have been recently considered as a promising technique in the early diagnosis of SOS [50]. However, elastography has some limitations, such as the high cost of the device and operator-related reliability.\n\nBChE activity level is an inexpensive and quick marker feasible in any laboratory. Its degree of reduction during myeloablative conditioning including cyclophosphamide, correlates with the risk of subsequent SOS development and can be used to identify the high-risk patients.\n\nIn conclusion, we suggest that it could be reasonable to start a prophylactic therapy with defibrotide at the first signs of hepatic dysfunction, even before official diagnostic criteria for SOS are met, in patients at high risk for liver complications in whom a drop in BChE activity values <1800 UI/L is detected.\n\nTo our knowledge, this is the first study addressing the association between BChE reduction during conditioning regimen and transplant outcomes with particular attention to liver damage.\n\nHowever, this study has some limitations that should be considered when interpreting the current findings: First of all, the sample size was relatively small and the follow-up was short term; second, the study was retrospective and monocentric in its nature.\n\nFurther research with a prospective study should be pursued to determine the role of BChE with particular attention to hepatic damage in patients undergoing a conditioning regimen with cyclophosphamide and its association with transplant outcomes.\n\nAcknowledgments\nThis work was supported by an intramural grant from the Institute for Maternal and Child Health–IRCCS “Burlo Garofolo”, Trieste, Italy.\n\nAuthor Contributions\nConception, design of the study, and writing, N.M. and G.C.; collection and analysis of the clinical data, D.Z. and A.M.; original draft preparation, review, and editing, R.S. All authors read and approved the final manuscript.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nConsent for Publication\nInformed consent for publication was obtained and is available for review by the editor.\n\nFigure 1 Diagnostic performance of butyrylcholinesterase (BuChE) activity in predicting the onset of transplant-related liver damage. Receiver operating characteristic (ROC) curves for absolute baseline BuChE activity values (A) and absolute BChE activity values on day −1 (B).\n\nFigure 2 Box-and-whisker plots show a trend of butyrylcholinesterase (BuChE) activity during and after cyclophosphamide treatment.\n\nFigure 3 Predictive performance of butyrylcholinesterase (BuChE) activity on day −1 in the diagnosis of sinusoidal obstruction syndrome (SOS). Receiver operating characteristic (ROC) curves for absolute BuChE activity values (A) and percentage reduction in BChE activity (B).\n\nFigure 4 Kaplan–Meier curve analysis of the survival probability (A) and transplant-related mortality (B).\n\njcm-08-00825-t001_Table 1Table 1 Patient demographics.\n\nPre-Transplant Baseline Characteristics\tWhole Cohort\t\n\nNumber of patients (%)\n\t176 (100)\t\n\nSex:\n\t\n\t\nMale (%)\t110 (62.5)\t\nFemale (%)\t66 (37.5)\t\n\nAge at transplant, years (mean [± SD])\n\t9.2 (5.1)\t\n\nUnderlying disease, number (%):\n\t\n\t\nAcute lymphoblastic leukemia\t65 (36.9)\t\nAcute myeloid leukemia\t33 (18.8)\t\nMyelodysplastic syndrome\t22 (11.9)\t\nSolid tumour\t22 (11.9)\t\nNonmalignant disorders\t34 (19.3)\t\n\nDisease risk, number (%): *\n\t\n\t\nLow\t109 (61.9)\t\nHigh\t67 (38.1)\t\n\nMyeloablative conditioning, number (%):\n\t\n\t\nMCHT-based\t113 (64.2)\t\nTBI-based\t63 (35.8)\t\n\nCyclophosphamide total dose, mg/m2, (mean [± SD])\n\t3499.4 (217.7)\t\n\nType of transplantation, number (%):\n\t\n\t\nAllogeneic\t162 (92.0)\t\nAutologous\t14 (8.0)\t\n\nGraft source, number (%):\n\t\n\t\nBone marrow\t127 (72.2)\t\nPeripheral blood stem cells\t39 (22.2)\t\nUmbilical cord blood\t10 (5.7)\t\n\nAllogeneic donor type, number (%):\n\t\n\t\nMatched related donor\t51 (31.5)\t\nMatched unrelated donor \t77 (47.5)\t\nHaploidentical donor\t34 (21.0)\t\n\nLiver disorders at transplant, number (%):\n\t\n\t\nSiderosis\t126 (71.6)\t\nViral hepatitis\t11 (6.3)\t\nMetabolic liver disease\t11 (6.3)\t\nAutoimmune hepatitis\t5 (2.8)\t\nMCHT, myeloablative chemotherapy; TBI, total body irradiation; SD, standard deviation. * Disease risk was defined according to previously published classification.\n\njcm-08-00825-t002_Table 2Table 2 Diagnostic performance of serum biochemical markers in predicting transplant-related liver dysfunction.\n\nBiochemical Markers *\tAUC—ROC\n(95% CI)\tROC—Significant Value (p)\tMaximum Youden Index (Cut-Off)\tSensitivity\n(%)\tSpecificity\n(%)\t\n\nC-reactive protein (mg/dL)\n\t0.591 (0.514–0.664)\tNS\t0.5\t86.2\t34.7\t\n\nγGT (U/mL)\n\t0.607 (0.530–0.681)\tNS\t77\t27.6\t93.7\t\n\nALT (U/mL)\n\t0.598 (0.521–0.672)\tNS\t28\t55.2\t65.5\t\n\nAST (U/mL)\n\t0.554 (0.477–0.630)\tNS\t20\t62.1\t57.2\t\n\nTotal bilirubin (mg/dL)\n\t0.583 (0.506–0.657)\tNS\t0.29\t100\t22.1\t\n\nBChE (U/L)\n\t0.800 (0.733–0.857)\t<0.0001\t1799\t72.4\t80.8\t\n* Biochemical markers evaluated the day before HSCT (day −1). γGT, γ-glutamyltranspeptidase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BChE, butyrylcholinesterase; AUC-ROC, area under the receiver operating characteristic curve; CI, confidence interval.\n\njcm-08-00825-t003_Table 3Table 3 Patient characteristics associated with drop of BChE absolute values on day −1.\n\nVariables\tBChE > 2000 U/L\tBChE < 2000 U/L \tp-Value *\t\n\nNumber of patients (%)\n\t111 (63.1)\t65 (36.9)\t-\t\n\nGender:\n\t\n\t\n\t\n\t\nMale (%)\t73 (65.8)\t41 (63.1)\tNS\t\nFemale (%)\t38 (34.2)\t24 (36.9)\t-\t\n\nAge at transplant, (years, median [IQR])\n\t9 (4–13) \t9 (5–14) \tNS **\t\n\nUnderlying disease, number (%):\n\t\n\t\n\t\n\t\nAcute lymphoblastic leukemia\t36 (32.4)\t29 (44.6)\tNS\t\nAcute myeloid leukemia\t25 (22.5)\t8 (12.3)\tNS\t\nMyelodysplastic syndrome\t16 (14.4)\t6 (9.2)\tNS\t\nSolid tumor\t11 (9.9)\t11 (16.9)\tNS\t\nNonmalignant disorders\t23 (20.7)\t11 (16.9)\tNS\t\n\nDisease risk, number (%):\n\t\n\t\n\t\n\t\nLow\t86 (77.5)\t24 (36.9)\t<0.0001\t\nHigh\t25 (22.5)\t41 (63.1)\t-\t\n\nMyeloablative conditioning, number (%):\n\t\n\t\n\t\n\t\nMCHT-based\t78 (70.3)\t35 (53.8)\t<0.05\t\nTBI-based\t33 (29.7)\t30 (46.2)\t-\t\n\nLiver iron overload, number (%):\n\t\n\t\n\t\n\t\nAbsent\t34 (30.6)\t16 (24.6)\tNS\t\nMild\t22 (19.8)\t9 (13.8)\tNS\t\nModerate\t22 (19.8)\t8 (12.3)\tNS\t\nSevere\t33 (29.7)\t32 (49.2)\t<0.05\t\n\nBaseline BChE value, (U/L, median [IQR])\n\t7789 (6028–9218)\t6780 (4889–8031)\t<0.05 **\t\n\nSerum ferritin, (μg/L, median [IQR])\n\t989 (343–2012)\t1680 (402–2877)\tNS **\t\n\nLiver disease, number (%)\n\t16 (14.4)\t17 (26.1)\tNS\t\n\nDefibrotide prophylaxis, number (%)\n\t41 (36.9)\t27 (41.5)\tNS\t\n\nUDCA prophylaxis, number (%)\n\t109 (98.2)\t60 (92.3)\tNS\t\n\nHDNAC prophylaxis, number (%)\n\t72 (64.8)\t39 (60.0)\tNS\t\nFerritin normal range 3.0–88.0 μg/L. IQR, interquartile range; UDCA, ursodeoxycholic acid; HDNAC, high-dose N-acetylcysteine. * Fisher’s test. ** U-Test (Mann–Whitney).\n\njcm-08-00825-t004_Table 4Table 4 Patient characteristics associated with percentage drop of BChE values on day −1.\n\nVariables\tBChE Drop < 70%\tBChE Drop > 70%\tp-Value *\t\n\nNumber of patients (%)\n\t94 (53.4) \t82 (46.6)\t-\t\n\nGender:\n\t\n\t\n\t\n\t\nMale (%)\t66 (70.2)\t48 (58.5)\tNS\t\nFemale (%)\t28 (29.8)\t34 (41.5)\t-\t\n\nAge at transplant, (years, median [IQR])\n\t7 (4–13)\t10 (6–13)\tNS **\t\n\nUnderlying disease, number (%):\n\t\n\t\n\t\n\t\nAcute lymphoblastic leukemia\t26 (27.7)\t39 (47.6)\t<0.001\t\nAcute myeloid leukemia\t20 (19.7)\t13 (9.7)\tNS\t\nMyelodysplastic syndrome\t16 (17.0)\t6 (7.3)\tNS\t\nSolid tumor\t12 (12.8)\t10 (12.2)\tNS\t\nNonmalignant disorders\t20 (19.7)\t14 (17.1)\tNS\t\n\nDisease risk, number (%):\n\t\n\t\n\t\n\t\nLow\t67 (71.3)\t34 (41.5)\t<0.0001\t\nHigh\t27 (28.7)\t48 (58.5)\t-\t\n\nMyeloablative conditioning, number (%):\n\t\n\t\n\t\n\t\nMCHT-based\t71 (75.5)\t42 (51.2)\t<0.001\t\nTBI-based\t23 (24.4)\t40 (48.8)\t-\t\n\nLiver iron overload, number (%):\n\t\n\t\n\t\n\t\nAbsent\t29 (30.9)\t21 (25.6)\tNS\t\nMild\t19 (20.2)\t12 (14.6)\tNS\t\nModerate\t20 (21.3)\t10 (12.2)\tNS\t\nSevere\t26 (27.7)\t39 (47.6)\t<0.05\t\n\nBaseline BChE value, (U/L, median [IQR])\n\t6815 (5115–8361)\t7897 (6706–9408)\t<0.001 **\t\n\nSerum ferritin, (μg/L, median [IQR])\n\t950.1 (322–2135)\t1474.4 (406–2440)\tNS **\t\n\nLiver disease, number (%):\n\t19 (20.2)\t16 (19.5)\tNS\t\n\nDefibrotide prophylaxis, number (%)\n\t31 (33.0)\t37 (45.1)\tNS\t\n\nUDCA prophylaxis, number (%)\n\t92 (97.9)\t77 (93.9)\tNS\t\n\nHDNAC prophylaxis, number (%)\n\t58 (61.7)\t53 (64.6)\tNS\t\nBChE, butyrylcholinesterase (normal range for male 4620–11,500 U/L, for female 3930–10,800 U/L). Ferritin normal range 3.0–88.0 μg/L. IQR, interquartile range; UDCA, ursodeoxycholic acid; HDNAC, high dose N-acetylcysteine. * Fisher’s test. ** U-Test (Mann–Whitney).\n\njcm-08-00825-t005_Table 5Table 5 Association between minimum values of BChE activity and transplant outcomes.\n\nVariables\tBChE > 2000 U/L\tBChE < 2000 U/L\tp-Value *\t\n\nPatients, number (%)\n\t111 (63.1)\t65 (36.9)\t-\t\n\nLiver dysfunction, number (%)\n\t47 (42.3)\t42 (64.6)\t<0.05\t\n\nSOS, number (%)\n\t5 (4.5)\t11 (16.9)\t<0.05\t\n\nAllogeneic recipients, number (%)\n\t103 (58.5)\t59 (33.5)\t-\t\n\nLiver GVHD, number (%): #\n\t\n\t\n\t\n\t\nAbsent\t68 (66.0)\t33 (55.9)\tNS\t\nI grade\t12 (11.6)\t4 (6.8)\tNS\t\nII grade\t8 (7.8)\t8 (13.6)\tNS\t\nIII grade\t10 (9.7)\t7 (11.9)\tNS\t\nIV grade\t5 (4.9)\t7 (11.9)\tNS\t\n\nOverall survival, number (%)\n\t94 (84.7)\t38 (58.5)\t<0.001\t\n\nDeath, number (%):\n\t17 (15.3)\t27 (41.5)\t<0.001\t\nTransplant-related\t9 (8.1)\t15 (23.1)\t<0.05\t\nRelapse\t8 (7.2)\t12 (18.5)\t<0.05\t\nBChE, butyrylcholinesterase (normal range for male 4620–11,500 U/L, for female 3930–10,800 U/L). SOS, sinusoidal obstruction syndrome. * Fisher’s test. # Percentages of liver GVHD calculated on the population of allogeneic recipients.\n\njcm-08-00825-t006_Table 6Table 6 Association between percentage drop of BChE values and transplant outcomes.\n\nVariables\tBChE Drop < 70%\tBChE Drop > 70%\tp-Value *\t\n\nPatients, number (%)\n\t94 (53.4)\t82 (46.6)\t-\t\n\nLiver dysfunction, number (%)\n\t53 (56.4)\t36 (43.9)\tNS\t\n\nSOS, number (%)\n\t2 (2.1)\t14 (17.1)\t<0.005\t\n\nAllogeneic recipients, number (%)\n\t86 (48.9)\t76 (43.2)\t-\t\n\nLiver GVHD, number (%): #\n\t\n\t\n\t\n\t\nAbsent\t57 (66.3)\t44 (57.9)\tNS\t\nI grade\t8 (9.3)\t8 (10.5)\tNS\t\nII grade\t8 (9.3)\t8 (10.5)\tNS\t\nIII grade\t7 (8.1)\t10 (13.2)\tNS\t\nIV grade\t6 (7.0)\t6 (7.9)\tNS\t\n\nOverall survival, number (%)\n\t75 (79.8)\t57 (75.0)\tNS\t\n\nDeath, number (%):\n\t19 (20.2)\t25 (30.5)\tNS\t\nTransplant-related\t9 (9.6)\t15 (18.3)\tNS\t\nRelapse\t10 (10.6)\t10 (12.2)\tNS\t\nBChE, butyrylcholinesterase (normal range for male 4620–11,500 U/L, for female 3930–10,800 U/L); SOS, sinusoidal obstruction syndrome. * Fisher’s test. # Percentages of liver GVHD calculated on the population of allogeneic recipients.\n\njcm-08-00825-t007_Table 7Table 7 Association between patient transplant-related characteristics and transplant-related liver disease.\n\nVariables\tSevere Liver Damage\tLiver Damage Absent or Mild\tp-Value *\t\n\nNumber of patients (%)\n\t44 (25)\t132 (75)\t-\t\n\nUnderlying disease, number (%):\n\t\n\t\n\t\n\t\nAcute lymphoblastic leukemia\t18 (40.9)\t47 (35.6)\tNS\t\nAcute myeloid leukemia\t11 (25)\t22 (16.7)\tNS\t\nOther\t15 (34.1)\t63 (47.7)\tNS\t\n\nDisease risk, number (%):\n\t\n\t\n\t\n\t\nLow\t12 (27.3)\t97 (73.5)\t<0.0001\t\nHigh\t32 (72.7)\t35 (26.5)\t-\t\n\nMyeloablative conditioning, number (%)\n\t\n\t\n\t\n\t\nMCHT-based\t31 (70.5)\t82 (62.1)\tNS\t\nTBI-based\t13 (29.5)\t50 (37.9)\tNS\t\n\nIron overload, number (%)\n\t\n\t\n\t\n\t\nFrom absent to moderate\t13 (29.5)\t98 (74.2)\t<0.0001\t\nSevere\t31 (70.5)\t34 (25.8)\t<0.0001\t\n\nBaseline BChE value, (U/L, median [IQR])\n\t6815 (4934–8640)\t7655(5773–8827)\tNS **\t\n\nSerum ferritin, (μg/L, median [IQR])\n\t2052 (1329–3112)\t974 (329–2048)\t<0.05 **\t\n\nPre-transplant liver disease, number (%):\n\t9 (20.4)\t28 (21.2)\tNS\t\n\nDefibrotide prophylaxis, number (%)\n\t-\t68 (51.5)\t<0.0001\t\n\nHDNAC prophylaxis, number (%)\n\t25 (56.8)\t86 (65.2)\tNS\t\n\nOverall survival, number (%)\n\t19 (43.2)\t113 (85.6)\t<0.0001\t\n\nDeath, number (%):\n\t25 (56.8)\t19 (14.4)\t<0.0001\t\nTransplant-related\t23 (52.3)\t1 (0.8)\t<0.0001\t\nRelapse\t2 (4.5)\t18 (13.6)\t<0.0001\t\nSevere liver damage group included patients with SOS and liver dysfunction grade 3. BChE, butyrylcholinesterase; HDNAC, high-dose N-acetylcysteine. * Fisher’s test. ** U-Test (Mann–Whitney).\n==== Refs\nReferences\n1. Niederwieser D. Baldomero H. Szer J. Gratwohl M. Aljurf M. Atsuta Y. Bouzas L.F. Confer D. Greinix H. Horowitz M. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey Bone Marrow Transplant. 2016 51 778 785 10.1038/bmt.2016.18 26901703 \n2. Shenoy S. Smith F.O. Hematopoietic stem cell transplantation for childhood malignancies of myeloid origin Bone Marrow Transplant. 2008 41 141 148 10.1038/sj.bmt.1705961 18176616 \n3. Jessop H. Farge D. Saccardi R. Alexander T. Rovira M. Sharrack B. Greco R. Wulffraat N. Moore J. Kazmi M. General information for patients and carers considering haematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (ADs): A position statement from the EBMT Autoimmune Diseases Working Party (ADWP), the EBMT Nurses Group, the EBMT Patient, Family and Donor Committee and the Joint Accreditation Committee of ISCT and EBMT (JACIE) Bone Marrow Transplant. 2019 10.1038/s41409-019-0430-7 \n4. Thorvaldson L. Remberger M. Winiarski J. Omazic B. Fischler B. Sundin M. HLA, GVHD, and parenteral nutrition are risk factors for hepatic complications in pediatric HSCT Pediatr. Transplant. 2016 20 96 104 10.1111/petr.12623 26518451 \n5. Strasser S.I. Myerson D. Spurgeon C.L. Sullivan K.M. Storer B. Schoch H.G. Kim S. Flowers M.E. McDonald G.B. Hepatitis C virus infection and bone marrow transplantation: A cohort study with 10-year follow-up Hepatology 1999 29 1893 1899 10.1002/hep.510290609 10347135 \n6. Nakasone H. Kurosawa S. Yakushijin K. Taniguchi S. Murata M. Ikegame K. Kobayashi T. Eto T. Miyamura K. Sakamaki H. Impact of hepatitis C virus infection on clinical outcome in recipients after allogeneic hematopoietic cell transplantation Am. J. Hematol. 2013 88 477 484 10.1002/ajh.23436 23483626 \n7. McDonald G.B. Frieze D. A problem-oriented approach to liver disease in oncology patients Gut 2008 57 987 1003 10.1136/gut.2007.131136 18559388 \n8. Sakamoto S. Kawabata H. Kanda J. Uchiyama T. Mizumoto C. Kondo T. Yamashita K. Ichinohe T. Ishikawa T. Kadowaki N. Differing impacts of pretransplant serum ferritin and C-reactive protein levels on the incidence of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation Int. J. Hematol. 2013 97 109 116 10.1007/s12185-012-1229-0 23225486 \n9. Maximova N. Sonzogni A. Matarazzo L. Ghirardi A. D’Antiga L. 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Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: A new classification from the European society for blood and marrow transplantation Bone Marrow Transplant. 2018 53 138 145 10.1038/bmt.2017.161 28759025 \n13. Peng Z.L. Huang L.W. Yin J. Zhang K.N. Xiao K. Qing G.Z. Association between early serum cholinesterase activity and 30-day mortality in sepsis-3 patients: A retrospective cohort study PLoS ONE 2018 13 e0203128 10.1371/journal.pone.0203128 30161257 \n14. Sun L. Qi X. Tan Q. Yang H. Qi X. Low Serum-Butyrylcholinesterase Activity as a Prognostic Marker of Mortality Associates with Poor Cardiac Function in Acute Myocardial Infarction Clin. Lab. 2016 62 1093 1099 10.7754/Clin.Lab.2015.151013 27468571 \n15. Ba L. Wu D.Q. Qian A.Y. Zhang M. Xiong B. Dynamic changes of serum cholinesterase activity after severe trauma J. Zhejiang Univ. Sci. B 2014 15 1023 1031 10.1631/jzus.B1400129 25471831 \n16. Chiarla C. Giovannini I. Giuliante F. Vellone M. Ardito F. Nuzzo G. Plasma cholinesterase correlations in acute surgical and critical illness Minerva Chir. 2011 66 323 327 21873967 \n17. Lampón N. Hermida-Cadahia E.F. Riveiro A. Tutor J.C. Association between butyrylcholinesterase activity and low-grade systemic inflammation Ann. Hepatol. 2012 11 356 363 10.1016/S1665-2681(19)30932-9 22481455 \n18. Feng W. Tang C. Guo H. Bao Y. Wen X. Xue T. Gong H. Prognostic value of serum cholinesterase activities in sepsis patients Hepato-Gastroenterology 2013 60 1001 1005 23719062 \n19. Arndt C. Beck J.F. Gruhn B. A pediatric prognostic score for patients undergoing allogeneic hematopoietic stem cell transplantation Eur. J. Haematol. 2014 93 509 515 10.1111/ejh.12390 24889859 \n20. Maximova N. Schillani G. Simeone R. Maestro A. Zanon D. Comparison of Efficacy and Safety of Caspofungin Versus Micafungin in Pediatric Allogeneic Stem Cell Transplant Recipients: A Retrospective Analysis Adv. Ther. 2017 34 1184 1199 10.1007/s12325-017-0534-7 28429246 \n21. Jensen P.D. Jensen F.T. Christensen T. Ellegaard J. Evaluation of transfusional iron overload before and during iron chelation by magnetic resonance imaging of the liver and determination of serum ferritin in adult non-thalassaemic patients Br. J. Haematol. 1995 89 880 889 10.1111/j.1365-2141.1995.tb08428.x 7772526 \n22. Maximova N. Gregori M. Zennaro F. Sonzogni A. Simeone R. Zanon D. Hepatic Gadolinium Deposition and Reversibility after Contrast Agent-enhanced MR Imaging of Pediatric Hematopoietic Stem Cell Transplant Recipients Radiology 2016 281 418 426 10.1148/radiol.2016152846 27276243 \n23. Yoon J.H. Yoo K.H. Sung K.W. Jung C.W. Kim J.S. Hahn S.M. Kang H.J. Lee J.H. Im H.J. Ahn J.S. Validation of treatment outcomes according to revised severity criteria from European Society for Blood and Marrow Transplantation (EBMT) for sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) Bone Marrow Transplant. 2019 10.1038/s41409-019-0492-6 \n24. Przepiorka D. Weisdorf D. Martin P. Klingemann H.G. Beatty P. Hows J. Thomas E.D. 1994 consensus conference on acute GVHD grading Bone Marrow Transplant. 1995 15 825 828 7581076 \n25. Bahloul M. Baccouch N. Chtara K. Turki M. Turki O. Hamida C.B. Chelly H. Ayedi F. Chaari A. Bouaziz M. Value of Serum Cholinesterase Activity in the Diagnosis of Septic Shock Due to Bacterial Infections J. Intensive Care Med. 2017 32 346 352 10.1177/0885066616636549 26951579 \n26. Ahlmann M. Hempel G. The effect of cyclophosphamide on the immune system: Implications for clinical cancer therapy Cancer Chemother. Pharmacol. 2016 78 661 671 10.1007/s00280-016-3152-1 27646791 \n27. Yule S.M. Boddy A.V. Cole M. Price L. Wyllie R. Tasso M.J. Pearson A.D. Idle J.R. Cyclophosphamide metabolism in children Cancer Res. 1995 55 803 809 7850793 \n28. Shokrzadeh M. Ahmadi A. Naghshvar F. Chabra A. Jafarinejhad M. Prophylactic efficacy of melatonin on cyclophosphamide-induced liver toxicity in mice BioMed Res. Int. 2014 2014 470425 10.1155/2014/470425 25101283 \n29. Zhai X. Zhang Z. Liu W. Liu B. Zhang R. Wang W. Zheng W. Xu F. Wang J. Chen Y. Protective effect of ALDH2 against cyclophosphamide-induced acute hepatotoxicity via attenuating oxidative stress and reactive aldehydes Biochem. Biophys. Res. Commun. 2018 499 93 98 10.1016/j.bbrc.2018.03.041 29524404 \n30. Bodur E. Human serum butyrylcholinesterase interactions with cisplatin and cyclophosphamide Biochimie 2010 92 979 984 10.1016/j.biochi.2010.04.010 20417682 \n31. Zsigmond E.K. Robins G. The effect of a series of anti-cancer drugs on plasma cholinesterase activity Can. Anaesth. Soc. J. 1972 19 75 82 10.1007/BF03006910 4257896 \n32. Bellardo A. Pecchio F. Manca A. Sartoris S. Airoldi M. Fazio M. Administration of cyclophosphamide determines the lowering of serum cholinesterase levels Boll. Soc. Ital. Biol. Sper. 1980 56 1329 1333 7448029 \n33. Wang R.I. Ross C.A. Prolonged apnea following succinylcholine in cancer patients receiving AB-132 Anesthesiology 1963 24 363 367 10.1097/00000542-196305000-00018 13998795 \n34. Al-Jafari A.A. Duhaiman A.S. Kamal M.A. Inhibition of human acetylcholinesterase by cyclophosphamide Toxicology 1995 96 1 6 10.1016/0300-483X(94)02848-O 7863507 \n35. Corbacioglu S. Jabbour E.J. Mohty M. Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Biol. Blood Marrow Transplant. 2019 10.1016/j.bbmt.2019.02.018 \n36. Maximova N. Gregori M. Boz G. Simeone R. Zanon D. Schillani G. Zennaro F. MRI-based evaluation of multiorgan iron overload is a predictor of adverse outcomes in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation Oncotarget 2017 8 79650 79661 10.18632/oncotarget.19021 29108345 \n37. Barker C.C. Butzner J.D. Anderson R.A. Brant R. Sauve R.S. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients Bone Marrow Transplant. 2003 32 79 87 10.1038/sj.bmt.1704069 12815482 \n38. Maximova N. Ferrara G. Minute M. Pizzol A. Kiren V. Montico M. Gregori M. Tamaro P. Experience from a single paediatric transplant centre with identification of some protective and risk factors concerning the development of hepatic veno-occlusive disease in children after allogeneic hematopoietic stem cell transplant Int. J. Hematol. 2014 99 766 772 10.1007/s12185-014-1578-y 24715523 \n39. Dalle J.H. Giralt S.A. 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Escolar G. Carreras E. Defibrotide prevents the activation of macrovascular and microvascular endothelia caused by soluble factors released to blood by autologous hematopoietic stem cell transplantation Biol. Blood Marrow Transplant. 2011 17 497 506 10.1016/j.bbmt.2010.11.019 21126597 \n44. Mohty M. Malard F. Abecassis M. Aerts E. Alaskar A.S. Aljurf M. Arat M. Bader P. Baron F. Bazarbachi A. Sinusoidal obstruction syndrome/veno-occlusive disease: Current situation and perspectives—A position statement from the European Society for Blood and Marrow Transplantation (EBMT) Bone Marrow Transplant. 2015 50 781 789 10.1038/bmt.2015.52 25798682 \n45. Richardson P.G. Carreras E. Iacobelli M. Nejadnik B. The use of defibrotide in blood and marrow transplantation Blood Adv. 2018 2 1495 1509 10.1182/bloodadvances.2017008375 29945939 \n46. Defitelio (Defibrotide Sodium) Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/defitelio-defibrotide-sodium (accessed on 28 October 2018) \n47. Park Y.D. Yasui M. Yoshimoto T. Chayama K. Shimono T. Okamura T. Inoue M. Yumura-Yagi K. Kawa-Ha K. Changes in hemostatic parameters in hepatic veno-occlusive disease following bone marrow transplantation Bone Marrow Transplant. 1997 19 915 920 10.1038/sj.bmt.1700760 9156266 \n48. Pihusch M. Wegner H. Goehring P. Salat C. Pihusch V. Hiller E. Andreesen R. Kolb H.J. Holler E. Pihusch R. Diagnosis of hepatic veno-occlusive disease by plasminogen activator inhibitor-1 plasma antigen levels: A prospective analysis in 350 allogeneic hematopoietic stem cell recipients Transplantation 2005 80 1376 1382 10.1097/01.tp.0000183288.67746.44 16340778 \n49. Ravaioli F. Colecchia A. Alemanni L.V. Vestito A. Dajti E. Marasco G. Sessa M. Pession A. Bonifazi F. Festi D. Role of imaging techniques in liver veno-occlusive disease diagnosis: Recent advances and literature review Expert Rev. Gastroenterol. Hepatol. 2019 13 463 484 10.1080/17474124.2019.1588111 30895833 \n50. Colecchia A. Ravaioli F. Sessa M. Alemanni V.L. Dajti E. Marasco G. Vestito A. Zagari R.M. Barbato F. Arpinati M. Liver Stiffness Measurement Allows Early Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Adult Patients Who Undergo Hematopoietic Stem Cell Transplantation: Results from a Monocentric Prospective Study Biol. Blood Marrow Transplant. 2019 25 995 1003 10.1016/j.bbmt.2019.01.019 30660772\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "8(6)",
"journal": "Journal of clinical medicine",
"keywords": "cyclophosphamide; defibrotide; liver transplant-related complications; pediatric transplant recipients; serum butyrylcholinesterase activity",
"medline_ta": "J Clin Med",
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"pages": null,
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"pmid": "31185690",
"pubdate": "2019-06-10",
"publication_types": "D016428:Journal Article",
"references": "10347135;12098067;12815482;13998795;16340778;18176616;18559388;19041609;19456210;19766729;20417682;21126597;21873967;22481455;23225486;23483626;23719062;24715523;24889859;25101283;25315987;25471831;25798682;26431626;26518451;26901703;26951579;27276243;27468571;27646791;28429246;28759025;29108345;29524404;29945939;30026108;30161257;30660772;30705338;30797942;30809031;30895833;4257896;7448029;7581076;7772526;7850793;7863507;9156266",
"title": "Drop of Butyrylcholinesterase Activity after Cyclophosphamide Conditioning as a Predictive Marker of Liver Transplant-Related Complications and Its Correlation with Transplant-Related Mortality in Pediatric Hematopoietic Stem Cell Recipients.",
"title_normalized": "drop of butyrylcholinesterase activity after cyclophosphamide conditioning as a predictive marker of liver transplant related complications and its correlation with transplant related mortality in pediatric hematopoietic stem cell recipients"
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"abstract": "Checkpoint inhibitors are introduced as a therapy for clinical use for various cancers, and clinicians are documenting new adverse effects. This is the first case report to the best of our knowledge of a patient on checkpoint inhibitor presenting with both polyendocrinopathy and gangrenous gallbladder disease with a mass negative for malignancy.71-year-old man presented four years after his initial diagnosis of stage IV, unresectable, non-ulcerated, acryl, lentiginous malignant melanoma. On presentation, he had gangrenous cholecystitis and was treated with laparoscopic cholecystectomy. Incidentally, the patient was diagnosed two years ago with hypothyroidism, hypophysitis, secondary adrenal insufficiency, and pneumonitis, each suspected to be secondary to treatment with pembrolizumab (Keytruda), a monoclonal anti-programmed cell death-1 antibody. He presented to the emergency department for a gallbladder attack and underwent successful laparoscopic cholecystectomy. The intra-operative finding on opening the specimen was an unusual looking exophytic mass but was negative for malignancy on pathology report and reported as gangrenous cholecystitis. His clinical condition before and after surgery was complicated by worsening comorbidities thought to be secondary to pembrolizumab therapy, which required acute care hospitalizations in the weeks before and after his presentation with cholecystitis. The patient had a few admissions from other co-morbidities post-surgery and was doing better. Immunotherapy with pembrolizumab may have secondary and tertiary effects with unusual presentations that are difficult to interpret for the primary oncology team and even tougher to do for community physicians who may subsequently encounter these patients. The relationship of this patient's comorbidities with immune-related adverse events was not apparent until record requests were conducted after surgery and are still not entirely clear after a literature review. More data is needed to guide decision algorithms and to predict which patients may experience these effects.",
"affiliations": "Surgery, California Northstate University, Elk Grove, USA.;Internal Medicine, San Joaquin General Hospital, French Camp, USA.;Surgery, San Joaquin General Hospital, French Camp, USA.;Bioengineering, University of California, Berkeley, USA.;Surgery, San Joaquin General Hospital, French Camp, USA.",
"authors": "Fernandes|Nayson L|NL|;Sodavarapu|Soujanya|S|;Nedopil|Sukhmine|S|;Mohapatra|Nikita|N|;Vyas|Dinesh|D|",
"chemical_list": null,
"country": "United States",
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"doi": "10.7759/cureus.8786",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8786\nGeneral Surgery\nOncology\nCheckpoint Inhibitor in a Melanoma Patient With Polyendocrinopathy and Gangrenous Gallbladder With a Mass\nMuacevic Alexander Adler John R Fernandes Nayson L 1 Sodavarapu Soujanya 2 Nedopil Sukhmine 3 Mohapatra Nikita 4 Vyas Dinesh 3 \n1 \nSurgery, California Northstate University, Elk Grove, USA \n\n2 \nInternal Medicine, San Joaquin General Hospital, French Camp, USA \n\n3 \nSurgery, San Joaquin General Hospital, French Camp, USA \n\n4 \nBioengineering, University of California, Berkeley, USA \n\nDinesh Vyas dineshvyas@yahoo.com\n23 6 2020 \n6 2020 \n12 6 e87864 6 2020 23 6 2020 Copyright © 2020, Fernandes et al.2020Fernandes 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/34719-checkpoint-inhibitor-in-a-melanoma-patient-with-polyendocrinopathy-and-gangrenous-gallbladder-with-a-massCheckpoint inhibitors are introduced as a therapy for clinical use for various cancers, and clinicians are documenting new adverse effects. This is the first case report to the best of our knowledge of a patient on checkpoint inhibitor presenting with both polyendocrinopathy and gangrenous gallbladder disease with a mass negative for malignancy.71-year-old man presented four years after his initial diagnosis of stage IV, unresectable, non-ulcerated, acryl, lentiginous malignant melanoma. On presentation, he had gangrenous cholecystitis and was treated with laparoscopic cholecystectomy. Incidentally, the patient was diagnosed two years ago with hypothyroidism, hypophysitis, secondary adrenal insufficiency, and pneumonitis, each suspected to be secondary to treatment with pembrolizumab (Keytruda), a monoclonal anti-programmed cell death-1 antibody. He presented to the emergency department for a gallbladder attack and underwent successful laparoscopic cholecystectomy. The intra-operative finding on opening the specimen was an unusual looking exophytic mass but was negative for malignancy on pathology report and reported as gangrenous cholecystitis. His clinical condition before and after surgery was complicated by worsening comorbidities thought to be secondary to pembrolizumab therapy, which required acute care hospitalizations in the weeks before and after his presentation with cholecystitis. The patient had a few admissions from other co-morbidities post-surgery and was doing better. Immunotherapy with pembrolizumab may have secondary and tertiary effects with unusual presentations that are difficult to interpret for the primary oncology team and even tougher to do for community physicians who may subsequently encounter these patients. The relationship of this patient’s comorbidities with immune-related adverse events was not apparent until record requests were conducted after surgery and are still not entirely clear after a literature review. More data is needed to guide decision algorithms and to predict which patients may experience these effects.\n\npembrolizumabkeytrudacheckpoint inhibitorsmalignant melanomapolyendocrinopathycholecystitistransaminitischolecystectomyhypophysitisadrenal insufficiencyThe 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\nImmunotherapy with checkpoint inhibitors has revolutionized the care of advanced melanoma. Patients with inoperable metastatic melanoma have a chance to not only slow cancer progression but to stop and reverse it, with fewer side effects as compared to conventional chemotherapy [1-2]. These promises have led to a rapid increase in the use of checkpoint inhibitors and increased longevity for terminally ill cancer patients. Side effects, while rare, can be life-threatening and require early recognition and prompt interventions to ensure survival. We describe a case of a 71-year-old man with inoperable metastatic melanoma on pembrolizumab treatment who presented to a community hospital not involved with his oncology care with acute acalculous cholecystitis superimposed over chronic pneumonitis and polyendocrinopathy secondary to pembrolizumab treatment.\n\nCase presentation\nA 71-year-old man, with a history of hypertension, diabetes, gout, hypothyroidism from radioactive ablation of Grave’s disease, atrial fibrillation, and metastatic melanoma, complained of fever, abdominal pain associated with nausea, and non-bloody vomitus since two days. The patient has a history of wide lesion excision with a split-thickness graft a year prior, treated with pembrolizumab (cycle 11), and side effects secondary to pembrolizumab, including dermatitis, pneumonitis, hypophysitis, and adrenal insufficiency treated with high dose steroids. At presentation, the patient was febrile, tachycardic at 90 beats/min, and tachypneic at 23/minute. The physical exam was significant tenderness to palpation in the right lower quadrant, with a negative Murphy’s sign. Blood workup showed elevated liver function tests with alkaline phosphatase 492.0 IU/L, alanine transaminase 146 IU/L, aspartate transaminase 125 IU/L, and total bilirubin 4.8 mg/dL. Ultrasound of the abdomen showed an abnormal thick-walled gallbladder with pericholecystic fluid, internal debris/ sludge, and common bile duct (CBD) diameter of 6 mm. Ultrasound done four weeks prior was unremarkable. Computed tomography (CT) of the abdomen with contrast showed distended gallbladder with internal debris, pericholecystic fluid, and wall thickening highly suggestive of cholecystitis (Figure 1). Magnetic resonance imaging (MRI) abdomen showed acute cholecystitis, nobiliary dilatation, or choledocholithiasis. Subsequently, endoscopic retrograde cholangiopancreatography (ERCP) was done with biliary sphincterotomy, and multiple balloon sweeps of the CBD showed a normal appearance. The Cholangiogram at the end of ERCP was normal as well. The patient was diagnosed with acute acalculous cholecystitis and laparoscopic cholecystectomy was performed without complications.\n\nFigure 1 Computed tomography of the abdomen with contrast showing distended gallbladder with surrounding inflammatory changes \nMicroscopic analysis of the gallbladder specimen revealed acute and chronic inflammatory cells, necrotizing inflammation, and gangrenous necrosis. Blood cultures have been negative. No dysplasia or malignancy was identified. Postoperatively, the patient was hemodynamically stable and was discharged. The patient had shock-like episodes over the next month, requiring multiple hospitalizations. Workup during these hospitalizations was consistent with pneumonitis and continued transaminitis that his primary oncology team suspected to be melanoma metastases. The patient’s hemodynamic instability was considered to be secondary to polyendocrinopathy and prompted his oncology team to hold pembrolizumab.\n\nPer outside records, the patient first experienced dermatitis, requiring high-dose steroids after eight cycles (five months) on pembrolizumab, which was later held. During the taper down from prednisone treatment, the patient demonstrated adrenal insufficiency consistent with hypopituitarism, was transitioned to hydrocortisone, and his symptoms stabilized. He was re-initiated on pembrolizumab after a five-month period due to disease progression and subsequently completed an additional three cycles over six weeks (11 cycles total, over 11 months). Less than one month after his eleventh infusion, he developed hypoxic acute respiratory failure and septic shock followed by acalculous cholecystitis two weeks later. Records from subsequent hospitalizations suggest continued pneumonitis and transaminitis of unknown etiology. After these events, his oncologists decided to hold pembrolizumab treatment for the second time.\n\nDiscussion\nImmunotherapy with checkpoint inhibitors has revolutionized the care of advanced melanoma. The programmed death 1 (PD-1) pathway belongs to a class of checkpoint inhibitors that utilize B7/CD28 co-stimulatory receptors to modulate immune responses [3]. Malignant melanoma cells can express PD-L1 and mimic the antigenic milieu of their surroundings, thus evading an immune response [4]. PD-1 and PD-L1 inhibitors prevent this downregulation, thus aiding the immune detection and response to cancer cells (Figure 2) [5].\n\nFigure 2 Mechanism of action of PDL1 inhibitors on immune cells\nPD1: programmed cell death protein 1\n\nPD-1 checkpoint signaling inhibition is found to increase longevity and be more tolerable compared to conventional chemotherapy for the treatment of certain cancers [5]. Current data suggest that PD-1 inhibitors are effective treatments for metastatic melanoma [3,6-10]. Though preliminary data suggest that improved survival is seen in patients whose tumor cells show high PD-L1 expression [11-12], the relationship between the side effects and effectiveness of PD-1 inhibition is still unclear. Figure 3 (original) depicts these immune-related effects. One odd feature of PD-1 inhibition is that side effects may present seemingly with immune-related adverse events, many months or years after treatment [13].\n\nFigure 3 Potential sites of organs affected by PD1 inhibitors\nPD1: programmed cell death protein 1\n\nA recent review suggested that additional gastrointestinal effects, such as vanishing bile duct syndrome and acute liver failure, may also be related to pembrolizumab treatment [14]. Cholecystitis due to other PD-1 inhibitors like nivolumab and avelumab treatment have been reported [15-16]. Another case series reported cholecystitis in 0.4% of patients after receiving immune checkpoint inhibitor treatment but have not mentioned which particular drug was used [17]. However, no cases of cholecystitis subsequent to pembrolizumab treatment have been published.\n\nHere, we report a case of cholecystitis in a patient with malignant melanoma and several comorbidities likely secondary to pembrolizumab treatment. Determining the origin of new symptoms in such a patient is difficult; symptoms may be the result of cancer progression, secondary effects of pembrolizumab, side-effects of the treatments for secondary effects of pembrolizumab, or unrelated new disease. Differentiating the origin of symptoms is even more challenging when the patient presents to physicians at a community hospital who are unaware or unable to fully appreciate the complex past medical history of such patients on an emergent basis.\n\nAn interesting aspect of this case is the order of events and the time frame it took for each of these patient’s side effects to be teased apart as primary, secondary, or unrelated causes of pembrolizumab treatment. Our patient presented with multiple endocrine abnormalities requiring management, including poorly controlled diabetes mellitus, hypothyroidism, and adrenal insufficiency, in addition to his primary signs and symptoms of acute cholecystitis. Record requests from the hospital managing his oncology care, after the surgery was conducted, revealed that most of these comorbidities were related to the patient’s pembrolizumab treatment. A timeline of this patient’s pembrolizumab infusions and the disease course is depicted in Figure 4.\n\nFigure 4 Timeline of patient history and treatment with Keytruda\nThus, the order of suspected immune-related events in our patient was dermatitis, followed by hypophysitis, secondary adrenal insufficiency, pneumonitis, cholecystitis, and, finally, transaminitis. Prior cases have revealed similar comorbidities attributed to pembrolizumab treatment, with one similar case of polyendocrinopathy showing thyroiditis preceding adrenal insufficiency [18]. Our patient had hypothyroidism prior to his treatment with pembrolizumab due to radioactive ablation for Graves disease. This raises an important question - is there a relationship between pre-existing autoimmune disease and the development of autoimmune-related side-effects of pembrolizumab treatment, as patients with prior autoimmune diseases are excluded in many trials.\n\nSome evidence suggests that patients prone to adverse effects related to immunotherapy treatment may also be among the highest responders to treatment [19-20]. While this news is positive, we were unable to find published data regarding the relationship of autoimmune side effects of pembrolizumab with previous autoimmune disease burden or efficacy of response.\n\nIn this case, the first immunotherapy-related adverse event noted on record review is dermatitis that was at first attributed to amoxicillin treatment for a dental procedure. Next, adrenal insufficiency was thought to be secondary to steroid withdrawal for dermatitis and was not attributed to hypophysitis for nearly two months. Our patient’s multiple episodes of shock prior to and after cholecystectomy may have been preventable with closer titration of steroid treatments. However, the precise hypothalamic pituitary adrenal (HPA) axis dysfunction and an appropriate treatment algorithm were not elucidated due to a delay in recognizing symptoms. More definitive diagnostic testing with MRI is also missing due to the patient’s acute delirium at the time and positive response to steroid treatment. Of note here, the patient had oncology care at an academic hospital that was in a different county than his home community hospital in which he presented for several immune-related adverse events that have added to the complexity of our patient’s care.\n\nConclusions\nTreatment with pembrolizumab may result in life-threatening, immune-related comorbidities that may be hard to detect and treat, particularly for community physicians who are not part of the patient’s oncology care team. Effective acute care of such patients will require clinicians to be mindful of a broad range of side-effects and their presentations. The relationship between pre-existing auto-immune disease and treatment efficacy is unclear. Severe immune-related adverse events with these treatments need to be considered. More data are needed to predict responders and to guide treatment algorithms in those with adverse immune reactions. Physicians and all members of an immunotherapy patient’s care team must be educated and prepared to address novel side effects and the complex care required to treat these patients.\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 Immunotherapy of malignant melanoma Surg Clin North Am Kadison AS Morton DL 343 370 83 2003 12744613 \n2 Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma Cancer Treat Rev McDermott D Lebbé C Hodi FS 1056 1064 40 2014 25060490 \n3 Role of anti-PD-1 antibodies in advanced melanoma: the era of immunotherapy Cureus Sahni S Valecha G Sahni A 0 10 2018 \n4 Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade Proc Natl Acad Sci USA Iwai Y Ishida M Tanaka Y Okazaki T Honjo T Minato N 12293 12297 99 2002 12218188 \n5 Comparative analysis of immune checkpoint inhibitors and chemotherapy in the treatment of advanced non-small cell lung cancer. A meta-analysis of randomized controlled trials Medicine Khan M Lin J Liao G 0 97 2018 \n6 Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway Pharmgenomics Pers Med Momtaz P Postow MA 357 365 7 2014 25484597 \n7 Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies Clin Cancer Res Berger R Rotem-Yehudar R Slama G 3044 3051 14 2008 18483370 \n8 Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma N Engl J Med Hamid O Robert C Daud A 134 144 29 2018 \n9 Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE- 002): a randomised, controlled, phase 2 trial Lancet Oncol Ribas A Puzanov I Dummer R 908 918 16 2015 26115796 \n10 Pembrolizumab versus Ipilimumab in advanced melanoma N Engl J Med Robert C Schachter J Long GV 2521 2532 372 2015 25891173 \n11 Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma Cancer Hino R Kabashima K Kato Y 1757 1766 116 2010 20143437 \n12 PD-L1 expression as a predictive biomarker in cancer immunotherapy Mol Cancer Ther Patel SP Kurzrock R 847 856 14 2015 25695955 \n13 Management of immune-related adverse events associated with immune checkpoint inhibitor therapy: a minireview of current clinical guidelines Asia Pac J Oncol Nurs Trinh S Le A Gowani S La-Beck NM 154 160 6 2019 30931360 \n14 Adverse effects of immune checkpoint inhibitors (programmed death-1 inhibitors and cytotoxic T-lymphocyte-associated protein-4 inhibitors): results of a retrospective study J Clin Med Res Bajwa R Cheema A Khan T 225 236 11 2019 30937112 \n15 Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report Cancer Immunol Immunother Kashima J Okuma Y Shimizuguchi R Chiba K 61 65 67 2018 28913619 \n16 Late-onset cholecystitis with cholangitis after avelumab treatment in non-small cell lung cancer J Thorac Oncol Cho JH Sun JM Lee SH Ahn JS Park K Ahn MJ 34 36 13 2018 \n17 Polyendocrinopathy resulting from pembrolizumab in a patient with a malignant melanoma J Endocr Soc Paepegaey AC Lheure C Ratour C 646 649 1 2017 29264517 \n18 Anti-PD1 following ipilimumab for mucosal melanoma: durable tumor response associated with severe hypothyroidism and rhabdomyolysis Cancer Immunol Res Min L Hodi FS 15 18 2 2014 24778161 \n19 Hypothyroidism as a predictive clinical marker of better treatment response to sunitinib therapy Anticancer Res Kust D Prpić M Murgić J 3177 3184 34 2014 http://ar.iiarjournals.org/content/34/6/3177.long 24922691 \n20 Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis Future Oncol Abdel-Rahman O ElHalawani H Fouad M 2471 2484 11 2015 26274495\n\n",
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"keywords": "adrenal insufficiency; checkpoint inhibitors; cholecystectomy; cholecystitis; hypophysitis; keytruda; malignant melanoma; pembrolizumab; polyendocrinopathy; transaminitis",
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"pubdate": "2020-06-23",
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"title": "Checkpoint Inhibitor in a Melanoma Patient With Polyendocrinopathy and Gangrenous Gallbladder With a Mass.",
"title_normalized": "checkpoint inhibitor in a melanoma patient with polyendocrinopathy and gangrenous gallbladder with a mass"
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"abstract": "This study examines phenotypic presentation and perioperative outcomes of cleft-related procedures for infants with cleft lip and/or palate (CL/P) and prenatal opioid exposure.\nThis is a retrospective review of infants with prenatal opioid exposure treated for CL/P from 2008 to 2018.\nPatients cared for at a tertiary center from 2008 to 2018.\nEighteen patients with documented prenatal opioid exposure and CL/P had primary repairs in our unit.\nThe phenotypes of CL/P were characterized. Demographic data regarding additional exposures, as well as associated medical and social comorbidities were recorded. Outcome variables included operative delays, perioperative complications, and loss of follow-up.\nIsolated cleft palate (CP; 67%) was overrepresented among patients with prenatal opioid exposure and CL/P, as was Robin sequence (50% in isolated CP). Fifty-six percent had exposure to additional substances. A majority (67%) had other medical conditions or anomalies, and 17% had known genetic syndromes. Seventy-two percent were in state custody. Thirty-nine percent of exposed patients had delays in their planned operative dates due to medical and/or social factors. There were no postoperative readmissions following cleft procedures. Lack of follow-up was noted in 33% of patients.\nInfants with CL/P who have prenatal opioid exposure are likely to have additional medical conditions and complex social challenges.",
"affiliations": "Department of Plastic and Oral Surgery, 1862Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.;Department of Plastic and Oral Surgery, 1862Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.;Department of Plastic and Oral Surgery, 1862Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.",
"authors": "Langa|Olivia|O|https://orcid.org/0000-0002-3427-0370;Cappitelli|Alex T|AT|;Ganske|Ingrid M|IM|https://orcid.org/0000-0001-6751-6990",
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"journal": "The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association",
"keywords": "cleft lip and palate; neonatal abstinence syndrome; opioid exposure",
"medline_ta": "Cleft Palate Craniofac J",
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"pubdate": "2021-04-28",
"publication_types": "D016428:Journal Article",
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"title": "Cleft Lip and Palate in Infants With Prenatal Opioid Exposure.",
"title_normalized": "cleft lip and palate in infants with prenatal opioid exposure"
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"abstract": "Most cases of stroke associated with coronavirus disease 2019 (COVID-19) occur during the course of a characteristic COVID-19 respiratory illness. We report three patients where the presenting feature of COVID-19 was stroke. Two patients had no respiratory symptoms throughout their clinical course. In each case, COVID-19 was confirmed by a reverse transcription polymerase chain reaction (RT-PCR) test and the diagnosis of ischaemic stroke by brain imaging. The patients were relatively young (40, 45 and 50 years). None had a prior history of cerebrovascular events. Stroke risk factors were absent in one, limited to overweight and smoking in another but more prominent in the third patient. Two patients had large vessel occlusion and elevated D-dimer levels. Multiple infarcts were seen in two patients. Clinicians should consider the possibility of COVID-19 in patients presenting with stroke and conversely consider investigating for stroke if a patient with COVID-19, even if mildly ill, develops acute neurological symptoms.",
"affiliations": "Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar.;Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar.;Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar.;Department of Neurology, Hamad Medical Corporation, Doha, Qatar.;Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Iqbal|Yousaf|Y|0000-0002-8249-0116;Haddad|Peter M|PM|;Latoo|Javed|J|;Alhatou|Mohammed Ibrahim|MI|;Alabdulla|Majid|M|",
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"doi": "10.1093/omcr/omab006",
"fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855\nOxford University Press\n\n10.1093/omcr/omab006\nomab006\nCase Report\nAcademicSubjects/MED00010\nomcrep/1300\nomcrep/7600\nIschaemic stroke as the presenting feature of COVID-19: a series of three cases from Qatar\nhttp://orcid.org/0000-0002-8249-0116\nIqbal Yousaf 1\nHaddad Peter M 1\nLatoo Javed 1\nAlhatou Mohammed Ibrahim 2\nAlabdulla Majid 1\n1 Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar\n2 Department of Neurology, Hamad Medical Corporation, Doha, Qatar\nCorrespondence address. Psychiatry Hospital, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar. Tel: 00974 40240903; E-mail: yiqbal@hamad.qa\nYousaf Iqbal, Orcid number 0000-0002-8249-0116; Peter M. Haddad, Orcid number 0000-0003-3383-9294; Majid Alabdulla, Orcid number 0000-0002-3631-2650\n\n3 2021\n08 3 2021\n08 3 2021\n2021 3 omab00621 9 2020\n8 12 2020\n17 1 2021\n© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com\n2021\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nMost cases of stroke associated with coronavirus disease 2019 (COVID-19) occur during the course of a characteristic COVID-19 respiratory illness. We report three patients where the presenting feature of COVID-19 was stroke. Two patients had no respiratory symptoms throughout their clinical course. In each case, COVID-19 was confirmed by a reverse transcription polymerase chain reaction (RT-PCR) test and the diagnosis of ischaemic stroke by brain imaging. The patients were relatively young (40, 45 and 50 years). None had a prior history of cerebrovascular events. Stroke risk factors were absent in one, limited to overweight and smoking in another but more prominent in the third patient. Two patients had large vessel occlusion and elevated D-dimer levels. Multiple infarcts were seen in two patients. Clinicians should consider the possibility of COVID-19 in patients presenting with stroke and conversely consider investigating for stroke if a patient with COVID-19, even if mildly ill, develops acute neurological symptoms.\n==== Body\nINTRODUCTION\n\nCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It typically presents with respiratory symptoms, but many systems can be involved [1]. A retrospective analysis of hospital patients in Wuhan, China conducted early in the pandemic showed a wide range of neurological complications including central and peripheral nervous system manifestations and skeletal muscular injury [2]. Since then, neurological and neuropsychiatric features, including stroke, have been increasingly recognized [3]. A study from New York reported that 0.9% of hospitalized patients with COVID-19 suffered a radiologically proven ischaemic stroke [4]. An earlier study from China reported a higher incidence of stroke (4.6%) [5]. In the New York study, the median age of the stroke patients was 62.5 years and the median time between onset of first COVID-19 symptoms and stroke was 10 days [4].\n\nWe report three cases seen in Qatar where stroke was the presenting feature of COVID-19. All three patients were taken by ambulance to the Emergency Department of a major hospital, with a tertiary stroke centre, in Doha, the capital of Qatar. The time between the onset of neurological symptoms and arrival at hospital was no more than a few hours. In all cases COVID-19 was diagnosed by a reverse transcription polymerase chain reaction (RT-PCR) test and stroke was confirmed by brain imaging. Clinical features are summarized in Table 1 and below. One patient was diagnosed with diabetes and hypertension during his admission (case 3). Risk factors for stroke were absent in another (case 2) and limited to smoking and overweight in the third (case 1). All three patients had normal echocardiograms and electrocardiograms (ECGs) showed no significant abnormalities. All received comprehensive care from the multidisciplinary stroke team. None received thrombolysis or thrombectomy. All three patients had neuropsychiatric features and two received input from the psychiatric consultation-liaison team (Table 1).\n\nFigure 1:A DWI axial image with three small restricted diffusion in left MCA territory. B: Axial DWI showing acute strokes in right cerebellum, pons and left cerebellum.\n\nTable 1 Clinical details of the three cases\n\n\tCase 1\tCase 2\tCase 3\t\nAge (years)\t45\t50\t40\t\nBMI (kg/m 2 )\t27.0\t24.5\t30.5\t\nSmoking status\tSmoker\tNon-smoker\tNon-smoker\t\nOther stroke risk factors 1\tNil\tNil\tDiabetes and hypertension diagnosed on admission\t\nNeuropsychiatric features\tImpaired memory and orientation, visual hallucinations, labile mood, agitation and disturbed sleep during course of admission2\tImpaired memory and orientation, agitation and disturbed sleep during course of admission2\tConfusion and drowsiness prior to admission\t\nCOVID respiratory disease\tPneumonia\tNo respiratory symptoms (bilateral apical pulmonary ground glass opacities seen on chest x-ray)\tNo respiratory symptoms (mild pyrexia for several days prior to stroke)\t\nSite of infarct on brain imaging\tRight pontine paramedian, left cerebellar, right PCA, right SCA and left MCA territory infarcts.\tRight MCA territory infarct. Subsequent subacute stroke size expansion.\tMultiple small infarcts in right frontal lobe. Subsequent new acute lacunar infarct in posterior limb of right internal capsule.\t\nIntensive care unit required\tYes (intubated)\tYes (not intubated)\tNo\t\nD-dimer level (around appearance of stroke symptoms) (normal: 0.00–0.44 mg/L)\t0.90\t11.62\tNot measured\t\nOther imaging\t\tSubsequent pulmonary embolus\t\t\nTreatment\tAtorvastatin3\nAspirin\nEnoxaparin\nLevetiracetam4\tAtorvastatin3\nAspirin\nEnoxaparin\nRivaroxaban\nBaclofen\tAtorvastatin3\nAspirin\nEnoxaparin\nLevetiracetam4\t\nStroke outcome\tReceiving inpatient rehabilitation\tReceiving inpatient rehabilitation\tFull recovery. Discharged home\t\n1Other stroke risk factors refers to any of the following: atrial fibrillation, diabetes, hypertension, hyperlipidaemia or past history of stroke, transient ischaemic attack or myocardial infarction.\n\n2Case 1 and 2 received additional input from the consultation-liaison psychiatry team to assist with the management of delirium and behavioural disturbance.\n\n3For secondary stroke prevention.\n\n4To treat seizures.\n\nFigure 2:A CT Scan showing right MCA hypodensity. B and C: CT Perfusion scan showing decreased cerebral blood flow and increased mean transit time indicating right MCA stroke.\n\nFigures 3A and 3B FLAIR axial image. Two small right frontal subcortical T2 hyperintensities, one seen in A and the second in B.\n\nCASE REPORTS\n\nCase 1\n\nA 45-year-old man presented with a sudden onset of generalized tonic–clonic seizures, dysarthria, right-sided facial weakness, weakness of the left side of the body and confusion. He had a recent COVID-19 exposure. On admission, a COVID-19 PRC test was positive. Computer tomography (CT) brain showed a right posterior cerebral artery (PCA) territory infarct. CT angiogram showed occluded P2 segment of right PCA and absent non-opacified intracranial right vertebral artery. Subsequent magnetic resonance imaging (MRI) confirmed the right-sided PCA infarct but showed additional right pontine paramedian, left cerebellar, right superior cerebellar artery (SCA) and left-sided middle cerebral artery (MCA) territory acute infarcts (see Fig. 1). He required intubation and treatment for COVID-19 and aspiration pneumonia. Subsequently he experienced a prolonged period of delirium. His clinical course was marked by multiple generalized tonic–clonic seizures that required treatment with levetiracetam.\n\nCase 2\n\nA 50-year-old man was admitted following sudden onset of left-sided weakness, confusion and agitation. He had decreased level of consciousness, left hemianopia, left upper and lower limb weakness and sensory loss. CT showed a right MCA territory acute infarct (see Fig. 2), right proximal internal carotid artery (ICA) severe stenosis and severe stenosis/occlusion of M2 branches of right MCA. He had no respiratory symptoms, but chest X-ray showed bilateral apical pulmonary ground glass opacities. He tested positive for COVID-19 (PRC test). He developed a pulmonary embolism 3 weeks post-admission. MRI brain performed on Day 54 confirmed the right MCA distribution stroke with subacute extension. His clinical course was complicated by delirium.\n\nCase 3\n\nA 40-year-old man presented with a sudden onset facial dropping, slurred speech, left arm weakness, confusion and focal facial seizures. A week earlier, he had tested positive for COVID-19 but was asymptomatic other than having a mild fever. CT brain showed a hypodense lesion in the right frontal region suggestive of small acute infarct. MRI brain showed multiple small acute frontal strokes (see Fig. 3) with focal meningeal enhancement suggestive of an underlying vasculitis. Subsequent MRI showed another infarct in the posterior limb of the internal capsule. He was commenced on levetiracetam for focal seizures. At presentation he has was diagnosed with diabetes and hypertension which were brought under control with treatment.\n\nDISCUSSION\n\nMost cases of stroke associated with COVID-19 occur during the course of a characteristic COVID-19 respiratory illness [4]. The three cases we report are unusual in several regards. First, in all three cases the presenting feature that led to admission was stroke. Furthermore, prior to the onset of stroke symptoms, symptoms of COVID-19 were absent in two cases (case 1 and 2) and restricted to a mild fever in the remaining patient (case 3). Stroke has previously been reported to be the presenting feature of COVID-19 [6]. Second, two patients (case 2 and 3) had no respiratory symptoms throughout their clinical course. Third, the patients were relatively young being aged between 40 and 50 years. This partly reflects the demographics of Qatar; nearly 90% of the population are foreign workers and the median age of the population is 32 years [7]. Nevertheless, other countries are recognizing that younger patients with COVID-19 can suffer strokes [8, 9].\n\nWe cannot prove the strokes were causally linked to COVID-19 but the young age, the absent/limited risk factors for stroke in two cases (cases 1 and 2) and the close temporal association of stroke and a positive COVID-19 PCR test are highly suggestive. Potential mechanisms for ischemic strokes in COVID-19 patients include a hypercoagulable state, vasculitis and cardiomyopathy [10]. Hypercoagulability reflects elevated plasma prothrombotic factors including von Willebrand factor (vWF), factor VIII, D-dimer, fibrinogen and anionic phospholipids and increased inflammatory cytokines (cytokine storm) [11]. Data are conflicting regarding whether anti-phospholipid antibodies (aPLs) also play a role in COVID-19 coagulopathy [12, 13]. Case 1 and case 2 involved large vessel occlusion. This could reflect in situ thrombosis but embolization due to hypercoagulability state or from an intracardiac thrombus is more probable [10]. The elevated D-dimer level in these two patients is consistent with hypercoagulability and may reflect the effect of pro-inflammatory cytokines. Hypercoagulability may have implications for offering more aggressive anticoagulant treatment for ischaemic stroke but needs to be balanced against potential risk of bleeding. The brain imaging in case 3 suggested multiple acute infarcts secondary to vasculitis.\n\nIn summary, ischaemic stroke can be the presenting feature of COVID-19. This can occur in young otherwise healthy individuals and in the absence of COVID-19 respiratory symptoms. Consequently, the possibility of COVID-19 infection needs to be considered in patients who present with stroke. The corollary is that investigations for stroke need to be considered in patients with COVID-19 illness, even if mild, who develop acute neurological symptoms [9]. These recommendations apply to young as well as older patients.\n\nACKNOWLEDGEMENTS\n\nWe thank the patients/next of kin for consenting to their cases being reported.\n\nFUNDING\n\nNil.\n\nCONFLICT OF INTEREST STATEMENT\n\nP.M.H. reports personal fees from Janssen, Lundbeck, Otsuka, NewBridge Pharmaceuticals and Sunovion, outside the submitted work. The other authors report no conflicts of interest.\n\nETHICAL APPROVAL\n\nEthical approval to report these cases was obtained from the Medical Research Center at Hamad Medical Corporation (MRC-04-20-831).\n\nCONSENT\n\nWritten informed consent was obtained from two patients and next of kin for the third patient who was unable to give consent.\n\nGUARANTOR\n\nDr Yousaf Iqbal.\n\nAUTHOR CONTRIBUTIONS\n\nAll authors have been involved in all stages of the preparation of this case report and they have all read and approved the final version of this report.\n==== Refs\nREFERENCES\n\n1. Pascarella G, Strumia A, Piliego C, Bruno F, Del Buono R, Costa F et al. COVID-19 diagnosis and management: a comprehensive review. J Intern Med 2020;288 :192–206. doi: 10.1111/joim.13091.32348588\n2. Mao L, Jin H, Wang M, Wang M, Hu Y, Chen S et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77 :683–90. doi: 10.1001/jamaneurol.2020.1127.32275288\n3. Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA, Tenorio EL et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry 2020;7 :875–82. doi: 10.1016/S2215-0366(20)30287-X 32593341\n4. Yaghi S, Ishida K, Torres J, Mac Grory B, Raz E, Humbert K et al. SARS-CoV-2 and stroke in a New York healthcare system [published correction appears in Stroke 2020;51(8):e179]. Stroke 2020;51 :2002–11. doi: 10.1161/STROKEAHA.120.030335.32432996\n5. Li Y, Li M, Wang M, Zhou Y, Chang J, Xian Y et al. Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Stroke Vasc Neurol 2020 svn-2020-000431;5 :279–84.32616524\n6. Avulaa A, Nalleballeb K, Narulaa N, Sapozhnikovc S, Dandub V, Toom S et al. COVID-19 presenting as stroke. Brain Behav Immun 2020;87 :115–9. doi: 10.1016/j.bbi.2020.04.077.32360439\n7. Worldometer Qatar population. Available at: https://www.worldometers.info/world-population/qatar-population/ (1 July 2020, date last accessed)\n8. Taylor BES, Khandelwal P, Rallo MS, Patel P, Smith L, Sun H et al. Outcomes and spectrum of major neurovascular events among COVID-19 patients: a 3-center experience. Neurosurg Open 2020;1 :okaa008. doi: 10.1093/neuopn/okaa008.\n9. Fifi JT, Mocco J. COVID-19 related stroke in young individuals. Lancet Neurol 2020;19 :713–5. doi: 10.1016/S1474-4422(20)30272-6.32822622\n10. Spence JD, de Freitas GR, Pettigrew LC, Ay H, Liebeskind DS, Kase CS et al. Mechanisms of stroke in COVID-19. Cerebrovasc Dis 2020;20 :1–8. doi: 10.1159/000509581.\n11. Singhania N, Bansal S, Nimmatoori DP, Ejaz AA, McCullough PA, Singhania G. Current overview on hypercoagulability in COVID-19. Am J Cardiovasc Drugs 2020;20 :393–403. doi: 10.1007/s40256-020-00431-z.32748336\n12. Amezcua-Guerra LM, Rojas-Velasco G, Brianza-Padilla M, Vázquez-Rangel A, Márquez-Velasco R, Baranda-Tovar F et al. Presence of antiphospholipid antibodies in COVID-19: case series study. Ann Rheum Dis 2020;annrheumdis-2020-218100. doi: 10.1136/annrheumdis-2020-218100.\n13. Gkrouzman E, Barbhaiya M, Erkan D, Lockshin MD. A reality check on Antiphospholipid antibodies in COVID-19-associated coagulopathy. Arthritis Rheumatol 2020. doi: 10.1002/art.41472.\n\n",
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"title": "Ischaemic stroke as the presenting feature of COVID-19: a series of three cases from Qatar.",
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"abstract": "BACKGROUND\nAntipsychotic drugs are well established to alter serum prolactin levels, often resulting in adverse effects including amenorrhea, galactorrhea, osteoporosis, and loss of libido. There is growing preclinical evidence that prolactin-elevating drugs can instigate the progression of precancerous lesions to breast cancer and that genes activated by prolactin are associated with the development and proliferation of breast cancer. Current guides advise a cautious approach (weighing risks and benefits) to the administration of prolactin-elevating antipsychotic drugs in women with a previously detected breast cancer. Aripiprazole is known to be a prolactin-sparing antipsychotic; however, data regarding its effects on prolactin and estrogens in postmenopausal women are lacking.\n\n\nMETHODS\nWe examined serum hormone levels in n = 66 women who participated in a randomized, double-blind, placebo-controlled, multicenter trial of aripiprazole (high and low doses) added to an antidepressant in adults older than 60 years. Aripiprazole or placebo tablets were administered for 12 weeks as an augmentation strategy in venlafaxine-treated women. The primary outcomes were the difference in prolactin and estrogen levels.\n\n\nRESULTS\nThere was no significant effect of aripiprazole treatment on prolactin or estrogen levels, including in models that divided groups into low and high doses: prolactin (P = 0.075), estrone (P = 0.67), and estradiol (P = 0.96).\n\n\nCONCLUSIONS\nAripiprazole addition to an antidepressant did not alter serum estrogens or prolactin. These findings may be relevant in the treatment of some postmenopausal women with depression.",
"affiliations": "From the Department of Psychiatry, Washington University in St. Louis, School of Medicine, St Louis, MO.;From the Department of Psychiatry, Washington University in St. Louis, School of Medicine, St Louis, MO.;From the Department of Psychiatry, Washington University in St. Louis, School of Medicine, St Louis, MO.;From the Department of Psychiatry, Washington University in St. Louis, School of Medicine, St Louis, MO.;University of Pittsburgh School of Medicine, Pittsburgh, PA.;University of Toronto, Toronto, Ontario, Canada.;From the Department of Psychiatry, Washington University in St. Louis, School of Medicine, St Louis, MO.;Department of Psychiatry, Statistical Data Analyst, Healthy Mind Lab, Washington University in St. Louis, School of Medicine.;From the Department of Psychiatry, Washington University in St. Louis, School of Medicine, St Louis, MO.",
"authors": "Rahman|Tahir|T|;Patrick|Cory|C|;Ma|Cynthia|C|;Nicol|Ginger E|GE|;Reynolds|Charles F|CF|;Mulsant|Benoit H|BH|;Hartz|Sarah M|SM|;Yingling|Michael|M|;Lenze|Eric J|EJ|",
"chemical_list": "D014150:Antipsychotic Agents; D004967:Estrogens; D000068180:Aripiprazole; D011388:Prolactin",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D001943:Breast Neoplasms; D003863:Depression; D004311:Double-Blind Method; D004967:Estrogens; D005260:Female; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause; D011388:Prolactin",
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"title": "Prolactin and Estrogen Levels in Postmenopausal Women Receiving Aripiprazole Augmentation Treatment for Depression.",
"title_normalized": "prolactin and estrogen levels in postmenopausal women receiving aripiprazole augmentation treatment for depression"
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"abstract": "Involvement of cardiac muscle is felt to be very uncommon in anti-HMGCR myopathy, and therefore early cardiac evaluation is not considered a high priority for this condition. We herein present the case of a 72 year-old woman admitted due to dyspnea and orthopnea, who, in retrospect, suffered from proximal more than distal muscle weakness for 3 months prior to admission. She was found to have acute systolic heart failure. Serologic testing showed positive 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) IgG antibodies, and muscle biopsy showed necrotizing myopathy. No alternative explanation for heart failure was found. Despite immunotherapy and symptomatic treatment, she died from multiorgan failure. Our study suggests that heart failure in anti HMGCR myopathy may not be as rare as previously thought, and therefore early cardiac evaluation should be considered in patients with this diagnosis, to minimize morbidity and mortality.",
"affiliations": "Department of Neurology, University of Minnesota, Minneapolis, MN, United States.;Department of Neurology, University of Minnesota, Minneapolis, MN, United States.",
"authors": "Ghannam|Malik|M|;Manousakis|Georgios|G|",
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"doi": "10.3389/fneur.2020.571716",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.571716\nNeurology\nCase Report\nCase Report: Immune Mediated Necrotizing Myopathy With IgG Antibodies to 3-Hydroxy-3-Methylglutaryl-Coenzyme a Reductase (HMGCR) May Present With Acute Systolic Heart Failure\nGhannam Malik * Manousakis Georgios * Department of Neurology, University of Minnesota, Minneapolis, MN, United States\nEdited by: Edoardo Malfatti, INSERM U1179 Handicap Neuromusculaire: Physiopathologie, Biothérapie et Pharmacologie Appliquées (END-ICAP), France\n\nReviewed by: Gabriella Silvestri, Catholic University of the Sacred Heart, Italy; Olivier Boyer, Université de Rouen, France\n\n*Correspondence: Georgios Manousakis gmanousa@umn.eduMalik Ghannam mghannam@umn.eduThis article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology\n\n\n25 11 2020 \n2020 \n11 57171611 6 2020 04 11 2020 Copyright © 2020 Ghannam and Manousakis.2020Ghannam and ManousakisThis 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.Involvement of cardiac muscle is felt to be very uncommon in anti-HMGCR myopathy, and therefore early cardiac evaluation is not considered a high priority for this condition. We herein present the case of a 72 year-old woman admitted due to dyspnea and orthopnea, who, in retrospect, suffered from proximal more than distal muscle weakness for 3 months prior to admission. She was found to have acute systolic heart failure. Serologic testing showed positive 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) IgG antibodies, and muscle biopsy showed necrotizing myopathy. No alternative explanation for heart failure was found. Despite immunotherapy and symptomatic treatment, she died from multiorgan failure. Our study suggests that heart failure in anti HMGCR myopathy may not be as rare as previously thought, and therefore early cardiac evaluation should be considered in patients with this diagnosis, to minimize morbidity and mortality.\n\nanti-HMGCR antibodiesmyopathicinflammationsystolic heart failurecritical diagnosis\n==== Body\nBackground\nAnti-HMGCR myopathy is a rare form of immune mediated necrotizing myopathy that was initially described in patients with a history of statin exposure, although up to one third of affected patients report no such history (1). It is characterized by progressive limb-girdle muscle weakness with marked creatine kinase elevation (CK), commonly in the range of 1,000–20,000 IU/L (2). Clinical features also include fatigue and myalgia (20–60%), dysphagia (16–30%) and truncal weakness (2). Interestingly, some patients may present with a very indolent, chronic course, mimicking limb-girdle muscular dystrophy, and few may have additional extra-muscular features such as rashes mimicking dermatomyositis (Gottron's and heliotrope) (3, 4). Fewer than 5% of patients develop interstitial lung disease (5). We report a case of acute systolic heart failure secondary to anti-HMGCR myopathy, which is not a typical feature of this condition.\n\nPresentation\nA 72 year-old female with a past medical history of childhood poliomyelitis with residual left hemiplegia, and hyperlipidemia on simvastatin, was admitted to our hospital due to dyspnea and orthopnea. She reported a 3 month history of progressive, painless, right-sided proximal more than distal weakness of upper and lower extremities, which were not previously affected by polio. Three months prior to admission she required a cane to ambulate, and 3 weeks prior to admission she began using a wheelchair. She denied any sensory symptoms other than tingling at the toes on her right foot. A full physical examination performed by her primary care physician 3 months prior to admission showed no abnormal cardiac signs, specifically normal S1, S2 sounds, lack of jugular venous distention, pedal edema, rales, or rhonchi.\n\nExamination on admission showed that she was afebrile, but tachypneic (25 breaths/min) and tachycardic with heart rate 110–125 per minute. Blood pressure ranged between 101 and 150 mm Hg systolic and 53–103 diastolic. Jugular venous pressure was 10 cm H2O. Auscultation of lungs revealed bibasilar rales. There was no pedal edema. Neurological examination showed flaccid left hemiplegia (Medical Research Council (MRC) 0/5 strength, except for 3/5 left knee extension) and marked muscular atrophy. Right shoulder abduction and hip flexion were 2/5, right elbow flexion, extension, wrist extension, knee extension, and foot dorsiflexion were 4/5, right knee flexion was 3/5, and distal right upper extremity muscles were normal. The rest of her neurological exam was unremarkable except for absent reflexes on the left side.\n\nEchocardiography 2 days prior to admission showed ejection fraction of 30%, and a week later 14%, and severe diffuse hypokinesis. Cardiac MRI confirmed those findings; there was no valvular disease and no late gadolinium enhancement (Figure 1). N-Terminal Pro BNP was 5,951 pg/ml. CK was 3,802 U/L. Aldolase was 29.1 U/L. White blood count was 28,700/ul. Sedimentation rate was 79 mm/h. C-Reactive Protein was 6.5 mg/dl. Troponin was elevated but peaked at 1.935 ug/l. Serum myositis antibodies including Jo1, PL7, PL12, EJ, OJ, SRP, Mi-2, NXP2, TIF1-gamma, MDA5, SAE1, were negative. Thyroid stimulating hormone was normal. CT angiography of chest was negative for pulmonary embolism but showed pulmonary edema with bilateral pleural effusions. Cardiology was consulted and working diagnosis was non-ischemic cardiomyopathy related to myositis. Diuresis with intravenous furosemide 40 mg twice a day and captopril 12.5 mg three times a day was recommended. Patient's dyspnea and orthopnea significantly improved after diuresis. MRI of the right shoulder with contrast revealed muscular and deep fascial edema as well as mild diffuse enhancement consistent with myositis. Similar findings were appreciated at the posterior paraspinal muscles on a lumbar spine MRI. Infectious workup for myositis was negative including Interferon Gamma Release Assay, Hepatitis B Surface antigen, Adenovirus PCR, Enterovirus PCR, Echovirus, Coxsackie, HTLV I, II, hepatitis C, and HIV antibodies, and respiratory virus Panel. The patient was empirically treated with 1 gram of intravenous methylprednisolone daily for 3 days followed by 50 mg oral prednisone daily with a plan for right deltoid muscle biopsy. EMG showed large, long duration motor unit potentials with reduced recruitment in all muscles of the right upper and lower extremities, consistent with chronic neurogenic disorder like poliomyelitis. However, extensive abnormal spontaneous activity was also detected, including fibrillations, complex repetitive, and occasional pseudomyotonic discharges, which were not typical for remote poliomyelitis, and suggested a superimposed myopathy with membrane irritability.\n\nFigure 1 Severe cardiomyopathy. Left ventricular ejection fraction was calculated at 10–20%. Right ventricular ejection fraction was normal. There is no myocardial fibrosis or enhancement.\n\nThe patient's condition continued to deteriorate with more weakness and dyspnea. Furosemide was increased to 60 mg twice a day and she was started on intravenous immunoglobulin, 2 grams/kg over 3 days. IgG antibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) measured by ELISA assay (ARUP Lab) came back strongly positive (>200 units, normal is 0–19), consistent with the diagnosis of necrotizing myopathy. Her condition continued to deteriorate, and she became acutely encephalopathic due to hypercapnic respiratory failure, requiring intubation. She became hyponatremic, and therefore furosemide was stopped. Captopril was increased to 50 mg three times a day.\n\nPatient was given rituximab 1,000 mg intravenously, with plan to repeat the same dose in 2 weeks. A deltoid muscle biopsy revealed multifocal fiber necrosis and regeneration, with occasional foci of perimysial and perivascular inflammation, which was consistent with the diagnosis of acute necrotizing myopathy (Figure 2). The patient clinical course deteriorated further with multiorgan failure. After a family meeting, the patient was placed on comfort care orders, and she died shortly after palliative extubation, 1 month after the hospital admission. Autopsy was not performed.\n\nFigure 2 Deltoid muscle biopsy, transverse sections. (A) Hematoxylin and Eosin (H&E) stain, 10x. Note the presence of multiple fibers at different stages of necrosis (transparent arrows), regenerating basophilic fibers (solid arrow) and lymphocytic inflammation in perimysium surrounding a blood vessel (arrowhead). (B) Acid phosphatase stain, 4x. Note necrotic fibers (transparent arrows) and perimysial histiocytic inflammation (arrowhead). (C) CD4 stain, 10x. Note mild endomysial (arrowhead) and perivascular (arrow) staining. (D) CD8 stain, 10x. Scattered positive endomysial cellularity. (E) CD68, 10x. Note prominent expression in necrotic fibers (arrowheads) and perimysial/perivascular regions (arrow). CD20 staining was negative (not shown).\n\nDiscussion\nIn the presence of high pretest probability like muscle weakness, elevated CK or typical biopsy findings, detection of anti-HMGCR antibody by ELISA assay has high specificity for diagnosing anti-HMGCR myopathy. Importantly, those antibodies are not detected in patients with myalgia or reversible toxic rhabdomyolysis related to statins (2). Muscle biopsy typically reveals patchy myofiber necrosis, and regeneration. While inflammatory infiltrates are much less prominent than dermatomyositis or polymyositis, more than half of patients may have perimysial pathology, with thickening, fragmentation, and histiocytic inflammation, and 30% may show occasional perivascular lymphocytic collections, similarly to our case (6).\n\nThe first step of treating anti-HMGCR myopathy is to stop statin drugs, but aggressive immunotherapy is required to achieve remission of the disease. While randomized controlled trials to guide treatment are lacking, expert opinion suggests that a multi-drug regimen including intravenous immunoglobulin, corticosteroids, and a steroid sparing immunosuppressive agent like azathioprine, mycophenolate, methotrexate or rituximab should be offered. Given that passive transfer experiments in mice showed that the antibodies are directly pathogenic (7), removal of the antibodies with plasma exchange may also be considered to produce a transient improvement. While rare patients may experience spontaneous remissions, most patients require some immunotherapy to maintain remission, and relapses upon discontinuation are not uncommon (2, 8).\n\nCardiac involvement is a well-known feature of other immune myopathies, such as polymyositis, dermatomyositis (PM & DM), and anti-SRP antibody necrotizing myopathy (5, 9). PM and DM can exhibit a wide spectrum of cardiac abnormalities, including pericarditis, myocarditis, conduction system abnormalities and mitral valve prolapse (10). Cardiomyopathy with heart failure is the most common cardiac abnormality in PM, it is one of the main prognostic factors for this condition and can cause death in 10–20% of patients (9, 11). The existing literature suggests that cardiomyopathy is not a typical feature of anti-HMGCR myopathy (2). Our findings, in addition to two previous case reports (12, 13), indicate that acute systolic heart failure can occur in HMGCR myopathy, and since this is a serious, treatable complication, early diagnosis is critical.\n\nOur study has some limitations, making the association of the cardiac disease with the necrotizing myopathy putative, rather than fully proven. There was no evidence of pre-existing heart disorder, based on recent pre-admission physical examination, and alternative causes, including infections, thyroid disease, and illicit drug use were eliminated by serological testing and history. However, a coronary angiogram was not performed, therefore ischemic cardiomyopathy cannot be completely excluded, although the findings of global hypokinesis on echocardiogram and cardiac MRI are not typical for ischemia, where regional wall motion abnormalities are frequently encountered. Second, the MRI findings did not meet the Lake Louise criteria of myocarditis (14), specifically there was no edema on T2 and no late gadolinium enhancement. The sensitivity of those imaging criteria is 80%. Third, there was no autopsy or endomyocardial biopsy performed to evaluate the histopathologic changes of the myocardium and compare to the ones identified on the skeletal muscle biopsy. Fourth, the patient did not improve with immunotherapy, although severe cases of necrotizing autoimmune myopathy may not always respond to treatment. Nevertheless, our case, added to the two previously reported cases with similar phenotype, suggests that heart failure in anti HMGCR myopathy may not be as rare as previously thought, and therefore early cardiac evaluation with electrocardiogram and imaging should be considered in patients with this diagnosis, to minimize morbidity and mortality.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\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\nMG and GM were responsible for the clinical management of the patient. MG was responsible for drafting and editing of the manuscript. GM participated in critical revision of the manuscript for intellectual content. All authors read and approved the final manuscript.\n\nConflict of Interest\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==== Refs\nReferences\n1. Shimizu T Kondo Y Kanazawa N Kaneko A Tominaga N Nagai M . Anti-HMGCR myopathy following acute Epstein-Barr virus infection\n. Muscle Nerve. (2020 ) 61 :E5 –8\n. 10.1002/mus.26729 31588573 \n2. Mohassel P Mammen AL . Anti-HMGCR myopathy\n. J Neuromuscul Dis. (2018 ) 5 :11 –20\n. 10.3233/JND-170282 29480216 \n3. Mohassel P Landon-Cardinal O Foley AR Donkervoort S Pak KS Wahl C . Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy\n. Neurol Neuroimmunol Neuroinflamm. (2019 ) 6 :e523 . 10.1212/NXI.0000000000000523 30588482 \n4. Parikh P Tavee J Soltanzadeh P Mammen AL McKeever P Li Y . Anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase autoantibody-positive necrotizing autoimmune myopathy with dermatomyositis-like eruption\n. Muscle Nerve. (2018 ) 57 :E135 –6\n. 10.1002/mus.26072 29346706 \n5. Pinal-Fernandez I Casal-Dominguez M Mammen AL . Immune-mediated necrotizing myopathy\n. Curr Rheumatol Rep. (2018 ) 20 :21 . 10.1007/s11926-018-0732-6 29582188 \n6. Alshehri A Choksi R Bucelli R Pestronk A . Myopathy with anti-HMGCR antibodies: perimysium and myofiber pathology\n. Neurol Neuroimmunol Neuroinflamm. (2015 ) 2 :e124 . 10.1212/NXI.0000000000000124 26090508 \n7. Bergua C Chiavelli H Allenbach Y Arouche-Delaperche L Arnoult C Bourdenet G \nIn vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy\n. Ann Rheum Dis. (2019 ) 78 :131 –39\n. 10.1136/annrheumdis-2018-213518 30309969 \n8. Glaubitz S Zeng R Schmidt J . New insights into the treatment of myositis\n. Ther Adv Musculoskelet Dis. (2020 ) 12 :1759720x19886494 . 10.1177/1759720X19886494 31949477 \n9. Hara A Amano R Yokote H Ijima M Zeniya S Uchihara T . Secondary cardiac involvement in anti-SRP-antibody-positive myopathy: an 87-year-old woman with heart failure symptoms as the first clinical presentation\n. BMC Neurol. (2020 ) 20 :29 . 10.1186/s12883-020-1599-5 31952503 \n10. Sharma K Orbai AM Desai D Cingolani OH Halushka MK Christopher-Stine L . Brief report: antisynthetase syndrome-associated myocarditis\n. J Card Fail. (2014 ) 20 :939 –45\n. 10.1016/j.cardfail.2014.07.012 25084215 \n11. Zhang L Wang GC Ma L Zu N \nCardiac involvement in adult polymyositis or dermatomyositis: a systematic review\n. Clin Cardiol. (2012 ) 35 :686 –91\n. 10.1002/clc.22026 22847365 \n12. Pitlick M Ernste F . Anti-HMGCR myopathy presenting with acute systolic heart failure\n. BMJ Case Rep. (2019 ) 12 :e230213 . 10.1136/bcr-2019-230213 31068355 \n13. Reddy P Hayes S \nAn unusual presentation of heart failure due to immune-mediated necrotizing myopathy in a statin exposed patient\n. J Am Coll Cardiol. (2019 ) 73 (Suppl. 1 ):2161 \n10.1016/S0735-1097(19)32767-6 \n14. Lagan J Schmitt M Miller CA . Clinical applications of multi-parametric CMR in myocarditis and systemic inflammatory diseases\n. Int J Cardiovasc Imaging. (2018 ) 34 :35 –54\n\n10.1007/s10554-017-1063-9 \n28130644\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "11()",
"journal": "Frontiers in neurology",
"keywords": "anti-HMGCR antibodies; critical diagnosis; inflammation; myopathic; systolic heart failure",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
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"pubdate": "2020",
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"title": "Case Report: Immune Mediated Necrotizing Myopathy With IgG Antibodies to 3-Hydroxy-3-Methylglutaryl-Coenzyme a Reductase (HMGCR) May Present With Acute Systolic Heart Failure.",
"title_normalized": "case report immune mediated necrotizing myopathy with igg antibodies to 3 hydroxy 3 methylglutaryl coenzyme a reductase hmgcr may present with acute systolic heart failure"
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"abstract": "Acute promyelocytic leukemia (APL), is a distinct subtype of acute myeloid leukemia (AML) characterized by a tendency to hemorrhage and excellent response to all-trans retinoic acid (ATRA). In this retrospective study, we aimed to determine the incidence, clinical symptoms, toxicities, and outcome of children with APL in our center.\nWe retrospectively reviewed the medical records of children (age < 18 years) diagnosed with APL in our pediatric hematology department between January 2006-December 2016.\nPediatric APL represents 20.5% of AML cases in this cohort. Most of the cases presented as classical M3, albeit hypogranular variant was described in 12% of the cohort. Patients with hypogranular variant APL were differed from classical APL by co-expression of CD2 and CD34. About ¾ of APL patients had hemorrhagic findings at admission or the induction treatment. Severe bleeding manifested as intracranial hemorrhage was present in three patients and intracranial arterial thrombosis was present in one. Six patients showed side effects of ATRA such as pseudotumor cerebri, differentiation syndrome resulting in dilated cardiomyopathy, and pulmonary infiltrates. Five-year overall survival (OS) and early death rate were found to be 82.5% and 12% respectively.\nA high frequency (20.5%) of APL was noted among children with AML in this single-center study. The overall mortality rate was 17.5%. Since the induction death rate was 12% and life-threatening bleeding was the primary problem, awareness and urgent treatment are critical factors to reduce early losses.",
"affiliations": "Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.;Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.",
"authors": "Aksu|Tekin|T|;Fettah|Ali|A|;Bozkaya|İkbal Ok|İO|;Baştemur|Mehmet|M|;Kara|Abdurrahman|A|;Çulha|Vildan Koşan|VK|;Özbek|Namık Yaşar|NY|;Yaralı|Neşe|N|",
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"fulltext": "\n==== Front\nMediterr J Hematol Infect DisMediterr J Hematol Infect DisMediterranean Journal of Hematology and Infectious DiseasesMediterranean Journal of Hematology and Infectious Diseases2035-3006Università Cattolica del Sacro Cuore 10.4084/MJHID.2018.045mjhid-10-1-e2018045Original ArticleAcute Promyelocytic Leukemia in Children: A Single Centre Experience from Turkey Aksu Tekin Fettah Ali Bozkaya İkbal Ok Baştemur Mehmet Kara Abdurrahman Çulha Vildan Koşan Özbek Namık Yaşar Yaralı Neşe Pediatric Hematology and Oncology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, TurkeyCorrespondence to: Tekin Aksu, Şehit Ömer Halisdemir Cad. Kurtdereli Sok. Altındağ / ANKARA. Tel: 00903125969674, Fax: 00903123472330. E-mail: tekinaksu@gmail.com2018 01 7 2018 10 1 e201804520 1 2018 21 6 2018 2018This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background and objectives\nAcute promyelocytic leukemia (APL), is a distinct subtype of acute myeloid leukemia (AML) characterized by a tendency to hemorrhage and excellent response to all-trans retinoic acid (ATRA). In this retrospective study, we aimed to determine the incidence, clinical symptoms, toxicities, and outcome of children with APL in our center.\n\nMethods\nWe retrospectively reviewed the medical records of children (age < 18 years) diagnosed with APL in our pediatric hematology department between January 2006-December 2016.\n\nResults\nPediatric APL represents 20.5% of AML cases in this cohort. Most of the cases presented as classical M3, albeit hypogranular variant was described in 12% of the cohort. Patients with hypogranular variant APL were differed from classical APL by co-expression of CD2 and CD34. About ¾ of APL patients had hemorrhagic findings at admission or the induction treatment. Severe bleeding manifested as intracranial hemorrhage was present in three patients and intracranial arterial thrombosis was present in one. Six patients showed side effects of ATRA such as pseudotumor cerebri, differentiation syndrome resulting in dilated cardiomyopathy, and pulmonary infiltrates. Five-year overall survival (OS) and early death rate were found to be 82.5% and 12% respectively.\n\nConclusions\nA high frequency (20.5%) of APL was noted among children with AML in this single-center study. The overall mortality rate was 17.5%. Since the induction death rate was 12% and life-threatening bleeding was the primary problem, awareness and urgent treatment are critical factors to reduce early losses.\n\nAcute promyelocytic leukemiaHypogranular variant APLATRA toxicity\n==== Body\nIntroduction\nAcute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) which is classified as M3 by French-American-British (FAB) Cooperative group.1 The incidence of APL among the AML cases in children and adolescents vary from 2% in Switzerland to >50% in Nicaragua.2 However, APL incidence among eastern Mediterranean countries is not well documented. A multicenter study from Lebanon reported 25% APL cases among AML patients.3 In Turkey, a study disclosed an incidence of APL as 8.8% among 34 AML patients at childhood.4\n\nAcute promyelocytic leukemia is characterized by the presence of reciprocal translocation between chromosomes 15 and 17 [t(15;17); promyelocytic leukemia gene (PML) - retinoic acid receptor gene alpha (RARA) fusion].5,6 In addition to PML, rare partner genes such as nucleophosmin (NPM1; 5q35), nuclear mitotic apparatus protein 1 (NUMA1; 11q13), promyelocytic leukemia zinc finger (PLZF; 11q23), and signal transducer and activator of transcription (STAT) 5β (STAT5b; 17q21) have been defined.7 PML-RARA fusion protein impairs differentiation of the myeloid progenitor cells and leads to arrested maturation at the promyelocytic stage. By binding to the PML-RARA fusion protein, ATRA induces differentiation of leukemic cells into mature granulocytes and ultimately apoptosis.8,9 Coagulopathy and signs of clinical hemorrhage or thrombotic complications and an excellent response to all-trans retinoic acid (ATRA) are distinctive features of APL.10 Anthracycline-based chemotherapy and ATRA combination are curative for at least 80% of newly diagnosed APL patients.10,11,12 Arsenic trioxide (ATO) initially was introduced into the treatment of relapsed APL. Subsequently, it was used as first-line APL therapy, which can achieve remission rates of 86%.13,14,15\n\nHere, we report clinical, and laboratory findings, toxicities of ATRA treatment and outcome of APL patients, followed in our department.\n\nMaterials and Methods\nWe retrospectively reviewed the medical records of children (age < 18 years) diagnosed with AML in our pediatric hematology department between January 2006–December 2016. Demographic, clinical, and laboratory data (hematological and biochemical findings; bone marrow morphology, immune phenotype, chromosomal and cytogenetic analysis; radiologic and echocardiographic findings), chemotherapy protocols, toxicities and the prognosis of the children were recorded for all APL patients. Morphologic diagnosis of APL was based on FAB criteria.1Leukemic cells were analyzed by flow cytometry, and the diagnosis was confirmed by the presence of t(15;17) with fluorescence in situ hybridization (FISH) analysis. Patients were treated according to APL-93 trial, GIMEMA-AIEOP AIDA between 2006–2010 and AML-BFM Interim 2004 therapy protocol between 2011–2016.11,16,17 ATRA courses were used in all protocols with a dose of 25 to 45 mg/m2/d from the induction to during with maintenance treatment. Maintenance treatment was planned for 1 to 2 years in AML-BFM 2004, APL-93 and AIDA protocols. However, none of the regimens included ATO. Complete remission was defined according to the report of the National Cancer Institute workshop criteria.18 Cytogenetic remission using FISH analysis was defined as the disappearance of the t(15;17). Early death was defined as the death of any cause within 30 days of admission.19 The overall survival (OS) was calculated from the date of diagnosis to death of any cause or last follow-up. ATRA related adverse effects such as fever, weight gain, dyspnea, interstitial pulmonary infiltrate, hypotension, renal insufficiency, and hyperbilirubinemia was also recorded as differentiation syndrome (DS) which was defined according to Frankel et al.20\n\nStatistical analysis\nStatistical analysis was performed by using Statistical Package for the Social Sciences for Windows (SPSS) version 18.0 (SPSS Inc., South Wacker Drive, Chicago, IL, USA). The variables were investigated using visual and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk’s test) to determine whether or not they are normally distributed. Descriptive analyses were presented using means and standard deviations for normally distributed and median and minimum-maximum for non-normally distributed variables. The overall survivals of APL patients were calculated using the Kaplan–Meier methods and the log-rank test.\n\nResults\nBetween January 2006 - December 2016, 83 children diagnosed with AML at our center. Among them, 17 patients (20.5%) with newly diagnosed APL were included in the study. Eight girls and nine boys [median age 13.5 years (range 1.5–17)] were included in the study. Pretreatment laboratory findings and detailed characteristics of the patients are reported in Table 1 and Table 2.\n\nBleeding (76.5%), fever (58.8%), and fatigue (47%) were the most common presenting signs and symptoms. Bone pain and the headache were seen in four and three patients. Bleeding was cutaneous in 6, and mucosal (e.g., wet purpura, epistaxis, and gingival bleeding) in 7 patients. Furthermore, hematuria, hemoptysis, and retinal hemorrhage were presented, each in one patient. Intracranial hemorrhage (ICH) was demonstrated in three patients; one of them at admission and two others were during 11th and 23rd days of induction treatment. The patient who had ICH demonstrated 23rd days of induction had coagulopathy at admission that recovered with ATRA treatment. Unfortunately, subacute/chronic subdural hematoma with midline shift was revealed while she had a neutropenic fever period with thrombocytopenia. One patient who initially diagnosed with left middle cerebral artery thrombosis, diagnosed with APL on the 5th day of admission. Organomegaly was present in seven (41%) patients, including splenomegaly in five and hepatomegaly in five patients. Additionally, lymphadenopathy or central nervous involvement detected in one patient each.\n\nMedian hemoglobin, white blood cell (WBC) and platelet counts were summarized in Table 1. Patients reclassified with Sanz high-risk (WBC ≥ 10 ×103/μL) versus low-intermediate-risk (WBC <10 ×103/μL) in Table 1.21 Peripheral blasts were presented in 16 (94%) of 17 patients at admission. Fourteen patients (82%) had coagulopathy (increased PT, aPTT, and decreased fibrinogen levels). D-dimer levels were elevated in the 11 of the 15 patient.\n\nFifteen patients (88%) had classical FAB M3 type blasts at bone marrow morphology; two patients (12%) had M3v blasts which was estimated by morphology and then confirmed by flow cytometric findings. Blasts of 15 patients who had classical hypergranular APL were positive for CD117, CD13, CD33 markers. Out of 15, three patients’ blasts were positive for CD34 and/or HLA DR. But, flow cytometric analysis of 2 patients with M3v APL differed from classical APL by co-expression of CD2 and CD34 in addition to CD117, CD13. Meanwhile, CD2 expression was present at a low level (24%) in only one patient with classical M3. All of the patients had t(15;17) by FISH analysis, and three patients (18%) had hypodiploid karyotype as well. Fifteen patients (88%) achieved complete remission. Mean morphologic remission and complete cytogenetic remission intervals were 30.4 ± 9.1 days (15–45 days) and 51.7 ± 19.6 days (26–98 days), respectively. There were no relapses during the entire follow-up period through June 2017 (follow-up range: 10–106 months). Two patients died at the induction before hematological response achieved. The induction death rate and the overall mortality were 12% and 17.5%, respectively. One of them, a 15-year old girl who admitted in a coma with massive ICH. Her history revealed that she had been followed 72 hours in a local hospital before diagnosis. Unfortunately, despite ATRA and supportive treatment, she died at day 4 of admission to our hospital. We suggested that delay in the ATRA treatment that caused ICH was the main cause of death. Another patient, a 14-year old boy died due to acute renal failure, pulmonary edema, and ICH at day 11 of induction treatment. Though DS was suggested, sepsis and DIC were the additional causative factors that ultimately caused death. Additionally, a 14-year-old girl died due to sepsis four months after the diagnosis. After excluding these three patients, median follow up period of the patients was 69 months (range 10 – 106). Estimated 5-year overall survival rate was 82.5 ± 9.1 (95 CI: 64.7 – 100.4).\n\nSeveral complications were detected during APL treatment (Table 2). Three patients (18%) developed pseudotumor cerebri (PTC); one of them diagnosed at the fifth month, at the early phase of maintenance therapy. She treated with topiramate and repeated lumbar punctures. The second patient developed PTC 10 months after APL diagnosis while receiving maintenance treatment. He was treated with acetazolamide and serial lumbar punctures. The last patient developed PTC 45 days after diagnosis of APL and treated with acetazolamide, serial lumbar punctures, and dexamethasone. A 14-y-old boy developed pulmonary infiltrates, tinnitus and hypotension on the sixth day of induction treatment, diagnosed with DS, responded to dexamethasone. Additionally, he suffered from cholecystitis and pancreatitis at the second month of APL treatment. A previously described 9-year old girl from our department who developed endocarditis and myocarditis at the induction of the APL treatment, recovered after cessation of ATRA who has been reported elsewhere.22 However, readministration of ATRA at the maintenance therapy caused pancarditis and severe pulmonary edema that might have been part of DS, which recovered with corticosteroids treatment and discontinuation of ATRA. Unfortunately, she developed dilated cardiomyopathy and still ongoing with digitalis treatment. The clinical picture strongly suggested the ATRA treatment as the causative factor even if anthracyclines were an additional risk factor. Febrile neutropenia has been observed during induction treatment in 15 patients (88%), including septicemia and typhilitis. Median febrile neutropenia attack rate was 3.5 (range 1–7) during the treatment period.\n\nDiscussion\nPediatric APL represents 20.5% of AML cases in our cohort. Even if our center is a reference hospital in Ankara, this high incidence of APL needs to be confirmed in larger pediatric series among Turkey. Early diagnosis and immediate treatment with ATRA may reduce hemorrhagic complications that lead to early morbidity and mortality, and significant concern is discrimination of APL from other subtypes of AML. In our patients whose presenting, symptoms are bleeding and/or coagulopathy, expeditious immunophenotypic analysis to exclude M3 or M3v is performed. We started ATRA as soon as possible, although two patients experienced ICH after the first week of ATRA. Unfortunately, delays in diagnosis contributed to mortality in one of the patient. However, favorable response to ATRA has been achieved in the rest of the patients. Morphology and immunophenotypic analysis are still essential tools for rapid recognition of APL. Most of our APL cases presented as hypergranular or classical M3, albeit morphological hypogranular or microgranular variant type, M3v, was also described in 2 patients (12%). Hypogranular variant type accounts for 15–20% of APL cases which is characterized by promyelocytes with bilobed-multilobed or angel wing shaped nucleus look as if monoblastic leukemia.8,23 On both occasions, identification of the cytogenetic abnormality, t(15;17) or PML/RARA translocation has utmost importance. M3v morphology is not diagnostic; however, co-expression of CD2 and CD34 markers are remarkable and useful for early diagnosis.24,25 The absence of HLA-DR, low expression or absence of CD34, and positivity for CD13 and/or CD33 markers has been reported on both forms.24,25 In our cohort, fifteen patients (88%) expressed CD117, CD13, CD33 markers. They did not express CD34 and/or HLA-DR except for three cases (17.5%) who diagnosed with APL ultimately. Two patients with hypogranular variant were differed from classical APL by co-expression of CD2 and CD34 (100%) in this study.\n\nAPL cases were frequently presented with consumptive coagulopathy that may cause life-threatening hemorrhages.26 Furthermore, thrombotic complications may also be seen infrequently.26 About ¾ of our APL patients had hemorrhagic findings at admission or induction treatment. Severe bleeding manifested as intracranial hemorrhage was present in three patients. One of them admitted with severe ICH, but we demonstrated ICH in two patients after the first week of ATRA treatment. The other patient who had bleeding on day 11 of induction, had been diagnosed with sepsis and DIC, and also possible DS. Patients with ICH has been supported with aggressive platelet and fibrinogen replacement along with ATRA therapy guided by numerous coagulation studies. ATRA has dramatically enhanced survival rates and diminished relapse rates in APL patients. In the present study, five-year overall survival (OS) and early death rate were found to be 82.5% and 12%, respectively. ATRA resistance and relapse were not observed in any patient. Our results were comparable to those obtained in population-based studies and also to early death rates for APL.27,28 Nevertheless, Abla et al.19 reported the incidence of early death as 4.7%, recently.\n\nHigh WBC, high peripheral blast count, M3v and black ethnicity were independent predictors of early hemorrhagic death in several studies.19,29 However, our patients who died due to early ICH had low WBC counts (1.8 and 2.6 ×103/μL), and their peripheral blast percentages were also low (10 and 58%, Table 2). Hypogranular APL patients of our cohort did not have severe hemorrhagic complications. The patients who relieved from early hemorrhagic complications have an excellent OS after ATRA era, as is our patients.\n\nIn our study, mean morphologic and cytogenetic remission by FISH analysis has been obtained at days 30.4 (15–45 days) and 51.7 (26–98 days), respectively. One may speculate that mean cytogenetic remission times were early because the FISH analysis is not sensitive to polymerase chain reaction (PCR) based methods to detect PML/RARA. We were not able to analyze PML/RARA translocation during treatment for all patients. Zhou et al.14 reported that PML/RARA disappeared within 3 to 9 months after complete hematological response using PCR.\n\nAlthough excellent remission rates, different from other AML types, might be attributable to ATRA, six patients in this study have experienced severe side effects such as PTC, pancarditis, and pulmonary infiltrates. Two patients suffered from DS while they were receiving AIDA protocol, but no DS was seen with AML BFM 2004 protocol. Otherwise, there was no difference in toxicity (e.g., heart) and efficacy between these protocols in this study. Pseudotumor cerebri incidence was reported to be 1.7 – 16% in patients on ATRA therapy.30,31 In our study, PTC incidence was 17.6%, but clear definitions and incidence of this complication were not established. Botton et al.31 recommended lower ATRA (25mg/m2) doses to avoid from PTC. In contrast to that study, our patients were receiving low dose ATRA (25mg/m2) courses when they developed PTC.\n\nConclusions\nA high frequency (20.5%) of APL was noted among children with AML in this single-center study. The overall mortality rate was 17.5%. Since the induction death rate was 12% and life-threatening bleeding was the primary problem, awareness and urgent treatment are critical factors to reduce early losses.\n\nCompeting interests: The authors have declared that no competing interests exist.\n\nTable 1 Pretreatment laboratory characteristics of the patients\n\nComplete blood counts\tMedian\tRange\t\n\n\t\nHemoglobin, g/dL\t8.7\t4.7–13.4\t\nWBC, ×103/μL\t4\t1–23.1\t\nHigh-risk+ n= (%)\t4 (23.5)\t\t\nLow-intermediate-risk+ n= (%)\t13 (76.5)\t\t\nPlatelet, ×103/μ\t21\t4–209\t\nLCirculating blasts*, %\t38\t0–100%\t\n\n\t\nFibrinogen level, g/L\t149.5\t73–505\t\n+ Patients with Sanz high risk (WBC >/= 10 ×103/μ) versus low-intermediate risk (WBC <10 ×103/μL).\n\n* Data missing for 4 patients.\n\nTable 2 Detailed data of the patients.\n\nPatient no\tAge (year)\tSex\tDiagnosis\tWBC (x 103/μL)\tPB blast (%)\tTreatment protocol\tATRA toxicity\tComplications\tFollow-up (month)\tOutcome\t\n1\t8.5\tF\tM3v\t10.8\t76\tAML BFM 2004\tPTC\t\t62\tAlive\t\n2*\t9\tF\tM3\t23.1\t100\tAPL-93\tDS (Pancarditis, dilated cardiomyopathy)\t\t101\tAlive\t\n3\t3.2\tM\tM3\t1.7\tN/A\tAIDA\tPTC\t\t91\tAlive\t\n4\t15\tM\tM3\t2.8\t100\tAPL-93\t\tRetinal hemorrhage\t105\tAlive\t\n5\t17\tM\tM3\t5.6\t12\tAML BFM 2004\t\tNone\t32\tAlive\t\n6\t6\tF\tM3v\t7.8\t56\tAIDA\t\tNone\t103\tAlive\t\n7\t13.5\tM\tM3\t7.3\t22\tAIDA\t\tNone\t105\tAlive\t\n8\t14\tM\tM3\t3.6\t60\tAIDA\tDS (Pulmonary infiltrates)\tCholecystitis – Pancreatitis\t25\tAlive\t\n9\t1.5\tM\tM3\t11.2\t14\tAML BFM 2004\t\tNone\t69\tAlive\t\n10\t10\tM\tM3\t1\t0\tAIDA\t\tNone\t106\tAlive\t\n11\t16\tF\tM3\t1\tN/A\tAIDA\t\tNone\t97\tAlive\t\n12\t14\tM\tM3\t1.8\t10\tAIDA\tDS\tICH, ARF, pulmonary edema\t11 days\tDied, ICH\t\n13\t14\tF\tM3\t2.7\t50\tAML BFM 2004\tPTC\tICH\t46\tAlive\t\n14\t6\tF\tM3\t10.9\t100\tAML BFM 2004\t\tNone\t47\tAlive\t\n15\t7.5\tM\tM3\t4\tN/A\tAML BFM 2004\t\tLeft MCA thrombosis\t20\tAlive\t\n16\t15.3\tF\tM3\t2.6\t58\tAML BFM 2004\t\tICH\t4 days\tDied, ICH\t\n17*\t14\tF\tM3\t2.3\tN/A\tAIDA\t\tARF + Sepsis\t4\tDied, Sepsis\t\nARF=Acute renal failure; ATRA=All-trans retinoic acid; DS=Differentiation syndrome; ICH=Intracranial hemorrhage; MCA=Middle cerebral artery; N/A=Not available; PB=Peripheral blast; PTC=Pseudotumor cerebri;\n\n* Published before.\n==== Refs\nReferences\n1 Bennett JM Catovsky D Daniel MT Flandrin G Galton DA Gralnick HR Sultan C Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group Ann Intern Med 1985 103 620 5 10.7326/0003-4819-103-4-620 3862359 \n2 Zhang L Samad A Pombo-de-Oliveira MS Scelo G Smith MT Feusner J Wiemels JL Metayer C Global characteristics of childhood acute promyelocytic leukemia Blood Rev 2015 29 101 25 10.1016/j.blre.2014.09.013 25445717 \n3 Farah RA Horkos JG Bustros YD Farhat HZ Abla O A Multicenter Experience from Lebanon in Childhood and Adolescent Acute Myeloid Leukemia: High rate of Early Death in Childhood Acute Promyelocytic Leukemia Mediterr J Hematol Infect Dis 2015 7 1 e2015012 10.4084/mjhid.2015.012 25574371 \n4 Kömür M Erbey F Bayram I Tanyeli A Incidence and prognostic importance of molecular genetic defects in children with acute myeloblastic leukemia Asian Pac J Cancer Prev 2010 11 1393 5 21198299 \n5 Longo L Pandolfi PP Biondi A Rambaldi A Mencarelli A Lo Coco F Diverio D Pegoraro L Avanzi G Tabilio A Zangrilli D Alcalay M Donti E Grignani F Pelicci PG Rearrangements and aberrant expression of the retinoic acid receptor alpha gene in acute promyelocytic leukemias J Exp Med 1990 172 1571 5 10.1084/jem.172.6.1571 2175343 \n6 Lo-Coco F Ammatuna E Montesinos P Sanz MA Acute promyelocytic leukemia: recent advances in diagnosis and management Semin Oncol 2008 35 401 9 10.1053/j.seminoncol.2008.04.010 18692690 \n7 Yan W Zhang G Molecular Characteristics and Clinical Significance of 12 Fusion Genes in Acute Promyelocytic Leukemia: A Systematic Review Acta Haematol 2016 136 1 15 10.1159/000444514 27089249 \n8 Calleja EM Warrell RP Jr Differentiating agents in pediatric malignancies: all-trans-retinoic acid and arsenic in acute promyelocytic leukemia Curr Oncol Rep 2000 2 6 519 23 10.1007/s11912-000-0105-x 11122887 \n9 Huang ME Ye YC Chen SR Chai JR Lu JX Zhoa L Gu LJ Wanq ZY Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia Blood 1988 72 567 72 3165295 \n10 Abla O Ribeiro RC How I treat children and adolescents with acute promyelocytic leukaemia Br J Haematol 2014 164 24 38 10.1111/bjh.12584 24117210 \n11 Testi AM Biondi A Lo Coco F Moleti ML Giona F Vignetti M Menna G Locatelli F Pession A Barisone E De Rossi G Diverio D Micalizzi C Aricò M Basso G Foa R Mandelli F GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children Blood 2005 106 447 53 10.1182/blood-2004-05-1971 15677559 \n12 Creutzig U Zimmermann M Dworzak M Urban C Henze G Kremens B Lakomek M Bourquin JP Stary J Reinhardt D Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses Br J Haematol 2010 149 3 399 409 10.1111/j.1365-2141.2010.08107.x 20230404 \n13 Mathews V George B Lakshmi KM Viswabandya A Bajel A Balasubramanian P Shaji RV Srivastava VM Chandy M Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity Blood 2006 107 2627 32 10.1182/blood-2005-08-3532 16352810 \n14 Zhou J Zhang Y Li J Li X Hou J Zhao Y Liu X Han X Hu L Wang S Zhao Y Zhang Y Fan S Lv C Li L Zhu L Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia Blood 2010 115 1697 702 10.1182/blood-2009-07-230805 20029047 \n15 Kutny MA Alonzo TA Gerbing RB Wang YC Raimondi SC Hirsch BA Fu CH Meshinchi S Gamis AS Feusner JH Gregory JJ Jr Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children’s Oncology Group Phase III Historically Controlled Trial AAML0631 J Clin Oncol 2017 35 26 3021 3029 10.1200/JCO.2016.71.6183 28767288 \n16 Kelaidi C Chevret S De Botton S Raffoux E Guerci A Thomas X Pigneux A Lamy T Rigal-Huguet F Meyer-Monard S Chevallier P Maloisel F Deconinck E Ferrant A Fegueux N Ifrah N Sanz M Dombret H Fenaux P Adès L Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience J Clin Oncol 2009 27 2668 76 10.1200/JCO.2008.18.4119 19414681 \n17 Creutzig U Zimmermann M Bourquin JP Dworzak MN Fleischhack G Graf N Klingebiel T Kremens B Lehrnbecher T von Neuhoff C Ritter J Sander A Schrauder A von Stackelberg A Starý J Reinhardt D Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004 Blood 2013 122 37 43 10.1182/blood-2013-02-484097 23704089 \n18 Cheson BD Cassileth PA Head DR Schiffer CA Bennett JM Bloomfield CD Brunning R Gale RP Grever MR Keating MJ Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia J Clin Oncol 1990 8 813 9 10.1200/JCO.1990.8.5.813 2185339 \n19 Abla O Ribeiro RC Testi AM Montesinos P Creutzig U Sung L Di Giuseppe G Stephens D Feusner JH Powell BL Hasle H Kaspers GJL Dalla-Pozza L Lassaletta A Tallman MS Locatelli F Reinhardt D Lo-Coco F Hitzler J Sanz MA Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy Ann Hematol 2017 96 9 1449 1456 10.1007/s00277-017-3042-6 28597167 \n20 Frankel SR Eardley A Lauwers G Weiss M Warrell RP Jr The “retinoic acid syndrome” in acute promyelocytic leukemia Ann Intern Med 1992 117 292 6 10.7326/0003-4819-117-4-292 1637024 \n21 Sanz MA Lo Coco F Martín G Avvisati G Rayón C Barbui T Díaz-Mediavilla J Fioritoni G González JD Liso V Esteve J Ferrara F Bolufer P Bernasconi C Gonzalez M Rodeghiero F Colomer D Petti MC Ribera JM Mandelli F Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups Blood 2000 96 4 1247 53 10942364 \n22 Işık P Çetin I Tavil B Azik F Kara A Yarali N Tunc B All-transretinoic acid (ATRA) treatment-related pancarditis and severe pulmonary edema in a child with acute promyelocytic leukemia J Pediatr Hematol Oncol 2010 32 8 e346 8 10.1097/MPH.0b013e3181e75731 20881874 \n23 Sainty D Liso V Cantù-Rajnoldi A Head D Mozziconacci MJ Arnoulet C Benattar L Fenu S Mancini M Duchayne E Mahon FX Gutierrez N Birg F Biondi A Grimwade D Lafage-Pochitaloff M Hagemeijer A Flandrin G Groupe Français d’Hématologie Cellulaire; Groupe Français de Cytogénétique Hématologique; UK Cancer Cytogenetics Group; BIOMED 1 European Community-Concerted Action “Molecular Cytogenetic Diagnosis in Haematological Malignancies” A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements Blood 2000 96 1287 96 10942370 \n24 Gorczyca W Acute promyelocytic leukemia: four distinct patterns by flow cytometry immunophenotyping Pol J Pathol 2012 63 8 17 22535601 \n25 Albano F Mestice A Pannunzio A Lanza F Martino B Pastore D Ferrara F Carluccio P Nobile F Castoldi G Liso V Specchia G The biological characteristics of CD34+ CD2+ adult acute promyelocytic leukemia and the CD34 CD2 hypergranular (M3) and microgranular (M3v) phenotypes Haematologica 2006 91 311 6 16531253 \n26 Cicconi L Lo-Coco F Current management of newly diagnosed acute promyelocytic leukemia Ann Oncol 2016 27 1474 81 10.1093/annonc/mdw171 27084953 \n27 Stein EM Tallman MS Acute promyelocytic leukemia in children and adolescents Acta Haematol 2014 132 307 12 10.1159/000365117 25228556 \n28 Takahashi H Watanabe T Kinoshita A Yuza Y Moritake H Terui K Iwamoto S Nakayama H Shimada A Kudo K Taki T Yabe M Matsushita H Yamashita Y Koike K Ogawa A Kosaka Y Tomizawa D Taga T Saito AM Horibe K Nakahata T Miyachi H Tawa A Adachi S High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group Br J Haematol 2016 174 437 43 10.1111/bjh.14068 27029412 \n29 Mantha S Goldman DA Devlin SM Lee JW Zannino D Collins M Douer D Iland HJ Litzow MR Stein EM Appelbaum FR Larson RA Stone R Powell BL Geyer S Laumann K Rowe JM Erba H Coutre S Othus M Park JH Wiernik PH Tallman MS Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era Blood 2017 129 1763 1767 10.1182/blood-2016-10-747170 28082441 \n30 Coombs CC DeAngelis LM Feusner JH Rowe JM Tallman MS Pseudotumor Cerebri in Acute Promyelocytic Leukemia Patients on Intergroup Protocol 0129: Clinical Description and Recommendations for New Diagnostic Criteria Clin Lymphoma Myeloma Leuk 2016 16 146 51 10.1016/j.clml.2015.11.018 26724834 \n31 de Botton S Coiteux V Chevret S Rayon C Vilmer E Sanz M de La Serna J Philippe N Baruchel A Leverger G Robert A San Miguel J Conde E Sotto JJ Bordessoule D Fegueux N Fey M Parry A Chomienne C Degos L Fenaux P Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy J Clin Oncol 2004 22 1404 12 10.1200/JCO.2004.09.008 15084614\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2035-3006",
"issue": "10(1)",
"journal": "Mediterranean journal of hematology and infectious diseases",
"keywords": "ATRA toxicity; Acute promyelocytic leukemia; Hypogranular variant APL",
"medline_ta": "Mediterr J Hematol Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101530512",
"other_id": null,
"pages": "e2018045",
"pmc": null,
"pmid": "30002801",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "2175343;21198299;27089249;20230404;23704089;11122887;20029047;15677559;28767288;3862359;19414681;10942370;26724834;28082441;18692690;25574371;16352810;22535601;28597167;3165295;27084953;20881874;2185339;25445717;1637024;25228556;27029412;10942364;16531253;15084614;24117210",
"title": "Acute Promyelocytic Leukemia in Children: A Single Centre Experience from Turkey.",
"title_normalized": "acute promyelocytic leukemia in children a single centre experience from turkey"
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"abstract": "As many as 5% of patients using oral anticoagulants suffer from a major bleeding event annually. Spontaneous retroperitoneal hemorrhage is a rare but serious complication, with a mortality rate as high as 20%. Oral anticoagulants were responsible for 2.83 million office visits per quarter in 2014 and use is increasing, therefore, rapid recognition of life threatening complications is critical. We present a case of an 86-year-old female taking apixaban for atrial fibrillation who presented with right hip pain upon standing. Laboratory tests revealed leukocytosis and anemia. A CT scan of the right hip revealed a moderately sized retroperitoneal hematoma. She was transferred to the intensive care unit, treated with supportive care, and was discharged two days later without any invasive intervention needed. Due to vague presentations, spontaneous retroperitoneal hemorrhages can be misdiagnosed as a number of abdominal or pelvic processes. While our patient presented with hip pain, other presentations include abdominal masses, back pain, or hypotension. Some patients may progress to hemodynamic instability, femoral neuropathy, or abdominal compartment syndrome requiring rapid intervention to prevent further morbidity. In patients with vague abdominal or pelvic complaints who have risk factors such as advanced age and the use of anticoagulation therapy, spontaneous retroperitoneal hemorrhage should be considered to allow for early diagnosis before severe complications arise.",
"affiliations": "Western Michigan University Homer Stryker M.D. School of Medicine, United States of America.;Department of Emergency Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, United States of America.;Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, United States of America. Electronic address: Laura.bauler@med.wmich.edu.",
"authors": "Khan|Adil|A|;Mastenbrook|Joshua|J|;Bauler|Laura|L|",
"chemical_list": "D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2019.12.049",
"fulltext": null,
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"issn_linking": "0735-6757",
"issue": "38(5)",
"journal": "The American journal of emergency medicine",
"keywords": "Apixiban; Oral anticoagulants; Retroperitoneal hematoma; Rupture, spontaneous; Spontaneous retroperitoneal hemorrhage",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006406:Hematoma; D006615:Hip; D006801:Humans; D010146:Pain; D011720:Pyrazoles; D011728:Pyridones; D012187:Retroperitoneal Space; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1046.e1-1046.e3",
"pmc": null,
"pmid": "31932125",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pain in the hip: Spontaneous retroperitoneal hemorrhage in an elderly patient on apixaban.",
"title_normalized": "pain in the hip spontaneous retroperitoneal hemorrhage in an elderly patient on apixaban"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-006609",
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"activesubstancename": "APIXABAN"
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{
"abstract": "Combined immunotherapy is associated with a significant risk of severe and potentially fatal immune-related adverse events (irAEs). Therefore, we retrospectively analyzed the side profile and efficacy of low-dose ipilimumab (1 mg/kg, IPI1) combined with anti-PD-1 immunotherapy in patients who progressed after anti-PD-1 monotherapy. Nine patients with unresectable stage III or IV melanoma treated with combined low-dose ipilimumab (1 mg/kg, IPI1) and anti-PD-1 immunotherapy, following progression after anti-PD-1 treatment, were identified. Treatment response and irAEs were recorded. Grade 3 irAEs occurred in one-third of patients. Interestingly, there were no grade 4 or 5 irAEs. In fact, four out of the nine patients experienced no irAEs at all. One patient discontinued combined immunotherapy due to immune-related colitis. The mean time to the onset of grade 3 irAEs was 14.3 weeks. The objective response rate was 33.3% and a disease control rate of 66.7% was achieved. Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 21.6 months. The median PFS when IPI1 and anti-PD-1 treatment was administered in the second-line setting was not reached, but only 2.8 months when used in subsequent treatment settings. Combined IPI1 and anti-PD-1 immunotherapy was well tolerated. Its use in the third-line or above setting was associated with a significantly poorer prognosis than in the second-line setting. Larger, prospective studies are required to evaluate the safety and efficacy of this dosing regimen following anti-PD-1 treatment failure.",
"affiliations": "Department of Dermatology, University of Luebeck, Luebeck, Germany.;Department of Dermatology, University of Luebeck, Luebeck, Germany.;Department of Dermatology, University of Luebeck, Luebeck, Germany.;Department of Dermatology, University of Luebeck, Luebeck, Germany.;Department of Dermatology, University of Luebeck, Luebeck, Germany.;Department of Dermatology, University of Luebeck, Luebeck, Germany.;Department of Dermatology, University of Luebeck, Luebeck, Germany.",
"authors": "Klee|Gina|G|;Kurzhals|Jonas|J|;Hagelstein|Victoria|V|;Zillikens|Detlef|D|;Recke|Andreas|A|;Langan|Ewan A|EA|;Terheyden|Patrick|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000760",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8931",
"issue": "31(5)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": null,
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "464-471",
"pmc": null,
"pmid": "34284462",
"pubdate": "2021-10-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Low-dose ipilimumab combined with anti-PD-1 immunotherapy in patients with metastatic melanoma following anti-PD-1 treatment failure.",
"title_normalized": "low dose ipilimumab combined with anti pd 1 immunotherapy in patients with metastatic melanoma following anti pd 1 treatment failure"
} | [
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"companynumb": "DE-009507513-2109DEU005539",
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"activesubstancename": "PEMBROLIZUMAB"
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... |
{
"abstract": "Limited data are available concerning the clinical features of toxic gastrointestinal (GI) effects of taxane-based therapy. We describe the clinical, endoscopic and histologic features of taxane-induced colitis.\nThis retrospective study included cancer patients who received taxane therapy and underwent colonoscopy for GI symptoms from 2000-2018.\nOf the 45,527 patients who received taxane therapy during the study period, 76 (0.2%) met the inclusion criteria. Most patients (54%) received paclitaxel, 37% docetaxel, and 9% nab-paclitaxel. The median time from taxane therapy initiation to colitis symptom onset was 31 days. The median duration of colitis symptoms was 30 days. Colitis treatment comprised immunosuppressive therapy in 8 patients (11%), antibiotics in 17 (22%), antimotility agents in 18 (24%), and octreotide or somatostatin in 2 (3%). Thirty-five patients (46%) required hospitalization and seven (9%) required admission to the intensive care unit (ICU). Endoscopy revealed mucosal ulceration in 19 patients (25%), nonulcerative inflammation in 32 (42%), and normal findings in 25 (33%). Seventeen patients (22%) had features of lymphocytic colitis. One patient had spontaneous colonic perforation that required surgical intervention. Colitis symptoms recurred in 7 patients (9%) after initial improvement. Patients who received nab-paclitaxel developed GI toxicity earlier (P=0.003), required colitis-related hospitalization more frequently (P=0.005), and received intravenous fluids more frequently (P=0.025), compared with patients who received other taxanes.\nTaxane-related colitis can present with significant inflammation on colonoscopy, and in a minority of patients as microscopic colitis. Taxane-induced colitis, although uncommon, can lead to ICU admission and colonic perforation.",
"affiliations": "Department of Medicine, Baylor College of Medicine (Ellie Chen, Niharika Mallepally).;Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center (Hamzah Abu-Sbeih, Selvi Thirumurthi, Yinghong Wang).;Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center (Hamzah Abu-Sbeih, Selvi Thirumurthi, Yinghong Wang).;Department of Medicine, Baylor College of Medicine (Ellie Chen, Niharika Mallepally).;Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center (Shruti Khurana).;Department of Pathology and Lab Medicine, The University of Texas MD Anderson Cancer Center (Dongguang Wei, Dongfeng Tan).;Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson, Cancer Center (Mehmet Altan).;Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center (Van K. Morris).;Department of Pathology and Lab Medicine, The University of Texas MD Anderson Cancer Center (Dongguang Wei, Dongfeng Tan).;Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center (Carlos H. Barcenas), Houston, Texas, USA.;Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center (Hamzah Abu-Sbeih, Selvi Thirumurthi, Yinghong Wang).",
"authors": "Chen|Ellie|E|;Abu-Sbeih|Hamzah|H|;Thirumurthi|Selvi|S|;Mallepally|Niharika|N|;Khurana|Shruti|S|;Wei|Dongguang|D|;Altan|Mehmet|M|;Morris|Van K|VK|;Tan|Dongfeng|D|;Barcenas|Carlos H|CH|;Wang|Yinghong|Y|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.20524/aog.2019.0431",
"fulltext": "\n==== Front\nAnn GastroenterolAnn GastroenterolAnnals of Gastroenterology1108-74711792-7463Hellenic Society of Gastroenterology Greece AnnGastroenterol-33-5910.20524/aog.2019.0431Original ArticleClinical characteristics of colitis induced by taxane-based chemotherapy Chen Ellie a*Abu-Sbeih Hamzah b*Thirumurthi Selvi bMallepally Niharika aKhurana Shruti cWei Dongguang dAltan Mehmet eMorris Van K. fTan Dongfeng dBarcenas Carlos H. gWang Yinghong ba Department of Medicine, Baylor College of Medicine (Ellie Chen, Niharika Mallepally)b Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center (Hamzah Abu-Sbeih, Selvi Thirumurthi, Yinghong Wang)c Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center (Shruti Khurana)d Department of Pathology and Lab Medicine, The University of Texas MD Anderson Cancer Center (Dongguang Wei, Dongfeng Tan)e Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson, Cancer Center (Mehmet Altan)f Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center (Van K. Morris)g Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center (Carlos H. Barcenas), Houston, Texas, USACorrespondence to: Yinghong Wang, MD, PhD, Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1466, Houston, TX 77030, USA, e-mail: ywang59@mdanderson.org* Co-first authors\n\nJan-Feb 2020 21 11 2019 33 1 59 67 17 7 2019 07 10 2019 Copyright: © Hellenic Society of Gastroenterology2020This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nLimited data are available concerning the clinical features of toxic gastrointestinal (GI) effects of taxane-based therapy. We describe the clinical, endoscopic and histologic features of taxane-induced colitis.\n\nMethods:\nThis retrospective study included cancer patients who received taxane therapy and underwent colonoscopy for GI symptoms from 2000-2018.\n\nResults:\nOf the 45,527 patients who received taxane therapy during the study period, 76 (0.2%) met the inclusion criteria. Most patients (54%) received paclitaxel, 37% docetaxel, and 9% nab-paclitaxel. The median time from taxane therapy initiation to colitis symptom onset was 31 days. The median duration of colitis symptoms was 30 days. Colitis treatment comprised immunosuppressive therapy in 8 patients (11%), antibiotics in 17 (22%), antimotility agents in 18 (24%), and octreotide or somatostatin in 2 (3%). Thirty-five patients (46%) required hospitalization and seven (9%) required admission to the intensive care unit (ICU). Endoscopy revealed mucosal ulceration in 19 patients (25%), nonulcerative inflammation in 32 (42%), and normal findings in 25 (33%). Seventeen patients (22%) had features of lymphocytic colitis. One patient had spontaneous colonic perforation that required surgical intervention. Colitis symptoms recurred in 7 patients (9%) after initial improvement. Patients who received nab-paclitaxel developed GI toxicity earlier (P=0.003), required colitis-related hospitalization more frequently (P=0.005), and received intravenous fluids more frequently (P=0.025), compared with patients who received other taxanes.\n\nConclusions:\nTaxane-related colitis can present with significant inflammation on colonoscopy, and in a minority of patients as microscopic colitis. Taxane-induced colitis, although uncommon, can lead to ICU admission and colonic perforation.\n\nTaxanepaclitaxeldocetaxelchemotherapycolitisdiarrheagastrointestinal adverse events\n==== Body\nIntroduction\nTaxanes are a widely used class of potent chemotherapy agents for breast, lung, head and neck, pancreatic, esophageal, gastric, anal, and ovarian cancers [1-7]. The first taxane, named paclitaxel, was purified from the bark of the pacific yew tree, Taxus brevifolia, as a part of a large plant-screening program led by the US National Cancer Institute and Department of Agriculture [8-10].\n\nPaclitaxel’s mechanism of cytotoxicity is unique, as it promotes microtubule polymer formation in cells, thus stabilizing the microtubule polymer structure and inhibiting microtubule depolymerization back to tubulin. This process depletes free tubulin and creates arrays of disorganized microtubules inefficient for cell replication, thereby blocking mitosis [11,12]. Because paclitaxel arrests mitosis, the toxic effects of paclitaxel are most evident in tissues with rapid cell turnover, including hematopoietic, lymphatic, gastrointestinal (GI), and reproductive tissues, as well as tissue affected by alopecia. Studies have identified neutropenia, neuropathy, mucositis, asymptomatic bradycardia, myalgia, arthralgia and diarrhea as major side effects of paclitaxel therapy [13].\n\nOnly a limited number of studies have investigated the GI effects of taxanes. These could present as nausea, vomiting, and diarrhea [13,14]. A few case reports showed that taxane-induced colitis can even lead to colonic perforation, requiring surgery, and has histological features similar to ischemic colitis, characterized by a thinned attenuated surface epithelium, increased fibrosis, neutrophil infiltration and focal hemorrhage [15-17]. The largest study to date was conducted at MD Anderson in 2004 and included 14 patients diagnosed with colitis while receiving taxane therapy. During the study period of 2 years, the incidence of colitis in patients who received docetaxel was 1.9%, while in those treated with paclitaxel it was 0.5%. Colitis was defined as symptoms of acute abdominal pain, direct or rebound tenderness with associated fever, neutropenia, and/or diarrhea. Colonoscopy was performed in 2 patients and showed features that raised concern for ischemic colitis. All patients received supportive care, including antibiotics, fluid resuscitation and monitoring. However, no clear conclusion was derived from this study as to whether these treatments helped to alleviate symptoms. One patient died from sepsis and 2 had bowel perforation requiring surgery, which demonstrated that taxane-induced colitis could be a serious side effect in the treatment of breast cancer [18]. Despite these descriptive studies, our knowledge of the clinical features, endoscopic/histologic findings, treatments and outcomes of taxane-induced colitis is still limited.\n\nDespite the low incidence (0.5-1.9%) of taxane-induced colitis, it remains a significant clinical problem. Yet, to date, no existing guidelines describe the clinical course and management recommendations for taxane-induced colitis. For clinicians (including gastroenterologists) caring for patients with taxane-induced colitis, a better understanding of this disease is needed to inform their management. The purpose of this study was to address this gap in knowledge by using our large database at a tertiary cancer center to describe the clinical, endoscopic and histological features of taxane-induced colitis.\n\nPatients and methods\nStudy design and population\nThis was a retrospective cohort study of adult patients with any type of cancer who received taxane-based chemotherapy at the University of Texas MD Anderson Cancer Center between 2000 and 2018. After institutional review board approval, we extracted data from electronic medical and pharmacy records to screen for all adult cancer patients at our center who received taxane-based chemotherapy and also underwent a lower GI endoscopy evaluation for GI symptoms or anemia during this time. Patients were included if they received paclitaxel, docetaxel or nab-paclitaxel, either as single agents or as part of a multi-agent therapy regimen. Patients diagnosed with infectious colitis (confirmed by laboratory test), graft-versus-host disease (confirmed by pathology assessment), or radiation proctocolitis (confirmed by colonoscopy and pathologic assessment) were not included in this study.\n\nWe included patients who had undergone either colonoscopy or flexible sigmoidoscopy with endoscopic and/or histologic findings suggestive of colitis related to taxane treatment (Fig. 1). Patients were excluded if their histologic examination revealed no colitis or if the endoscopic evaluation was performed more than 1 year after the last dose of taxane treatment. Patients were also excluded if symptoms or colonoscopy findings suggestive of colitis were present prior to the initiation of taxane therapy. Patients with a diagnosis of underlying ulcerative colitis or Crohn’s disease were also excluded from this study.\n\nFigure 1 Flowchart of included patients\n\nOncologic data and cancer treatment course\nAfter the study cohort was identified, data pertaining to demographics, comorbidities, oncologic history, taxane regimen, taxane treatment-related non-GI adverse effects and clinical presentation of colitis were collected from their electronic medical charts. Patients’ demographics included age, sex, and race/ethnicity. Clinical history variables consisted of smoking, non-steroidal anti-inflammatory drug (NSAID) use, history of inflammatory bowel disease, comorbidities (according to the Charlson comorbidity index) [19], cancer type and stage, GI tract involvement by cancer, and radiation to the abdomen. We ascertained details of patients’ most recent taxane regimen, including the taxane agent, date of initiation, dose, frequency, date of last dose, reason for discontinuation, and concurrent chemotherapy agents.\n\nClinical features of GI adverse events\nWe identified the clinical features of taxane-induced colitis, including onset, duration, symptoms, and initial and peak grades of diarrhea or colitis, based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0 [20]. Colitis was defined as abrupt onset, when the highest grade of colitis occurred at the time of initial presentation, or gradual onset, when a milder grade of colitis occurred at the time of initial presentation then progressed to a more severe grade. Symptoms of colitis included abdominal pain, abdominal distension and blood or mucus with stool. We also noted colitis treatments received and their duration, whether each patient was hospitalized for colitis, and complications from colitis. We gathered laboratory results regarding patients’ nadir absolute neutrophil count (ANC) within 1 week of colitis onset, stool cultures, and lactoferrin and calprotectin levels. The level of ANC at the time of an event was collected to clarify other differential diagnoses, e.g. neutropenic colitis. We also evaluated any computed tomography (CT) studies of the abdomen and pelvis obtained 1 week either before or after endoscopy. Characteristics and location of colitis on CT scans, such as wall thickening, pericolic fat stranding, mucosal enhancement, and bowel loop dilation, were recorded.\n\nEndoscopic and histologic features\nPatients’ endoscopy reports were reviewed. A spectrum of endoscopic findings of colitis was described, from the presence of mucosal ulcerations, to nonulcerative inflammation (erythema, exudate, loss of vascular pattern, edema, erosions), or a normal appearance (Fig. 2). The distribution of colitis was classified as left colon only, right colon only, both left and right colon, or ileum. We used extensive colitis to describe inflammation in more than 1 segment of colon. The pattern of inflammation was categorized as diffuse, patchy or segmental. Pathology reports for each colonoscopy were reviewed as well. Inflammation patterns were categorized as active, chronic or lymphocytic (Fig. 3). Features of active inflammation included neutrophilic or eosinophilic infiltrate, cryptitis and crypt abscess. Features of chronicity were basal lymphocytic infiltrate, cryptic architecture distortion, apoptosis and Paneth cell metaplasia. Lymphocytic colitis was reported separately as showing the classical histological features of increased intraepithelial lymphocyte infiltration.\n\nFigure 2 Endoscopic features of colitis. There is a spectrum of inflammatory presentations on the endoscopy evaluation. (A) Patchy inflammation with superficial ulceration; (B) Diffuse erythema and loss of vascular pattern; (C, D) Patchy inflammation with large deep ulceration\n\nFigure 3 Pathological features of colonic inflammation. Cryptitis, crypt distortion, crypt abscesses. (A) H&E 10X; (B) H&E, 20X\n\nTreatment and outcomes of toxic GI effects\nFor all patients who received taxane therapy and developed colitis, we noted whether or not they received treatment for their colitis symptoms. If patients received colitis treatment, the type and duration of such treatment, including start and end dates, were recorded. The antibiotic treatment recorded in our cohort was exclusively for empirical purpose, as we excluded patients with a confirmed GI infection. The outcomes of colitis were defined as duration of colitis symptoms, requirement of hospitalization or intensive care unit (ICU) admission, duration of hospitalization, and recurrence of GI symptoms. Complications of colitis, such as colonic perforations, were also noted. Colitis resolution was defined as the return of clinical symptoms to baseline clinical presentation before the colitis event.\n\nStatistical analysis\nWe used SAS version 9.4 (SAS Institute, Cary, NC) and SPSS version 24.0 (IBM Corporation, Armonk, NY) for our statistical analysis. Each continuous variable distribution was summarized using medians and interquartile ranges. Distributions of categorical variables were summarized using frequencies and percentages. Continuous variables were compared using the Wilcoxon rank sum or Kruskal-Wallis test for comparisons among groups. The Fisher exact test or chi-square test was used to evaluate associations between 2 categorical variables. All statistical evaluations were 2-sided. P values of 0.05 or less were considered statistically significant.\n\nResults\nPatient characteristics\nOf the 45,527 patients who received taxane-based therapy during the study period, 76 were included in our analyses (Fig. 1). The median age was 59 years and 58% were female (Table 1). The majority of patients were Caucasian (n=59, 78%). About half of our cohort were smokers (n=37, 49%), half used NSAIDs (n=41, 54%), and more than half had comorbidities (n=50, 66%). Breast cancer was the most common cancer type (n=26, 34%), while thoracic and head and neck cancers were the second most common (n=23, 30%). Fifty-four percent of patients received paclitaxel, 37% received docetaxel and 9% received nab-paclitaxel. More than half the patients received a regimen containing concurrent platinum therapy (n=44, 58%), and less than half received adjuvant radiotherapy (n=33, 43%).\n\nTable 1 Patients’ characteristics\n\nClinical features\nThe median duration of taxane therapy was 59 days, with a wide variation of infusion interval between weekly and bimonthly, and a median cycle number of 4. The median time from the start of taxane therapy to colitis onset was 31 days (Table 1). Chemotherapy was discontinued because of cancer progression in 21% of patients, colitis in 16% and other adverse events in 16%; chemotherapy was not interrupted in the other patients. The onset of colitis symptoms was usually gradual (n=61, 80%), and the median duration of symptoms was 30 days. The median ANC at time of colitis onset was 3.0 K/mm3, well above the level of neutropenia.\n\nOf our patients, 88% were symptomatic, while 12% were clinically asymptomatic but had anemia. The presence of symptoms was not associated with the type of taxane chemotherapy received. Of the common symptoms, diarrhea and vomiting were most likely to be treated (P<0.001 and P=0.044, respectively), especially higher grades of diarrhea (P=0.036; Table 2).\n\nTable 2 Patient characteristics stratified by colitis treatment\n\nThe clinical presentation also differed according to the type of chemotherapy received. The onset of symptoms was earliest for nab-paclitaxel and latest for paclitaxel (P=0.003); however, colitis symptoms were not different among the different taxanes. Nab-paclitaxel therapy was associated with hospitalization (P=0.005). Both docetaxel- and nab-paclitaxel–associated colitis were more likely than paclitaxel-associated colitis to be treated with intravenous fluid (P=0.025; Table 3). On the other hand, the clinical characteristics of colitis, treatment requirement and outcomes were similar between the patients who received taxane monotherapy versus taxane with adjuvant platinum-based therapy (Supplementary Table 1).\n\nTable 3 Patient characteristics stratified by taxane therapy type\n\nEndoscopic and histologic features\nAll 76 patients underwent a colonoscopy for GI symptoms or anemia, and all had abnormal endoscopic or histologic features (Fig. 2, 3). Symptoms, type of chemotherapy received, and whether or not patients received treatment for colitis were not associated with endoscopic features such as normal appearance, ulceration, or nonulcerative inflammation (Tables 2, 3). Patients with lymphocytic colitis on histology had the whole spectrum of endoscopic presentations. Of symptomatic patients, 27% had mucosal ulceration, 42% had nonulcerative inflammation, and 31% had normal colonoscopy findings. Compared with asymptomatic patients, symptomatic patients had a different pattern of inflammation (P=0.019) but similar locations of inflammation on endoscopy.\n\nHistologic features were similar between symptomatic and asymptomatic patients, regardless of the treatment requirement for GI symptoms and the type of taxane (Tables 2, 3). Endoscopic features were similar between patients who received antibiotics and those who did not. However, endoscopic features differed between patients who received intravenous fluids and those who did not (P=0.044) (Table 4). Among patients who received intravenous fluids, 50% had mucosal ulceration, 36% had nonulcerative inflammation, and 14% had normal endoscopic findings. Among patients who did not receive intravenous fluids, ulceration was less prevalent (19%) than nonulcerative inflammation (44%).\n\nTable 4 Patient characteristics stratified by antibiotic and IV fluid treatments for GI symptoms\n\nTreatment and outcomes\nFifty patients (66%) were treated for colitis symptoms; 46% received fluids, 24% received antimotility agents, 22% received antibiotics, 11% received immunosuppressants (systemic steroid in 5, and topical steroid in 3), and 3% received octreotide or somatostatin. Twenty-six patients (34%) did not receive any medical treatment. Treatment was started an average of 6 days from symptom onset, with an average duration of 14 days. About half (46%) of the patients were hospitalized for their colitis symptoms, but only a minority (9%) of patients required ICU admission. Among the 35 hospitalized patients, 18 received: intravenous fluids (n=4), or antibiotics (n=5), or both (n=9). Three patients also received an antimotility agent and/or immunosuppressant. One patient whose course was complicated by colitis-related colonic perforation died soon after transition to hospice; this patient was receiving nab-paclitaxel and gemcitabine. Taxane therapy was restarted in 25% of patients after colitis onset, and colitis symptoms recurred in 9%. Patients who received treatment for colitis had the same rate of recurrent GI symptoms as patients who did not receive treatment. Smoking and NSAID use did not appear to affect the endoscopic findings and clinical outcomes, except that NSAID use was associated with a higher hospitalization requirement (P=0.006) (Supplementary Table 2).\n\nPatients with diarrhea, abdominal pain, or vomiting were more likely to receive antibiotic treatment (P= 0.002, 0.004, and <0.001 respectively; Table 4). These were administered either as monotherapy or combination therapy, with a median duration of 12 days (Table 1 and Supplementary Table 3). Patients with abdominal pain or vomiting were more likely to be treated with intravenous fluids (P= 0.013 and <0.001 respectively) than patients without these symptoms. Hospitalized patients were also more likely to be treated with antibiotics and intravenous fluids (P=0.006 and <0.001 respectively) than were patients who did not require hospitalization. In our cohort, 9 patients received both antibiotics and intravenous fluids. Patients who received antibiotics had a shorter duration of symptoms, with a mean duration of 24 days, while those who did not receive antibiotics had a mean duration of 63 days (P=0.025). Likewise, patients who received intravenous fluids had a shorter duration of symptoms compared with those who did not (P=0.037). More patients who received antibiotics for taxane-induced colitis were able to resume taxane therapy after resolution of colitis, but this difference was not significant (P=0.080).\n\nDiscussion\nTo our knowledge, this cohort of 76 patients represents the largest study to date to evaluate the characteristics of taxane-induced colitis. In this study, taxane-induced colitis did not occur immediately after chemotherapy induction, but rather gradually and slowly; the average time from taxane therapy to colitis onset was around 1 month. Colitis can have a wide array of symptoms, most commonly diarrhea or blood in stool, and less commonly abdominal pain and nausea. Most patients received treatment for colitis symptoms; these treatments included intravenous fluids, antimotility agents, antibiotics, immunosuppressants, and octreotide and somatostatin. Treatment with intravenous fluids and antibiotics reduced the duration of symptoms. However, antibiotics and intravenous fluids did not prevent the recurrence of colitis symptoms. The consequences of taxane-induced colitis were found to be severe, leading to treatment discontinuation, hospitalization, ICU admission, and even colon perforation.\n\nPrevious case reports of taxane-induced colitis had nonspecific histologic findings, including pseudomembranous colitis and ischemic colitis [21,22]. However, the small number of reported cases has made it difficult to fully characterize the effects of taxanes on the colon. In our study, the endoscopic findings of colitis were mostly nonulcerative inflammation or normal appearance, while only a minority of patients had mucosal ulcerations. The endoscopic features were comparable between symptomatic and asymptomatic patients. While most of the patients evaluated had nonspecific endoscopy findings, most were found to have signs of colitis on histology. Around 83% of symptomatic and 78% of asymptomatic patients had evidence of active inflammation on histology, and the majority had evidence of chronicity. On the basis of these findings, we can conclude that while endoscopic findings may not be specific, a biopsy should be performed to determine the presence of chemotherapy-induced colitis. This was the main reason we studied only patients who had undergone endoscopic evaluation: to clarify the role of endoscopic and histologic evaluation. However, it remains a challenge to clearly delineate the specific triggering medication.\n\nOur study is unique in that it compares colitis characteristics among patients who received different taxane agents. We found that nab-paclitaxel therapy was associated with more severe colitis, while paclitaxel therapy seemed to lead to a milder form. The duration from taxane treatment to colitis symptom onset was shortest for nab-paclitaxel therapy and longest for paclitaxel therapy. Nab-paclitaxel–induced colitis was associated with a 100% rate of hospitalization in our cohort, compared to only 34% among patients who developed paclitaxel-induced colitis. Interestingly, nab-paclitaxel is a solvent-free, albumin-bound formulation of paclitaxel developed to avoid toxicities associated with the cremophor solvent used in paclitaxel. However, the toxicities of cremophor were mostly hypersensitivity reactions, neutropenia, prolonged peripheral neuropathy and fluid retention [23]. In phase II and III trials, nab-paclitaxel therapy yielded fewer hypersensitivity reactions, but had a similar profile to that of paclitaxel for side effects such as neutropenia, neuropathy, alopecia and mild GI symptoms [10,24-27]. The fact that nab-paclitaxel seemed to be associated with more severe colitis in our cohort may be partially explained by its mechanism of action. Nab-paclitaxel is albumin-bound and utilizes the leaky vasculature of the tumor interstitium and albumin receptors to mediate drug transport across the microvasculature to reach high concentrations in the cancer cells [28]. The GI tract also contains albumin receptors, which may contribute to accumulation of nab-paclitaxel in the GI tract, causing more severe colitis symptoms [29]. Interestingly, adjuvant platinum-based therapy to taxane did not augment the level of severity of diarrhea/colitis or worsen the clinical outcomes in our cohort. However, this could be confounded by the limited sample size for subgroup analysis.\n\nNotably, the ANC at the onset of taxane-induced colitis was recorded to help distinguish chemotherapy-induced colitis from neutropenic colitis, as cancer patients who receive chemotherapy are at high risk of neutropenia [30]. We observed a normal range of ANCs at the time of colitis presentation. This suggests that a temporary immunocompromised status is less likely to contribute to taxane-induced colitis.\n\nWe found that, although treatment of colitis with intravenous fluids and/or antibiotics reduced the duration of symptoms, these treatments did not prevent symptom recurrence. This observation could be explained by the fact that patients who received any type of GI symptom treatment had more severe colitis initially. Intravenous fluids can replenish fluids lost with diarrhea, while antibiotics have been shown to have some beneficial effect on colon inflammation, such as inflammatory bowel disease [31-33]. Presumably the alteration of the gut microbiome by the antibiotics could play a critical role in the colon’s health. Exactly how the antibiotic treatment benefits this colitis condition and whether antibiotics should be given as a part of routine practice still require further clarification. Unlike patients with checkpoint-inhibitor–induced colitis, for which the main treatment is corticosteroids [34], only a few patients in our cohort received steroid therapy.\n\nIn recent years, colitis induced by cancer therapies, especially immune checkpoint inhibitors, has drawn the interest of gastroenterologists worldwide [35-39]. Some even argue that immune checkpoint-inhibitor–induced colitis should be recognized as a new inflammatory bowel disease entity [35,40-42]. A treatment algorithm was established for checkpoint-inhibitor–induced colitis [43-45], but not much is known regarding taxane-induced colitis. This rare event should be more closely followed, especially with the increasing use of chemotherapy and immunotherapy combinations [46,47]. For instance, in non-small cell lung cancer, the combination of atezolizumab, carboplatin, bevacizumab, and paclitaxel recently received approval from the US Food and Drug Agency for clinical use [48]. While the rate of grade 3 or higher diarrhea in the study of that drug combination was 1.3%, the rate of grade 1-2 diarrhea was 17.8%. Thus, recognizing the colitis risk with taxanes will be more important when they are used with immunotherapy combinations in unselected patient populations (i.e. outside of clinical trials), in which the rates of side effects are expected to be higher.\n\nOur study had several limitations. First, it was a retrospective review of electronic medical records, and details of the colitis symptoms and treatments could have been missed because of the conversion to an electronic medical record during the study period. Second, the sample size of this study was underpowered in the subgroup analyses. Third, this was a single-center study, and the common practice at our center may not represent the practice at other centers, especially since there are no standard treatment recommendations for this entity. Fourth, a selection bias likely resulted from the inclusion of only patients who underwent colonoscopy, since patients who require such evaluation usually have more severe GI symptoms, which could have underestimated the overall incidence of taxane-related colitis in the larger cancer population. Lastly, many cases of colitis were diagnosed by biopsy, and the resulting delay in treatment may have led to a longer symptom duration and recurrence of symptoms.\n\nTo conclude, although colitis is not a common adverse event of taxane-based chemotherapy, it can have serious consequences. Taxane-induced colitis can lead to cancer treatment discontinuation, ICU admission, and even colonic perforation. Symptoms of taxane-induced colitis presented slowly and gradually in our cohort, mostly as bloody diarrhea and uncommonly as abdominal pain and nausea. Nab-paclitaxel therapy led to a more serious form of colitis in our cohort compared with the more commonly used taxanes. Although most patients had nonspecific endoscopic findings, significant and prevalent histologic inflammation prompted our attention to consider this evaluation tool to discern the presence of chemotherapy-induced colitis. Treatment with intravenous fluids and antibiotics shortened the duration of symptoms. Thus, these treatments should be encouraged once taxane-induced colitis is confirmed by endoscopy and/or histology. Large-scale prospective studies are needed to investigate the appropriate treatment for this entity.\n\nSummary Box\nWhat is already known:\n\n\nTaxane therapy is effective for a number of malignancies\n\nTaxane therapy has been reported to be associated with gastrointestinal side effects\n\nDetailed characterization of the clinical, endoscopic and histopathological features of taxane therapy-related gastrointestinal toxicities is lacking\n\n\n\n\nWhat the new findings are:\n\n\nColitis is not a common adverse event of taxane-based chemotherapy, but it can have serious consequences, such as cancer treatment discontinuation, intensive care unit admission, and even colonic perforation\n\nNab-paclitaxel therapy was associated with more serious forms of colitis in our cohort compared with the more commonly used taxanes\n\nTreatment of taxane-induced colitis with intravenous fluids and antibiotics shortened the duration of symptoms\n\n\n\n\nSupplementary Table 1 Patient characteristics stratified by colitis treatment\n\nClick here for additional data file.\n\n Supplementary Table 2 Effect of NSAID and smoking on endoscopy finding and clinical outcome of colitis\n\nClick here for additional data file.\n\n Supplementary Table 3 Detailed information regarding the antibiotics administered\n\nClick here for additional data file.\n\n Acknowledgment\nMedical editing of this paper was provided by the Department of Scientific Publications at MD Anderson Cancer Center\n\nConflict of Interest: None\n\nBaylor College of Medicine; The University of Texas MD Anderson Cancer Center; McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA\n==== Refs\nReferences\n1 Sparano JA Zhao F Martino S Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer J Clin Oncol 2015 33 2353 2360 26077235 \n2 Nowak AK Wilcken NR Stockler MR Hamilton A Ghersi D Systematic review of taxane-containing versus non-taxane-containing regimens for adjuvant and neoadjuvant treatment of early breast cancer Lancet Oncol 2004 5 372 380 15172358 \n3 Kumar A Hoskins PJ Tinker AV Dose-dense paclitaxel in advanced ovarian cancer Clin Oncol (R Coll Radiol) 2015 27 40 47 25455846 \n4 Jin Y Sun Y Shi X Meta-analysis to assess the efficacy and toxicity of docetaxel-based doublet compared with docetaxel alone for patients with advanced NSCLC who failed first-line treatment Clin Ther 2014 36 1980 1990 25256387 \n5 Fossella FV Docetaxel for previously treated non-small-cell lung cancer Oncology (Williston Park) 2002 16 6 Suppl 6 45 51 \n6 He X Wang J Li Y Efficacy and safety of docetaxel for advanced non-small-cell lung cancer:a meta-analysis of Phase III randomized controlled trials Onco Targets Ther 2015 8 2023 2031 26346649 \n7 Vermorken JB Remenar E van Herpen C EORTC 24971/TAX 323 Study Group Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer N Engl J Med 2007 357 1695 1704 17960012 \n8 Wani MC Taylor HL Wall ME Coggon P McPhail AT Plant antitumor agents. 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Inflamm Bowel Dis 2018 25 385 393 \n42 Abu-Sbeih H Ali FS Luo W Qiao W Raju GS Wang Y Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis J Immunother Cancer 2018 6 95 30253811 \n43 Haanen J Carbonnel F Robert C Management of toxicities from immunotherapy:ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2017 28 Suppl_4 iv119 iv142 28881921 \n44 Johnson DH Zobniw CM Trinh VA Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis J Immunother Cancer 2018 6 103 30305177 \n45 Wang Y Wiesnoski DH Helmink BA Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis Nat Med 2018 24 1804 1808 30420754 \n46 Socinski MA Jotte RM Cappuzzo F IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC N Engl J Med 2018 378 2288 2301 29863955 \n47 Gandhi L Rodríguez-Abreu D Gadgeel S KEYNOTE-189 Investigators Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer N Engl J Med 2018 378 2078 2092 29658856 \n48 FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastaticnon-squamous NSCLC Accessed 01 November, 2019 Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627874.htm\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1108-7471",
"issue": "33(1)",
"journal": "Annals of gastroenterology",
"keywords": "Taxane; chemotherapy; colitis; diarrhea; docetaxel; gastrointestinal adverse events; paclitaxel",
"medline_ta": "Ann Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101121847",
"other_id": null,
"pages": "59-67",
"pmc": null,
"pmid": "31892799",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "29863955;12526980;25213191;16172456;3558716;1973737;30715364;25161624;423966;16361642;29722812;26811648;7850785;15378497;16740598;21603258;30253811;29198330;29747688;17960012;7909688;21160890;30518410;26346649;29043290;30539510;21330767;30666357;16135470;29718308;21569998;25455846;30420754;26925240;30305177;26077235;25256387;30169584;12108897;5553076;11468447;29658856;21497382;15172358;28881921",
"title": "Clinical characteristics of colitis induced by taxane-based chemotherapy.",
"title_normalized": "clinical characteristics of colitis induced by taxane based chemotherapy"
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"abstract": "Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) often suffer from severe toxicities during treatment, especially with high-dose methotrexate (HD-MTX). Systematic data on methotrexate (MTX) toxicity in these patients are rare. We analyzed seven MTX-associated toxicities during consolidation therapy in 103 DS- and 1,109 non-DS-patients (NDS) with ALL (NDS-ALL) enrolled in ALL-Berlin-Frankfurt-Münster (ALL-BFM) trials between 1995-2016 and 1995-2007, respectively. Patients received four courses MTX (5 g/m2 each) plus intrathecal MTX and 6-mercaptopurine (6-MP). From 2004 onwards, a dose of 0.5 g/m2 in the first MTX course has been recommended for DS-patients. DS-patients showed higher rates of grade 3/4 toxicities after the first course with 5 g/m2 MTX compared to NDS-patients (grade 3/4 toxicities 62 in 45 DS-patients vs 516 in 1,089 NDS-patients, P<0.001). The dose reduction (0.5 g/m2) in DS-patients has reduced toxicity (39 in 51 patients, P<0.001) without increasing the relapse risk (reduced dose, 5-year cumulative relapse incidence = 0.09±0.04 vs high dose, 0.10±0.05, P=0.51). MTX dose escalation to 1.0 g/m2 for DS-patients who tolerated 0.5 g/m2 (n= 28 of 51 patients) did not result in an increased rate of grade 3/4 toxicities after the second course (P=0.285). Differences in MTX plasma levels at 42 and 48 hours after the start of the first methotrexate infusion did not explain higher toxicity rates in DS-patients treated with 0.5 g/m2 compared to NDS-patients treated with 5 g/m2 Within the DS cohort a higher MTX plasma level was associated with increased toxicity. In conclusion, dose reduction in the first MTX course reduced severe toxicities without increasing the risk of relapse. (ClinicalTrials.gov identifier: NTC00430118, NCT01117441).",
"affiliations": "Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel.;Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel.;Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel.;Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel.;Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel.;Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.;Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel.;Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel gunnar.cario@uksh.de.",
"authors": "Kroll|Mirko|M|;Kaupat-Bleckmann|Kirsten|K|;Mörickel|Anja|A|;Altenl|Julia|J|;Schewel|Denis M|DM|;Stanullal|Martin|M|;Zimmermann|Martin|M|;Schrappe|Martin|M|;Cario|Gunnar|G|",
"chemical_list": "D015122:Mercaptopurine; D008727:Methotrexate",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2019.224774",
"fulltext": "\n==== Front\nHaematologica\nHaematologica\nHaematologica\nhaematol\nHaematologica\n0390-6078 1592-8721 Ferrata Storti Foundation \n\n10.3324/haematol.2019.224774\n1051013\nArticle\nAcute Lymphoblastic Leukemia\nMethotrexate-associated toxicity in children with Down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to ALL-BFM treatment regimen\nKroll Mirko 1 Kaupat-Bleckmann Kirsten 1 Mörickel Anja 1 Altenl Julia 1 Schewel Denis M. 1 Stanullal Martin 2 Zimmermann Martin 2 Schrappe Martin 1 Cario Gunnar 1 \n1 Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel\n\n2 Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany\nCorrespondence:GUNNAR CARIOgunnar.cario@uksh.de\n4 2020 \n01 8 2019 \n105 4 1013 1020\n15 4 2019 24 7 2019 Copyright© 2020 Ferrata Storti Foundation2020Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) often suffer from severe toxicities during treatment, especially with high-dose methotrexate (HD-MTX). Systematic data on methotrexate (MTX) toxicity in these patients are rare. We analyzed seven MTX-associated toxicities during consolidation therapy in 103 DS- and 1,109 non-DS-patients (NDS) with ALL (NDS-ALL) enrolled in ALL-Berlin–Frankfurt–Münster (ALL-BFM) trials between 1995–2016 and 1995–2007, respectively. Patients received four courses MTX (5 g/m2 each) plus intrathecal MTX and 6-mercaptopurine (6-MP). From 2004 onwards, a dose of 0.5 g/m2 in the first MTX course has been recommended for DS-patients. DS-patients showed higher rates of grade 3/4 toxicities after the first course with 5 g/m2 MTX compared to NDS-patients (grade 3/4 toxicities 62 in 45 DS-patients vs. 516 in 1,089 NDS-patients, P<0.001). The dose reduction (0.5 g/m2) in DS-patients has reduced toxicity (39 in 51 patients, P<0.001) without increasing the relapse risk (reduced dose, 5-year cumulative relapse incidence = 0.09±0.04 vs. high dose, 0.10±0.05, P=0.51). MTX dose escalation to 1.0 g/m2 for DS-patients who tolerated 0.5 g/m2 (n= 28 of 51 patients) did not result in an increased rate of grade 3/4 toxicities after the second course (P=0.285). Differences in MTX plasma levels at 42 and 48 hours after the start of the first methotrexate infusion did not explain higher toxicity rates in DS-patients treated with 0.5 g/m2 compared to NDS-patients treated with 5 g/m2. Within the DS cohort a higher MTX plasma level was associated with increased toxicity. In conclusion, dose reduction in the first MTX course reduced severe toxicities without increasing the risk of relapse. (ClinicalTrials.gov identifier: NTC00430118, NCT01117441).\n==== Body\nIntroduction\nChildren and adolescents with Down syndrome (DS) DS have an approximately 10-fold higher risk of acquiring acute lymphoblastic leukemia (ALL)1 and have shown an inferior outcome compared to children with NDS-ALL.2–5 The worse outcome for DS-ALL has been attributed to a higher risk of relapse as well as higher levels of chemotherapy-associated toxicities and treatment-related mortality.2,6–8 Severe toxicities may eventually lead to chemotherapy dose reduction which in turn might increase the risk of relapse.2,5,6\n\nMethotrexate (MTX is a folate antagonist that interferes with the de novo synthesis of nucleotides in proliferating cells and plays a crucial role in the treatment of pediatric ALL in which MTX is administered in high doses (HD-MTX, ≥ 0.5 g/m2 per intravenous [i.v.] application).9 Many patients with DS-ALL suffer from severe side effects after receiving HD-MTX. Common MTX-associated side effects in DS-ALL are severe mucositis and stomatitis, infections, bone marrow suppression, hepato-, nephro- and neurotoxicity.2,6–8\n\nIn order to extend our knowledge on MTX-associated toxicities in DS-ALL, we analyzed clinical data from DS-ALL and NDS-ALL patients who were treated according to ALL-BFM protocols in Germany and Switzerland (ALL-BFM 1995, ALL-BFM 2000 and AIEOP-BFM ALL 2009). We focused on toxicities occurring after HD-MTX administrations during the consolidation element Protocol M in which patients receive four courses of i.v. HD-MTX (5 g/m2 each, 24-hour infusion).\n\nAdditionally, we investigated the influence of the rs1051266 80G>A polymorphism of the chromosome 21-encoded folate carrier SLC19A1 (RFC1) on MTX toxicity in DS-ALL. SLC19A1 functions as the main transporter for MTX into cells. Therefore rs1051266 may alter the transportation rate of MTX into cells and thus may affect the severity of toxicities.10–12\n\nMethods\nPatients\nA total of 1,212 patients were selected from three consecutive multicenter ALL-BFM trials (ALL-BFM 95, ALL-BFM 2000 and AIEOP-BFM ALL 2009; diagnosed between January 13, 1996 and September 6, 2016 for DS-ALL and between April 11, 1995 and May 4, 2007 for NDS-ALL patients) according to the following inclusion criteria: age at diagnosis between ≥ 1 year and ≤ 18 years, no initial high risk (HR) features, consolidation treatment with HD-MTX (Protocol M) and availability of treatment and toxicity data. Detailed information on the different recruitment periods and treatment stratification is given in the Online Supplementary Materials and Methods. Informed consent from the patients and/or guardians was obtained and the studies were approved by the responsible ethical committees.\n\nConsolidation Protocol M is an 8-week therapy element given to non-HR patients only. Patients receive four courses of i.v. HD-MTX (5 g/m2 each, 24-hour infusion) every second week in addition to an age-adapted intrathecal MTX and daily oral 6-MP (25 mg/m2 /day). MTX plasma levels were measured at various time points after the start of each MTX infusion and each HD-MTX course was followed by an i.v. leucovorine (LCV) rescue (15 mg/m2) at 42, 48 and 54 hours after the start of the MTX infusion (for details on Protocol M see the Online Supplementary Material and Methods).13 Patients who qualified for the HR group only after the start of Protocol M and who were therefore allocated to the HR treatment arm of the respective study were included in the toxicity analysis for the HD-MTX courses they had received (usually only the first course) but not for outcome analysis.\n\nAs of 2004, the study group recommended to administer the first HD-MTX course with a reduced dose of 0.5 g/m2 in order to reduce severe toxicities in DS-ALL patients. A subsequent increase of MTX dosages could be performed if no severe toxicity had occurred. After each HD-MTX course, toxicity grading was performed for leukopenia, thrombocytopenia, infections, stomatitis, hepatotoxicity, nephrotoxicity and bilirubinemia according to the Common Terminology Criteria for Adverse Events (CTCAE) version 2.0 (for details see the Online Supplementary Materials and Methods and Online Supplementary Table S1). In some patients reporting was incomplete covering only some of the seven toxicities.\n\nStatistical analysis\nStatistical analysis included χ2-, Fisher’s exact, Mann-Whitney-U and McNemar tests as indicated in the figure legends and tables. The 5-year-cumulative incidence risk of relapse was calculated according to Kalbfleisch and Prentice and compared using the Gray’s test. Analyses were done using IBM SPSS 22 and SAS 9.4. A P-value ≤ 0.05 was considered to be statistically significant.\n\nDNA and allelic discrimination assay\nInformation on patient DNA preparation and SLC19A1 rs1051266 80G>A genotyping can be found in the Online Supplementary Materials and Methods.\n\nResults\nPatients, treatment discontinuation and MTX dosages\n1,212 patients were included in this study, 103 DS-ALL and 1,109 NDS-ALL. The comparison of both groups showed no significant differences in the median age at diagnosis, sex distribution, and white blood cell counts at diagnosis (Table 1). None of the DS patients had T-cell ALL in contrast to 12.4% of the NDS-ALL group (P=0.006) and a hyperdiploid karyotype was less frequent in DS-ALL compared to NDS-ALL patients (P=0.002). Furthermore, NDS-ALL had more ETV6-RUNX1 rearrangements compared to DS-ALL patients (P<0.001) (Table 1).\n\nTable 1. Patient characteristics, methotrexate dosages in the first high-dose methotrexate course and total methotrexate dosage trend during consolidation for Down syndrome and non-Down syndrome acute lymphoblastic leukemia patients.\n\nOf the 103 DS-ALL patients who started HD-MTX consolidation 95 patients (92.2%) completed the protocol. Seven DS-ALL patients discontinued consolidation treatment at various time points due to a switch to HR treatment (n= 4) or severe infections (n= 2). Analysis could not be performed in one patient with DS-ALL for the fourth HD-MTX course due to incomplete toxicity data. One DS-ALL patient died after the second course from septic shock in neutropenia after receiving 5 g/m2 MTX doses in the first and second course. In contrast, 1,083 of 1,109 NDS-ALL patients (97.7%) completed consolidation. Consolidation discontinuation in 26 NDS-ALL patients was due to a switch to HR treatment (n=24) or severe toxicities (neurotoxicity, n=1 and severe infection, n=1). Three additional patients could not be analyzed due to incomplete data. None of the NDS-ALL patients died during HD-MTX consolidation (Figure 1).\n\nFigure 1. Flow chart showing patient numbers in individual high-dose methotrexate courses including drop outs during high dose methotrexate consolidation.\n\nAs of 2004, the ALL-BFM study group recommended for DS-ALL patients to administer a reduced MTX dose of 0.5 g/m2 in the first HD-MTX course and to subsequently increase the dose if no severe side effects occur. Therefore, 51 of 103 (49.5%) DS-ALL patients received the first HD-MTX course with a dose of 0.5 g/m2 (±10%) and 45 of 103 (43.7%) received 5 g/m2 (±10%) in the first course (Table 1). Of note, in some DS-ALL patients a MTX dose of 0.5 g/m2 was given already before 2004 and some DS-ALL patients still received 5 g/m2 doses after the 2004 recommendation, (DS-ALL with 0.5 g/m2 MTX in the first course before 2004, n= 6 of 42 [14.3%] and 5.0 g/m2 in first course since 2004, n=11 of 61 [18.0%]).\n\nIn contrast, 1,089 of 1,109 (98.2%) non-DS-ALL patients received 5 g/m2 MTX. As expected, the MTX dosages in the course of the consolidation treatment were more heterogeneous in DS-ALL as compared to NDS-ALL (Table 1).\n\nToxicities after HD-MTX\nInitially we focused on toxicities after the first HD-MTX course because latter courses might be more biased by toxicities and MTX dosages from previous HD-MTX courses, especially in those patients for whom the dose has been adopted after the recommendation in 2004. After receiving a MTX dose of 5 g/m2 patients with DS-ALL showed significantly higher rates of grade 3/4 leukopenia, thrombocytopenia, infections and stomatitis compared to NDS-ALL who received the same dose (leukopenia, DS-ALL n=19 of 44 [43.2%] vs. NDS-ALL n=255 of 961 [26.5%], P=0.023; thrombocytopenia, 14 of 43 [32.6%] vs. 84 of 957 [8.8%], P<0.001; infections, 4 of 43 [9.3%] vs. 15 of 939 [1.6%], P=0.008; stomatitis, 18 of 43 [41.9%] vs. 56 of 951 [5.9%], P<0.001) (Figure 2A). An initial MTX dose of 0.5 g/m2 led to a significantly reduced rate of grade 3/4 leukopenia, thrombocytopenia and stomatitis in DS-ALL compared to DS-ALL who received 5 g/m2 (leukopenia, 0.5 g/m2 n=11 of 50 [22.0%] vs. 5 g/m2 n= 19 of 44 [43.2%], P=0.045; thrombocytopenia, 7 of 50 [14.0%] vs. 14 of 43 [32.6%], P=0.046; stomatitis, 9 of 49 [18.4%] vs. 18 of 43 [41.9%], P=0.021). However, DS-ALL patients treated with a reduced MTX dose still suffered from significantly higher rates of grade 3/4 infections, stomatitis and hepatotoxicity compared to NDS-ALL who received 5 g/m2 MTX (infections, DS-ALL n= 3 of 48 [6.3%] vs. NDS-ALL n= 15 of 939 [1.6%], P=0.05; stomatitis, 9 of 49 [18.4%] vs. 56 of 951 [5.9%], P=0.003; hepatotoxicity, 9 of 49 [18.4%] vs. 59 of 945 [6.2%], P=0.004). An increase of MTX after the first dose to a median dose of 1.0 g/m2 (range 0.94–2.06 g/m2) in the second course was feasible in 28 of 51 (54.9%) DS-ALL patients who initially received 0.5 g/m2 (Figure 2B). Dose escalation did not result in an increased rate of toxicities (11 grade 3/4 toxicities in 28 patients after the first course with 0.5 g/m2 MTX vs. 16 of 28 patients after the second course with 1.0 g/m2 MTX, P=0.285).\n\nFigure 2. Comparison of toxicities after first high-dose methotrexate (HD-MTX) course in Down syndrome acute lymphoblastic leukemia (DS-ALL) versus non-Down syndrome acute lymphoblastic leukemia (NDS-ALL) and comparison of toxicities in DS-ALL after the initial and later HD-MTX courses. (A) Comparison of grade 3/4 toxicities after application of the first HD-MTX course in DS-ALL patients who received 5 g/m2 (n=45 of 103) or 0.5 g/m2 methotrexate (MTX) (n=51 of 103) and NDS-ALL patients who received 5 g/m2 MTX (n=1,089/1,109). *P≤0.05, Fisher’s exact test. (B) Comparison of grade 3/4 toxicities after the first and second HD-MTX course in DS-ALL patients who initially received 0.5 g/m2 MTX and were escalated to a median MTX dose of 1.0 g/m2 in the second course (n=28 of 51). No significant differences according to McNemar test. (C) and (D) Comparison of grade 3/4 toxicities after the first and last HD-MTX course in all DS-ALL (C) and NDS-ALL patients (D), including patients with intermediate MTX doses. *P≤0.05 according to McNemar-test. The number on top of each bar represents the number of patients.\n\nFurther dose escalation in subsequent HD-MTX courses occurred in 15 of these 28 dose escalated patients: 12 patients (23.5% of the initial 51 DS-ALL patients with 0.5 g/m2 MTX in the first course) received 5 g/m2 from the third course on and three additional patients in the fourth course. In the remaining 13 of the 28 patients, an intermediate MTX dose was either continued throughout the remaining consolidation (n= 10), or was reduced to a low dose in the fourth course (n= 1), or was decreased to an intermediate dose in the fourth course after being increased to 5 g/m2 in the third course (n= 1) or the therapy was switched to HR treatment after the second course (n=1). In 4 of 51 patients who were initially treated with 0.5 g/m2 MTX in the first course, MTX dose escalation was performed later in the course of consolidation, i.e. in the third (n=3) or the fourth course (n=1). The remaining 19 of the 51 patients were treated with a 0.5 g/m2 MTX dose throughout the whole consolidation phase.\n\nNext we analyzed toxicities after the first and the forth HD-MTX course of all the DS-ALL patients who completed consolidation (n=95) (Figure 2C-D). DS-ALL patients showed a significant decrease in the rate of grade 3/4 stomatitis after the last course as compared to the initial course (stomatitis, in the first course n=27 of 93 [29.0%], in the fourth course n=9 of 91 [9.9%], P=0.002). In contrast, the number of patients with grade 3/4 leukopenia significantly increased (30 of 94 [31.9%] vs. 45 of 89 [50.6%], P=0.01). Similarly, NDS-ALL patients showed a decrease in grade 3/4 stomatitis and an increase in grade 3/4 leukopenia during the course of consolidation therapy (stomatitis, 53 of 942 [5.6%] vs. 9 of 923 [1.0%], P<0.001; leukopenia, 250 of 952 [26.3%] vs. 477 of 935 [51.0%], P<0.001).\n\nImpact of MTX dose reduction on cumulative incidence of relapses\nThe 5-year-cumulative incidence risk of relapse (5y-CIR) was compared between DS-ALL patients who received a dose of 0.5 g/m2 in the first HD-MTX course with those who received 5 g/m2 (Figure 3A). No significant differences in 5y-CIR were observed (0.5 g/m2 subgroup n=5 of 50, 5y-CIR±SE=0.09±0.04 vs. 5 g/m2 subgroup n=7 of 41, 5y-CIR=0.10±0.05, P=0.51). Next we compared the 5y-CIR of DS-ALL patients who received a 0.5 g/m2 MTX dose in the first course and increased dosages in subsequent courses with those of patients who were treated with a MTX dose of 0.5 g/m2 throughout the whole consolidation phase. No significant CIR difference between both groups was observed (0.5 g/m2 and escalated, 5y-CIR= 0.14±0.07 vs. 0.5 g/m2 and continued, 5y-CIR=0.00±0.00, P=0.42) (Figure 3B).\n\nFigure 3. Five-year-cumulative incidence risk of relapse in Down syndrome acute lymphoblastic leukemia. (A) Comparison of the 5-year-cumulative incidence risk (5y-CIR) of Down syndrome acute lym-phoblastic leukemia (DS-ALL) patients who received a first high dose methotrexate (HD-MTX) course of 0.5 g/m2 (blue) or 5 g/m2 MTX (red). No significant differences according to Gray’s test. (B) Comparison of the 5y-CIR of DS-ALL who initially received 0.5 g/m2 MTX in the first course and were eventually dose escalated in the course of consolidation with DS-ALL who received 0.5 g/m2 MTX throughout the whole consolidation therapy. No significant differences were found according to Gray’s test.\n\nAssociation of MTX plasma levels and toxicity\nTo investigate whether differences in MTX plasma levels might explain the high rates of severe toxicities observed in DS-ALL we analyzed MTX plasma levels of all patients at 42 and 48 hours after the start of the initial MTX infusion (Figure 4A-B). At 42 hours median MTX plasma levels in DS-ALL were 0.21 μmol/L (range 0.05–3.40 μmol/L) for 0.5 g/m2 MTX and 0.90 μmol/L (0.17–4.60) for 5 g/m2 MTX (P<0.001). At 48 hours DS-ALL median plasma levels were 0.16 μmol/L (0.01–1.80) and 0.43 μmol/L (0.22–3.60), respectively (P<0.001). For NDS-ALL patients who received a 5 g/m2 MTX dose median MTX plasma levels were 0.50 μmol/L (0.04–21.60) at 42 hours and 0.31 μmol/L (0.00–10.99) at 48 hours after the start of the first MTX infusion. Thus, at both time points DS-ALL patients showed significantly higher MTX plasma levels after 5 g/m2 MTX compared to NDS-ALL who received the same dose. DS-ALL patients treated with 0.5 g/m2 MTX had significantly lower MTX plasma levels compared to DS-ALL treated with 5 g/m2 MTX and NDS-ALL treated with 5 g/m2 at both time points (P<0.001 for each comparison). To further analyze whether MTX plasma levels may have an impact on toxicity within the DS-ALL cohort we analyzed the occurrence of grade 3/4 toxicities according to MTX plasma level quartiles at 42 and 48 hours (Figure 4C-D). At 42 hours DS-ALL patients with MTX plasma levels within the highest quartile (≥0.905 μmol/L, n=23) suffered from grade 3/4 leukopenia, thrombocytopenia and stomatitis significantly more often compared to patients within the lowest quartile (≤0.200 μmol/L, n=24) (leukopenia, highest quartile n=7 of 22 [31.8%] vs. lowest quartile n=1 of 22 [4.6%], P=0.046; thrombocytopenia, 7 of 22 [31.8%] vs. 0 of 22 [0%], P=0.009; stomatitis, 9 of 21 [42.9%] vs. 0 of 22 [0%], P=0.001). DS-ALL patients with MTX levels within the highest quartile at 48 hours (≥0.470 μmol/L, n=22) showed significantly higher rates of grade 3/4 thrombocytopenia and stomatitis compared to the lowest quartile (≤0.160 μmol/L, n=25) (thrombocytopenia, 9 of 21 [42.9%] vs. 1 of 25 [4.0%], P=0.003; stomatitis, 10 of 20 [50.0%] vs. 2 of 25 [8.0%], P=0.002).\n\nFigure 4. Methotrexate (MTX) plasma levels at 42 and 48 hours after the start of the first high dose MTX course and grade 3/4 toxicities in Down syndrome acute lymphoblastic leukemia according to MTX plasma levels. (A) and B) MTX plasma levels at 42 h (A) and 48 h (B) after start of the first HD-MTX administration. MTX dosage subgroups are indicated. *P≤0.05, Mann-Whitney U test. (C and D) Comparison of grade 3/4 toxicities in DS-ALL according to MTX plasma level quartiles at 42 hours (C) and 48 hours (D) after the start of the first high dose MTX (HD-MTX) administration. Q1: first/lowest quartile; Q4: fourth/highest quartile; respective MTX plasma concentration is given in μmol/L. *P≤0.05, Fisher’s exact test. The number on top of each bar represents the number of patients.\n\nSLC19A1 polymorphism rs1051266\nThe chromosome 21-encoded and ubiquitously expressed folate carrier SLC19A1 (RFC1) functions as the main MTX transporter into cells.10 The single nucleotide polymorphism (SNP) rs1051266 80G>A has been described to affect the transportation rate of the SLC19A1 carrier.11 To gain further insight into MTX-associated toxicities in DS-ALL patients, we investigated whether rs1051266 allele combinations were associated with higher rates of toxicity in DS-ALL patients. Therefore, we genotyped rs1051266 80G>A in n=95 of 103 DS-ALL patients and compared grade 3/4 toxicities after the initial HD-MTX course between the homozygous allele carriers (i.e. GGG and AAA) (Online Supplementary Table S2). After subgrouping according to the administered MTX dose, no statistically significant association between the occurrence of grade 3/4 toxicities and the allele status was observed, except for a significant higher rate of grade 3/4 leukopenia after the first HD-MTX course in GGG allele carriers who received 5 g/m2 MTX compared to AAA carriers that received the same dose (GGG n= 8 of 9 [88.9%] vs. AAA n= 0 of 5 [0%], P=0.003). However, this finding could not be reproduced for subsequent courses. Moreover, no significant correlation between other allele combinations and toxicities as well as allele carrier status and median MTX plasma levels at 42 and 48 h after the start of the initial MTX infusion were observed.\n\nDiscussion\nIn order to increase our knowledge of MTX-associated toxicities in DS-ALL patients after HD-MTX administration, we analyzed treatment and toxicity data of a large DS-ALL cohort uniformly treated according to ALL-BFM protocols. DS-ALL patient characteristics differed slightly from those in published studies,2,6,14 most likely because only patients who underwent HD-MTX consolidation treatment in the non-HR arm were included.\n\nMTX dosages in DS-ALL were heterogeneous, especially since the release of the 2004 study group recommendations of a MTX starting dose of 0.5 g/m2 for the first course which can eventually be increased in the following courses in the absence of severe toxicity. MTX dose heterogeneity and higher levels of MTX-associated toxicities have already been described by us and others.2,5,8,15,16 Together, these findings point to an increased awareness of the higher susceptibility of DS-ALL patients to MTX-related toxicity and the need of MTX dose modifications in recent years.\n\nIn DS-ALL patients who received a MTX dose of 5 g/m2 in the first course we observed significantly higher rates of grade 3/4 leukopenia, thrombocytopenia, infection and stomatitis compared to NDS-ALL. Similar results in smaller cohorts of heterogeneously treated DS-ALL patients have also been observed by other groups.5,8,15,16 However, here we showed for the first time that the administration of a low MTX dose of 0.5 g/m2 to patients with DS-ALL leads to a significant reduction of grade 3/4 toxicity. Furthermore, the MTX dose could subsequently be escalated to 1.0 g/m2 in more than half of the patients without resulting in higher rates of grade 3/4 toxicities after the second course compared to the initial course. These data support the study group’s recommendation to increase the MTX dose if no severe toxicity occurrs in the previous course. However, since reduced doses still bear a risk of severe side effects in individual DS-ALL patients, consolidation treatment should be administered cautiously and under close clinical control.\n\nDose reduction of chemotherapeutic drugs during cancer treatment may raise the concern of impairing long-term outcomes in the affected patients. Here, we did not find any differences in the 5y-CIR in DS-ALL patients who started consolidation with 5 g/m2 MTX compared to patients who received 0.5 g/m2 MTX. These findings raise the question whether DS-ALL patients require a high MTX dose in consolidation or whether a low dose between 0.5-1.0 g/m2 might be sufficient to optimize their outcome by balancing treatment-related complications with relapse rates. While others found impaired outcome of DS-ALL patients who were treated with reduced drug doses,2,5 two studies described no differences in event free and overall survival between patients with or without dose reductions.15,16 The authors speculate that modern, more effective ALL therapy and supportive treatment may contribute to an improved outcome in DS patients treated with a reduced dose. Other groups also described a trend towards a better outcome for DS-ALL in recent times.6,14 Goto et al. proposed a lower MTX dose (< 3.0 g/m2) for DS-ALL patients and possible treatment modifications with novel therapeutics considering the biology of DS-ALL, e.g. JAK2 inhibitors in those cases with JAK/STAT pathway activation.5 In addition, the use of the bispecific antibody blinatumomab might be beneficial to patients with DS-ALL.17\n\nOf note, in contrast to published data recently summarized18 none of the patients included in our study suffered from grade 3/4 nephrotoxicity after the first HD-MTX course. There is no obvious explanation for this difference and we can only speculate that vigorous hydration and alkalization in our patients as described in detail in the protocol was sufficient to prevent MTX crystal precipitation in the kidneys and subsequent impairment of renal function.19,20 Moreover, cut-offs to define nephrotoxicity might differ between the studies.\n\nAmong the DS-ALL cohort we found a MTX plasma level-toxicity correlation as patients with high plasma levels at 42 and 48 hours after the start of the first MTX infusion showed higher rates of grade 3/4 toxicities compared to patients within the lowest MTX plasma level quartile. This observation is consistent with another report showing higher rates of grade 3/4 mucositis in pediatric patients with osteosarcoma that had higher median MTX plasma levels at 48 hours. In addition, MTX plasma levels were higher in DS-ALL compared to NDS-ALL when the same doses were given, which could partially explain the higher toxicity in DS-ALL. In contrast, Buitenkamp et al. observed neither higher MTX levels in DS-ALL compared to NDS-ALL nor any association between MTX area under the curve (AUC) and toxicity.8 The authors applied a case-control study approach and the number of DS-ALL patients was lower than this study. Moreover in this study, MTX AUC and not plasma levels were considered when looking at toxicity, and therefore the results are not directly comparable with ours. However, we agree with the conclusion made by Buitenkamp et al. that differences in pharmacodynamics could also significantly contribute to the higher MTX toxicity in DS-ALL patients.8 This hypothesis is supported by our observation that DS-ALL patients who showed lower MTX plasma levels after 0.5 g/m2 MTX than NDS-ALL with 5 g/m2 still experienced higher rates of toxicity after the first HD-MTX course.\n\nBased on our data one might speculate that lower cut offs for forced diuresis and LCV rescue may reduce toxicities in DS-ALL patients. Furthermore, since DS-ALL had higher MTX plasma levels after receiving 5 g/m2 MTX compared to NDS-ALL one could further argue that DS-ALL patients do not require MTX doses as high as 5 g/m2 to get the same plasma levels and subsequent effect with respect to relapse prevention.\n\nIn an attempt to shed further light on MTX susceptibility in DS-ALL patients we genotyped the rs1051266 80G>A SNP of the folate and MTX transporter SLC19A1 on chromosome.21 The allele frequencies in our DS-ALL cohort are consistent with previous published frequencies in a healthy DS cohort.22 Since Baslund et al. found the A-variant of the transporter to be more effective in taking up fluorescence labeled MTX into lymphocytes of healthy euploide blood donors,11 we speculated that more MTX might be taken up into cells of DS-ALL patients that are homozygous for the presumably higher active A-variant (AAA) and that this may lead to higher rates of severe MTX-related toxicities compared to patients with the GGG allele combination. Thus, we hypothesized that genotyping of rs1051266 might be a diagnostic tool to predict the severity of toxicities in DS-ALL patients, but we were unable to confirm this hypothesis. However, pharmacokinetics of a single drug or the impact of a single SNP of a transporter in complex chemotherapy regimens may have limited power to explain the differences in effects and side effects. Other SNP in SLC19A1 and SNP in other genes of transporters or enzymes in the folate/MTX metabolism may also play a role. Therefore, further research including haplotype analysis, investigations of the effect of trisomy 21 on MTX metabolism by using transcriptomics or microarrays and the evaluation of SLC19A1 expression profile on mRNA and protein level as well as its transportation activity are needed. Moreover, 6-MP co-medication during consolidation should be considered as differences in DS patients with regards to 6-MP metabolism have been described.23 This might be important in HD-MTX consolidation but also in maintenance therapy, in which both MTX and 6-MP are administered since up to 40% of treatment-related deaths in DS-ALL occur during maintenance therapy.6,24\n\nIn conclusion, dose reduction in the first HD-MTX course of consolidation therapy led to a decrease of severe MTX-associated toxicities without increasing the risk of relapse for DS-ALL patients.\n\nCheck the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/1013\n\nFunding\n\nThe authors would like to thank Deutsche Krebshilfe, Deutsche José Carreras Leukämie-Stiftung (DJCLS), Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH), José Carreras-GPOH Promotionsstipendium 03 PSG/2017 for financial support.\n==== Refs\nReferences\n1. Hasle H Friedman JM Olsen JH Rasmussen SA \nLow risk of solid tumors in persons with Down syndrome\n. Genet Med . 2016 ;18 (11 ): 1151 –1157\n.27031084 \n2. Dordelmann M Schrappe M Reiter A \nDown’s syndrome in childhood acute lymphoblastic leukemia: clinical characteristics and treatment outcome in four consecutive BFM trials. Berlin-Frankfurt-Münster Group\n. Leukemia . 1998 ;12 (5 ): 645 –651\n.9593260 \n3. Whitlock JA \nDown syndrome and acute lymphoblastic leukaemia\n. Br J Haematol . 2006 ;135 (5 ):595 –602\n.17054672 \n4. Arico M Ziino O Valsecchi MG \nAcute lymphoblastic leukemia and Down syndrome\n. Cancer . 2008 ;113 (3 ):515 –521\n.18521927 \n5. Goto H Inukai T Inoue H \nAcute lymphoblastic leukemia and Down syndrome: the collaborative study of the Tokyo Children“s Cancer Study Group and the Kyushu Yamaguchi Children”s Cancer Study Group\n. Int J Hematol . 2011 ; 93 (2 ):192 –198\n.21286878 \n6. Buitenkamp TD Izraeli S Zimmermann M \nAcute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group\n. Blood . 2014 ;123 (1 ):70 –77\n.24222333 \n7. Taub JW Ge Y \nDown syndrome, drug metabolism and chromosome 21\n. Pediatr Blood Cancer . 2004 ;44 (1 ):33 –39\n.\n8. Buitenkamp TD Mathot RAA de Haas V Pieters R Zwaan CM \nMethotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia\n. Haematologica . 2010 ;95 (7 ): 1106 –1113\n.20418240 \n9. Schmiegelow K \nAdvances in individual prediction of methotrexate toxicity: a review\n. Br J Haematol . 2009 ;146 (5 ):489 –503\n.19538530 \n10. Matherly LH Wilson MR Hou Z \nThe major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer\n. Drug Metabolism and Disposition . 2014 ;42 (4 ):632 –649\n.24396145 \n11. Baslund B Gregers J Nielsen CH \nReduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells\n. Rheumatology . 2007 ;47 (4 ):451 –453\n.\n12. Whetstine JR Gifford AJ Witt T \nSingle nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers\n. Clin Cancer Res . 2001 ;7 (11 ):3416 –3422\n.11705857 \n13. Radtke S Zolk O Renner B \nGermline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia\n. Blood . 2013 ; 121 (26 ):5145 –5153\n.23652803 \n14. Whitlock JA Sather HN Gaynon P \nClinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children’s Cancer Group study\n. Blood . 2005 ;106 (13 ):4043 –4049\n.16109782 \n15. Shah N Al-Ahmari A Al-Yamani A Dupuis L Stephens D Hitzler J \nOutcome and toxicity of chemotherapy for acute lymphoblastic leukemia in children with down syndrome\n. Pediatr Blood Cancer . 2009 ;52 (1 ):14 –19\n.18802938 \n16. Derouet A Petit A Baruchel A \nImpact of therapy in a cohort of unselected children with Down Syndrome-associated Acute Lymphoblastic Leukaemia\n. Br J Haematol . 2016 ;174 (6 ):983 –985\n.26457881 \n17. Wadhwa A Kutny MA Xavier AC \nBlinatumomab activity in a patient with Down syndrome B-precursor acute lymphoblastic leukemia\n. Pediatr Blood Cancer . 2017 ;65 (2 ):e26824 .\n18. Schmiegelow K Müller K Mogensen SS \nNon-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy\n. F1000Res . 2017 ;6 :444 .28413626 \n19. Sand TE Jacobsen S \nEffect of urine pH and flow on renal clearance of methotrexate\n. Eur J Clin Pharmacol . 1981 ;19 (6 ):453 –456\n.7250179 \n20. Garneau AP Riopel J Isenring P \nAcute methotrexate-induced crystal nephropathy\n. N Engl J Med . 2015 ; 373 (27 ):2691 –2693\n.26716929 \n21. Park JA Shin HY \nInfluence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma\n. Blood Res . 2016 ; 51 (1 ):50 –57\n.27104192 \n22. Chango A Willequet F Fillon-Emery N Nicolas JP Bléhaut H \nThe single nucleotide polymorphism (80G-->A) of reduced folate carrier gene in trisomy 21\n. Am J Clin Nutr . 2004 ;80 (6 ):1667 –1669\n.15585786 \n23. Palle J Frost BM Britt-Marie F \nThioguanine pharmacokinetics in induction therapy of children with acute myeloid leukemia\n. Anti-Cancer Drugs . 2009 ;20 (1 ):7 –14\n.19342996 \n24. O’Connor D Bate J Wade R \nInfection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003\n. Blood . 2014 ;124 (7 ): 1056 –1061\n.24904116\n\n",
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"mesh_terms": "D002648:Child; D060830:Consolidation Chemotherapy; D004314:Down Syndrome; D006801:Humans; D015122:Mercaptopurine; D008727:Methotrexate; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
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"title": "Methotrexate-associated toxicity in children with Down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to ALL-BFM treatment regimen.",
"title_normalized": "methotrexate associated toxicity in children with down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to all bfm treatment regimen"
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"abstract": "A case of multiple myeloma with testicular involvement is rare. We report a 72-year-old male with testicular infiltration as extramedullary disease of IgD λ-type multiple myeloma. The patient received systemic treatment, which included high orchiectomy, anticancer chemotherapy, and radiation therapy for bone metastasis. Eight months after the initial diagnosis, he remains alive. The testis is a rare location for extramedullary disease of multiple myeloma. Testicular involvement of multiple myeloma indicates a poor prognosis. The particular treatment strategy for extramedullary disease in multiple myeloma remains unclear. Testicular involvement of multiple myeloma is reviewed and discussed in this paper.",
"affiliations": "Department of Urology, Tokyo Women's Medical University, Medical Center East, 2-1-10, Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.;Department of Urology, Tokyo Women's Medical University, Medical Center East, 2-1-10, Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.;Department of Urology, Tokyo Women's Medical University, Medical Center East, 2-1-10, Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.;Department of Urology, Tokyo Women's Medical University, Medical Center East, 2-1-10, Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.;Department of Urology, Tokyo Women's Medical University, Medical Center East, 2-1-10, Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.;Department of Urology, Tokyo Women's Medical University, Medical Center East, 2-1-10, Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan.",
"authors": "Yamashita|Kaori|K|;Horiuchi|Toshihide|T|;Hayashida|Akihiro|A|;Tachibana|Hidekazu|H|;Toki|Daisuke|D|;Kondo|Tsunenori|T|",
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"doi": "10.1016/j.eucr.2019.100971",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(19)30205-010.1016/j.eucr.2019.100971100971OncologyMultiple myeloma with testicular involvement: A case report Yamashita Kaori yamashita.kaori@twmu.ac.jp∗Horiuchi Toshihide Hayashida Akihiro Tachibana Hidekazu Toki Daisuke Kondo Tsunenori Department of Urology, Tokyo Women's Medical University, Medical Center East, 2-1-10, Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan∗ Corresponding author. yamashita.kaori@twmu.ac.jp17 7 2019 9 2019 17 7 2019 26 1009712 6 2019 15 7 2019 16 7 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A case of multiple myeloma with testicular involvement is rare. We report a 72-year-old male with testicular infiltration as extramedullary disease of IgD λ-type multiple myeloma. The patient received systemic treatment, which included high orchiectomy, anticancer chemotherapy, and radiation therapy for bone metastasis. Eight months after the initial diagnosis, he remains alive.\n\nThe testis is a rare location for extramedullary disease of multiple myeloma. Testicular involvement of multiple myeloma indicates a poor prognosis. The particular treatment strategy for extramedullary disease in multiple myeloma remains unclear. Testicular involvement of multiple myeloma is reviewed and discussed in this paper.\n==== Body\nIntroduction\nMultiple myeloma is a cancer of plasma cells. Testicular involvement in the course of multiple myeloma is rare and indicates a poor prognosis. In this paper, we report a patient with a case of testicular infiltration of multiple myeloma. The testis is a rare site for the localization of multiple myeloma. The particular treatment strategy for extramedullary disease in multiple myeloma remains unclear. Therefore, it is important to describe case reports of multiple myeloma with testicular involvement.\n\nPresentation of the case\nA 72-year-old Japanese man experienced chest pain and was referred to the department of internal medicine at our hospital in September 2018. His hemoglobin level was 10.1 g/dL (normal, 14.0–18.0 g/dL), and calcium level and renal function were normal. His total protein was 8.8 g/dL (normal, 6.1–8.0 g/dL), albumin was 3.4 g/dL (normal, 3.7–5.2 g/dL), and β2-microgloblin was 4.7 mg/L (normal, 1.0–1.9 mg/L). His serum immunoglobulin D (IgD) level was 8.810 mg/dL (normal, <9.0 mg/dL). The levels of the other immunoglobulin classes were as follows: IgG, <398.1 mg/dL (normal, 870–1700 mg/dL); IgA, <15.8 mg/dL (normal, 110–410 mg/dL); and IgM, 9.0 mg/dL (normal, 33–190 mg/dL). Serum protein electrophoresis showed M-protein in the gamma-zone. Immunoelectrophoresis revealed IgD λ-type M-protein and Bence Jones protein λ-type M-protein in the serum, and Bence Jones protein λ-type M-protein in the urine. Bone marrow aspiration showed 60% plasma cell infiltration. Computed tomography showed osteolytic lesions in multiple ribs and vertebrae. Therefore, he was diagnosed as having IgD λ-type multiple myeloma. Bortezomib and Dexamethasone were commenced for treatment.\n\nAt the initial diagnosis, he also had unpainful left testicular swelling. He was referred to our department of urology. The levels of germ cell tumor markers (e.g., alpha-fetoprotein, beta-human chorionic gonadotropin, and lactate dehydrogenase) were normal. Ultrasonography examination showed an enlarged left testis with low echoic areas. Computer tomography image demonstrated an enlarged left testis and hydrocele (Fig. 1). He underwent left high orchiectomy in November 2018.Fig. 1 Computer tomography image demonstrated an enlarged left testis and hydrocele (arrow).\n\nFig. 1\n\nThe macroscopic specimen was a grossly enlarged testis (65 mm × 50 mm × 50 mm) in which white nodular tumor components had replaced most of the normal testicular tissue (Fig. 2). Pathological specimen revealed myeloma cell infiltration in the testis and spermatic cord (Fig. 3a). Immunohistochemistry staining showed the specimen was positive for IgD (Fig. 3b) and for light chain λ (Fig. 3c). Therefore, he was diagnosed has having IgD λ-type myeloma cell infiltration in the left testis.Fig. 2 The macroscopic specimen is a grossly enlarged testis (65 mm × 50 mm × 50 mm). White nodular tumor components have replaced the normal testicular tissue.\n\nFig. 2Fig. 3 Histopathological analyses. (a) The pathological specimen shows myeloma cell infiltration in the testis (hematoxylin and eosin stain). Immunohistochemistry staining is positive for (b) IgD and (c) light chain λ.\n\nFig. 3\n\nHe had flaccid paraplegia because of metastases to thoracic vertebrae T5, T8, and T9. He underwent radiation therapy to these metastases. He was administered four cycles of Bortezomib and Dexamethasone, until he experienced a Bortezomib-induced peripheral nerve disorder. Melphalan and Prednisone were initiated in March 2019 for the second line anticancer chemotherapy. Eight months after the initial diagnosis, he remains alive.\n\nDiscussion\nMultiple myeloma is the second most common hematologic malignancy,1 and represents 10%–15% of all hematological neoplasms.2 Multiple myeloma is the malignant production and proliferation of the monoclonal body of plasma cells. Neoplastic plasma cells multiply in the bone marrow. Extramedullary disease in multiple myeloma is a plasma cell neoplasm that occurs outside of the bone marrow. The most common sites of extramedullary disease in multiple myeloma are parenchymous organs such as the liver and kidneys1, however, testicular involvement in the course of multiple myeloma is rare.3,4\n\nAt the initial diagnosis, our patient had testicular involvement as extramedullary disease in multiple myeloma. However, there was secondary testicular involvement in multiple myeloma at the time of the multiple myeloma relapse. Wei et al.5 reported a patient who had a late relapse of multiple myeloma with testicular plasmacytoma at 3 years after autologous hematopoietic stem-cell transplantation for a previous diagnosis of multiple myeloma. Rosenberg et al.3 reported their experience with a case of testicular plasmacytoma without evidence of a relapse of multiple myeloma of the bone marrow in a patient who had been diagnosed with multiple myeloma 9 years earlier.\n\nThe testes provide a sanctuary site for hematologic malignancy because of the testicular blood barrier. Therefore, hematologic malignant cells may remain in the testes, even after systemic anticancer chemotherapy for a previous hematologic malignancy such as multiple myeloma. Urologist and hematologists or oncologists should pay attention to physical examination findings such as testicular swelling and nodules when following up patients with a history of hematologic malignancy. High orchiectomy is needed for surgical therapy and a pathologic diagnosis.\n\nSevcikova et al.1 found longer overall survival in patients with multiple myeloma without extramedullary disease than in patients with extramedullary disease. The prognosis of patients with testicular involvement of multiple myeloma is believed to be poor. However, in our investigations, we found no published prospective studies of a specific treatment for extramedullary disease with multiple myeloma.\n\nProteasome inhibitor-based regimens (e.g., Bortezomib therapy) have recently been used to treat testicular involvement of multiple myeloma after high orchiectomy.3,4 Reporting cases of testicular involvement of multiple myeloma is essential for understanding the condition and for treating multiple myeloma with extramedullary disease with testicular involvement.\n\nConclusion\nTesticular involvement as extramedullary disease of multiple myeloma is rare and indicates a poor prognosis. The testes provide a sanctuary site for hematologic malignancy because of the testicular blood barrier. Urologists have to consider conducting a physical examination of the testes when following up with patients who have a history of hematologic malignancies such as multiple myeloma.\n\nConflicts of interest\nThe authors declare no conflict of interest.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgments\nNo funding was provided for this case report.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.eucr.2019.100971.\n==== Refs\nReferences\n1 Savcikova S. Minarik J. Stork M. Jelinek T. Pour L. Hajek R. Extramedullary disease in multiple myeloma — controversies and future directions Blood Rev 2019 10.1016/j.blre.2019.04.002 \n2 Gerecke C. Fuhrmann S. Strifler S. Schmidt-Hieber M. Einsele H. Knop S. The diagnosis and treatment of multiple myeloma Dtsch Arzteblatt Int 2016 https://doi.10.3238/arztebl.2016.0470 \n3 Rosenberg S. Shapur N. Gofrit O. Or R. Plasmacytoma of the testis in a patient with previous multiple myeloma: is the testis a santuary site? J Clin Oncol 2010 https://doi.10.1200/JCO.2009.27.6519 \n4 Hwang Y.Y. Chim C.S. Shek T.W. Multiple myeloma with testicular involvement J Clin Oncol 2008 https://doi.10.1200/JCO.2007.15.1316 \n5 Wei Z.L. Pac C.M. Jiang Y.Z. Yan-Dai Huanguang L.Q. Huang D.P. Late relapse of multiple myeloma with testicular plasmacytoma after autologous hematopoietic stem cell transplantation: a case report and review of the literature Ann Clin Lab Sci 48 2018 120 125 29531008\n\n",
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"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": "18349409;20679613;27476706;29531008;31005420",
"title": "Multiple myeloma with testicular involvement: A case report.",
"title_normalized": "multiple myeloma with testicular involvement a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-218651",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drug... |
{
"abstract": "Treatment-emergent central sleep apnea (TECSA) is a central sleep-related breathing disorder, characterized by either the persistence or emergence of central sleep apnea during the initiation of positive airway pressure therapy for obstructive sleep apnea. The purpose of this study was to review the perioperative course of patients diagnosed with TECSA.\n\n\n\nWe reviewed medical records of patients with TECSA who had a procedure or surgery with general anesthesia between January 1, 2009 and May 1, 2018. We describe postoperative outcomes including respiratory complications, unplanned intensive care unit (ICU) admissions, and other postoperative outcomes.\n\n\n\nWe identified 150 (116 male, 34 female) patients with TECSA. Of these, 39 (26%) had their anesthesia recovery associated with moderate to profound sedation, 22 (14.7%) required unplanned transfer to ICU (8 for hypoxemia). Compared to patients without ICU admissions, patients with unplanned ICU admissions had higher rates of cardiovascular disease, Charlson comorbid scores, and perioperative benzodiazepines. Within the first 30 postoperative days there were 23 (16%) hospital re-admissions, and 7 (4.6%) deaths.\n\n\n\nPatients with TECSA have high rates of postoperative complications, characterized by an increased rate of unplanned intensive care admissions and both high 30-day readmission and mortality rates. When dealing with these patients perioperative physicians should implement an increased level of respiratory monitoring, and early postoperative use of their home prescribed non-invasive ventilation devices.",
"affiliations": "Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA.;Mayo Clinic Alix School of Medicine, Mayo Clinic, Scottsdale, AZ, USA.;Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA.;Center for Sleep Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA. weingarten.toby@mayo.edu.",
"authors": "Barman|Ross A|RA|;Fields|Amanda R|AR|;Eells|Austin J|AJ|;Kouri|Ioanna|I|;Mansukhani|Meghna P|MP|;Gali|Bhargavi|B|;Sprung|Juraj|J|;Weingarten|Toby N|TN|0000-0002-8405-1328",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s00540-020-02828-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0913-8668",
"issue": "34(6)",
"journal": "Journal of anesthesia",
"keywords": "Anesthetic management; Central sleep apnea; Postoperative complications; Sleep-disordered breathing; Treatment-emergent central sleep apnea",
"medline_ta": "J Anesth",
"mesh_terms": "D000758:Anesthesia; D005260:Female; D006801:Humans; D008297:Male; D011183:Postoperative Complications; D011184:Postoperative Period; D020182:Sleep Apnea, Central; D020181:Sleep Apnea, Obstructive",
"nlm_unique_id": "8905667",
"other_id": null,
"pages": "841-848",
"pmc": null,
"pmid": "32696093",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28355752",
"title": "Postoperative outcomes in patients with treatment-emergent central sleep apnea: a case series.",
"title_normalized": "postoperative outcomes in patients with treatment emergent central sleep apnea a case series"
} | [
{
"companynumb": "US-TEVA-2021-US-1917550",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe benefit of adding docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy to chemoradiotherapy (CRT) in head and neck squamous cell carcinoma (HNSCC) remains uncertain. We aimed to investigate whether ICT is well tolerated when given with prophylactic treatment against predicted adverse effects and which patients benefit most.\n\n\nMETHODS\nA single-centre audit identified 132 HNSCC patients with stage IVa/b neck node-positive disease, prescribed TPF followed by CRT. TPF involved three cycles of docetaxel (75 mg/m2 IV) and cisplatin (75 mg/m2 IV) on day 1 plus 5-FU (750 mg/m2 IV) on days 2-5. Planned CRT was 66 Gy in 30 fractions of intensity-modulated radiotherapy with concurrent cisplatin (100 mg/m2 IV) at the beginning of week 1 and 4 (days 1 and 22). All patients received prophylactic antibiotics and granulocyte colony-stimulating factor.\n\n\nRESULTS\nMedian follow-up was 39.5 months. 92.4% of patients completed three cycles of TPF; 95.5% of patients started chemoradiotherapy. Grade 3/4 adverse events were low (febrile neutropenia 3.0%), with no toxicity-related deaths. 3-year overall survival was 67.2%; disease-specific survival was 78.7%; locoregional control was 78.3%. Distant metastases rate was 9.8% (3.0% in those without locoregional recurrence). Good performance status (p = 0.002) and poor tumour differentiation (p = 0.018) were associated with improved overall survival on multivariate analysis.\n\n\nCONCLUSIONS\nWith prophylactic antibiotics and granulocyte colony-stimulating factor TPF was well tolerated with good survival outcomes. TPF should remain a treatment option for stage IV neck node-positive patients with a good performance status. The use of tumour grade to aid patient selection for TPF warrants investigation.",
"affiliations": "Translational Radiobiology Group, Division of Cancer Sciences, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester, England, M20 4BX, UK. nataliemarielowe@gmail.com.;Translational Radiobiology Group, Division of Cancer Sciences, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester, England, M20 4BX, UK.;Head and Neck Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, England, M20 4BX, UK.;Head and Neck Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, England, M20 4BX, UK.;Head and Neck Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, England, M20 4BX, UK.;Head and Neck Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, England, M20 4BX, UK.;Translational Radiobiology Group, Division of Cancer Sciences, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester, England, M20 4BX, UK.;Translational Radiobiology Group, Division of Cancer Sciences, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester, England, M20 4BX, UK.;Translational Radiobiology Group, Division of Cancer Sciences, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester, England, M20 4BX, UK.;Translational Radiobiology Group, Division of Cancer Sciences, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester, England, M20 4BX, UK.",
"authors": "Lowe|Natalie M|NM|;Bernstein|Jonathan M|JM|;Mais|Kathleen|K|;Garcez|Kate|K|;Lee|Lip W|LW|;Sykes|Andrew|A|;Thomson|David J|DJ|;Homer|Jarrod J|JJ|;West|Catharine M|CM|;Slevin|Nicholas J|NJ|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00432-017-2553-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0171-5216",
"issue": "144(2)",
"journal": "Journal of cancer research and clinical oncology",
"keywords": "Head and neck; Induction chemotherapy; Outcomes; Squamous cell carcinoma; Tolerability",
"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D060828:Induction Chemotherapy; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D043823:Taxoids",
"nlm_unique_id": "7902060",
"other_id": null,
"pages": "389-401",
"pmc": null,
"pmid": "29222650",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": "24211084;21233014;16386890;10435800;25275078;9288840;19917840;28410291;14530167;21330105;15816106;25049329;21317223;25474250;26041604;15277256;28301079;19446902;19318632;22800881;17960012;17960013;23188165;20950953;7165009;25782027;10225552;24256848;16110017;11689578;20697746;25742025;16847186;25700703;9165136;28911070;10758303;25782685;23606404;22410204;12506176;22261362;21620580;25366680;25154822;12855639;18486742;26589131;20530316;20587061;23247234;10793107",
"title": "Taxane, platinum and 5-FU prior to chemoradiotherapy benefits patients with stage IV neck node-positive head and neck cancer and a good performance status.",
"title_normalized": "taxane platinum and 5 fu prior to chemoradiotherapy benefits patients with stage iv neck node positive head and neck cancer and a good performance status"
} | [
{
"companynumb": "GB-BAUSCH-BL-2017-036449",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAn acute infusion reaction during infliximab infusions could lead to drug withdrawal and limit the therapeutic armamentarium in inflammatory bowel diseases.\n\n\nOBJECTIVE\nTo determine the risk and protective factors of an acute infusion reaction.\n\n\nMETHODS\nData were retrieved retrospectively from electronic charts of patients from the 'Clermont-Ferrand IBD cohort'.\n\n\nRESULTS\nAmong 80 patients, including 51 (63.8%) patients with Crohn's disease, 23 (28.8%) experienced an acute infusion reaction. In multivariate analysis, the Crohn's disease nonstricturing nonfistulizing phenotype predicted an acute infusion reaction (odds ratio=11.40, 95% confidence interval 1.5-87.6; P=0.019).Among 1107 infusions, we observed 38 acute infusion reactions (3.4%). In multivariate analysis, only resumption of infliximab after drug holiday was a major risk factor (odds ratio=24.87, 95% confidence interval 4.4-140.0; P<0.001). Concomitant premedication or immunosuppressant therapies did not prevent an acute infusion reaction.The patients who experienced an acute infusion reaction had a trend toward a higher rate of infliximab discontinuation (69.6 vs. 50.9%, P=0.14).\n\n\nCONCLUSIONS\nAn acute infusion reaction is a major event in the history of inflammatory bowel diseases patients treated with infliximab as it could lead to drug discontinuation and thus limits the therapeutic armamentarium considerably. The resumption of infliximab after drug holiday is a major risk factor for an acute infusion reaction. Premedication efficacy remains questionable and should be limited to these high-risk patients.",
"affiliations": "aDepartment of Gastroenterology, University Hospital Estaing of Clermont-Ferrand bMicrobes, Inflammation, Intestine and Susceptibility of the Host, UMR 1071 INSERM/Auvergne University USC-INRA 2018 cBiostatistics Unit, University Hospital of Clermont-Ferrand, DRCI, Clermont-Ferrand, France.",
"authors": "Duron|Cédric|C|;Goutte|Marion|M|;Pereira|Bruno|B|;Bommelaer|Gilles|G|;Buisson|Anthony|A|",
"chemical_list": "D005765:Gastrointestinal Agents; D006633:Histamine Antagonists; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000354",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "27(6)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D003875:Drug Eruptions; D005260:Female; D005765:Gastrointestinal Agents; D006633:Histamine Antagonists; D006801:Humans; D000069285:Infliximab; D007262:Infusions, Intravenous; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D028761:Withholding Treatment; D055815:Young Adult",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "705-11",
"pmc": null,
"pmid": "25856689",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Factors influencing acute infusion reactions in inflammatory bowel disease patients treated with infliximab in the era of scheduled maintenance therapy.",
"title_normalized": "factors influencing acute infusion reactions in inflammatory bowel disease patients treated with infliximab in the era of scheduled maintenance therapy"
} | [
{
"companynumb": "FR-JNJFOC-20140405930",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Ketamine is a standard anaesthetic drug that has been studied as a possible treatment for acute suicidal ideation. Aside to the potential psychotropic effects of ketamine, a Cochrane review reported that available studies suggest a modest effect of ketamine for chronic pain months to years after surgical intervention. We present a patient with acute suicidal ideation who required immediate inpatient psychiatric admission in the setting of concurrent chronic pain on cannabinoids which could not be prescribed within our inpatient hospital setting. This presented a clinical dilemma to rapidly reverse the patient's suicidality while substituting the patient's prescribed cannabinoid products with an alternative pain regimen. Since there is emerging support in the use of ketamine in suicidality and chronic pain, we administered ketamine while withholding cannabinoid products and found evidence to support its use in rapid reversal of suicidal ideation and temporary chronic pain relief.",
"affiliations": "Department of Psychiatry, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey, USA.;Department of Psychiatry, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey, USA.;Department of Psychiatry, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey, USA.",
"authors": "Bigman|Daniel|D|;Kunaparaju|Sindhura|S|;Bobrin|Bradford|B|",
"chemical_list": "D002186:Cannabinoids; D007649:Ketamine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222059",
"fulltext": "\n==== Front\nBMJ Case RepBMJ Case RepcasereportsbmjcasereportsBMJ Case Reports1757-790XBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR bcr-2017-22205910.1136/bcr-2017-222059Novel Treatment (New Drug/Intervention; Established Drug/Procedure in New Situation)15061522Case ReportUse of ketamine for acute suicidal ideation in a patient with chronic pain on prescribed cannabinoids Bigman Daniel Kunaparaju Sindhura Bobrin Bradford Department of Psychiatry, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, New Jersey, USACorrespondence to Dr. Daniel Bigman, bigman-daniel@cooperhealth.edu2017 12 11 2017 12 11 2017 2017 bcr201722205927 10 2017 © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.2017This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Ketamine is a standard anaesthetic drug that has been studied as a possible treatment for acute suicidal ideation. Aside to the potential psychotropic effects of ketamine, a Cochrane review reported that available studies suggest a modest effect of ketamine for chronic pain months to years after surgical intervention. We present a patient with acute suicidal ideation who required immediate inpatient psychiatric admission in the setting of concurrent chronic pain on cannabinoids which could not be prescribed within our inpatient hospital setting. This presented a clinical dilemma to rapidly reverse the patient’s suicidality while substituting the patient’s prescribed cannabinoid products with an alternative pain regimen. Since there is emerging support in the use of ketamine in suicidality and chronic pain, we administered ketamine while withholding cannabinoid products and found evidence to support its use in rapid reversal of suicidal ideation and temporary chronic pain relief.\n\npainsuicide (psychiatry)drugs: psychiatrypain (neurology)pain (palliative Care)special-featureunlocked\n==== Body\nBackground\nThere is emerging evidence that glutamatergic system dysfunction might play an important role in the pathophysiology of bipolar depression.1 Ketamine is a dissociative anaesthetic that produces analgesia and amnesia. Its contemporary use can have a variety of side effects; agitation, hallucinations, hypertension or emergence of other excitation symptoms.2 In comparison to bipolar depression, there is greater evidence that long-term treatment of chronic pain with ketamine will cause prolonged pain relief. Of importance is that no effect on functionality or on depressive symptoms was observed.2 Still, although ketamine treatment is linked to a variety of side effects, we feel that benefits outweigh the risks in specific patient populations and further research is needed to address the use of ketamine in suicidality and chronic pain.\n\nCase presentation\nJM is a 46-year-old African-American man with a self-reported history of bipolar disorder, chronic shoulder pain on prescribed cannabinoids, who presents to the emergency department with suicidal ideation. The patient states that he has been having progressed depressed mood over the past week and started to have suicidal ideation for a few days. He endorsed to a plan of drinking bleach or any toxic liquid he could purchase in the grocery store. These thoughts were associated with insomnia, decreased appetite, feelings of hopelessness and helplessness. He states that over the past 2 days, he has noticed increased anxiety associated with ‘shadows’ which have been occurring more frequently in the evening. He reports medication non-compliance in the past 3–4 weeks; quetiapine 400 mg at bedtime and bupropion SR 150 mg twice daily. He states that he got into a verbal altercation with his girlfriend after she found out about his ‘infidelities’ and was kicked out of their home in Delaware. He decided to seek shelter with his aunt in New Jersey. He reports a long psychiatric history with initial 3-week inpatient hospitalisation in his mid-late twenties for decreased need for sleep, impulsive financial spending and hypersexual behaviour. He has experienced elated mood which cycles with periods of depression every few months. He reports a history of two suicide attempts; first in his 20s for overdose of pills and second 2 years ago when he ingested bleach and was subsequently hospitalised. The patient’s medical history is significant for a gunshot wound to his right shoulder which required emergent surgical stabilisation. He subsequently underwent over a dozen reconstructive surgeries to his right shoulder. The patient reports an allergy to aspirin and non-steroidal anti-inflammatory drugs and chart review is notable for anaphylaxis during a previous hospitalisation after the administration of ketorolac. He was ultimately prescribed medicinal marijuana through the state of Delaware for his debilitating chronic shoulder pain. He denied any history of substance dependence with tobacco, alcohol, opiate, benzodiazepines, cocaine or hallucinogens. To note, the patient’s quetiapine and bupropion prescriptions were confirmed at his local pharmacy in Delaware and marijuana card validated through the state of Delaware. In addition, the patient’s aunt provided collateral information which corroborated the patient’s presenting history.\n\nThe patient appeared in no apparent distress, normal posture, wearing a hospital gown, thin with no obvious skin lesions. There is obvious right shoulder atrophy and asymmetry with at least six visible scars throughout the anterior shoulder extending to the posterior shoulder blades and upper back. The right shoulder is in fixed position with no range of motion. There is some hypersensitivity to the surgical scars. There are no signs of erythema, fluctuance, effusion or discharge. The patient has a steady gait. The rest of the musculoskeletal examination is with normal tone, no rigidity or spasticity. The patient is cooperative and engaged with the examination. The patient displays normal psychomotor activity, appropriate eye contact and normal speech. Reports depressed mood with appropriate and congruent sad affect. His thought content was with suicidal ideations with plans to overdose on toxic liquids. He denies any homicidal ideation or delusions. His thought process is linear, clear and coherent. The patient is alert and awake to person, place and time. He denies any active perceptual disturbances. His memory, concentration, abstraction, language and vocabulary are grossly normal. His intelligence is noted to be average. The patient demonstrates questionable impulse control, fair insight and fair judgement.\n\nInvestigations\nMedical screening labs were ordered and yielded the following: urine screen positive for tetrahydrocannabinoids and negative for phencyclidine, benzodiazepine, cocaine metabolites, amphetamines, opiate, barbiturates, methadone and ethanol; white cell count 8.38 10^3/uL, haemoglobin 14.8 g/dL, haematocrit 43 %, platelet count 321 10^3/uL, Na 140 mmol/L, K 3.9 mmol/L, Cl 101 mmol/L, CO2 24 mmol/L, blood urea nitrogen 13 mg/dL, Cr 0.93 mg/dL, glucose 88 mg/dL, alkaline phosphatase 111, total bilirubin 0.2 mg/dL, direct bilirubin <0.2 mg/dL, alanine aminotransferase 16 U/L, aspartate aminotransferase 15 U/L, albumin 4.2 g/dL, protein 6.7 g/dL, and thyroid-stimulating hormone 2.64 u[IU]/ml.\n\nChest radiograph (posterioranterior, lateral): no acute cardiopulmonary disease.\n\nRight shoulder radiograph (two view): right shoulder images demonstrate surgical arthrodesis of the glenohumeral joint with two cannulated screws, unchanged in appearance from prior exam. Impression: stable appearance of the right shoulder post arthrodesis.\n\nPatient Health Questionnaire (PHQ-9) for depression: 21 (severe).\n\nTreatment\nThe patient was agreeable for a voluntary psychiatric admission for re-initiation of his psychotropics and monitoring his progress due to safety concerns. The patient reported smoking prescribed medical marijuana every 2 days for his chronic shoulder pain for the past 2 years. Last use was one day prior to admission. However, the patient expressed concern to not being able to smoke during his inpatient course. The patient refused oral acetaminophen or opiates, reporting a history of poor palliation of his chronic pain. In addition, the patient was averse to receiving prescription opiates due to random drug testing that the marijuana prescriber would use to screen. Efforts to contact the medical marijuana prescriber were unsuccessful. Ultimately, the patient agreed to a trial of ketamine for acute stabilisation of his suicidal ideation and temporary pain control while admitted to the inpatient psychiatric unit.\n\nThe patient was administered ketamine 30 mg intramuscularly based on a 0.5 mg/kg dosing. The patient was monitored in the Emergency Department with ongoing pulse oximeter and vitals every 15 min for 1 hour. The patient tolerated the administration and was subsequently medically cleared for inpatient psychiatric admission. The patient endorsed to 3–4 weeks of medication non-compliance and a plan was agreed to re-start quetiapine and bupropion the following morning at 50 mg and 150 mg, respectively. The patient complained of chronic dull throbbing pain with occasional burning sensation to his right shoulder with a severity of 5/10.\n\nOutcome and follow-up\nOn day 2 of admission, the patient had a dramatic improvement in mood with resolution of his suicidality. In addition, the patient stated that his chronic shoulder pain was controlled with decreased feeling of the dull throbbing pain. By day 3 of the patient’s hospital course, he was doing well, slept throughout the night, increased appetite and participating in group therapy with complete resolution of his suicidal ideation and depressed mood. The patient was discharged on day 3 with instructions to follow-up with his psychiatrist in 1–2 weeks after he completed the quetiapine titration to home dose of 400 mg at bedtime. At 30-day follow-up, the patient reports to be doing well, tolerating his home medications; quetiapine 400 mg at bedtime and bupropion SR 150 mg daily. Denied any depressed mood, suicidal ideation, perceptual disturbances, increased anxiety, decreased need for sleep, insomnia, loss of appetite or other complaints. Chronic pain was described similar to presentation with a pain severity of 2–3/10. PHQ-9 depression questionnaire score of 2. In addition, he reported that 4 days post discharge, he did not use any prescribed marijuana due to tolerable chronic pain. The patient claims to be in the process of undergoing an evaluation for intravenous ketamine infusion in hopes of discontinuing medicinal cannabinoid products.\n\nDiscussion\nA Cochran, Google Scholar and PubMed search yielded no literature to indicate the use of ketamine for concurrent suicidal ideation and chronic pain. We present a patient with complex psychiatric and pain concerns; acute suicidality due to bipolar depression secondary to his recent medication non-compliance and chronic shoulder pain on prescribed cannabinoid products which could not be prescribed while the patient was admitted to the inpatient psychiatric unit due to formulary issues and being a non-smoking facility.3 The patient agreed for voluntary admission for escalation of psychiatric care. However, the patient was averse to receiving any opioids for his chronic pain in fear of random drug screening that would be given by his medical marijuana prescriber. Thus, an effort was made for rapid reversal of the patient’s mood, with anticipation for discharge so the patient could return to self-administration of prescribed cannabinoids. Other alternative pain management options were considered such as non-narcotic medication for neuropathic pain. This was not feasible since gabapentin, pregabalin or antiepileptic drugs need weeks of therapeutic titration. In addition, we thought of rapid re-initiation of the patient’s home dose of quetiapine 400 mg at bedtime but were paused by the package insert recommendations to re-titrate at 50–100 mg/day since this patient had discontinued therapy for in the past 3–4 weeks.4 The patient’s home dose of bupropion 300 mg/day was also retitrated at starting dose of 150 mg as per package insert recommendations.5\n\nWhile administration of ketamine intravenous or intramuscular remains off label in the use for chronic pain and acute on chronic episodes of neuropathic pain, there is widespread literature supporting its use of continuous intravenous infusion with initial dosing of 0.5 mg/kg.6 7 In addition, there is an increasing data suggesting the use of single-dose, intravenous administration of ketamine (0.2–0.5 mg/kg) for the reversal of suicidal ideation while reporting reversal as early as 40 min postadministration and sustained effects lasting up to 7–10 days.8 9 There has also been case reports indicating similar outcomes with intramuscular administration.10 11 The decision to administer ketamine intramuscular was due to knowledge that the patient would be admitted to the inpatient psychiatry unit in which intravenous access is restricted due to safety concerns. We saw significant improvement in clinical appearance and noted PHQ-9 scores before and after ketamine administration. In addition, the patient’s pain was controlled without the need of alternative pain management intervention during the hospital course.\n\nLearning points\nAdministration of ketamine while withholding cannabinoid products can be considered for temporary management of chronic pain.\n\nAdministration of ketamine for acute suicidal ideation can be considered for rapid reversal of suicidal ideation.\n\nAdministration of ketamine for patients presenting with suicidal ideation and chronic pain may benefit due to its potential dual treatment of symptomatology.\n\nFurther research is needed to address the use of ketamine in suicidality and chronic pain.\n\nContributors: DB designed data collection tools, monitored data collection for the whole study, wrote the statistical analysis plan, cleaned and analysed the data, and drafted and revised the paper. He is the guarantor. SK, analysed the data and drafted and revised the paper. BB analysed the data and drafted and revised the paper.\n\nCompeting interests: None declared.\n\nPatient consent: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 McCloud TL , Caddy C , Jochim J , et al \nKetamine and other glutamate receptor modulators for depression in bipolar disorder in adults . Cochrane Database Syst Rev \n2015 (9 ):CD011611 \n10.1002/14651858.CD011611.pub2 26415966 \n2 Niesters M , Martini C , Dahan A \nKetamine for chronic pain: risks and benefits . Br J Clin Pharmacol \n2014 ;77 :357 –67 . 10.1111/bcp.12094 23432384 \n3 National Conference of State Legistators . State medical marijuana laws . 2017 ;4 \nhttp://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx\n4 Seroquel (quetiapine) [prescribing information . Mississauga, Ontario, Canada : AstraZeneca Canada Inc , 2014 .\n5 Wellbutrin SR (bupropion hydrochloride) [prescribing information . Research Triangle Park, NC : GlaxoSmithKline , 2014 .\n6 Hocking G , Cousins MJ \nKetamine in chronic pain management: an evidence-based review . Anesth Analg \n2003 ;97 :1730 –9 . 10.1213/01.ANE.0000086618.28845.9B 14633551 \n7 Prommer EE \nKetamine for pain: an update of uses in palliative care . J Palliat Med \n2012 ;15 :474 –83 . 10.1089/jpm.2011.0244 22500483 \n8 Larkin GL , Beautrais AL \nA preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department . Int J Neuropsychopharmacol \n2011 ;14 :1127 –31 . 10.1017/S1461145711000629 21557878 \n9 Murrough JW , Soleimani L , DeWilde KE , et al \nKetamine for rapid reduction of suicidal ideation: a randomized controlled trial . Psychol Med \n2015 ;45 :3571 –80 . 10.1017/S0033291715001506 26266877 \n10 Aan Het Rot M , Zarate CA , Charney DS , et al \nKetamine for depression: where do we go from here? \nBiol Psychiatry \n2012 ;72 :537 –47 . 10.1016/j.biopsych.2012.05.003 22705040 \n11 Reinstatler L , Youssef NA \nKetamine as a potential treatment for suicidal ideation: a systematic review of the literature . Drugs R D \n2015 ;15 :37 –43 . 10.1007/s40268-015-0081-0 25773961 \n12 Price RB , Iosifescu DV , Murrough JW , et al \nEffects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression . Depress Anxiety \n2014 ;31 :335 –43 . 10.1002/da.22253 24668760 \n13 Chaparro LE , Smith SA , Moore RA , et al \nPharmacotherapy for the prevention of chronic pain after surgery in adults . Cochrane Database Syst Rev \n2013 :CD008307 \n10.1002/14651858.CD008307.pub2 23881791\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "drugs: psychiatry; pain; pain (neurology); pain (palliative Care); suicide (psychiatry)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001714:Bipolar Disorder; D002186:Cannabinoids; D059350:Chronic Pain; D006801:Humans; D007273:Injections, Intramuscular; D007649:Ketamine; D008297:Male; D056687:Off-Label Use; D012074:Remission Induction; D059020:Suicidal Ideation; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29133582",
"pubdate": "2017-11-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23881791;24668760;26266877;23432384;21557878;26415966;14633551;25773961;22705040;22500483",
"title": "Use of ketamine for acute suicidal ideation in a patient with chronic pain on prescribed cannabinoids.",
"title_normalized": "use of ketamine for acute suicidal ideation in a patient with chronic pain on prescribed cannabinoids"
} | [
{
"companynumb": "US-APOTEX-2017AP022644",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPROPION HYDROCHLORIDE"
},
"drugadditional": nu... |
{
"abstract": "BACKGROUND\nAmong oncologic patients, Syndrome of Inappropriate Antidiuretic Hormone is a common cause of hyponatremia, a prevalent electrolyte disorder. There are many causes for Syndrome of Inappropriate Antidiuretic Hormone, including chemotherapy medications. To date, only three cases associating vinorelbine and Syndrome of Inappropriate Antidiuretic Hormone have been published.\n\n\nMETHODS\nA 47-year-old woman with stage IIIC serous ovarian adenocarcinoma developed life-threatening hyponatremia (124 mmol/L) after three cycles of vinorelbine. Assessment revealed Syndrome of Inappropriate Antidiuretic Hormone as the most likely culprit. Conservative managements including free fluid restriction normalized her sodium level and Syndrome of Inappropriate Antidiuretic Hormone resolved after vinorelbine discontinuation.\n\n\nCONCLUSIONS\nVinorelbine can cause Syndrome of Inappropriate Antidiuretic Hormone. It is important to monitor sodium concentration during vinorelbine treatment to avoid serious neurological complications of hyponatremia and to improve patient's quality of life.",
"affiliations": "Department of Obstetrics and Gynecology, Yale New Haven Hospital, CT, USA.",
"authors": "Hoang|Mai|M|;Varughese|Joyce|J|;Ratner|Elena|E|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D012964:Sodium; D000077235:Vinorelbine",
"country": "England",
"delete": false,
"doi": "10.1177/1078155212473003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "19(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Syndrome of Inappropriate Antidiuretic Hormone; ovarian cancer; vinorelbine",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D018284:Cystadenocarcinoma, Serous; D005260:Female; D006801:Humans; D007177:Inappropriate ADH Syndrome; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms; D011788:Quality of Life; D012964:Sodium; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "380-3",
"pmc": null,
"pmid": "23353713",
"pubdate": "2013-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Syndrome of Inappropriate Antidiuretic Hormone after vinorelbine treatment.",
"title_normalized": "syndrome of inappropriate antidiuretic hormone after vinorelbine treatment"
} | [
{
"companynumb": "US-ACTAVIS-2014-17483",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE"
},
"drugadditi... |
{
"abstract": "A 51-year-old man with no relevant medical history presents to the emergency department complaining of a recent worsening of few months upper abdominal pain with back radiation and postprandial fullness, without B symptoms. Laboratory analysis showed hyperamylasaemia, elevated lactate dehydrogenase and inflammatory parameters. Abdominal ultrasonography revealed a heterogeneous solid mass in the spleen/splenic hilum with pancreatic parenchyma continuity and no biliary tract dilation or gallstones. A mild acalculous acute pancreatitis diagnosis was made. Abdominopelvic CT revealed a large heterogeneous mass infiltrating the spleen and pancreas and obstructing the common bile duct at the pancreatic level with upstream dilation of biliary and pancreatic ducts, with splenic vein invasion. Several necrotic, peripancreatic and hepatic hilar adenopathies were also observed. Ultrasound-guided biopsy showed a primary splenic diffuse large B-cell non-Hodgkin's lymphoma. Chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) was performed with lack of response and the patient died within 10 months of diagnosis onset.",
"affiliations": "Department of Gastroenterology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Department of Gastroenterology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Department of Gastroenterology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Department of Gastroenterology, Centro Hospitalar e Universitário de Coimbra and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.",
"authors": "Gravito-Soares|Elisa|E|;Gravito-Soares|Marta|M|;Pina-Cabral|José Eduardo|JE|;Tomé|Luis|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222643",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "chemotherapy; haematology (including blood transfusion); malignant and benign haematology; pancreas and biliary tract; pancreatitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D017809:Fatal Outcome; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D013160:Splenic Neoplasms; D017211:Treatment Failure",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29018018",
"pubdate": "2017-10-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20931475;17659747;23896955;28493517;24273125;23846949;17828824;21296460;12138234",
"title": "Acute pancreatitis as an unusual presentation of primary splenic lymphoma.",
"title_normalized": "acute pancreatitis as an unusual presentation of primary splenic lymphoma"
} | [
{
"companynumb": "PT-BAXTER-2018BAX002872",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Baclofen is a γ-aminobutyric acid (GABA)-β receptor agonist with a muscle relaxant effect. It increases GABA activity and reduces the production of glutamate and dopamine. The GABA precursor γ-hydroxybutyrate (GHB) has gained popularity as a drug of abuse. For the first time, we report a case of a GHB-dependent patient, who ingested several days' doses of baclofen (80 mg) simultaneously with 0.3 L (215 g) of illicit GHB. Baclofen (40 mg/d) was prescribed to prevent relapse after a successful detoxification. The patient developed a rapid coma (E2M5V1 with oxygen support), bradypnea, and hypotonia. Physicians should be alert to the danger of this combination because of the hazards of coma and respiratory distress.",
"affiliations": "From the Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA) (RMK, CAJDJ), Vught, the Netherlands; and Novadic-Kentron Addiction Care Network (RMK, RQ), Vught, the Netherlands.",
"authors": "Kamal|Rama M|RM|;Qurishi|Rouhollah|R|;De Jong|Cornelis A J|CA|",
"chemical_list": "D058786:GABA-B Receptor Agonists; D012978:Sodium Oxybate; D001418:Baclofen",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "9(1)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D001418:Baclofen; D003128:Coma; D005260:Female; D058786:GABA-B Receptor Agonists; D006801:Humans; D009123:Muscle Hypotonia; D012128:Respiratory Distress Syndrome; D012978:Sodium Oxybate; D055815:Young Adult",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "75-7",
"pmc": null,
"pmid": "25494007",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Baclofen and γ-hydroxybutyrate (GHB), a dangerous combination.",
"title_normalized": "baclofen and hydroxybutyrate ghb a dangerous combination"
} | [
{
"companynumb": "NL-WATSON-2015-27038",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND The hallmark of bullous pemphigoid (BP) is widespread tense blisters arising on normal or erythematous skin, often with marked pruritus, the diagnosis of which is confirmed by direct immunofluorescence (DIF). BP is an autoimmune process that can be induced, though rarely, by medications. Drug-induced BP often has atypical clinical presentation, which requires a good understanding of other dermatological conditions with similar presentations, in particular, bullous subtype of erythema multiforme. End organ involvement warrants differentiating it from one of the severe cutaneous adverse reaction (SCAR) syndromes. CASE REPORT A 76-year-old African American male presented with extensive targetoid purplish skin lesions that clinically resembled atypical erythema multiforme, and one tense blister that raised a concern for BP. The patient presented 6 weeks after treatment with cephalexin for a urinary tract infection. Initial workup showed serum eosinophilia, acute kidney injury and eosinophiluria requiring deliberations on SCAR syndromes. A skin biopsy at an intralesional location showed a negative DIF, however, a skin biopsy at a perilesional site showed a positive DIF, confirming the diagnosis of BP. CONCLUSIONS This case demonstrates an atypical presentation of BP induced by drugs. It emphasizes the need for a greater level of awareness of diagnosis and treatment of the various entities that fall under adverse drug reactions in the elderly. It also highlights the need for appropriate choice of skin biopsy techniques (intralesional versus perilesional) to avoid misdiagnosis, as well as lessons on how to approach dermatologic conditions with end organ involvement for hospitalists and other medical professionals who routinely deal with undifferentiated disease conditions.",
"affiliations": "Department of Internal Medicine, Mount Sinai Hospital, Chicago, IL, USA.;Department of Internal Medicine, Mount Sinai Hospital, Chicago, IL, USA.;Department of Internal Medicine, Mount Sinai Hospital, Chicago, IL, USA.;Department of Pathology, Mount Sinai Hospital, Chicago, IL, USA.;Department of Internal Medicine, Mount Sinai Hospital, Chicago, IL, USA.;Department of Internal Medicine, Mount Sinai Hospital, Chicago, IL, USA.",
"authors": "Ganapathineedi|Bindu|B|;Mehta|Alaap|A|;Dande|Susmitha|S|;Shinde|Anjali|A|;Barsky|Gary|G|;Sebro|Nadew|N|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002506:Cephalexin",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.911422",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3077352810.12659/AJCR.911422911422ArticlesBullous Pemphigoid with Atypical Skin Lesions and Acute Interstitial Nephritis: A Case Report and Focused Literature Review Ganapathineedi Bindu ABCDEF1Mehta Alaap ABCDEF1Dande Susmitha EF1Shinde Anjali B2Barsky Gary BDE1Sebro Nadew ABCDEFG1\n1 Department of Internal Medicine, Mount Sinai Hospital, Chicago, IL, U.S.A.\n2 Department of Pathology, Mount Sinai Hospital, Chicago, IL, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nSource of support: This work was supported in part by a grant from the Everest Foundation to Graduate Medical Education Training, Research and Innovation Program (GME TRIP) of Mount Sinai Hospital, Chicago\n\nCorresponding Author: Nadew Sebro, e-mail: nadew@post.harvard.edu2019 18 2 2019 20 212 218 30 5 2018 14 10 2018 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 76\n\nFinal Diagnosis: Drug induced bullous pemphigoid\n\nSymptoms: Skin rash\n\nMedication: Cephalexin\n\nClinical Procedure: Skin biopsy\n\nSpecialty: General and Internal Medicine\n\nObjective:\nUnusual clinical course\n\nBackground:\nThe hallmark of bullous pemphigoid (BP) is widespread tense blisters arising on normal or erythematous skin, often with marked pruritus, the diagnosis of which is confirmed by direct immunofluorescence (DIF). BP is an autoimmune process that can be induced, though rarely, by medications. Drug-induced BP often has atypical clinical presentation, which requires a good understanding of other dermatological conditions with similar presentations, in particular, bullous subtype of erythema multiforme. End organ involvement warrants differentiating it from one of the severe cutaneous adverse reaction (SCAR) syndromes.\n\nCase Report:\nA 76-year-old African American male presented with extensive targetoid purplish skin lesions that clinically resembled atypical erythema multiforme, and one tense blister that raised a concern for BP. The patient presented 6 weeks after treatment with cephalexin for a urinary tract infection. Initial workup showed serum eosinophilia, acute kidney injury and eosinophiluria requiring deliberations on SCAR syndromes. A skin biopsy at an intralesional location showed a negative DIF, however, a skin biopsy at a perilesional site showed a positive DIF, confirming the diagnosis of BP.\n\nConclusions:\nThis case demonstrates an atypical presentation of BP induced by drugs. It emphasizes the need for a greater level of awareness of diagnosis and treatment of the various entities that fall under adverse drug reactions in the elderly. It also highlights the need for appropriate choice of skin biopsy techniques (intralesional versus perilesional) to avoid misdiagnosis, as well as lessons on how to approach dermatologic conditions with end organ involvement for hospitalists and other medical professionals who routinely deal with undifferentiated disease conditions.\n\nMeSH Keywords:\nDrug Hypersensitivity SyndromeDrug-Related Side Effects and Adverse ReactionsErythema MultiformeHypereosinophilic SyndromeNephritis, InterstitialPemphigoid, Bullous\n==== Body\nBackground\nBullous pemphigoid (BP) is an autoimmune subepidermal blistering disease that clinically presents with tense bullae with widespread erythema primarily in the elderly population. It is often idiopathic, but may be associated with malignancy, medications, and rarely, other autoimmune disorders [1]. Its pathophysiology is mediated by autoantibodies to antigens on hemidesmosomes that attach epithelial cells to underlying basement membrane. Diagnosis is based on direct immunofluorescence (DIF) study on skin biopsy samples that confirms the presence of immunoglobulins and complements in the epidermal basement membrane zone and other serological tests. Drug-induced BP, however, tends to have an atypical clinical presentation that poses a diagnostic challenge [2], such as was the case for this patient, who required a repeat skin biopsy due to our high degree of clinical suspicion.\n\nThis patient case peaked our interest for an academic discussion because it embodied a unique set of challenges faced by those in medical disciplines who routinely deal with undifferentiated disease conditions such as those who practice in internal medicine, family medicine, and emergency medicine [3]. This is acutely relevant for hospitalists, since most dermatologic conditions are managed in outpatient settings depriving them of exposure to a wider range of dermatologic conditions. In the inpatient setting, hospitalists are often the ones who will first encounter these cases, diagnose, determine illness severity, and initiate therapy and consultations.\n\nThe clinical care in this case was surrounded with dilemmas. The initial therapeutic dilemma was inpatient versus outpatient care, since it was not clear if the presence of just one small active bullous lesion (Figure 1) on presentation should warrant a higher-level of concern for potentially life-threatening skin disorders. After an inpatient admission, the second diagnostic dilemma was triggered by the presence of multiple potential etiologies on further history and workup, including a positive syphilis serology and patient use of multiple medications. Third, further workup also showed the presence of systemic eosinophilia (serum eosinophilia, eosinophiluria, and eosinophilic infiltration of the dermis) with end organ involvement (acute kidney injury), which raised the question of the role of eosinophils either as a primary hematologic disorder with a different prognosis or a relatively benign secondary marker of another etiology.\n\nCase Report\nA 76-year-old African American male nursing home resident presented to the emergency department with a diffuse rash and worsening renal function of 3 weeks duration. His past medical history included hypertension, diabetes mellitus type II, chronic kidney disease stage 2, treated secondary syphilis, and a prior ischemic stroke. The pruritic rash was first noticed on his lower back and gradually spread to his upper and front parts of his trunk and extremities. The rash was reported to include “pockets of fluids” initially, but bulla was only visible only at one location (Figure 1) on presentation. The patient denied any sores or blisters in his mouth. He was treated with cephalexin for 7 days for a urinary tract infection 6 weeks prior to admission. His list of preadmission medications included losartan, metformin, gabapentin, atorvastatin, tolterodine, and aspirin.\n\nOn physical examination, the patient was afebrile with stable vital signs. There was a mix of purplish discrete and confluent targetoid macules (Figure 2) and diffuse plaques, which were symmetrically distributed on the trunk, arms, legs, palms, and soles (Figures 3, 4). The distribution spared the face and oral mucous membranes. There was a single tense blister on the dorsal left hand, with minimal surrounding erythema (Figure 1). The targetoid lesions were partially blanching, non-palpable, non-tender, with a darker central area and scaling in some cases, which appears to be a secondary change after the rupture of blisters (Figure 2).\n\nPertinent initial laboratory findings include: total white cell count of 9700 cells/mL with eosinophilia 11.0%, absolute eosinophil count (AEC) of 1200 cells/mL), serum creatinine of 2.1 mg/dL (increased from a baseline of 1.3 mg/dL), and urine Hansel’s stain showed presence of 4.3% eosinophils. Serology showed rapid positive plasma reagin (RPR) with 1: 4 titers and a reactive T. pallidum microhemagglutination assay (MHA-TP). A detailed further infectious disease and autoimmune serology workup was unremarkable.\n\nPunch biopsy\nEpidermis showed mild spongiosis and interface vacuolar changes. The dermal venules were dilated and contained neutrophils. Inflammatory infiltrate composed of lymphocytes, neutrophils, and eosinophils were present in the dermis. There was focal vacuolar alteration of the basal cell layer. There were also necrotic keratinocytes, mild superficial, and mid dermal perivascular inflammatory cell infiltrate containing frequent eosinophils and dilated vessels (Figure 5).\n\nDirect immunofluorescence (DIF) (performed twice)\nDIF on intralesional biopsy was negative for fibrinogen, C1q, C3, IgA, IgM, and IgG within the epidermis, at the dermal epidermal junction and around the dermal blood vessels. However, on a perilesional biopsy, stains for C3 and IgG showed linear positivity of the basement membrane zone. DIF stain for fibrinogen showed nonspecific staining. Stains for IgM, IgA, and C1q were negative.\n\nHospital course\nThe patient was started on oral prednisone, topical clobetasol (clobetasol propionate 0.05% cream), and oral diphenhydramine. The skin lesions showed clinical improvement after 36 hours; however, serum eosinophilia increased from an initial 11.0% to 22.4% with an AEC increase from 1200 cells/mL to 3423 cells/mL. Treatment with topical and systemic steroids was continued and the patient was discharged improved. On a 10-day post-discharge clinic follow-up visit, there was a significant improvement in the skin lesions and resolution of eosinophilia and acute kidney injury.\n\nDiscussion\nThis discussion, with the benefit of hindsight, outlines a general approach framework and delves deeper into relevant diagnostic and treatment topics in a focused literature review format.\n\nBroad differentials\nThe differential diagnosis for a combination of skin lesions and serum eosinophilia encompasses a wide range of diseases, including allergy or hypersensitivity, parasitosis, fungal infections, neoplasm or hyperplastic disorders, HIV-related eruptions, cutaneous vasculitis, autoimmune blistering skin disorders, pregnancy-related disorders, pediatric specific disorders, and other systemic diseases [4,5]. The overwhelming majority of eosinophilic dermatoses epidemiologically, however, lie in the allergy related group, which includes allergic drug eruption, urticaria, allergic contact dermatitis, atopic dermatitis, and eczema [5,6].\n\nAllergic drug eruptions, also referred to as “drug allergy” or adverse drug reactions (ADR), comprise various entities. Thus, reaching at a specific diagnosis required familiarity with the various disease entities and classifications under ADR. Of note, ADR should not be confused with the broader concept of adverse drug events (ADE) which, in addition to ADR, includes other non-pharmacologic events like inappropriate use of drugs and medication administration errors [7,8].\n\nDermatologic manifestations of drug allergy\nThe most common types of ADR are referred to as type-A reactions and occur directly due to the pharmacologic action of a drug [9]. However, most drug-related dermatologic conditions, such as in this patient case, are due to ADR and belong to its type-B subcategory referred to as drug hypersensitivity reactions (DHR) [9]. Type B reactions are not related to the known pharmacologic action of the drug. Their underlying mechanisms are not entirely understood but are often mediated through immunologic reactions to an otherwise safe and effective therapeutic agent and are often associated with high mortality [7,8,10].\n\nClinically, DHR are classified as immediate, typically <1 hour following the last intake of the culprit drug, or delayed-type DHR (DTH), typically >1 hour to days after the start of a treatment with the culprit drug [9,11,12]. This patient presented 2 months after a course of cephalexin, most likely fitting delayed DHR timeline [12]. On the other hand, to correlate clinical presentations with underlying immune mechanism, drug hypersensitivity, and other immune reactions are frequently classified into 4 categories described by Coombs and Gell in 1963 [9]. It is important to note that each of the 4 hypersensitivity class types have their own dermatologic clinical manifestations, although some reports find the classification limiting and not comprehensive enough [13–15].\n\nADR can virtually affect any organ, but skin, liver, and blood cells are the most common targets[16]. The clinical spectrum of ADR dermatologic manifestations ranges from fixed drug eruption (FDE), maculopapular eruption (MPE), general exfoliative dermatitis or erythroderma, drug reaction with eosinophilia, and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), other bullous reactions mimicking pemphigus vulgaris and bullous pemphigoid up to vasculitis [11,12].\n\nOne of the first tasks in the management of this patient was ruling out potentially life-threatening ADRs. Among the dermatologic manifestations of ADR, 4 entities with high mortality rate belong to a class referred to as severe cutaneous adverse reactions (SCAR): SJS, TEN, AGEP, and DRESS [17]. Studies show that SJS and TEN, do not usually produce eosinophilia, but rather neutrophilia and lymphocytopenia [18]. Furthermore, although AGEP and DRESS present with eosinophilia, AGEP does not typically involve end organs [19]. DRESS syndrome was strongly entertained as a possibility in this patient, as it is characterized by multi-systemic involvement and frequent eosinophilia. Nonetheless, although this patient had significant eosinophilia, end organ involvement, and body surface area involvement >50%; the absence of fever, lymphadenopathy, protracted resolution of rash >15 days and lack of characteristic biopsy features of the syndrome has made DRESS unlikely with a RegiSCAR-Group Diagnosis Score of 1 (no case) [17].\n\nAfter excluding SCAR, the next differential diagnosis considered among ADR was bullous pemphigoid (BP), given the presence of tense bulla.\n\nErythema multiforme (EM)-like BP versus bullous EM\nThis patient presented with skin lesions that were predominantly purplish erythema and only one blister (Figures 1–4). It was a dilemma whether the presence of a single blister should raise a possibility of a bullous disorder. Furthermore, the purplish erythema had central darkening that gave it a targetoid appearance, which, at best, clinically resembled atypical erythema multiforme (EM) (Figure 2).\n\nBP and EM represent 2 separate groups of pathologies; nonetheless several reports [20–23] have documented that the clinical diagnosis of BP can be challenging when EM-like lesions are present, such as in this patient case.\n\nThe hallmark of BP is widespread tense blisters arising on normal or erythematous skin in an elderly person, often with marked pruritus confirmed by DIF and histology [1]. Several clinical variants have been described, including classic (bullous), localized, nodular, vegetating, erythrodermic, erosive, childhood, and drug-induced forms [1]. On the other hand, EM, which also can present as different subtypes (major, minor, recurrent, bullous and persistent) is generally diagnosed clinically with its polymorphous eruption of macules, papules, and characteristic target lesions that are symmetrically distributed with or without mucosal involvement [24] Cutaneous manifestations of EM evolve over the course illness and vary widely [25].\n\nThe typical lesions for EM are target lesions, which are annular and red or purple with an iris configuration, that are symmetrically distributed with a propensity for the distal extremities and subsequently spread in a centripetal manner [24]. The characteristic feature is that the central area, which is slightly raised and cyanotic, is more involved than the periphery, hence the name target lesions. When the degree of damage to the skin is greater, the center of the target lesion becomes a vesicle or a bulla [26].\n\nThe correct clinical identification of BP from EM becomes difficult when BP is caused by a drug reaction. BP, in general, is usually idiopathic but may be associated with malignancy, medications, and rarely autoimmune disorders [2]. The drug-induced bullous pemphigoid subtype, compared to its idiopathic counterparts, is known to be difficult to diagnose clinically due to its EM like targetoid lesions [20,27,28]. Similarly, unlike other subtypes of EM, bullous type EM presents with multiple blisters posing a diagnostic challenge, and is most commonly associated with drug reactions, herpes simplex virus (HSV), varicella zoster virus (VZV), and rarely with mycoplasma pneumoniae infections [29,30].\n\nThe etiologic and clinical overlap between the 2 entities – EM-like BP and bullous EM – also carries over to a histological level. It is generally considered that BP and EM cannot be distinguished on the basis of histological features alone [31]. Histologically, BP demonstrates eosinophilic spongiosis or subepidermal bulla with numerous eosinophils [3]. On the other hand, EM shows a significantly wider spectrum of findings with varying degree of involvement of the histologic layers of the skin and inconsistent inflammatory cell infiltrate that is often predominantly lymphocytic or eosinophilic at times [32], as seen in this patient case. The stage of the disease, site of biopsy (center versus periphery) [33], clinical subtype [32], and etiology [30], contributes to the wide spectrum of histological appearance of EM. The predominantly eosinophilic infiltrate seen in BP is not diagnostic, since significant numbers of eosinophil infiltrate were present in 60% of bullous EM and 28% of macular EM lesions in other studies [32].\n\nPositive DIF for IgG, IgM, IgA, and C3 to confirm that bullae are due to antibody deposition at the dermo-epidermal junction, is the cornerstone test for the diagnosis of BP, along with the presence of circulating autoantibodies against hemidesmosomal molecules in select cases [1,34]. However, DIF results should be looked at closely since, according to Howland et al., positive DIF for C3 and IgM has been observed in EM [33].\n\nAn important lesson from this patient case is that unless DIF is performed with the right skin biopsy technique, it could result in a false negative finding [1], and in our patient case, we had to obtain a repeat biopsy based on our strong clinical suspicion. The biopsy site should be perilesional, as opposed to intralesional skin on the upper body within 2 cm of a bulla, or clinically uninvolved skin from the flexor aspect of a forearm or anterior thigh [1,35]. Biopsy specimen from the lower legs should be avoided because of false-negative results in up to a third of samples from this region [36,37].\n\nEosinophilia from bullous pemphigoid\nLastly, this patient presented with peak AEC of 3423/mm3. Literature defines AEC >1500/mm3 as hypereosinophilia, and it may be associated with secondary tissue damage just from the cytotoxic content of elevated eosinophils regardless of the etiology. Hypereosinophilia could be non-hematologic (secondary or reactive) or a primary hematologic clonal disorder [38,39].\n\nTherefore, hypereosinophilia, paradoxically, could be the primary cause of end organ damageor just a secondary result of end organ damage from other causes. This poses a challenge to clinicians in understanding the chronology and cause-and-effect association of various diseases that present with a combination of hypereosinophilia and end organ involvement. For example, this patient presented with skin lesions, acute kidney injury, and systemic eosinophilia (serum eosinophilia, eosinophiluria, and eosinophilic infiltration of the dermis). This left us pondering whether the acute kidney injury was caused by hypereosinophilia triggered by an adverse reaction to cephalexin or acute kidney injury from interstitial nephritis induced by cephalexin caused a secondary hypereosinophilia. Literature review shows that essentially all organ systems may be susceptible to the effects of sustained eosinophilia. During follow-up of patients with hypereosinophilia, dermatologic involvement was the most common clinical manifestation reported in 69% of patients, followed by pulmonary manifestation (44%) and gastrointestinal manifestations (38%) [38,40,41].\n\nAnother important lesson here is that if this patient had not presented early to receive the appropriate therapy, the eosinophilia would have continued to increase and led to additional end organ involvement, particularly the lungs and heart. Peripheral eosinophilia is seen in up to 50% of patients with BP with a median AEC of 1300/μL [4]. If untreated, this would obviously cause morbidity and mortality from the disease, as well as from additional invasive diagnostic tests. The quick resolution of eosinophilia in this patient fits the pattern of drug allergies [18], yet a persistent level would have warranted a different approach [42]. This highlights the need for proper diagnosis and treatment of the underlying cause of hypereosinophilia as early as possible, to prevent secondary end organ damages.\n\nConclusions\nThis report provides a showcase for the atypical presentation of drug induced BP. With a brief overview of drug reactions, it calls for higher degree of familiarity with entities under Adverse Drug Reactions by general practitioners. In addition, through a focused literature review on differences between BP and EM, it navigates the unique set of diagnostic challenges of various dermatologic syndromes with overlapping features. In particular, it highlights key features of life-threatening dermatologic conditions referred to as severe cutaneous adverse reactions (SCAR): SJS, TEN, AGEP and DRESS. It also underscores vital lessons on appropriate biopsy techniques for BP (intralesional versus perilesional) to avoid misdiagnosis and on the importance of early diagnosis and treatment of patients with hypereosinophilia.\n\nDepartment and Institution where work was done\n\nDepartment of Internal Medicine, Mount Sinai Hospital, Chicago, IL, U.S.A.\n\nConflicts of interest\n\nNone.\n\nFigure 1. A single tense blister on the dorsal left hand, with minimal surrounding erythema.\n\nFigure 2. Atypical purplish targetoid lesions comprising discrete macules with central darkening and confluent patches. The shallow central ulcerations and scaling in some appear to be a secondary change after the rupture of blisters.\n\nFigure 3. Symmetrical involvement the arms and trunk by a mix of diffuse plaque and discrete targetoid macules.\n\nFigure 4. Symmetrical involvement the lower extremities, including plantar surfaces, by a mix of diffuse plaque and discrete targetoid macules.\n\nFigure 5. Histologic sections of skin biopsy showing changes involving all skin layers, including superficial necrotic keratinocytes, epidermal spongiosis, vacuolar changes at the interface, and basal cell layer, along with dilated dermal venules with Inflammatory infiltrate composed of lymphocytes, neutrophils and eosinophils.\n==== Refs\nReferences:\n1. Walsh SR Hogg D Mydlarski PR Bullous pemphigoid: From bench to bedside Drugs 2005 65 7 905 26 15892587 \n2. Iwata H Ujiie H Complement-independent blistering mechanisms in bullous pemphigoid Exp Dermatol 2017 26 12 1235 39 28418613 \n3. O’Riordan M Dahinden A Akturk Z Dealing with uncertainty in general practice: An essential skill for the general practitioner Qual Prim Care 2011 19 3 175 81 21781433 \n4. Montgomery ND Dunphy CH Mooberry M Diagnostic complexities of eosinophilia Arch Pathol Lab Med 2013 137 2 259 69 23368869 \n5. Long H Zhang G Wang L Lu Q Eosinophilic skin diseases: A comprehensive review Clin Rev Allergy Immunol 2016 50 2 189 213 25876839 \n6. Heymann WR Eosinophilic dermatoses J Am Acad Dermatol 2006 55 1 114 15 16781301 \n7. Edwards IR Aronson JK Adverse drug reactions: Definitions, diagnosis, and management Lancet 2000 356 9237 1255 59 11072960 \n8. Nebeker JR Barach P Samore MH Clarifying adverse drug events: A clinician’s guide to terminology, documentation, and reporting Ann Intern Med 2004 140 10 795 801 15148066 \n9. Pichler WJ Delayed drug hypersensitivity reactions Ann Intern Med 2003 139 8 683 93 14568857 \n10. Riedl MA Casillas AM Adverse drug reactions: Types and treatment options Am Fam Physician 2003 68 9 1781 90 14620598 \n11. Schrijvers R Gilissen L Chiriac AM Demoly P Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back Clin Transl Allergy 2015 5 31 26339470 \n12. Demoly P Adkinson NF Brockow K International consensus on drug allergy Allergy 2014 69 4 420 37 24697291 \n13. van Beek N Schulze FS Zillikens D Schmidt E IgE-mediated mechanisms in bullous pemphigoid and other autoimmune bullous diseases Expert Rev Clin Immunol 2016 12 3 267 77 26588556 \n14. Descotes J Choquet-Kastylevsky G Gell and Coombs’s classification: Is it still valid? Toxicology 2001 158 1–2 43 49 11164991 \n15. Choquet-Kastylevsky G Vial T Descotes J Drug allergy diagnosis in humans: possibilities and pitfalls Toxicology 2001 158 1–2 1 10 11164987 \n16. Uetrecht J Naisbitt DJ Idiosyncratic adverse drug reactions: Current concepts Pharmacol Rev 2013 65 2 779 808 23476052 \n17. Roujeau JC Allanore L Liss Y Mockenhaupt M Severe cutaneous adverse reactions to drugs (SCAR): Definitions, diagnostic criteria, genetic predisposition Dermatol Sinica 2009 27 203 9 \n18. Kovalszki A Weller PF Eosinophilia Prim Care 2016 43 4 607 17 27866580 \n19. Schmid S Kuechler PC Britschgi M Acute generalized exanthematous pustulosis: Role of cytotoxic T cells in pustule formation Am J Pathol 2002 161 6 2079 86 12466124 \n20. Hirano SA Mason AR Harvey VM Hood AF Erythema multiforme-like bullous pemphigoid associated with furosemide J Clin Exp Dermatol Res 2011 2 123 \n21. Alcalay J David M Ingber A Bullous pemphigoid mimicking bullous erythema multiforme: an untoward side effect of penicillins J Am Acad Dermatol 1988 18 2 Pt 1 345 49 2964460 \n22. Hayakawa K Shiohara T Atypical bullous disease showing features of both erythema multiforme and bullous pemhigoid Acta Derm Venereol 2002 82 3 196 99 12353711 \n23. Mehravaran M Gyulai R Husz S Dobozy A Drug-induced erythema multi-forme-like bullous pemphigoid Acta Derm Venereol 1999 79 3 233 10384926 \n24. Lamoreux MR Sternbach MR Hsu WT Erythema multiforme Am Fam Physician 2006 74 11 1883 88 17168345 \n25. Sokumbi O Wetter DA Clinical features, diagnosis, and treatment of erythema multiforme: A review for the practicing dermatologist Int J Dermatol 2012 51 8 889 902 22788803 \n26. du Vivier A Atlas of clinical dermatology 3rd ed. Churchill Livingstone London 2002 \n27. Stavropoulos PG Soura E Antoniou C Drug-induced pemphigoid: A review of the literature J Eur Acad Dermatol Venereol 2014 28 9 1133 40 24404939 \n28. Kijima A Inui S Nakamura T Does drug-induced hypersensitivity syndrome elicit bullous pemphigoid? Allergol Int 2008 57 2 181 82 18427168 \n29. Weisman K Petersen CS Blichmann CW Bullous erythema multi-forme following herpes zoster and varicella-zoster virus infection J Eur Acad Dermatol Venereol 1998 11 2 147 50 9784041 \n30. Schalock PC Brennick JB Dinulos JG Mycoplasma pneumoniae infection associated with bullous erythema multiforme J Am Acad Dermatol 2005 52 4 705 6 15793531 \n31. Macvicar DN Graham JH Burgoon CF Jr Dermatitis herpetiformis, erythema multiforme and bullous pemphigoid: A comparative histopathological and histochemical study J Invest Dermatol 1963 41 289 300 14075453 \n32. Bedi TR Pinkus H Histopathological spectrum of erythema multiforme Br J Dermatol 1976 95 3 243 50 974014 \n33. Howland WW Golitz LE Weston WL Huff JC Erythema multiforme: Clinical, histopathologic, and immunologic study J Am Acad Dermatol 1984 10 3 438 46 6725656 \n34. Lo Schiavo A Ruocco E Brancaccio G Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies Clin Dermatol 2013 31 4 391 99 23806156 \n35. Kirtschig G Wojnarowska F Autoimmune blistering diseases: An up-date of diagnostic methods and investigations Clin Exp Dermatol 1994 19 2 97 112 8050161 \n36. Weigand DA Effect of anatomic region on immunofluorescence diagnosis of bullous pemphigoid J Am Acad Dermatol 1985 12 2 Pt 1 274 78 3882783 \n37. Koch CA Mazzaferri EL Larry JA Fanning TS Bullous pemphigoid after treatment with furosemide Cutis 1996 58 5 340 44 8934074 \n38. Gotlib J World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management Am J Hematol 2017 92 11 1243 59 29044676 \n39. Roufosse F Weller PF Practical approach to the patient with hypereosinophilia J Allergy Clin Immunol 2010 126 1 39 44 20538328 \n40. Valent P Pathogenesis, classification, and therapy of eosinophilia and eosinophil disorders Blood Rev 2009 23 4 157 65 19246139 \n41. Chusid MJ Dale DC West BC Wolff SM The hypereosinophilic syndrome: Analysis of fourteen cases with review of the literature Medicine (Baltimore) 1975 54 1 1 27 1090795 \n42. Nutman TB Evaluation and differential diagnosis of marked, persistent eosinophilia Immunol Allergy Clin North Am 2007 27 3 529 49 17868863\n\n",
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"issue": "20()",
"journal": "The American journal of case reports",
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"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002506:Cephalexin; D003937:Diagnosis, Differential; D004892:Erythema Multiforme; D006801:Humans; D008297:Male; D009395:Nephritis, Interstitial; D010391:Pemphigoid, Bullous",
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"pages": "212-218",
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"pmid": "30773528",
"pubdate": "2019-02-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10384926;1090795;11072960;11164987;11164991;12353711;12466124;14075453;14568857;14620598;15148066;15793531;15892587;16781301;17168345;17868863;18427168;19246139;20538328;21781433;22788803;23368869;23476052;23806156;24404939;24697291;25876839;26339470;26588556;27866580;28418613;29044676;2964460;3882783;6725656;8050161;8934074;974014;9784041",
"title": "Bullous Pemphigoid with Atypical Skin Lesions and Acute Interstitial Nephritis: A Case Report and Focused Literature Review.",
"title_normalized": "bullous pemphigoid with atypical skin lesions and acute interstitial nephritis a case report and focused literature review"
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"abstract": "The IMpower133 regimen, composed of atezolizumab/etoposide (VP-16)/carboplatin (CBDCA), is the standard first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, the safety and efficacy of triplet therapy in patients receiving dialysis have not been sufficiently evaluated. Here, we report two cases of dialysis patients with ES-SCLC who received the modified IMpower133 regimen. Patient 1 was a 69-year-old man, and patient 2 was a 73-year-old man who received dialysis because of end-stage renal failure caused by diabetic nephropathy. Both patients received a modified IMpower133 regimen in the following order: atezolizumab (1200 mg/body) on day 1, VP-16 (50 mg/m2 ) on days 1 and 3, and CBDCA (300 mg/m2 ) on day 1. Four hours of dialysis was performed 1 hour after completing the administration of CBDCA on Day 1 and 2 hours after completing the administration of VP-16 on Day 3. Both patients achieved a partial response and received atezolizumab maintenance therapy after four cycles of triplet therapy without uncontrollable adverse events. By modifying the dosage, the order of drugs, and the timing of dialysis, the IMpower133 regimen may be tolerable and effective for patients receiving dialysis.",
"affiliations": "Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, Hiroshima University Hospital, Hiroshima, Japan.",
"authors": "Watari|Naokazu|N|;Yamaguchi|Kakuhiro|K|https://orcid.org/0000-0002-9117-1934;Masuda|Takeshi|T|https://orcid.org/0000-0003-3557-0049;Ito|Noriaki|N|;Sakamoto|Shinjiro|S|;Horimasu|Yasushi|Y|;Miyamoto|Shintaro|S|;Nakashima|Taku|T|;Iwamoto|Hiroshi|H|;Fujitaka|Kazunori|K|;Hamada|Hironobu|H|;Hattori|Noboru|N|",
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"doi": "10.1111/1759-7714.14166",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n34587368\n10.1111/1759-7714.14166\nTCA14166\nCase Report\nCase Reports\nTolerability and efficacy of IMpower133 regimen modified for dialysis patients with extensive‐stage small cell lung cancer: Two case reports\nWatari et al.\nWatari Naokazu 1\nYamaguchi Kakuhiro https://orcid.org/0000-0002-9117-1934\n1 yamaguchikakuhiro@gmail.com\n\nMasuda Takeshi https://orcid.org/0000-0003-3557-0049\n1\nIto Noriaki 1\nSakamoto Shinjiro 1\nHorimasu Yasushi 1\nMiyamoto Shintaro 1\nNakashima Taku 1\nIwamoto Hiroshi 1\nFujitaka Kazunori 1\nHamada Hironobu 1\nHattori Noboru 1\n1 Department of Respiratory Medicine Hiroshima University Hospital Hiroshima Japan\n* Correspondence\nKakuhiro Yamaguchi, Department of Respiratory Medicine, Hiroshima University Hospital, 1‐2‐3 Kasumi, Minami‐ku, Hiroshima 734‐8551, Japan.\nEmail: yamaguchikakuhiro@gmail.com\n\n29 9 2021\n11 2021\n12 21 10.1111/tca.v12.21 29562960\n08 9 2021\n11 8 2021\n09 9 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\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\nThe IMpower133 regimen, composed of atezolizumab/etoposide (VP‐16)/carboplatin (CBDCA), is the standard first‐line treatment for extensive‐stage small cell lung cancer (ES‐SCLC). However, the safety and efficacy of triplet therapy in patients receiving dialysis have not been sufficiently evaluated. Here, we report two cases of dialysis patients with ES‐SCLC who received the modified IMpower133 regimen. Patient 1 was a 69‐year‐old man, and patient 2 was a 73‐year‐old man who received dialysis because of end‐stage renal failure caused by diabetic nephropathy. Both patients received a modified IMpower133 regimen in the following order: atezolizumab (1200 mg/body) on day 1, VP‐16 (50 mg/m2) on days 1 and 3, and CBDCA (300 mg/m2) on day 1. Four hours of dialysis was performed 1 hour after completing the administration of CBDCA on Day 1 and 2 hours after completing the administration of VP‐16 on Day 3. Both patients achieved a partial response and received atezolizumab maintenance therapy after four cycles of triplet therapy without uncontrollable adverse events. By modifying the dosage, the order of drugs, and the timing of dialysis, the IMpower133 regimen may be tolerable and effective for patients receiving dialysis.\n\nThe safety and efficacy of the IMpower133 regimen in dialysis patients has not been evaluated. We report on two dialysis patients with ES‐SCLC who received the modified IMpower133 regimen for dialysis patients. They achieved a partial response after four cycles of the triple therapy without uncontrollable adverse events. By modifying the dosage, the order of drugs, and the timing of dialysis, the IMpower133 regimen may be tolerable and effective for dialysis patients.\n\nadverse effects\ndialysis\nsmall cell lung carcinoma\nsource-schema-version-number2.0\ncover-dateNovember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:02.11.2021\nWatari N , Yamaguchi K , Masuda T , Ito N , Sakamoto S , Horimasu Y , et al. Tolerability and efficacy of IMpower133 regimen modified for dialysis patients with extensive‐stage small cell lung cancer: Two case reports. Thorac Cancer. 2021;12 :2956–2960. 10.1111/1759-7714.14166\n==== Body\npmcINTRODUCTION\n\nOne of the standard first‐line treatments for extensive‐stage small cell lung cancer (ES‐SCLC) has become a combination therapy of atezolizumab (an anti‐programmed death ligand‐1 [PD‐L1] antibody), carboplatin (CBDCA), and etoposide (VP‐16) because the IMpower133 trial has revealed that the addition of atezolizumab to CBDCA/VP‐16 prolongs overall survival. 1 However, the safety of this regimen has not been sufficiently elucidated in patients on dialysis. Herein, we report two cases of patients with ES‐SCLC undergoing dialysis who received a modified IMpower133 regimen and achieved partial response (PR) with controllable adverse events.\n\nCASE REPORTS\n\nTwo patients with ES‐SCLC on dialysis because of chronic renal failure caused by diabetic nephropathy were treated with the modified IMpower133 regimen, which was administered in the order of atezolizumab (1200 mg/body) on Day 1, VP‐16 (50 mg/m2) on Days 1 and 3, and CBDCA (300 mg/m2) on Day 1 (Table 1). Four hours of dialysis was performed 1 hour after completing the administration of CBDCA on Day 1 and 2 hours after completing the administration of VP‐16 on Day 3. The dose and the order of CBDCA/VP‐16 and the timing of dialysis were modified according to the previous reports analyzing the pharmacokinetics of these cytotoxic drugs in ES‐SCLC patients on dialysis. 2 , 3\n\nTABLE 1 Comparison of the IMpower133 regimen with a modified regimen for dialysis patients\n\n\tDrug sequence\tDrug\tSolution\tDosing time\t\nA. IMpower133 regimen\t\nDay 1\t1\t–\tSaline solution 100 mL\t10 min\t\n2\tAtezolizumab (1200 mg/body)\tSaline solution 250 mL\t60 min\t\n3\t–\tSaline solution 100 mL\t10 min\t\n4\tGranisetron 3.0 mg + dexamethasone 6.6 mg\tSaline solution 100 mL\t15 min\t\n5\tCBDCA (AUC: 5)\t5% glucose solution 250 ml\t60 min\t\n6\tVP‐16 (100 mg/m2)\tSaline solution 500 mL\t60 min\t\n7\t–\tSaline solution 100 mL\t10 min\t\nDay 2\t1\tGranisetron 3.0 mg + dexamethasone 6.6 mg\tSaline solution 100 mL\t15 min\t\n2\tVP‐16 (100 mg/m2)\tSaline solution 500 mL\t60 min\t\n3\t–\tSaline solution 100 mL\t10 min\t\nDay 3\t1\tGranisetron 3.0 mg + dexamethasone 6.6 mg\tSaline solution 100 mL\t15 min\t\n2\tVP‐16 (100 mg/m2)\tSaline solution 500 mL\t60 min\t\n3\t–\tSaline solution 100 mL\t10 min\t\nB. Modified IMpower133 regimen for dialysis patients\t\nDay 1\t1\t–\tSaline solution 50 mL\t10 min\t\n2\tAtezolizumab (1200 mg/body)\tSaline solution 250 mL\t60 min\t\n3\t–\tSaline solution 50 mL\t10 min\t\n4\tGranisetron 3.0 mg + dexamethasone 6.6 mg\tSaline solution 100 mL\t15 min\t\n5\tVP‐16 (50 mg/m2)\t5% glucose solution 250 mL\t60 min\t\n6\tCBDCA (300 mg/m2)\t5% glucose solution 250 mL\t60 min\t\n7\t–\tSaline solution 50 mL\t10 min\t\n\tDialysis (4 h) 1 h after CBDCA administration\t\nDay 2\t1\tGranisetron 3.0 mg + dexamethasone 6.6 mg\tSaline solution 100 mL\t15 min\t\nDay 3\t1\tGranisetron 3.0 mg + dexamethasone 6.6 mg\tSaline solution 100 mL\t15 min\t\n2\tVP‐16 (50 mg/m2)\t5% glucose solution 250 mL\t60 min\t\n3\t–\tSaline solution 50 mL\t10 min\t\n\tDialysis (4 h) 2 h after VP‐16 administration\t\n\nPatient 1 was a 69‐year‐old man and diagnosed with ES‐SCLC (cT1cN3M1a stage IVA). His performance status (PS) was 0. Blood tests revealed that the progastrin‐releasing peptide (ProGRP) levels were mildly elevated (Supporting Information Table S1). Contrast‐enhanced computed tomography (CT) revealed a 20‐mm‐sized nodule in the lower left lobe and lymphadenopathy in the bilateral hilar, mediastinum, and right supraclavicular fossa (Figure 1(a) and Figure S1(A)). Therefore, we chose the modified IMpower133 regimen (Table 1). He experienced grade 3 neutropenia and grade 4 thrombocytopenia in the first cycle. Consequently, we reduced CBDCA to 240 mg/m2 and used pegfilgrastim (3.6 mg) on day 5 from the second cycle. However, in the second and third cycles, he experienced grade 3 anemia. Therefore, VP‐16 was reduced to 40 mg/m2 in the fourth cycle. After three cycles of chemotherapy, the patient achieved PR (Figure 1(a)). In all, he received four cycles of chemotherapy followed by maintenance therapy with atezolizumab. After two cycles of atezolizumab, he was diagnosed with progressive disease because of an increased primary lesion and mediastinal lymph node metastasis.\n\nFIGURE 1 Clinical course of the chest CT findings. (a) Clinical course of the chest CT findings in patient 1. (a),(c) Chest CT on admission showed a 20‐mm‐sized nodule in the lower left lobe. Lymphadenopathies were found in the bilateral hilar region and mediastinal region. (b),(d) Chest CT after three cycles of modified IMpower133 regimen showed that all lesions were decreasing in size. (b) Clinical course of the chest CT findings in patient 2. (a) Chest CT on admission showed an 80‐mm‐sized mass in the left hilar region. (b) After two cycles of modified IMpower133 regimen, chest CT showed that the mass in the left hilar region decreased in size. CT, computed tomography\n\nPatient 2 was a 73‐year‐old man and diagnosed with ES‐SCLC (cT2aN1M1b stage IVA). His PS was 1. Blood tests showed elevated ProGRP levels (Supporting Information Table S2). Contrast‐enhanced CT showed an 80‐mm‐sized mass in the upper left lobe (Figure 1(b) and Figure S1(B)). Head magnetic resonance imaging revealed a 40‐mm‐sized mass with edema in the left frontal lobe. After stereotactic radiotherapy (39 Gy/13 in fractions) for brain metastasis, the modified IMpower133 regimen was administered (Table 1). Considering that his PS was 1 and that moderate to severe hematological toxicity was observed in patient 1, CBDCA was reduced to 240 mg/m2, and VP‐16 was decreased to 40 mg/m2. In the first cycle, hospitalization was required for febrile neutropenia. From the second cycle, CBDCA was reduced to 210 mg/m2. After two cycles of chemotherapy, the patient achieved PR (Figure 1(b)). He received four cycles of chemotherapy and maintenance therapy with atezolizumab for 4 months.\n\nDISCUSSION\n\nThis paper demonstrates that a combination therapy composed of atezolizumab/VP‐16/CBDCA can be safely and effectively administered to dialysis patients with ES‐SCLC. Monotherapy of anti‐PD‐1/PD‐L1 antibodies, including atezolizumab, has been reported to be safely administered to dialysis patients for several types of cancers, as shown in Table 2. 4 Additionally, the dose and the administration schedule of CBDCA/VP‐16 were modified according to the previous reports analyzing the pharmacokinetics of these cytotoxic drugs in ES‐SCLC patients on dialysis. 2 , 3 Although the dose of CBDCA/VP‐16 and the timing of dialysis were different, Imaji et al. 5 reported that atezolizumab/VP‐16 (40 mg/m2 on dayd 1, 2, and 3)/CBDCA (area under the concentration‐time curve = 5 on day 1) could be administered to dialysis patients with ES‐SCLC, as seen in this report. Therefore, the modified IMpower133 regimen can be a treatment option in patients with ES‐SCLC on dialysis.\n\nTABLE 2 Summary of prior studies in patients undergoing dialysis treated with an immune checkpoint inhibitor\n\nImmune checkpoint inhibitors\tMalignancy\tTumor response\tAdverse events\t\nATE\tUrothelial carcinoma: 3 cases, genitourinary cancer: 1 case, lung cancer: 1 case\tPR: 1 case\n\nSD: 1 case\n\nPD: 3 cases\n\n\tG1 pruritis (1/5), G1 asthenia (1/5), G1 nausea (1/5), G1 dysgeusia (1/5), G1 constipation (1/5), none (4/5)\t\nNIVO\tRenal cell carcinoma: 18 cases, genitourinary cancer: 3 cases, melanoma: 2 cases, urothelial carcinoma: 1 case, squamous cell lung cancer: 1 case, Merkel cell carcinoma: 1 case\tPR: 7 cases\n\nSD: 12 cases\n\nPD: 6 cases\n\nNA: 1 case\n\n\tG2 rash (1/26), G2 pneumonitis (1/26), G3 pneumonitis (1/26), G3‐4 myocarditis (1/26), G4 encephalitis (1/26), none (14/26)\t\nPEM\tMelanoma: 4 cases, head and neck cancer: 3 cases, cutaneous squamous cell cancer: 2 cases, genitourinary cancer: 2 cases, retroperitoneal sarcoma: 2 cases, urothelial carcinoma: 2 cases, angiosarcoma of thigh: 1 case, cholangiocarcinoma: 1 case, hodgkin lymphoma: 1 case, lung cancer: 1 case, renal cell carcinoma: 1 case, squamous cell lung cancer: 1 case\tCR: 1 case\n\nPR: 3 cases\n\nSD: 6 cases\n\nPD: 11 cases\n\n\tG1 fatigue (1/21), G1 rash (1/21), G2 fatigue (2/21), G2 pneumonitis (1/21), hearing loss (grade not reported) (1/21), myositis (Grade not reported) (1/21), hypothyroidism (grade not reported) (2/21), none (13/21)\t\nAVE\tMerkel cell carcinoma: 1 case\tPD\tHypothyroidism (grade not reported)\t\nAbbreviations: ATE, atezolizumab; AVE, avelumab; CR, complete response; NA, not available; NIVO, nivolumab PD, progressive disease; PEM, pembrolizumab; PR, partial response; SD, stable disease.\n\nAtezolizumab binds to PD‐L1 and inhibits the interaction between PD‐1 on T cells and tumor‐bearing PD‐L1, followed by enhanced antitumor immune responses. Although T cell function is generally impaired in dialysis patients, 6 the objective response rate of anti‐PD‐1/PD‐L1 antibody was 22.6% in 53 dialysis patients with various cancers (Table 2). 4 This is comparable to that of anti‐PD‐1/PD‐L1 antibody in non‐dialysis patients (20.21%). 7 In line with the antitumor effect, the incidence of immune‐related adverse events in dialysis patients was 5.8% for skin disorders, 5.8% for lung disorders, 5.8% for hypothyroidism, and 3.8% for neuromuscular and joint disorders, which were similar to those in non‐dialysis patients. 8 , 9 Additionally, the metabolism of atezolizumab does not differ between patients on dialysis and non‐dialysis patients. Atezolizumab binds extensively to target antigens in the plasma or on the cell surface, and then degrades via endocytosis and non‐specific proteolytic catabolism. These processes are not influenced by impaired renal function or dialysis. 10 One crucial point is that atezolizumab should be administered before CBDCA/VP‐16 in patients on dialysis to keep the interval between administration of cytotoxic drugs and dialysis and avoid volume overload caused by the volume of saline solution (100–375 mL) required to dilute the atezolizumab. Therefore, atezolizumab was intravenously injected before the administration of CBDCA/VP‐16 and dialysis in our cases.\n\nIn this report, we planned to administer CBDCA (300 mg/m2) on day 1 and VP‐16 (50 mg/m2) on days 1 and 3, according to the dialysis schedule (Table 1). Previous studies have shown that the pharmacokinetics of CBDCA in patients treated with hemodialysis 1 hour after the end of the CBDCA (300 mg/m2) infusion is similar to that of patients with normal renal function. 2 Additionally, initiating a 4‐hour dialysis 2 hours after completing VP‐16 (50 mg/m2) results in a similar drug metabolism pattern to that of non‐dialysis patients treated with VP‐16 (100 mg/m2), 3 allowing the volume of drug diluent to be reduced by the dose reduction of VP‐16. Following these findings, we modified the dose and schedule of CBDCA/VP‐16.\n\nIn conclusion, the IMpower133 regimen can be a treatment option in patients with ES‐SCLC on dialysis by modifying the doses, orders of drugs, and timing of dialysis, although further investigations are needed.\n\nSupporting information\n\nAppendix S1 Supporting Information\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nWe would also like to thank Editage for carefully proofreading the manuscript.\n==== Refs\nREFERENCES\n\n1 Horn L , Mansfield AS , Szczęsna A , Havel L , Krzakowski M , Hochmair MJ , et al. First‐line atezolizumab plus chemotherapy in extensive‐stage small‐cell lung cancer. N Engl J Med. 2018;379 :2220–9. 10.1056/NEJMoa1809064 30280641\n2 Inoue A , Saijo Y , Kikuchi T , Gomi K , Suzuki T , Maemondo M , et al. Pharmacokinetic analysis of combination chemotherapy with carboplatin and etoposide in small‐cell lung cancer patients undergoing hemodialysis. Ann Oncol. 2004;15 :51–4. 10.1093/annonc/mdh008 14679119\n3 Takezawa K , Okamoto I , Fukuoka M , Nakagawa K . Pharmacokinetic analysis of carboplatin and etoposide in a small cell lung cancer patient undergoing hemodialysis. J Thorac Oncol. 2008;3 :1073–5. 10.1097/JTO.0b013e318183af89 18758316\n4 Jain J , Stein J , Garje R . Evaluation of checkpoint inhibitors in cancer patients with end‐stage renal disease on hemodialysis: case series and review of the literature. J Immunother. 2020;43 :244–9. 10.1097/CJI.0000000000000327 32898386\n5 Imaji M , Fujimoto D , Kato M , Tanaka M , Furuta K , Yamamoto N . Chemotherapy plus atezolizumab for a patient with small cell lung cancer under haemodialysis: a case report and review of literature. Respirol Case Rep. 2021;9 :e00741. 10.1002/rcr2.741 33777399\n6 Kato S , Chmielewski M , Honda H , et al. Aspects of immune dysfunction in end‐stage renal disease. Clin J Am Soc Nephrol. 2008;3 :1526–33. 10.2215/CJN.00950208 18701615\n7 Zhao B , Zhao H , Zhao J . Efficacy of PD‐1/PD‐L1 blockade monotherapy in clinical trials. Ther Adv Med Oncol. 2020;12 :1–22. 10.1177/1758835920937612\n8 Chan KK , Bass AR . Autoimmune complications of immunotherapy: pathophysiology and management. BMJ. 2020;369 :m736. 10.1136/bmj.m736 32253223\n9 Hall KH , Liu Y , Jiang C , Harvey RD . New and worsening long‐term immune‐related adverse events with PD‐1/PD‐L1 pathway agents in patients with cancer. Pharmacotherapy. 2020;40 :133–41. 10.1002/phar.2354 31863604\n10 Centanni M , Moes DJAR , Trocóniz IF , Ciccolini J , van Hasselt JGC . Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet. 2019;58 :835–57. 10.1007/s40262-019-00748-2 30815848\n\n",
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"issue": "12(21)",
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"medline_ta": "Thorac Cancer",
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"title": "Tolerability and efficacy of IMpower133 regimen modified for dialysis patients with extensive-stage small cell lung cancer: Two case reports.",
"title_normalized": "tolerability and efficacy of impower133 regimen modified for dialysis patients with extensive stage small cell lung cancer two case reports"
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"abstract": "We describe the successful pediatric liver transplant for unresectable hepatoblastoma in a 4-year-old male with COVID-19 prior to transplant. The first negative NP swab was documented 1 month after initial diagnosis, when SARS-CoV-2 antibodies were also detected. The patient was actively listed for liver transplant after completing four blocks of a SIOPEL-4 based regimen due to his PRETEXT IV disease which remained unresectable. Following three additional negative NP swabs and resolution of symptoms for 4 weeks, he underwent a whole-organ pediatric liver transplant. COVID-19 positivity determined via NP swab SARS-CoV-2 real-time RT-PCR (Hologic Aptima SARS-CoV-2 RT-PCR assay). IgG and IgM total SARS- CoV-2 antibodies detected by Ortho Clinical Diagnostics VITROS® Immunodiagnostics Products Anti-SARS-CoV-2 Test. Patient received standard prednisone and tacrolimus-based immunosuppression without induction therapy following transplant. Post-transplant course was remarkable for neutropenia and thrombocytopenia, with discharge home on post-transplant day #11. Surveillance tests have remained negative with persistent SARS-CoV-2 IgG antibodies at 6 weeks after transplant. We describe one of the earliest, if not the first case of liver transplant following recent recovery from COVID-19 in a pediatric patient with a lethal malignant liver tumor. A better understanding of how to balance the risk profile of transplant in the setting of COVID-19 with disease progression if transplant is not performed is needed. We followed existing ASTS guidelines to document clearance of the viral infection and resolution of symptoms before transplant. This case highlights that pediatric liver transplantation can be safely performed upon clearance of COVID-19.",
"affiliations": "McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.;Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.;Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.;Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.;Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.;Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.;Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.;McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.;Division of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.;Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.;Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.",
"authors": "Goss|Matthew B|MB|0000-0003-4663-0086;Munoz|Flor M|FM|;Ruan|Wenly|W|;Galván|N Thao N|NTN|;O'Mahony|Christine A|CA|;Rana|Abbas|A|0000-0003-2979-0598;Cotton|Ronald T|RT|;Moreno|Nicolas F|NF|0000-0001-8661-676X;Heczey|Andras A|AA|;Leung|Daniel H|DH|;Goss|John A|JA|",
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"keywords": "hepatoblastoma; pediatric liver transplantation; viral infection",
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"mesh_terms": "D000086382:COVID-19; D000086742:COVID-19 Testing; D002675:Child, Preschool; D018450:Disease Progression; D018197:Hepatoblastoma; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D009503:Neutropenia; D011241:Prednisone; D016559:Tacrolimus; D013921:Thrombocytopenia; D016896:Treatment Outcome",
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"title": "Liver transplant in a recently COVID-19 positive child with hepatoblastoma.",
"title_normalized": "liver transplant in a recently covid 19 positive child with hepatoblastoma"
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"abstract": "We report on a case of fetal toxicity due to maternal treatment with olmesartan medoxomil. At 29 weeks' gestation, oligohydramnios was found, although the fetus had normal kidneys on ultrasound evaluation. Withdrawal of olmesartan medoxomil, maternal rehydration, and a single dose of furosemide reversed the renal impairment. After term delivery, the neonate was confirmed to have normal renal function. The case suggested that fetal renal impairment due to olmesartan medoxomil may be reversible.",
"affiliations": "Department of Obstetrics and Gynecology, University of Chieti, Via Sandro Pertini, 4, 65129, Pescara, Italy. ccelen@tin.it",
"authors": "Celentano|Claudio|C|;Prefumo|Federico|F|;di Vera|Elena|E|;Iannicco|Annamaria|A|;Gallo|Davide Pio|DP|;Liberati|Marco|M|",
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"title": "Reversible acute fetal renal failure due to maternal exposure to angiotensin receptor blocker.",
"title_normalized": "reversible acute fetal renal failure due to maternal exposure to angiotensin receptor blocker"
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"abstract": "A dobutamine stress echocardiogram was performed in a 72-year-old woman to assess an intermediate lesion in the left anterior descending artery. After administration of the echocardiography contrast agent, she presented with an anaphylactic reaction and in that context a subacute thrombosis of a drug-eluting stent implanted 15 days before. This is a case of the so-called type III Kounis syndrome.",
"affiliations": "Cardiology Department, University General Hospital of Albacete, Spain.;Cardiology Department, University General Hospital of Albacete, Spain.;Cardiology Department, University General Hospital of Albacete, Spain.",
"authors": "Portero-Portaz|Juan Jose|JJ|;Córdoba-Soriano|Juan Gabriel|JG|;Gallego-Page|Juan Carlos|JC|",
"chemical_list": "D003287:Contrast Media; D013459:Sulfur Hexafluoride",
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"mesh_terms": "D000368:Aged; D003287:Contrast Media; D017023:Coronary Angiography; D004452:Echocardiography; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D000074962:Kounis Syndrome; D000072657:ST Elevation Myocardial Infarction; D013459:Sulfur Hexafluoride; D041623:Tomography, Optical Coherence",
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"title": "Type III Kounis syndrome after administration of an echocardiography contrast agent.",
"title_normalized": "type iii kounis syndrome after administration of an echocardiography contrast agent"
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"abstract": "Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is caused by either a quantitative and/or qualitative defect of the multimeric glycoprotein vonWillebrand factor (VWF).[...].",
"affiliations": "UOSD Microcitemie-Emostasi e Trombosi, Grande Ospedale Metropolitano \"Bianchi-Melacrino Morelli\" Reggio Calabria, Reggio Calabria 89100, Italy. gianluca.sottilotta@virgilio.it.;UOSD Microcitemie-Emostasi e Trombosi, Grande Ospedale Metropolitano \"Bianchi-Melacrino Morelli\" Reggio Calabria, Reggio Calabria 89100, Italy. francescaluise@alice.it.;UOSD Microcitemie-Emostasi e Trombosi, Grande Ospedale Metropolitano \"Bianchi-Melacrino Morelli\" Reggio Calabria, Reggio Calabria 89100, Italy. elisabetta.massara@gmail.com.;UOSD Microcitemie-Emostasi e Trombosi, Grande Ospedale Metropolitano \"Bianchi-Melacrino Morelli\" Reggio Calabria, Reggio Calabria 89100, Italy. voriana@libero.it.;UOSD Microcitemie-Emostasi e Trombosi, Grande Ospedale Metropolitano \"Bianchi-Melacrino Morelli\" Reggio Calabria, Reggio Calabria 89100, Italy. a.piromalli@alice.it.",
"authors": "Sottilotta|Gianluca|G|;Luise|Francesca|F|;Massara|Elisabetta|E|;Oriana|Vincenzo|V|;Piromalli|Angela|A|",
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"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm6090085jcm-06-00085Case ReportEfficacy of Octocog Alfa (Advate) in a Child with Type 3 von Willebrand Disease and Alloantibodies Sottilotta Gianluca *Luise Francesca Massara Elisabetta Oriana Vincenzo Piromalli Angela Rubnitz Jeffrey E. Academic EditorUOSD Microcitemie–Emostasi e Trombosi, Grande Ospedale Metropolitano “Bianchi-Melacrino Morelli” Reggio Calabria, Reggio Calabria 89100, Italy; francescaluise@alice.it (F.L.); elisabetta.massara@gmail.com (E.M.); voriana@libero.it (V.O.); a.piromalli@alice.it (A.P.)* Correspondence: gianluca.sottilotta@virgilio.it; Tel.: +39-0965-39384118 9 2017 9 2017 6 9 8516 7 2017 12 9 2017 © 2017 by the authors.2017Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\n==== Body\n1. Introduction\nVon Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is caused by either a quantitative and/or qualitative defect of the multimeric glycoprotein von Willebrand factor (VWF). The revised classification identifies VWD Type 1 and Type 3 characterized by quantitative VWF defects, and the VWD Type 2 characterized by qualitative VWF defects [1]. Approximately 70% of patients have Type 1, usually associated with a mild bleeding history characterized by prolonged oozing after minor and major surgery and by mucosal tract hemorrhages such as epistaxis and menorrhagia. Twenty to twenty-five percent of patients have Type 2, characterized by frequent bleeding episodes in the mucosal tract and rarely soft tissue hemorrhages because patients have relatively high levels of Factor VIII (FVIII). VWD Type 3 involves a virtually complete quantitative VWF deficiency. Its inheritance is autosomal recessive, and is the result of the inheritance of two null alleles. The prevalence of Type 3 is relatively low, with 0.5–1 cases per million in the general population [2]. Patients with VWD Type 3—the most severe form—are characterized by a severe quantitative defect and very low levels of both VWF and FVIII, and are clinically characterized by excessive mucocutaneous bleeding as well as musculoskeletal bleeding such as muscle hematomas and hemarthroses [3]. In VWD, the aim of therapy is to correct the dual defect of haemostasis; i.e., the abnormal platelet adhesion—aggregation and the abnormal intrinsic coagulation due to low FVIII levels. The mainstays of treatment are autologous replacement therapy with desmopressin and allogenic replacement therapy with VWF/FVIII or VWF concentrates devoid of FVIII. Desmopressin is not an effective treatment for all VWD patients. There are also adjuvant therapies with antifibrinolytic amino acids such as tranexamic acid and epsilon aminocaproic acid, which improve haemostasis without affecting plasma VWF levels [4]. Anti-VWF alloantibodies develop after multiple infusions in 10% to 15% of patients with Type 3 VWD, in whom subsequent treatment with VWF concentrates is not only ineffective, but may cause post-infusion severe allergic reactions like abdominal pain, lumbar pain, hypotension, and anaphylactic shock, because of the formation of immune complexes that activate the complement system. These reactions may be life-threatening [5]. In contrast to FVIII antibodies, because assays for anti-VWF antibodies are not standardized, they can be difficult to measure. Treatment of patients with anti-VWF alloantibodies can be quite challenging, as experience in managing these patients is limited. Good hemostasis has been reported with the use of recombinant FVIII (rFVIII) [6]: despite the shortened half-life of FVIII in the absence of its stabilizer, VWF, high-dose infusions of rFVIII can maintain hemostatic levels of FVIII. Successful immune tolerance induction (ITI) similar to that seen in patients with inhibitors of FVIII has been reported; however, because of the lack of experience in VWD, whether or not ITI is safe or effective in all patients with anti-VWF antibodies remains to be seen [7]. Bypassing agents such as recombinant factor VIIa (rFVIIa) has been successful with either bolus dosing or continuous infusion [8]. Platelet concentrates can be considered as additional treatment options [9].\n\n2. Case Presentation\nWe report the case of an 18-month-old boy affected by VWD Type 3 who developed anti-VWF alloantibodies.\n\nFrequent bruising of the skin appeared since birth. At the age of two months, because of a left facial hematoma, he was subjected to radiological investigations that led to the diagnosis of a cystic ameloblastoma—a benign odontogenic tumor present in his left jaw bone. The diagnosis of ameloblastoma and the following surgical intervention were performed in another hospital before the diagnosis of VWD, because of the difficulty in having a quick assay of the coagulation factors whose deficiency could explain the prolonged activated partial thromboplastin time (aPTT) evidenced in the pre-operative blood testing. Fresh frozen plasma (FFP) was infused before the surgery, with a partial success in terms of anti-hemorrhagic efficacy because of a temporary bleeding from the surgical wound after two days. The diagnosis of VWD Type 3 was performed after surgery; the results evidenced FVIII: 3.5%, VWF Antigen (VWF:Ag): 2%, VWF Ristocetin Cofactor (VWF:RCo): 10%. An on-demand treatment with Talate (Human Coagulation Factor VIII, Human Von Willebrand Factor, Baxalta) was prescribed, but during the following months, the child was only treated with Ugurol (Tranexamic Acid, Rottapharm) 25 mL/kg administered orally when necessary, because of the absence of significant clinical bleedings. \n\nAfter several months, the child was hospitalized due to a palate bleeding after an injury; infusions of Talate (100 UI/kg) every 24 h were administered until hemorrhage stopped, then the patient was discharged with a prescription of Ugurol three times per day orally. After a week, the child was treated with Talate 100 UI/kg at home for a prolonged oral bleeding due a dental eruption: at the end of the infusion, onset of pallor, cyanosis, weakness, tremor, and hyperpyrexia occurred. These symptoms lasted about 10 min, and then disappeared. The following day after symptom onset, the patient underwent blood tests at our centre for dosing factors and anti-VWF alloantibodies. The exams performed 12 h after the infusion revealed the presence of anti-VWF antibodies: Anti VWF:Ag: 15.6 Bethesda Units (B.U.), Anti VWF:RCo 30.4 B.U., and low levels of FVIII and VWF (FVIII: 5.7%, VWF:Ag: 0%, VWF:RCo: 11%). A week later, the patient had a gingival bleeding: Novoseven (Activated Eptacog Alfa, Novonordisk) 100 mcg/kg every 2 h was started at home, but because the first infusion of Novoseven was not effective the child was also hospitalized because of severe bleeding. Blood tests showed a low hemoglobin (Hb) level (6 g/dL); the child was treated with red blood cell (RBC) transfusions, washed to remove the traces of VWF in order to avoid an anamnestic response; Novoseven 100 mcg/kg every two hours was continued for 24 h, but symptoms worsened with the onset of hematemesis and melena: because Hb level was 4.5 g/dL, additional RBC transfusions were administered. The therapy with Novoseven was stopped due to inefficacy and replaced with Octocog Alfa (Advate, Shire), a third-generation plasma/albumin-free rFVIII. It was started with a bolus of 100 IU/kg followed by continuous infusion at 50 IU/h. At the same time, intravenous omeprazole as gastroprotective and Ugurol by continuous infusion at 4 mL/h were started.\n\nThe first bolus of rFVIII stopped the gingival bleeding temporarily, but it started again as slow oozing after about two hours and continued throughout the first day of continuous infusion with Advate. The observation of short interruption of bleeding following the Octacog bolus led to the decision to change the mode of administration: we suspended the continuous infusion and started the administration of 100 IU/kg boluses every 6 h. After this therapeutic change, the bleeding stopped definitely. After two days without hemorrhages, the frequency of the boluses was reduced to every 8 h for the first day, then to every 12 h for another day, then it was discontinued. The day after Advate discontinuation, a coagulation assay was performed: results were FVIII: 3.5% VWF:Ag: 0%, VWF:RCo: 11%, Anti VWF:Ag: 3 B.U., Anti VWF:RCo: 5.4 B.U. The infusion of Ugurol was continued without any changes until complete discontinuation of Advate suspension, and then it was administered orally at 25 mg/kg every 8 h: the same therapy was prescribed after hospital discharge for the prevention of further gingival bleedings due to dental eruptions.\n\n3. Discussion\nAlloantibodies against VWF may develop in approximately 10% of patients suffering from VWD Type 3 who underwent multiple transfusions and especially in carriers of large deletions of the VWF gene. Because of severe anaphylactic life-threatening reactions, the use of concentrates rich in VWF is contraindicated in these patients [10]. In literature, clinical experience on the therapeutic management of this disease is limited [11]: some authors have described the clinical efficacy of rFVIII concentrates, and they also reported an allergic reaction after a first-generation rFVIII bolus, probably due to the presence of VWF traces. Novoseven has been used successfully in the management of bleeding [12], as intermittent bolus or as continuous infusion, at the same doses used in patients with severe haemophilia A and anti-FVIII inhibitor; in our case, however, the treatment with recombinant activated factor VII did not prove effective. Neither did the continuous infusion of rFVIII demonstrate a persistent anti-hemorrhagic action, probably because the FVIII levels were not sufficient to maintain the minimum haemostatic threshold.\n\nTherefore, after the observation of the temporary interruption of the gingival bleeding, due to the initial bolus of rFVIII, we decided to treat the patient with boluses of rFVIII only; this choice has proven effective and lasting. \n\n4. Conclusions\nOur experience shows the efficacy of Advate in the on-demand treatment of VWD Type 3 and inhibitor. The effectiveness of the rFVIII in our case is based on the temporary increase in FVIII levels. The difficult patient’s venous access due to the age did not allow us to test the FVIII levels after each rFVIII infusion, which would be useful in determining the frequency of administration. To date, there are no retrospective or prospective studies on the treatment of patients with VWD Type 3 and inhibitor: available data is derived from individual experiences described in few case reports only. Appropriate registers can contribute in the future to further improve the knowledge on this VWD complication and to establish appropriate treatment guidelines.\n\nAuthor Contributions\nAll the authors were responsible for data collection and contributed to the drafting and final revisions of the manuscript\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1. James P.D. Lillicrap D. Mannucci P.M. Alloantibodies in von Willebrand disease Blood 2013 122 636 640 23297130 \n2. Sadler J.E. A revised classification of von Willebrand disease Thromb. Haemost. 1994 71 520 525 8052974 \n3. Borel-Derlon A. Federici A.B. Roussel-Robert V. Goudemand J. Lee C.A. Scharrer I. Rothschild C. Berntorp E. Henriet C. Tellier Z. Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin® ): A prospective study of 50 patients J. Thromb. Haemost. 2007 5 1115 1124 17403090 \n4. Mannucci P.M. Franchini M. Castaman G. Federici A.B. Italian Association of Hemophilia Centers. Evidence-based recommendations on the treatment of von Willebrand disease in Italy Blood Transfus. 2009 7 117 126 19503633 \n5. Mannucci P.M. How I treat patients with von Willebrand disease Blood 2001 97 1915 1919 11264151 \n6. Federici A.B. Castaman G. Mannucci P.M. Italian Association of Hemophilia Centers (AICE) Guidelines for the diagnosis and management of von Willebrand disease in Italy Haemophilia 2002 8 607 621 12199668 \n7. Pergantou H. Xafaki P. Adamtziki E. Koletsi P. Komitopoulou A. Platokouki H. The challenging management of a child with Type 3 von Willebrand disease and antibodies to von Willebrand factor Haemophilia 2012 18 e66 e67 22531022 \n8. Ciavarella N. Schiavoni M. Valenzano E. Mangini F. Inchingolo F. Use of recombinant factor VIIa (NovoSeven) in the treatment of two patients with Type III von Willebrand’s disease and an inhibitor against von Willebrand factor Haemostasis 1996 26 150 154 8904191 \n9. Castaman G. Goodeve A. Eikenboom J. European Group on von Willebrand Disease Principles of care for the diagnosis and treatment of von Willebrand disease Haematologica 2013 98 667 674 23633542 \n10. Bergamaschini L. Mannucci P.M. Federici A.B. Coppola R. Guzzoni S. Agostoni A. Posttransfusional anaphylactic reactions in a patient with severe von Willebrand disease: Role of complement and alloantibodies to von Willebrand Factor J. Lab. Clin. Med. 1995 125 348 355 7897302 \n11. Boyer-Neumann C. Dreyfus M. Wolf M. Veyradier A. Meyer D. Multi-therapeutic approach to manage delivery in an alloimmunized patient with Type 3 von Willebrand disease J. Thromb. Haemost. 2003 1 190 191 12871560 \n12. Grossmann R.E. Geisen U. Schwender S. Keller F. Continuous infusion of recombinant factor VIIa (NovoSeven) in the treatment of a patient with Type III von Willebrand’s disease and alloantibodies against von Willebrand factor Thromb. Haemost. 2000 83 633 634 10780333\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "6(9)",
"journal": "Journal of clinical medicine",
"keywords": null,
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28926986",
"pubdate": "2017-09-18",
"publication_types": "D002363:Case Reports",
"references": "8052974;12871560;7897302;23633542;10780333;11264151;19503633;8904191;23297130;22531022;12199668;17403090",
"title": "Efficacy of Octocog Alfa (Advate) in a Child with Type 3 von Willebrand Disease and Alloantibodies.",
"title_normalized": "efficacy of octocog alfa advate in a child with type 3 von willebrand disease and alloantibodies"
} | [
{
"companynumb": "IT-NOVOPROD-569971",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "COAGULATION FACTOR VIIA RECOMBINANT HUMAN"
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{
"abstract": "OBJECTIVE\nPhenytoin is known to be able to induce cerebellar atrophy in patients with epilepsy. It is also known that a CYP2C9 mutation (*2 or *3) reduces phenytoin metabolism by 25-50% and can increase the risk of phenytoin-related side effects. We examined the influence of CYP2C9 polymorphisms on total cerebellar volume and cerebellar gray and white matter volumes in patients with epilepsy taking phenytoin.\n\n\nMETHODS\nFor the genotyping, 100 adult patients with documented epilepsy who had been taking phenytoin for >1 year were selected. From this group, we randomly selected 19 mutant individuals (MT group; CYP2C9*2 and *3) for a whole-brain volume measurement using MRI and 19 wild-type individuals (group WT; CYP2C9*1) with similar clinical and demographic characteristics to those in the MT group for comparison. Total intracranial volume measurements were used to normalize the acquired volumes, which were separated into gray matter volume, white matter volume, and total volume.\n\n\nRESULTS\nThe MT group exhibited a significant reduction in cerebellar white matter volume (p=0.002) but not in total cerebellar volume.\n\n\nCONCLUSIONS\nOur study is the first to report evidence linking CYP2C9 polymorphism and a reduction in cerebellar volume in epileptic users of phenytoin.",
"affiliations": "Neurology Service and Molecular Biology Laboratory, Hospital de Clínicas, Universidade Federal do Paraná, Brazil.",
"authors": "Twardowschy|Carlos A|CA|;Werneck|Lineu C|LC|;Scola|Rosana H|RH|;Borgio|João G|JG|;De Paola|Luciano|L|;Silvado|Carlos|C|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "22(3)",
"journal": "Seizure",
"keywords": null,
"medline_ta": "Seizure",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000927:Anticonvulsants; D001189:Aryl Hydrocarbon Hydroxylases; D001284:Atrophy; D002526:Cerebellar Diseases; D065729:Cytochrome P-450 CYP2C9; D004827:Epilepsy; D005260:Female; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin; D020641:Polymorphism, Single Nucleotide",
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "194-7",
"pmc": null,
"pmid": "23298603",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The role of CYP2C9 polymorphisms in phenytoin-related cerebellar atrophy.",
"title_normalized": "the role of cyp2c9 polymorphisms in phenytoin related cerebellar atrophy"
} | [
{
"companynumb": "BR-PFIZER INC-2015234371",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
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{
"actiondrug": "5",
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"activesubstancename": "PHENYTOIN"
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... |
{
"abstract": "OBJECTIVE\nThe present study aims to prospectively evaluate quality of life (QoL) of women using 52-mg levonorgestrel intrauterine system (LNG-IUS) for contraception determined through the Sociedad Española de Contracepción (Spanish contraception Society) (SEC)-QoL, a questionnaire specifically designed to assess the impact of contraceptive methods on QoL of fertile women.\n\n\nMETHODS\nWe conducted a prospective observational multicenter study of 201 reproductive age women who initiated the LNG-IUS for contraception. Sociodemographic and clinical data were collected at baseline and 12 months afterwards. Participants filled in the SEC-QoL questionnaire at both visits. SEQ-QoL scores range from 0 (worst QoL) to 100 (best QoL).\n\n\nRESULTS\nParticipants claimed an increased QoL 12 months after insertion in all five dimensions of SEC-QoL due to its high contraceptive efficacy and its capability to reduce other menstrual symptoms (e.g., heavy menstrual bleeding or dysmenorrhoea), overall exerting a positive impact on user's satisfaction. SEC-QoL general overall score went from a mean (S.D.) score of 46.3 (17.3) at baseline to 72.2 (14.8) 12 months afterwards (p<.001). Overall, 94.6% of women claimed having found additional benefits other than contraception. No pregnancies were reported during the 12 months of study duration, and only 14 women discontinued use of LNG-IUS (only two of them due to an adverse event), representing a continuation rate of 93%.\n\n\nCONCLUSIONS\nWomen using LNG-IUS for contraception have an increased QoL after 12 months of use, demonstrated by the increased score in all dimensions of the SEC-QoL questionnaire.\n\n\nCONCLUSIONS\nThe present study prospectively evaluated QoL of women using LNG-IUS for contraception through the SEC-QoL questionnaire. Participants claimed increased QoL 12 months afterwards, implying that women using LNG-IUS for contraception in usual clinical practise also benefit from the reduction of period-related symptoms, overall leading to very low discontinuation rates.",
"affiliations": "Obstetrics and Gynaecology, Hospital La Zarzuela Madrid, Universidad Francisco de Vitoria, C/Pleyades, 25, 28023, Madrid, Spain. Electronic address: icristobalg@sego.es.;Obstetrics and Gynaecology, University Hospital Araba, School of Medicine, Basque Country University, 01009, Vitoria, C/Jose Atxotegi, s/n, 01009, Vitoria-Gasteiz, Álava, Araba, Spain. Electronic address: Luisignacio.letelasa@osakidetza.net.;Obstetrics and Gynaecology, Hospital de Guadalajara, School of Medicine and Health Science, Alcala University, Guadalajara, C/Donante de Sangre, s/n, 19002, Guadalajara, Spain. Electronic address: edelaviuda@sego.es.;Health Economics and Outcomes Research Real World Evidence Solutions, IMS Health, C/Dr Ferran, 25-27, 08020, Barcelona, Spain. Electronic address: nperulero@es.imshealth.com.;Medical Department, Bayer Hispania, Avda. Baix Llobregat 3-5, 08970, Sant Joan Despí, Spain. Electronic address: agnes.arbat@bayer.com.;Medical Department, Bayer Hispania, Avda. Baix Llobregat 3-5, 08970, Sant Joan Despí, Spain. Electronic address: ignasi.canals@bayer.com.",
"authors": "Cristobal|Ignacio|I|;Lete|Luis Ignacio|LI|;Viuda|Esther de la|E|;Perulero|Nuria|N|;Arbat|Agnes|A|;Canals|Ignasi|I|",
"chemical_list": "D003271:Contraceptive Agents, Female; D016912:Levonorgestrel",
"country": "United States",
"delete": false,
"doi": "10.1016/j.contraception.2015.12.014",
"fulltext": null,
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"issn_linking": "0010-7824",
"issue": "93(4)",
"journal": "Contraception",
"keywords": "Contraception; Intrauterine system; Levonorgestrel; Quality of life; SEQ-QoL questionnaire",
"medline_ta": "Contraception",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003267:Contraception; D003271:Contraceptive Agents, Female; D005260:Female; D006801:Humans; D007436:Intrauterine Devices, Medicated; D016912:Levonorgestrel; D008595:Menorrhagia; D008875:Middle Aged; D017060:Patient Satisfaction; D011446:Prospective Studies; D011788:Quality of Life; D013030:Spain; D011795:Surveys and Questionnaires",
"nlm_unique_id": "0234361",
"other_id": null,
"pages": "367-371",
"pmc": null,
"pmid": "26764120",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "One year quality of life measured with SEC-QoL in levonorgestrel 52 mg IUS users.",
"title_normalized": "one year quality of life measured with sec qol in levonorgestrel 52 mg ius users"
} | [
{
"companynumb": "ES-MYLANLABS-2018M1030376",
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"occurcountry": "ES",
"patient": {
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
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"drugadditional": null,
... |
{
"abstract": "We present a case of a patient with treatment resistant hallucinatory experiences with incidental finding of an arachnoid cyst localized in the posterior infratentorial cranial fossa dorsally to the cerebellum. Psychological testing revealed significant deficit of cognitive functions to the level of mild intellectual disability in a person that had previously finished high school with good grades. A combination of clozapine and lamotrigine led to significant improvement in mood and reduction of hallucinations, but without improvement in cognitive functions. We also performed a literature review of previously published case reports or case series of co-occurring posterior fossa arachnoid cyst and schizophrenia or psychosis or psychiatric symptoms using PubMed search and discuss some controversies considering their treatment outcome.",
"affiliations": "1Department of Psychiatry, Dr. Ivan Barbot Neuropsychiatric Hospital, Popovača, Croatia; 2Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia.;1Department of Psychiatry, Dr. Ivan Barbot Neuropsychiatric Hospital, Popovača, Croatia; 2Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia.;1Department of Psychiatry, Dr. Ivan Barbot Neuropsychiatric Hospital, Popovača, Croatia; 2Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia.;1Department of Psychiatry, Dr. Ivan Barbot Neuropsychiatric Hospital, Popovača, Croatia; 2Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia.",
"authors": "Škarić|Maja|M|;Aukst Margetić|Branka|B|;Bogović Dijaković|Anamarija|A|;Karlović|Dalibor|D|",
"chemical_list": null,
"country": "Croatia",
"delete": false,
"doi": "10.20471/acc.2021.60.02.18",
"fulltext": "\n==== Front\nActa Clin Croat\nActa Clin Croat\nACC\nActa Clinica Croatica\n0353-9466\n1333-9451\nSestre Milosrdnice University Hospital and Institute of Clinical Medical Research, Vinogradska cesta c. 29 Zagreb\n\nacc-60-304\n10.20471/acc.2021.60.02.18\nCase Reports\nCOGNITIVE AND PSYCHOTIC SYMPTOMS IN A PATIENT WITH INFRATENTORIAL ARACHNOID CYST: CASE REPORT\nŠkarić Maja 1\nAukst Margetić Branka 2\nBogović Dijaković Anamarija 2\nKarlović Dalibor 2\n1Department of Psychiatry, Dr. Ivan Barbot Neuropsychiatric Hospital, Popovača, Croatia; 2Department of Psychiatry, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia\nCorrespondence to: Maja Škarić, MD, Davorina Jeića 2, HR-10040 Zagreb, Croatia, E-mail: maja.skaric@gmail.com\n6 2021\n6 2021\n60 2 304308\n15 10 2019\n20 8 2020\n2021\nSestre Milosrdnice University Hospital\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) 4.0 License.\nSUMMARY\n\nWe present a case of a patient with treatment resistant hallucinatory experiences with incidental finding of an arachnoid cyst localized in the posterior infratentorial cranial fossa dorsally to the cerebellum. Psychological testing revealed significant deficit of cognitive functions to the level of mild intellectual disability in a person that had previously finished high school with good grades. A combination of clozapine and lamotrigine led to significant improvement in mood and reduction of hallucinations, but without improvement in cognitive functions. We also performed a literature review of previously published case reports or case series of co-occurring posterior fossa arachnoid cyst and schizophrenia or psychosis or psychiatric symptoms using PubMed search and discuss some controversies considering their treatment outcome.\n\nKey words:\n\nArachnoid cyst\nCognitive disorder\nPsychotic symptoms\n==== Body\npmcIntroduction\n\nArachnoid cysts are benign lesions formed by arachnoid membrane filled with liquid similar to cerebrospinal fluid. Their prevalence goes to 1.4%, it is higher in male gender, and their detection is usually incidental. The most common location is middle fossa, followed by retrocerebellar and convexity (1). It appears that symptoms caused by an arachnoid cyst depend on the intracystic pressure, where high intracystic pressure had a significantly higher preoperative level of complaints (2). Functional imaging has shown that arachnoid cysts may cause reorganization of cortical functions and reduced cortical thickness of neighboring cortices (3). It has been reported that arachnoid cyst reduces perfusion and metabolism in the surrounding cortical regions (4, 5). The reports published so far do suggest that arachnoid cyst may affect mental functions (6, 7), such as affective disorders (8), psychotic symptoms in the form of hallucinations and delusions (9, 10), and even aggression and homicide (11). Dyscognition as a symptom has been described in several case reports on arachnoid cyst patients. In recent years, increasing attention is paid to cognitive disorders accompanying arachnoid cysts (12-15). Psychiatric symptoms and dyscognition usually are not an indication for neurosurgical intervention. However, there are reports that describe normalized mental functions after surgical cyst decompression (12-15). The aim of this case report is to describe a patient with a rare location of arachnoid cyst, presented with isolated imperative hallucinations of compulsory nature, and to discuss his treatment, as well as the potential treatment approaches.\n\nCase Report\n\nA 22-year-old male Caucasian was admitted to day hospital treatment for complaining of imperative auditory hallucinations as an isolated psychotic symptom. Three years before, he started to hear unknown voice in his head telling him to check if the water was leaking. He knew that it was not real but still had to do it. He felt that the voice was coming ‘from his small brain’, and that ‘in his head he was not himself’. The patient was born at term but was small for gestational age, birth weight of only 1900 g due to maternal hypertension during pregnancy. For a short time, he was treated in the neonatal intensive care unit. His development during the first year of life was checked with brain ultrasound, his further development was regularly checked and evaluated as normal. He graduated from primary and high school with good grades. His symptoms started in the last year of high school and coincided with death of his grandmother he was closely bonded to. He was described by his parents as timid and shy, having few friends. After finishing high school he started to work as a waiter but three months later quit his job because it was too stressful. Later he did not search for new employment. There was no known family history of a psychiatric disorder. Ten months before admission to the hospital, he started outpatient psychiatric treatment during which he received different psychopharmaceuticals (olanzapine 10 mg/d for three months, later switched to a combination of risperidone 4 mg/d, fluvoxamine 100 mg/d for another three months, later switched to a combination of vortioxetin 10 mg/d and aripiprazole 30 mg/d), all with no improvement. Upon admission to the hospital, he underwent psychological testing and magnetic resonance imaging (MRI) of the brain. Physical and neurological examination showed no abnormalities. Visual, auditory and somatosensory evoked potentials, as well as examination of the fundus oculi revealed no pathology. Psychological testing (BETA-II, WMS, Cornell index, WDCT, mosaic test, WCST) revealed deficit in logical thinking, learning ability and mental control, as well as impairment in executive functions. His intellectual efficacy, psychomotor speed and memorizing ability were decreased to the level of mild intellectual disability, and his concrete and abstract thinking to the level of moderate intellectual disability. At admission, his psychopathology was evaluated with Positive and Negative Syndrome Scale (PANSS) and scored 86, while Calgary Depression Scale showed a score of 7 points. MRI (2.0 T) of his central nervous system showed an arachnoid cyst in the posterior cranial fossa, infratentorial dorsally to the cerebellum, 6.3x5.9x4.4 cm in size (Fig. 1). Regular neurosurgery follow-up was recommended. The administration of clozapine 125 mg/day, lamotrigine 100 mg/day and diazepam 5 mg/day led to gradual but significant improvement of mood and reduction of hallucinations. On follow-up examination three months after treatment initiation, the patient reported the voice appearing from time to time, about three to four times a week, lasting for 10-15 minutes, he was less emotionally engaged about it and could disregard it almost completely. The PANSS decreased to 55 and Calgary Depression Scale to 0. He was more engaged in social contacts and worked in family business. At nine-month follow-up evaluation, the PANSS decreased to 52 and Calgary Depression Scale score was 0. The frequency of voice appearing decreased further to three to four times a week, lasting for a few minutes, and he could disregard the voices completely. Psychological testing (BETA-II, WMS, Cornell index, mosaic test) was repeated after 9 months and showed some improvement in mental control and concrete and abstract thinking; other findings where the same as before.\n\nFig. 1 Magnetic resonance image (2.0 T) of the arachnoid cyst (6.3x5.9x4.4 cm in size) in the posterior cranial fossa.\n\nDiscussion\n\nFor many years, the basis for a whole palette of schizophrenia spectrum symptoms has been associated with supratentorial structures. However, newer findings suggest an important role of cerebellum in their development (16). In other words, in a patient suffering from schizophrenia, error detection task of the cerebellum is impaired, so an auditory signal arising from the auditory cortex without an external stimulus is misinterpreted and experienced as auditory hallucination. Also, the importance of the right cerebellum in language processing has been shown by previous studies. Structural MRI study in patients with treatment resistant auditory verbal hallucinations has shown decreased gray matter volume in the right cerebellar hemisphere in the regions involved in different cognitive and language processes (17). Our patient described hearing a voice with a quality of imperative auditory hallucination (to check if the water was leaking) and although he had an insight, he could not resist obeying the command. It is possible that the patient’s cerebellar lesion was superimposed on an underlying psychiatric disorder and that the brain lesion was an incidental finding without functional importance. However, we cannot exclude the possibility that the arachnoid cyst located dorsally to the cerebellum caused thinning of the adjacent cortex and reorganization of cortical functions (3). So, it is possible to assume that pressure from the cyst may have caused malfunction of the cerebellum error detection task, which led to his experience of auditory hallucination. In addition, when the cerebellum fails to perform its error detection function, cognitive impairment is present (16). Our patient’s intellectual efficacy and psychomotor speed were reduced to the level of mild intellectual disability with concrete and abstract thinking at the level of moderate intellectual disability. One might assume that a person with such cognitive abilities would not be able to finish primary and high school with moderately good grades. So, we may presume that cognitive deficit was the result of cyst enlargement and that during his years of schooling the cyst was smaller and did not cause any pressure on the surroundings, and therefore his cognitive symptoms where not present or at least not to such an extent. There is evidence that cysts may grow considerably in childhood, thus indicating an increasing intracystic pressure over time (18). The association between arachnoid cysts at this localization and psychotic symptoms is poorly researched. We performed Medline search using the terms “arachnoid cyst” and “posterior fossa” or “cerebellar” and “schizophrenia”, “psychiatric symptom” or “psychosis”. Results are shown in Table 1. The issue of neurosurgical treatment of cysts is still debated among neurosurgeons, especially when they are asymptomatic in terms of neurological symptoms. Nevertheless, evidence on the normalization of mental functions has been reported in some studies (12-15). Operative cyst decompression is an option that still needs to be evaluated in larger studies. Psychotic symptoms treated with antipsychotic drugs in patients with brain malformations tend to show therapeutic resistance. Our patient was resistant to treatment with several antipsychotics and showed improvement when the reserve antipsychotic clozapine was introduced. Nevertheless, his cognitive symptoms were persistent and showed only slight improvement.\n\nTable 1 Medline search: association between arachnoid cysts in the posterior fossa and psychotic symptoms\n\nWu YY, Shen YC. Delusions of control in a case of schizophrenia coexisting with a large cerebellar arachnoid cyst. Ci Ji Yi Xue Za Zhi. 2017;29(2):115-7. (10)\t\nHeidrich A, Schmidtke A, Lesch KP, Hofmann E, Becker T. Cerebellar arachnoid cyst in a firesetter: the weight of organic lesions in arson. J Psychiatry Neurosci. 1996;21(3):202-6. (19)\t\nLarysz D, Blamek S, Larysz P, Pietras K, Mandera M. Posterior fossa brain tissue injury: developmental, neuropsychological, and neurological consequences of brain tumors in children. Acta Neurochir Suppl. 2010;106:271-4. (20)\t\nCuny ML, Pallone M, Piana H, Boddaert N, Sainte-Rose C, Vaivre-Douret L, Piolino P, Puget S. Neuropsychological improvement after posterior fossa arachnoid cyst drainage. Childs Nerv Syst. 2017;33(1):135-41. (21)\t\nManer F, Babalioglu M, Cetinkaya O, Ipekcioglu D, Ergen N, Yesil R, et al. The coexistence of arachnoid cyst with first episode psychosis: four cases. J Neurol Disord. 2014;2:186. (22)\t\nJurjus GJ, Weiss KM, Jaskiw GE. Schizophrenia-like psychosis and cerebellar degeneration. Schizophr Res. 1994;12(2):183-4. (23)\t\nBen Dahman A, David P, Massager N, Leistedt S, Loas G. A marsupialized retrovermian arachnoid cyst and psychotic symptoms. J Surg Case Rep. 2017;2017(8). (24)\t\nRabiei K, Hellström P, Högfeldt-Johansson M, Tisell M. Does subjective improvement in adults with intracranial arachnoid cysts justify surgical treatment? J Neurosurg. 2018;128(1):250-7. (25)\t\nBoltshauser E, Martin F, Altermatt S. Outcome in children with space-occupying posterior fossa arachnoid cysts. Neuropediatrics. 2002;33(3):118-21. (26)\t\nKalapatapu RK. Aripiprazole treatment of psychosis in a child with posterior fossa retrocerebellar arachnoid cyst. J Child Adolesc Psychopharmacol. 2009;19(3):321-5. (27)\t\nDas S. Posterior fossa arachnoid cyst presenting as negative symptoms of psychosis. Shanghai Arch Psychiatry. 2018;30(3):202-3. (28)\t\nNakano H, Ogashiwa M. Complete remission of narcolepsy after surgical treatment of an arachnoid cyst in the cerebellopontine angle. J Neurol Neurosurg Psychiatry. 1995;58(2):264. (29)\t\n\nThe outcome of operative treatment versus treatment with antipsychotics for arachnoid cysts presented with psychotic symptoms has never been evaluated and should be researched in further studies.\n==== Refs\nReferences\n\n1 Al-Holou WN Terman S Kilburg C Garton HJL Muraszko KM Maher CO . Prevalence and natural history of arachnoid cysts in adults. J Neurosurg. 2013;118 :222–31. 10.3171/2012.10.JNS12548 23140149\n2 Helland CA Wester K . Intracystic pressure in patients with temporal arachnoid cysts. A prospective study of pre-operative complaints and post-operative outcome. J Neurol Neurosurg Psychiatry. 2007;78 :620–3. 10.1136/jnnp.2006.101865 17158556\n3 Hund-Georgiadis M Yves von Cramon D Kruggel F Preul C . Do quiescent arachnoid cysts alter CNS functional organization? A fMRI and morphometric study. Neurology. 2002;59 :1935–9. 10.1212/01.WNL.0000038745.98689.6B 12499486\n4 De Volder AG Michel C Thauvoy C Willems G Ferrière G . Brain glucose utilisation in acquired childhood aphasia associated with a sylvian arachnoid cyst: recovery after shunting as demonstrated by PET. J Neurol Neurosurg Psychiatry. 1994;57 (3 ):296–300. 10.1136/jnnp.57.3.296 7512624\n5 Sgouros S Chapman S . Congenital middle fossa arachnoid cysts may cause global brain ischaemia: a study with 99Tc-hexamethylpropyleneamineoxime single photon emission computerised tomography scans. Pediatr Neurosurg. 2001;35 (4 ):188–94. 10.1159/000050420 11694796\n6 Kohn R Lilly RB Sokol MS Malloy PF . Psychiatric presentations of intracranial cysts. J Neuropsychiatry Clin Neurosci. 1989;1 (1 ):60–6. 10.1176/jnp.1.1.60 2577719\n7 Wester K . Intracranial arachnoid cysts – do they impair mental functions? J Neurol. 2008;255 :1113–20. 10.1007/s00415-008-0011-y 18677648\n8 Vidrih B Karlovic D Bosnjak Pasic M . Arachnoid cyst as the cause of bipolar affective disorder: case report. Acta Clin Croat. 2012;51 :655–9. https://hrcak.srce.hr/108098 23540175\n9 da Silva JA Alves A Talina M Carreiro S Guimarães J Xavier M . Arachnoid cyst in a patient with psychosis: case report. Ann Gen Psychiatry. 2007;6 :16–21. 10.1186/1744-859X-6-16 17598903\n10 Wu YY Shen YC . Delusions of control in a case of schizophrenia coexisting with a large cerebellar arachnoid cyst. Ci Ji Yi Xue Za Zhi. 2017;29 :115–7. 10.4103/tcmj.tcmj_23_17 28757777\n11 Margetić B Zarkovic Palijan T Kovacevic D . Homicide and subsequent catatonia associated with a large arachnoid cyst: case report. Acta Clin Croat. 2013;52 :497–505. https://hrcak.srce.hr/122563 24697002\n12 Raeder MB Helland CA Hugdahl K Wester K . Arachnoid cysts cause cognitive deficits that improve after surgery. Neurology. 2005;64 (1 ):160–2. 10.1212/01.WNL.0000148724.61966.A4 15642927\n13 Wester K Hugdahl K . Arachnoid cysts of the left temporal fossa: impaired preoperative cognition and postoperative improvement. J Neurol Neurosurg Psychiatry. 1995;59 (3 ):293–8. 10.1136/jnnp.59.3.293 7673959\n14 B Gjerde P Schmid M Hammar A Wester K . Intracranial arachnoid cysts: impairment of higher cognitive functions and postoperative improvement. J Neurodev Disord. 2013;5 :21. 10.1186/1866-1955-5-21 23985219\n15 Torgersen J Helland C Flaatten H Wester K . Reversible dyscognition in patients with a unilateral, middle fossa arachnoid cyst revealed by using a laptop based neuropsychological test battery (CANTAB). J Neurol. 2010;257 (11 ):1909–16. 10.1007/s00415-010-5634-0 20602236\n16 Andreasen NC Pierson R . The role of the cerebellum in schizophrenia. Biol Psychiatry. 2008;64 :81–8. 10.1016/j.biopsych.2008.01.003 18395701\n17 Cierpka M Wolf ND Kubera KM Schmitgen MM Vasic N Frasch K Cerebellar contributions to persistent auditory verbal hallucinations in patients with schizophrenia. Cerebellum. 2017;16 :964–72. 10.1007/s12311-017-0874-5 28710677\n18 Wester K. Arachnoid Cysts: Epidemiology, Biology, and Neuroimaging, Vol. 1., London: Academic Press, 2017;67-72.\n19 Heidrich A Schmidtke A Lesch KP Hofmann E Becker T . Cerebellar arachnoid cyst in a firesetter: the weight of organic lesions in arson. J Psychiatry Neurosci. 1996;21 (3 ):202–6.8935333\n20 Larysz D Blamek S Larysz P Pietras K Mandera M . Posterior fossa brain tissue injury: developmental, neuropsychological, and neurological consequences of brain tumors in children. Acta Neurochir Suppl. 2010;106 :271–4. 10.1007/978-3-211-98811-4_51 19812963\n21 Cuny ML Pallone M Piana H Boddaert N Sainte-Rose C Vaivre-Douret L Neuropsychological improvement after posterior fossa arachnoid cyst drainage. Childs Nerv Syst. 2017;33 (1 ):135–41. 10.1007/s00381-016-3285-x 27832354\n22 Maner F Babalioglu M Cetinkaya O Ipekcioglu D Ergen N Yesil R The coexistence of arachnoid cyst with first episode psychosis: four cases. J Neurol Disord. 2014;2 :186. 10.4172/2329-6895.1000186\n23 Jurjus GJ Weiss KM Jaskiw GE . Schizophrenia-like psychosis and cerebellar degeneration. Schizophr Res. 1994;12 (2 ):183–4. 10.1016/0920-9964(94)90076-0 8043529\n24 Ben Dahman A David P Massager N Leistedt S Loas G . A marsupialized retrovermian arachnoid cyst and psychotic symptoms. J Surg Case Rep. 2017;2017 (8 ): 10.1093/jscr/rjx162 29308182\n25 Rabiei K Hellström P Högfeldt-Johansson M Tisell M . Does subjective improvement in adults with intracranial arachnoid cysts justify surgical treatment? J Neurosurg. 2018;128 (1 ):250–7. 10.3171/2016.9.JNS161139 28298013\n26 Boltshauser E Martin F Altermatt S . Outcome in children with space-occupying posterior fossa arachnoid cysts. Neuropediatrics. 2002;33 (3 ):118–21. 10.1055/s-2002-33674 12200740\n27 Kalapatapu RK . Aripiprazole treatment of psychosis in a child with posterior fossa retrocerebellar arachnoid cyst. J Child Adolesc Psychopharmacol. 2009;19 (3 ):321–5. 10.1089/cap.2008.077 19519272\n28 Das S . Posterior fossa arachnoid cyst presenting as negative symptoms of psychosis. Shanghai Arch Psychiatry. 2018;30 (3 ):202–3. 10.11919/j.issn.1002-0829.218005 30858672\n29 Nakano H Ogashiwa M . Complete remission of narcolepsy after surgical treatment of an arachnoid cyst in the cerebellopontine angle. J Neurol Neurosurg Psychiatry. 1995;58 (2 ):264. 10.1136/jnnp.58.2.264 7876881\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0353-9466",
"issue": "60(2)",
"journal": "Acta clinica Croatica",
"keywords": "Arachnoid cyst; Cognitive disorder; Psychotic symptoms",
"medline_ta": "Acta Clin Croat",
"mesh_terms": "D016080:Arachnoid Cysts; D002531:Cerebellum; D003071:Cognition; D003388:Cranial Fossa, Posterior; D006801:Humans; D008279:Magnetic Resonance Imaging; D011618:Psychotic Disorders",
"nlm_unique_id": "9425483",
"other_id": null,
"pages": "304-308",
"pmc": null,
"pmid": "34744282",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "8043529;23985219;28298013;2577719;17158556;18395701;28757777;17598903;7512624;23540175;7876881;19812963;12499486;19519272;8935333;20602236;12200740;24697002;30858672;11694796;15642927;23140149;28710677;29308182;18677648;7673959;27832354",
"title": "COGNITIVE AND PSYCHOTIC SYMPTOMS IN A PATIENT WITH INFRATENTORIAL ARACHNOID CYST: CASE REPORT.",
"title_normalized": "cognitive and psychotic symptoms in a patient with infratentorial arachnoid cyst case report"
} | [
{
"companynumb": "HR-MYLANLABS-2021M1088941",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "A case of an adolescent with symptoms of Mania, who developed Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) syndrome on exposure to combination of oral Olanzapine and Sodium Valproate is presented. We have attempted to highlight the atypical presentation of DRESS syndrome in this patient as well as management difficulties in patient who develops DRESS syndrome with the conventional psychotropic medication. Hence, it is necessary for mental health professionals to be vigilant about this life threatening drug reaction associated with high morbidity and mortality, thus ensuring prompt diagnosis and management.",
"affiliations": "Senior Resident, Department of Psychiatry, Vinayaka Mission's Kirupananda Variyar Medical College & Hospitals, Salem, India. Electronic address: lakshmivenkat1@gmail.com.;Senior Resident, Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India. Electronic address: poojapatnaik.aiims@gmail.com.;Assistant Professor, Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India. Electronic address: preetikandasamy@gmail.com.;Assistant Professor, Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research Puducherry, India. Electronic address: bharadwaj.balaji@gmail.com.",
"authors": "Penchilaiya|Venkatalakshmi|V|;Kuppili|Pooja Patnaik|PP|;Preeti|K|K|;Bharadwaj|Balaji|B|",
"chemical_list": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D014635:Valproic Acid; D000077152:Olanzapine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ajp.2017.05.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-2018",
"issue": "28()",
"journal": "Asian journal of psychiatry",
"keywords": "DRESS syndrome; Olanzapine; Sodium Valproate",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D000293:Adolescent; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001714:Bipolar Disorder; D063926:Drug Hypersensitivity Syndrome; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D000077152:Olanzapine; D014635:Valproic Acid",
"nlm_unique_id": "101517820",
"other_id": null,
"pages": "175-176",
"pmc": null,
"pmid": "28784381",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "DRESS syndrome: Addressing the drug hypersensitivity syndrome on combination of Sodium Valproate and Olanzapine.",
"title_normalized": "dress syndrome addressing the drug hypersensitivity syndrome on combination of sodium valproate and olanzapine"
} | [
{
"companynumb": "IN-MYLANLABS-2018M1055433",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nLinear IgA bullous dermatosis (LABD) is an autoimmune subepidermal blistering disease that may be associated with drug exposure.\n\n\nOBJECTIVE\nOur purpose was to compare the clinical, pathologic, and immunofluorescence findings in drug-induced LABD with those in the idiopathic type.\n\n\nMETHODS\nSix patients with an acute drug eruption were identified who had linear IgA deposition at the basement membrane zone (BMZ). Lesional tissue was examined by brightfield microscopy, and perilesional tissue was examined by direct immunofluorescence (DIF). The presence of circulating BMZ antibody was assayed by indirect immunofluorescence (IIF) on monkey esophagus (ME) and salt-split human skin (SS).\n\n\nRESULTS\nHistopathologic examination showed subepidermal bullae with varying numbers of inflammatory cells. DIF showed linear IgA at the BMZ; three of the patients also had weak deposition of C3 at the BMZ. Serum from five patients was studied by IIF. One patient had circulating IgA BMZ antibodies in a titer of 1:80 on ME, localized to the dermal side on SS. All patients were free of lesions within 5 weeks after discontinuation of the drug.\n\n\nCONCLUSIONS\nDrug-induced LABD is a self-limited eruption characterized by linear deposition of IgA without IgG at the BMZ. Most patients lack circulating antibodies. The distribution of lesions and the course of the disease differ from those of idiopathic LABD.",
"affiliations": "Department of Dermatology, Mayo Clinic, Rochester, MN 55905.",
"authors": "Kuechle|M K|MK|;Stegemeir|E|E|;Maynard|B|B|;Gibson|L E|LE|;Leiferman|K M|KM|;Peters|M S|MS|",
"chemical_list": "D007070:Immunoglobulin A; D013004:Somatostatin; D010672:Phenytoin; D014640:Vancomycin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D002216:Captopril; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1016/s0190-9622(94)70015-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "30(2 Pt 1)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": null,
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000368:Aged; D001327:Autoimmune Diseases; D001485:Basement Membrane; D002216:Captopril; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D007070:Immunoglobulin A; D008297:Male; D010672:Phenytoin; D012293:Rifampin; D012867:Skin; D012872:Skin Diseases, Vesiculobullous; D013004:Somatostatin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014640:Vancomycin",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "187-92",
"pmc": null,
"pmid": "7904616",
"pubdate": "1994-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature.",
"title_normalized": "drug induced linear iga bullous dermatosis report of six cases and review of the literature"
} | [
{
"companynumb": "US-BAXTER-2019BAX024211",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThe purpose of this study was to assess the efficacy and safety of a de novo immunosuppressive regimen with everolimus (EVL) plus mycophenolate mofetil (MMF) without calcineurin inhibitors (CNI) for liver transplantation. The secondary purpose was to compare the renal function with a control group of patients treated with tacrolimus plus MMF.\n\n\nMETHODS\nSixteen male and 4 female liver transplant patients received immunosuppression with EVL plus MMF without CNI, with induction with steroids and 16 with basiliximab also. In 10 cases it was indicated as induction immunosuppression without CNI as prevention against nephrotoxicity and neurotoxicity or recurrence of hepatocarcinoma in predisposed patients and in another 10 after withdrawing CNI during the immediate post-transplant period, before hospital discharge, as the result of toxicity, mainly nephrotoxicity and neurotoxicity or the presence of hepatocarcinoma with a high risk of recurrence. A control group comprising 31 patients taking tacrolimus plus MMF was included to compare the renal function.\n\n\nRESULTS\nThe mean follow-up time was 24 months. One patient had a recurrence of hepatocarcinoma at 8 months after transplant. The cases of nephrotoxicity and neurotoxicity resolved favorably. There were 7 rejections (35%); 2 evolved to chronic rejection with both needing retransplantation, 2 resolved with dose adjustment, and 3 required conversion to CNI. The side effects were hyperlipidemia (25%), wound dehiscence (10%), lymphedema (10%), cytomegalovirus infection (25%), myelotoxicity (25%) and proteinuria >1 g in 1 case (5%). No differences were found in renal function between the two groups.\n\n\nCONCLUSIONS\nThis regimen was proven to be efficient to prevent and treat nephrotoxicity and neurotoxicity with an acceptable tolerability profile. However, the high associated rejection rate indicates that great caution is required in its use during the immediate post-transplant period. It is advisable to associate the regimen with low doses of CNI and to have agile methods available to monitor EVL to enable rapid dose adjustment.",
"affiliations": "Unidad de Hepatología-Trasplante Hepático, UGC de Aparato Digestivo, Hospital Regional Universitario de Málaga, Spain. Electronic address: mjimenezp@commalaga.com.;Unidad de Hepatología-Trasplante Hepático, UGC de Aparato Digestivo, Hospital Regional Universitario de Málaga, Spain.;Unidad de Hepatología-Trasplante Hepático, UGC de Aparato Digestivo, Hospital Regional Universitario de Málaga, Spain.;Unidad de Hepatología-Trasplante Hepático, UGC de Aparato Digestivo, Hospital Regional Universitario de Málaga, Spain.;Unidad de Cirugía HB y Trasplante Hepático, UGC de Cirugía Digestiva, Hospital Regional Universitario de Málaga, Spain.;Unidad de Cirugía HB y Trasplante Hepático, UGC de Cirugía Digestiva, Hospital Regional Universitario de Málaga, Spain.;Unidad de Cirugía HB y Trasplante Hepático, UGC de Cirugía Digestiva, Hospital Regional Universitario de Málaga, Spain.;Unidad de Cirugía HB y Trasplante Hepático, UGC de Cirugía Digestiva, Hospital Regional Universitario de Málaga, Spain.;Unidad de Hepatología-Trasplante Hepático, UGC de Aparato Digestivo, Hospital Regional Universitario de Málaga, Spain.;Unidad de Hepatología-Trasplante Hepático, UGC de Aparato Digestivo, Hospital Regional Universitario de Málaga, Spain.",
"authors": "Jiménez-Pérez|M|M|;González Grande|R|R|;Rando Muñoz|F J|FJ|;de la Cruz Lombardo|J|J|;Muñoz Suárez|M A|MA|;Fernández Aguilar|J L|JL|;Pérez Daga|J A|JA|;Santoyo-Santoyo|J|J|;Manteca González|R|R|;Rodrigo López|J M|JM|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "90-2",
"pmc": null,
"pmid": "25645779",
"pubdate": "2015",
"publication_types": "D003160:Comparative Study; D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Everolimus plus mycophenolate mofetil as initial immunosuppression in liver transplantation.",
"title_normalized": "everolimus plus mycophenolate mofetil as initial immunosuppression in liver transplantation"
} | [
{
"companynumb": "PHHY2019ES127656",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of a 1-year and 2-month-old girl with clinical features consistent with congenital hemidysplasia with ichthyosis and limb defects syndrome. Sterol analysis from skin flakes revealed increased levels of a mono 4-alpha methyl sterol also seen in plasma as well as the presence of 4-alpha-carboxy-4-methyl-cholest-8(9)-en-3beta-ol and several keto-sterols, which are usually below the limit of detection. This sterol pattern is consistent with abnormal function of the 4-alpha-methylsterol-4-demethylase complex. NSDHL gene testing revealed the presence of a variant of uncertain significance, c.130G>A (p.Gly44Ser). This missense mutation currently is not included in population databases (ExAC no frequency) and has not been reported in individuals with an NSDHL-related condition. Parental studies showed that neither parent carries the NSDHL variant. On this basis, this variant has been reclassified as likely pathogenic. Symptomatic treatment with keratolytic agents, emollients and ketoconazole was initiated.",
"affiliations": "Division of Clinical Genetics, Department of Pediatrics, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines egmaceda@up.edu.ph.;Biochemical Genetics Laboratory, Kennedy Krieger Institute, Baltimore, Maryland, USA.;Dermatology, University of the Philippines Manila, Manila, Philippines.;Division of Clinical Genetics, Department of Pediatrics, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines.",
"authors": "Maceda|Ebner Bon Gatus|EBG|http://orcid.org/0000-0001-5414-7030;Kratz|Lisa E|LE|;Ramos|Veronica Marie E|VME|;Abacan|Mary Ann R|MAR|",
"chemical_list": "D004247:DNA; D015096:3-Hydroxysteroid Dehydrogenases; C478776:Nsdhl protein, human",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236859",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "dermatology; genetics",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015096:3-Hydroxysteroid Dehydrogenases; D000015:Abnormalities, Multiple; D004247:DNA; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D040181:Genetic Diseases, X-Linked; D014644:Genetic Variation; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital; D007223:Infant; D017880:Limb Deformities, Congenital; D020125:Mutation, Missense; D011859:Radiography",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33139364",
"pubdate": "2020-11-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Novel NSDHL gene variant for congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome.",
"title_normalized": "novel nsdhl gene variant for congenital hemidysplasia with ichthyosiform erythroderma and limb defects child syndrome"
} | [
{
"companynumb": "PH-TOLMAR, INC.-20PH023924",
"fulfillexpeditecriteria": "2",
"occurcountry": "PH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "UREA"
},
"drugadditional": "3",
"d... |
{
"abstract": "An 81-year-old male with atherosclerosis had an episode of bacteraemia with Salmonella dublin six weeks prior to admission to hospital. He presented with confusion, fever and abdominal pain. Blood cultures revealed S. dublin, and an 18F-fluor deoxyglucose positron emission tomography/computed tomography showed aortitis. Ceftriaxon and ciprofloxacin was administered. The patient was not a candidate for surgery and two weeks later he died from multiple organ failure. Follow-up visits with blood cultures after the first bacteraemia episode might have allowed for earlier diagnosis of the relapse.",
"affiliations": "Klinisk Mikrobiologisk Afdeling, Odense Universitetshospital, J.B. Winsløws Vej 21, 2., 5000 Odense C. thomas.sydenham@dadlnet.dk.",
"authors": "Sydenham|Thomas Vognbjerg|TV|;Andersen|Åse Bengård|ÅB|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "177(2A)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001025:Aortitis; D016470:Bacteremia; D017809:Fatal Outcome; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012480:Salmonella Infections; D019779:Salmonella enterica; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": "90-1",
"pmc": null,
"pmid": "25612984",
"pubdate": "2015-01-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Follow-up after non-typhoidal Salmonella bacteraemia is important due to risk of endovascular infection.",
"title_normalized": "follow up after non typhoidal salmonella bacteraemia is important due to risk of endovascular infection"
} | [
{
"companynumb": "DK-BAYER-2015-026916",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFUROXIME"
},
"drugadditional": null,
... |
{
"abstract": "Ischemic stroke is caused by interruption or significant impairment of blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphologic damage. The changes in regional cerebral blood flow and regional metabolism can be assessed by radionuclide imaging, especially SPECT and PET. SPECT and PET have broadened our understanding of flow and metabolic thresholds critical for maintenance of brain function and morphology: PET was essential in the transfer of the concept of the penumbra to clinical stroke and thereby had a great impact on developing treatment strategies. Receptor ligands can be applied as early markers of irreversible neuronal damage and can predict the size of the final infarcts, which is important for decisions on invasive therapy in large (\"malignant\") infarction. With SPECT and PET, the reserve capacity of the blood supply can be tested in obstructive arteriosclerosis, which is essential for planning interventions. The effect of a stroke on surrounding and contralateral primarily unaffected tissue can be investigated, helping to understand symptoms caused by disturbance in functional networks. Activation studies are useful to demonstrate alternative pathways to compensate for lesions and to test the effect of rehabilitative therapy. Radioisotope studies help to detect neuroinflammation and its effect on extension of tissue damage. Despite the limitations of broad clinical application of radionuclide imaging, this technology has a great impact on research in cerebrovascular diseases and still has various applications in the management of stroke.",
"affiliations": "Max Planck Institute for Neurological Research, Cologne, Germany wdh@nf.mpg.de.",
"authors": "Heiss|Wolf-Dieter|WD|",
"chemical_list": "D002250:Carbon Radioisotopes; D011868:Radioisotopes; D005442:Flumazenil",
"country": "United States",
"delete": false,
"doi": "10.2967/jnumed.114.145003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0161-5505",
"issue": "55(11)",
"journal": "Journal of nuclear medicine : official publication, Society of Nuclear Medicine",
"keywords": "PET; SPECT; cerebral ischemia; diaschisis; functional activation; hemodynamic reserve; infarction; neuroinflammation; penumbra; reperfusion; stroke",
"medline_ta": "J Nucl Med",
"mesh_terms": "D000818:Animals; D001921:Brain; D002545:Brain Ischemia; D002250:Carbon Radioisotopes; D002561:Cerebrovascular Disorders; D005442:Flumazenil; D006801:Humans; D000860:Hypoxia; D007249:Inflammation; D017628:Microglia; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D020521:Stroke; D015899:Tomography, Emission-Computed, Single-Photon",
"nlm_unique_id": "0217410",
"other_id": null,
"pages": "1831-41",
"pmc": null,
"pmid": "25300599",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Radionuclide imaging in ischemic stroke.",
"title_normalized": "radionuclide imaging in ischemic stroke"
} | [
{
"companynumb": "DE-ROCHE-1526047",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nStatins have similar side effects that do not always occur at the same rate among the various statins. We present a case of simvastatin-induced muscle toxicity that disappeared when pravastatin was substituted for the original drug.\n\n\nMETHODS\nA 74-year-old male, a nonsmoker, complained of severe nocturnal leg cramps. The patient also complained that similar painful cramping occurred when he walked rapidly or jogged. Because some components of his lipid panel exceeded the'desirable' range, and as he had a history of myocardial infarction, his family physician prescribed simvastatin (40 mg/day). The patient had taken this medication for the past eight years. The painful nocturnal episodes started two years ago and affected either one or the other leg. Four months ago we discontinued his simvastatin and prescribed pravastatin (80 mg/day). At a follow-up visit six weeks later, the patient reported that his leg pains at night and the pain experienced after brisk walking had disappeared. Four months after the substitution of pravastatin for simvastatin, the patient reported that his complete lack of symptoms had continued.\n\n\nCONCLUSIONS\nThese painful muscle cramps were probably caused by an inadequate vascular supply to the calf and foot muscles. Perhaps a combination of advanced age and atherosclerotic changes created a predisposition for the simvastatin-induced leg cramps. Pravastatin differs from simvastatin in several ways.l It is not metabolized by cytochrome P450 (CYP) 3A4 oxidases, and thus is not influenced by CYP 3A4 inhibitors like simvastatin. Also, simvastatin is associated with single-nucleotide polymorphisms located within the SLCO1B1 gene on the chromosome 12 and established myopathy, while pravastatin lacks this association. These differences may contribute to increased tolerance to pravastatin in this particular case.",
"affiliations": "Department of Pharmacology, Toxicology, and Clinical Pharmacology, Medical School, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina.",
"authors": "Stojaković|Natasa|N|;Igić|Rajko|R|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D017035:Pravastatin",
"country": "Serbia",
"delete": false,
"doi": "10.2298/sarh1306387s",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0370-8179",
"issue": "141(5-6)",
"journal": "Srpski arhiv za celokupno lekarstvo",
"keywords": null,
"medline_ta": "Srp Arh Celok Lek",
"mesh_terms": "D000368:Aged; D057915:Drug Substitution; D050171:Dyslipidemias; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007866:Leg; D008297:Male; D009135:Muscular Diseases; D017035:Pravastatin; D019821:Simvastatin; D016896:Treatment Outcome",
"nlm_unique_id": "0027440",
"other_id": null,
"pages": "387-9",
"pmc": null,
"pmid": "23858814",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Simvastatin-lnduced nocturnal leg pain disappears with pravastatin substitution.",
"title_normalized": "simvastatin lnduced nocturnal leg pain disappears with pravastatin substitution"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2016-00128",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditiona... |
{
"abstract": "A 58 year-old male patient developed anaphylactic shock, possibly due to the use of chlorhexidine as ophthalmic wash solution. He was successfully resuscitated without any sequelae. The patient had increased levels of both histamine and tryptase. The skin test for allergy resulted in strong positive to chlorhexidine. There have been many reports regarding severe adverse reactions associated with use of chlorhexidine. It is necessary to pay attention to anaphylactic shock due to chlorhexidine.",
"affiliations": "Department of Anesthesiology, Kinki University School of Medicine, Osaka.",
"authors": "Okuda|T|T|;Funasaka|M|M|;Arimitsu|M|M|;Umeda|T|T|;Wakita|K|K|;Koga|Y|Y|",
"chemical_list": "D009883:Ophthalmic Solutions; D002710:Chlorhexidine",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "43(9)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000707:Anaphylaxis; D000768:Anesthesia, General; D002710:Chlorhexidine; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D012163:Retinal Detachment",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "1352-5",
"pmc": null,
"pmid": "7967032",
"pubdate": "1994-09",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Anaphylactic shock by ophthalmic wash solution containing chlorhexidine.",
"title_normalized": "anaphylactic shock by ophthalmic wash solution containing chlorhexidine"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1018532",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to assess the efficacy and safety of flow-directed catheter thrombolysis for treatment of submassive pulmonary embolism (PE).\n\n\nMETHODS\nIn this single-institution retrospective study, 19 patients (nine men and 10 women; mean age [± SD], 54 ± 13 years) with submassive PE underwent catheter-directed thrombolysis between 2009 and 2013. Presenting symptoms included dyspnea in 18 of 19 (95%) cases. Submassive PE was diagnosed by pulmonary CT arteriography and right ventricular strain. PE was bilateral in 17 of 19 (89%) and unilateral in two of 19 (11%) cases. Thrombolysis was performed via a pulmonary artery (PA) catheter infusing 0.5- 1.0 mg alteplase per hour and was continued to complete or near complete clot dissolution with reduction in PA pressure. IV systemic heparin was administered. Measured outcomes included procedural success, PA pressure reduction, clinical success, survival, and adverse events.\n\n\nRESULTS\nProcedural success, defined as successful PA catheter placement, fibrinolytic agent delivery, PA pressure reduction, and achievement of complete or near complete clot dissolution, was achieved in 18 of 19 (95%) cases. Thrombolysis required 57 ± 31 mg of alteplase administered over 89 ± 32 hours. Initial and final PA pressures were 30 ± 10 mm Hg and 20 ± 8 mm Hg (p < 0.001). All 18 (100%) technically successful cases achieved clinical success because all patients experienced symptomatic improvement. Eighteen of 19 (95%) patients survived to hospital discharge; 18 of 19 (95%) and 15 of 16 (94%) patients had documented 1-month and 3-month survival. One fatal case of intracranial hemorrhage was attributed to supratherapeutic anticoagulation because normal fibrinogen levels did not suggest remote fibrinolysis; procedural success was not achieved in this case because of early thrombolysis termination. No other complications were encountered.\n\n\nCONCLUSIONS\nAmong a small patient cohort, flow-directed catheter thrombolysis with alteplase effectively dissolved submassive PE and reduced PA pressure. Postprocedure short-term survival was high, and patients undergoing thrombolysis required close observation for bleeding events.",
"affiliations": "1 Department of Radiology, Division of Interventional Radiology, University of Illinois Hospital and Health Sciences System, 1740 W Taylor St, MC 931, Chicago, IL 60612.",
"authors": "Gaba|Ron C|RC|;Gundavaram|Madhu S|MS|;Parvinian|Ahmad|A|;Knuttinen|M Grace|MG|;Minocha|Jeet|J|;Owens|Charles A|CA|;Bui|James T|JT|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.2214/AJR.13.11366",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-803X",
"issue": "202(6)",
"journal": "AJR. American journal of roentgenology",
"keywords": null,
"medline_ta": "AJR Am J Roentgenol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001807:Blood Vessel Prosthesis; D002407:Catheterization, Swan-Ganz; D004867:Equipment Design; D004869:Equipment Safety; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D015641:Radiography, Interventional; D012189:Retrospective Studies; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "7708173",
"other_id": null,
"pages": "1355-60",
"pmc": null,
"pmid": "24848835",
"pubdate": "2014-06",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of flow-directed pulmonary artery catheter thrombolysis for treatment of submassive pulmonary embolism.",
"title_normalized": "efficacy and safety of flow directed pulmonary artery catheter thrombolysis for treatment of submassive pulmonary embolism"
} | [
{
"companynumb": "PHHY2014US151557",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nShivering is a common postanesthesia adverse event with multiple etiologies. At present tramadol is a widely used drug for the control of shivering. However, tramadol may cause a lot of nausea and vomiting. Hence, the need to find a better drug with less of side effects. The aim of this study was to compare the efficacy of dexmedetomidine and tramadol in the treatment of post-spinal anesthesia (SA) shivering as well as to compare their side-effect profile.\n\n\nMETHODS\nThis prospective, double-blind, randomized controlled trial was conducted in a tertiary care hospital. A total of 100 patients having shivering after SA were enrolled, out of which fifty received dexmedetomidine (Group A) and 50 received tramadol (Group B). The response rate, time to cessation of shivering and side effects (if any) was noted. All the results were analyzed using Student's t-test and Chi-square test.\n\n\nRESULTS\nAll patients who received dexmedetomidine as well as tramadol had cessation of shivering. The time to cessation of shivering was significantly less with dexmedetomidine (174.12 ± 14.366 s) than with tramadol (277.06 ± 23.374 s) (P < 0.001). The recurrence rate of shivering with dexmedetomidine was less (6%) as compared to tramadol (16%). Nausea and vomiting was found to be higher in the case of tramadol. On the other hand, dexmedetomidine caused moderate sedation (modified Ramsay sedation score = 3-4) from which the patient could be easily awoken up.\n\n\nCONCLUSIONS\nDexmedetomidine offers better results than tramadol with fewer side effects.",
"affiliations": "Department of Anaesthesia, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, India.;Department of Anaesthesia and Critical Care, SPS Hospitals, Ludhiana, Punjab, India.;Department of Anaesthesia and Critical Care, SPS Hospitals, Ludhiana, Punjab, India.;Department of Anaesthesia, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, India.",
"authors": "Kundra|Tanveer Singh|TS|;Kuthiala|Gaurav|G|;Shrivastava|Anupam|A|;Kaur|Parminder|P|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/1658-354X.197344",
"fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Medknow Publications & Media Pvt Ltd India SJA-11-210.4103/1658-354X.197344Original ArticleA comparative study on the efficacy of dexmedetomidine and tramadol on post-spinal anesthesia shivering Kundra Tanveer Singh Kuthiala Gaurav 1Shrivastava Anupam 1Kaur Parminder Department of Anaesthesia, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, India1 Department of Anaesthesia and Critical Care, SPS Hospitals, Ludhiana, Punjab, IndiaAddress for correspondence: Dr. Tanveer Singh Kundra, Kothi No. 184, Phase 4, Mohali, Punjab, India. E-mail: tvskundra@yahoo.co.inJan-Mar 2017 11 1 2 8 Copyright: © 2017 Saudi Journal of Anesthesia2017This 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:\nShivering is a common postanesthesia adverse event with multiple etiologies. At present tramadol is a widely used drug for the control of shivering. However, tramadol may cause a lot of nausea and vomiting. Hence, the need to find a better drug with less of side effects. The aim of this study was to compare the efficacy of dexmedetomidine and tramadol in the treatment of post-spinal anesthesia (SA) shivering as well as to compare their side-effect profile.\n\nMaterials and Methods:\nThis prospective, double-blind, randomized controlled trial was conducted in a tertiary care hospital. A total of 100 patients having shivering after SA were enrolled, out of which fifty received dexmedetomidine (Group A) and 50 received tramadol (Group B). The response rate, time to cessation of shivering and side effects (if any) was noted. All the results were analyzed using Student's t-test and Chi-square test.\n\nResults:\nAll patients who received dexmedetomidine as well as tramadol had cessation of shivering. The time to cessation of shivering was significantly less with dexmedetomidine (174.12 ± 14.366 s) than with tramadol (277.06 ± 23.374 s) (P < 0.001). The recurrence rate of shivering with dexmedetomidine was less (6%) as compared to tramadol (16%). Nausea and vomiting was found to be higher in the case of tramadol. On the other hand, dexmedetomidine caused moderate sedation (modified Ramsay sedation score = 3–4) from which the patient could be easily awoken up.\n\nConclusion:\nDexmedetomidine offers better results than tramadol with fewer side effects.\n\nKey words\nDexmedetomidinepostoperative nausea and vomitingshiveringtramadol\n==== Body\nIntroduction\nShivering is defined as an involuntary, repetitive activity of skeletal muscles. It is a common postanesthesia adverse event with an incidence of 40–70%.[1] Various mechanisms have been suggested for postanesthesia shivering. These include intraoperative heat loss, postoperative increased sympathetic tone, pain and systemic release of pyrogens.[2] Though hypothalamic thermoregulation remains intact during regional anesthesia, it is associated with greater heat loss than general anesthesia which is attributed to various reasons like abnormal heat loss due to vasodilatation, impairment of shivering in the area of block and rapid intravenous (IV) infusion of cold fluids.[3]\n\nShivering is not only physically distressing for the patient, but can have various other detrimental effects. It may lead to pain, patient discomfort, impede monitoring techniques,increase intraocular and intracranial pressures, double or even triple oxygen consumption and carbon dioxide production,[4] which might pose difficulties in patients with existing intrapulmonary shunts, fixed cardiac output or limited respiratory reserve.\n\nVarious modalities have been used for the prevention and treatment of postanesthesia shivering. Dexmedetomidine, a centrally acting alpha 2-adrenergic agonist, has been used as a sedative agent and is known to reduce the shivering threshold. Various studies have been performed using dexmedetomidine in the prophylaxis of postoperative shivering.[5] But until date, there are limited studies using dexmedetomidine in the treatment of postoperative shivering.\n\nTramadol, an opioid receptor agonist, is an inhibitor of the re-uptake of serotonin (5-hydroxytryptamine) and norepinephrine in the spinal cord. This facilitates 5-hydroxytryptamine release, which influences thermoregulatory control. Presently it is a widely used drug for the control of shivering. But tramadol may cause nausea and vomiting which is very distressing for the patient. Hence the need to find a better drug which has comparable efficacy to tramadol and at the same time has less of side effects. The aim of the study was to compare the efficacy of dexmedetomidine and tramadol in the treatment of post-spinal anesthesia shivering as well as their side-effect profile.\n\nMaterials and Methods\nThe present study was a prospective, double-blind, randomized controlled trial conducted on 100 American Society of Anesthesiologists (ASA) Grade I/II adult patients (>18 years) having shivering during surgeries under spinal anesthesia (SA) out of which fifty received dexmedetomidine (Group A) and 50 received tramadol (Group B). The sample size was determined keeping the value of alpha (α) = 0.05 and beta (β) = 0.2. We hypothesized that the test drug will be significantly better if it decreased the time taken to abolish shivering by 1 min as compared to control group drug (tramadol). We took the maximum standard deviation (SD) which was 1.69 as per previous study.[6] Applying the formula for a two-sided study:\n\nn (size per group) =2c/δ2 + 1\n\nwhere, δ = (µ2–µ1)/σ is the standardised effect size\n\nμ1 and μ2 are the means of the two treatment groups\n\nσ is the common SD\n\nc = 7.9 for 80% power\n\nHence, n = 2 × 7.9/(1/1.69)2 + 1 = 46.1.\n\nRounding off, we took the sample size as 50 per group. Patients with coagulopathy, elderly (age >65 years), bradycardia (heart rate [HR] <60/min), heart blocks, pregnant and nursing mothers or allergy to drugs used or to the drug group were excluded from the study.\n\nPatients were randomly allocated to Group A or Group B on the basis of computer-generated random table. The randomization scheme was generated using the Website Randomization.com (http://www.randomization.com). The computer generated Group number (A or B) was put in a closed opaque envelope. A person not related to study (anesthesia nurse) was asked to open the closed envelope containing computer generated group number on start of shivering in the patient. She prepared the drug in 50 ml syringe and sent it for use without labelling which drug it was, but she kept a record of the same. If the second dose of the drug was required, she again sent it in an unlabelled syringe. The administering anesthesiologist was not knowing which drug was being given. He would fill up the study proforma noting down the various parameters, and this proforma would be collected again by the anesthesia nurse who would put it back in the torn envelope. At the end of the study, these envelopes were handed to the principal investigator.\n\nAll patients were monitored by noninvasive blood pressure (NIBP), pulse rate, SpO2 and axillary temperature.\n\nInitiation of subarachnoid block was done by injection bupivacaine (0.5%) at L2-3 or L3-4 interspace. There was no active warming of patients and the fluids were used at room temperature. The room temperature in the entire operation theater complex, pharmacy area and surgical recovery room was kept constant between 21 and 24°C. Vitals including NIBP, pulse rate, SpO2 and axillary temperature were recorded in the beginning of the surgery and at the onset of shivering from the monitoring chart, after cessation of shivering and then every 10 min till the end point of study.\n\n\nIn Group A: Dexmedetomidine (0.5 mcg/kg) in the concentration of 1 mcg/ml was given over 10 min if there was shivering in patient after initiation of subarachnoid block\n\nIn Group B: Tramadol (0.5 mg/kg) in the concentration of 1 mg/ml was given over 10 min, if there was shivering in patient after initiation of subarachnoid block.\n\n\n\n\nGrading of shivering was done as follows:\n\n\nGrade 0: No shivering\n\nGrade 1: One or more of the following: Piloerection, peripheral vasoconstriction, peripheral cyanosis without other cause, but without visible muscle activity\n\nGrade 2: Visible muscle activity confined to one muscle group\n\nGrade 3: Visible muscle activity in more than one muscle group\n\nGrade 4: Gross muscle activity involving the whole body.\n\n\n\n\nPatients who developed either Grade 3 or Grade 4 of shivering were included in the study. Same criteria were used for grading shivering during recurrence and patients with Grade 3 or 4 shivering were included.\n\nThe attending anesthesiologist would record:\n\n\nThe time at which shivering started after SA (onset of shivering) and the time of recurrence, if present (defined as the time between cessation of shivering after the first dose of the drug and recurrence of shivering)\n\nSeverity of the shivering\n\nResponse rate (number of patients in which shivering ceased after treatment in 15 min)\n\nTime to disappearance of shivering (in seconds).\n\n\n\n\nThe total duration of surgery was noted and the duration of SA was recorded by assessing spontaneous recovery of sensory block using pin-prick method and observing spontaneous movements of limbs in the postoperative period. If the shivering did not subside by 15 min, the treatment was considered to be not effective. Recurrence of shivering was also noticed. Patients who did not respond or in whom recurrence of shivering occured were treated with additional dose of dexmedetomidine (0.25 μg/kg IV) or tramadol (0.25 mg/kg IV) in the respective groups. If some patients did not respond to the additional dose, they would be regarded as treatment failure. This would be used to calculate the response rate. Side effects like nausea, vomiting, itching, bradycardia (<60/min), hypotension (decrease >20% of baseline of systolic blood pressure/diastolic blood pressure [SBP/DBP]) and sedation score were recorded.\n\nSedation score was assessed as per modified Ramsay score:\n\n\n\nBradycardia, hypotension, and vomiting were treated with Inj atropine 0.6 mg i/v, Inj ephedrine in 6 mg boluses i/v titrated until blood pressure (BP) reached within 20% of baseline BP and Inj metoclopramide 10 mg i/v, respectively, when required.\n\nPostoperatively, after shifting patients to postanesthesia care unit (PACU), patients were not actively warmed and were given fluids at room temperature.\n\nThe end point for the study was either sensory (using pin-prick method) and motor recovery from subarachnoid block or the patient was given either of the two drugs twice for the treatment of shivering.\n\nFor motor recovery from subarachnoid block, the Bromage scale was used as per institutional practice which is as under:\n\n\nBromage 3: Unable to move feet or knees\n\nBromage 2: Able to move feet only\n\nBromage 1: Just able to move knees\n\nBromage 0: Full flexion of knees and feet.\n\n\n\n\nAll the results were analyzed using Student's t-test and Chi-square test. Data were expressed as mean ± SD or percentage. A p < 0.05 was considered statistically significant. A p < 0.001 was considered highly significant.\n\nResults\nThe incidence of shivering in our study came out to be 41%. Written informed consent was taken from 244 patients undergoing various surgeries under SA, until the time 100 patients developed shivering and were enrolled in the study. The consort diagram is shown in Figure 1.\n\nFigure 1 Consort transparent reporting of trials CONSORT 2010 flow diagram\n\nBoth the groups were comparable with respect to sex, age, weight, ASA grade, duration of surgery, type of procedure done and the duration of spinal block [Tables 1 and 2].\n\nTable 1 Demography of the two study groups\n\nTable 2 Distribution of patients according to the type of procedure done in the two study groups\n\nThe ambient temperature of the operation theatre in Group A was 21.56 ± 0.577°C while in Group B it was 21.60 ± 0.606°C (P = 0.736). Similarly, ambient temperature of recovery room in Group A was 23.62 ± 0.490°C while in Group B it was 23.60 ± 0.495°C (P = 0.840).\n\nShivering disappeared in 100% patients who received dexmedetomidine and tramadol. Both the drugs were found to be effective in reducing shivering.\n\nThree patients in Group A (6.00%) and eight patients (16.00%) in Group B had recurrence of shivering and were given second doses of dexmedetomidine or tramadol, respectively (P = 0.110).\n\nShivering disappeared in 100% patients who received the second dose of dexmedetomidine and tramadol.\n\nTime for onset of shivering and severity of shivering were not statistically significantly different between the two groups. Similarly, the time of recurrence of shivering, whenever it occurred was comparable in the two groups. The mean interval between the injection of drug (dexmedetomidine and tramadol) and the complete cessation of shivering was significantly lesser in the dexmedetomidine group [Table 3].\n\nTable 3 Comparison of the time of onset of shivering, severity of shivering, time to disappearance of shivering, and time of recurrence in the two study groups\n\nThere was no statistically significant difference with respect to SBP/DBP, axillary temperature, and oxygen saturation between the two groups [Figures 2a and b, 3, 4].\n\nFigure 2 (a) Comparison of systolic blood pressure at various time intervals in the two groups. (b) Comparison of diastolic blood pressure at various time intervals in the two groups\n\nFigure 3 Comparison of axillary temperature at various time intervals in the two groups\n\nFigure 4 Comparison of SpO2 at various time intervals in the two groups\n\nThere was no statistically significant difference with respect to baseline HR and HR at the onset of shivering. However, the HR decreased significantly in Group A as compared to Group B immediately after cessation of shivering. There was no statistically significant difference with respect to HR at all other time intervals [Figure 5].\n\nFigure 5 Comparison of pulse rate at various time intervals in the two groups\n\nComplication rates were significantly higher in Group B than in Group A. Nausea and vomiting were higher in Group B than in Group A. 28.00% patients in Group B had nausea compared to none in Group A with a highly significant P < 0.001. Furthermore, 8.00% patients in Group B had vomiting compared to none in Group A with a significant P = 0.041.\n\nNone of the patients in either group had itching and hypotension while one patient in Group A had bradycardia. No patient in Group B had bradycardia (P = 0.315).\n\nPatients of Group A were more sedated than of Group B. While 14 (28.00%) patients in Group A had Grade 3 sedation score, 36 (72.00%) patients had sedation of Grade 4. On the other hand, all the patients in Group B had a sedation of Grade 2 (P < 0.001).\n\nDiscussion\nShivering is known to be a frequent complication in patients undergoing surgery under neuraxial anesthesia. Shukla et al.[1] have reported the incidence of shivering in patients undergoing surgery under regional anesthesia at 40–70% based on previous studies. The incidence of shivering in our study was 41%.\n\nIn this study, we studied the efficacy of dexmedetomidine in the treatment of post-SA shivering in adults and compared its efficacy with tramadol for the treatment of shivering after SA in patients undergoing various elective surgeries.\n\nAlthough tramadol is an established drug in the treatment of shivering, in this study, we found that dexmedetomidine is equally effective as tramadol in treating post-SA shivering.\n\nThe efficacy of dexmedetomidine is similar to that of a previous study by Blaine Easley et al.[7] who studied the role of dexmedetomidine in the treatment of postoperative shivering in children. All children had a cessation of shivering behavior within 3.5 ± 0.9 min, while in our study cessation of shivering occurred in 2.9 ± 0.23 min (174.12 ± 14.366 s). This difference could be due to different methodology used to see the time for cessation of shivering. While Blaine Easley et al. recorded their results as the number of patients who had stopped shivering after 1 min, after 2 min and so on, and then extrapolated the time taken for cessation of shivering from these data. However, in our study, we directly observed the time taken for shivering to stop (in seconds). Second, while Blaine Easley et al. studied a small sample size of 24 patients, we had taken a much larger sample size of 50 patients. There is limited data where researchers have looked for time for cessation of shivering with dexmedetomidine.\n\nIn this study, the cessation of shivering with tramadol occurred in 277.06 ± 23.374 s (4.61 ± 0.38 min). This is in accordance with previous literature.[1]\n\nThere is a paucity of literature comparing the efficacy of dexmedetomidine with tramadol. However, from our study, we found that the time interval from the administration of treatment to cessation of shivering is significantly less with dexmedetomidine (174.12 ± 14.366 s) than with tramadol (277.06 ± 23.374 s) (P < 0.001).\n\nSix percent patients in dexmedetomidine group in the present study had recurrence of shivering. However, none of the patients had recurrence of shivering after receiving dexmedetomidine in earlier study conducted by Blaine Easley et al.[7] This could be due to the fact that in the study conducted by Blaine Easley et al. the surgeries were conducted under general anesthesia, while in our study the surgeries were performed under SA. While in general anesthesia patients, shivering occurs only on awakening, in SA patients it can occur at any time post-SA. This may lead to a higher incidence of shivering and recurrence of shivering in patients undergoing SA as compared to patients undergoing surgeries under general anesthesia.\n\nThe difference could also be due to the fact that the patients studied in Easley's study were children in the age group of 7–16 years. The incidence of shivering has been reported to be less in children as compared to adults.[8] To date, there have been very few studies regarding the treatment of shivering in children. Hence, it is quite difficult to interpret data regarding recurrence of shivering after administration of pharmacological treatment from the limited number of available studies.\n\nThe third reason for the difference in the recurrence rate between Easley's study and our present study could be due to their small sample size in which they studied only 24 children. Our sample size (n = 50) was nearly double than their sample size.\n\nAbout 16% patients who received tramadol in our study had recurrence of shivering. This incidence was similar to available literature.[9]\n\nIn this study, the incidence of recurrence of shivering with dexmedetomidine was less (6%) as compared to tramadol (16%), but the difference was not statistically significant (P = 0.110).\n\nThe side effects were found to be higher in the case of tramadol as compared to dexmedetomidine. In this study, the incidence of nausea was highly significant in tramadol group compared to the dexmedetomidine group (P < 0.001). Similarly, the incidence of vomiting was significantly higher in the tramadol group compared to dexmedetomidine group (P = 0.041).\n\nPostoperative nausea and vomiting (PONV) is a very unpleasant experience for the patient. Postoperative vomiting/retching can lead to rare but serious medical complications, such as aspiration of gastric contents, suture dehiscence, esophageal rupture, subcutaneous emphysema, or pneumothorax. PONV may delay discharge from PACUs and can be the leading cause of unexpected hospital admission after ambulatory anesthesia.[10]\n\nOne patient in the dexmedetomidine group of our study had bradycardia while none in the tramadol group had bradycardia. However, the incidence was not statistically significant (P = 0.315). Although dexmedetomidine decreases the HR significantly immediately after cessation of shivering, the incidence of bradycardia (HR <60/min) is not significant. The fall in HR immediately after cessation of shivering in Group A is due to the inherent property of dexmedetomidine to decrease HR due to postsynaptic activation of α2 adrenoceptors in the central nervous system. Gradually, the HR picked up in Group A and was comparable in the two groups at all other time intervals.\n\nIn our study, 28% patients of dexmedetomidine group exhibited a Ramsay Sedation Score of 3, while 72% patients had a Ramsay sedation score of 4. However, the level of sedation in these patients never went above Grade 4, and these patients were able to maintain their airway and SpO2 on room air. There was no incidence of hypoxia in our study consequent to the loss of airway due to deeper planes of sedation. This sedation was found to be beneficial in the post-SA patients who were more comfortable in the recovery room with some amount of sedation from which they could be easily awoken.\n\nThere was no incidence of hypotension in either group, which is similar to previous studies.[17] Similarly, none of the patients in either group had itching.\n\nOn overall analysis, more side effects were noted in tramadol group patients compared to dexmedetomidine group patients.\n\nA limitation of this study is that we could not measure the core body temperature. For measurement of core body temperature, the probe needs to be put in the mid-esophagus or near the tympanic membrane or in the urinary bladder. While a probe in the mid-esophagus or near the tympanic membrane is uncomfortable and unacceptable for patients who have been given SA, a probe in the urinary bladder would be an undue source of infection for the patient. Axillary temperature was recorded at regular intervals perioperatively until the end of the study.\n\nConclusion\nDexmedetomidine is a useful alternative to tramadol for cessation of post-SA shivering. Nausea and vomiting are lesser whereas it provides faster relief from shivering.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Shukla U Malhotra K Prabhakar T A comparative study of the effect of clonidine and tramadol on post-spinal anaesthesia shivering Indian J Anaesth 2011 55 242 6 21808395 \n2 Crowley LJ Buggy DJ Shivering and neuraxial anesthesia Reg Anesth Pain Med 2008 33 241 52 18433676 \n3 Chaturvedi S Domkondwar G Control of shivering under regional anaesthesia using tramadol Asian Arch Anaesthesiol Resusc 2002 57 491 6 \n4 De Witte J Sessler DI Perioperative shivering: Physiology and pharmacology Anesthesiology 2002 96 467 84 11818783 \n5 Usta B Gozdemir M Demircioglu RI Muslu B Sert H Yaldiz A Dexmedetomidine for the prevention of shivering during spinal anesthesia Clinics (Sao Paulo) 2011 66 1187 91 21876972 \n6 Sajedi P Khalili G Kyhanifard L Minimum effective dose of tramadol in the treatment of postanesthetic shivering J Res Med Sci 2008 13 75 9 \n7 Blaine Easley R Brady KM Tobias JD Dexmedetomidine for the treatment of postanesthesia shivering in children Paediatr Anaesth 2007 17 341 6 17359402 \n8 Akin A Esmaoglu A Boyaci A Postoperative shivering in children and causative factors Paediatr Anaesth 2005 15 1089 93 16324029 \n9 Joshi SS Arora A George A Shidhaye RV Comparison of intravenous butorphanol, ondansetron and tramadol for shivering during regional anesthesia: A prospective randomized double-blind study Anaesth Pain Intensive Care 2013 17 33 9 \n10 Apfel CC Eriksson LI Fleisher LA Wiener-Kronish JP Young WL Postoperative nausea and vomiting Miller's Anaesthesia 2010 7th ed New York Churchill Livingstone\n\n",
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"journal": "Saudi journal of anaesthesia",
"keywords": "Dexmedetomidine; postoperative nausea and vomiting; shivering; tramadol",
"medline_ta": "Saudi J Anaesth",
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"title": "A comparative study on the efficacy of dexmedetomidine and tramadol on post-spinal anesthesia shivering.",
"title_normalized": "a comparative study on the efficacy of dexmedetomidine and tramadol on post spinal anesthesia shivering"
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"abstract": "We report the use of anakinra to treat a case of a 64-year-old man diagnosed with haemophagocytic lymphohistiocytosis (HLH) with neurological involvement. After the administration of intravenous pulse corticosteroid therapy, immunoglobulin and anakinra the patient showed neurological recovery. However, the recovery was complicated by the perforation of a pre-existing bowel diverticulum. The effect of anakinra on bowel inflammation has not yet been clearly established. It can potentially augment bowel inflammation and contribute to the risk of bowel perforation associated with the concomitant use of corticosteroids.\nAnakinra can potentially augment bowel inflammation.The concomitant use of anakinra and corticosteroids may increase the risk of bowel perforation.Use of anakinra and corticosteroids in patients with pre-existing gastrointestinal diseases requires vigilant observation for abdominal symptoms.",
"affiliations": "Department of Anaesthesiology and Intensive Care, Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.;Department of Anaesthesiology and Intensive Care, Satakunta Central Hospital, Pori, Finland.;Department of Infectious Diseases, Satakunta Central Hospital, Pori, Finland.;Anaesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.",
"authors": "Adamski|Jan|J|;Jäschke|Björn|B|;Nieminen|Tuomas|T|;Weigl|Wojciech|W|",
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"issue": "8(10)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Diverticulitis; gastrointestinal diseases; gut; haemophagocytic lymphohistiocytosis (HLH); interkeukin-1 (IL-1) receptor antagonist",
"medline_ta": "Eur J Case Rep Intern Med",
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"title": "Bowel Perforation During Haemophagocytic Lymphohistiocytosis Treatment with Corticosteroids and Anakinra.",
"title_normalized": "bowel perforation during haemophagocytic lymphohistiocytosis treatment with corticosteroids and anakinra"
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"abstract": "Cryptococcal infection constitutes around 3% of opportunistic infections in solid organ transplant recipients. Most common organ affected in renal transplant recipients (RTRs) is central nervous system and usually presents with chronic meningoencephalitis (CME). Ischaemic stroke as a consequence of cryptococcal meningoencephalitisis rare and possibly due to the involvement of intracranial vessel by exudates causing vasculitis-related thrombosis. In this context, we describe an unusual case of asymptomatic cryptococcaemia in an RTR, progressing on to acute ischaemic stroke secondary to acute CME with near complete neurological recovery following timely diagnosis, early and appropriate antifungal treatment. The index case attempts to re-emphasise the significance of mandatory screening required to exclude the possibility of dissemination of cryptococcaemia in RTRs besides highlighting the requirement of prolonged induction phase with combination therapy, particularly in presence of stroke.",
"affiliations": "Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Sood|Vivek|V|;Pattanashetti|Navin|N|;Ramachandran|Raja|R|;Gupta|Krishan Lal|KL|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D005437:Flucytosine",
"country": "England",
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"doi": "10.1136/bcr-2018-228115",
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"issue": "12(4)",
"journal": "BMJ case reports",
"keywords": "cryptococcus; meningitis; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D058070:Asymptomatic Diseases; D002544:Cerebral Infarction; D003455:Cryptococcus neoformans; D005437:Flucytosine; D006801:Humans; D007121:Immunocompetence; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D016919:Meningitis, Cryptococcal; D066027:Transplant Recipients",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31005864",
"pubdate": "2019-04-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19441980;28149116;28421878;19541406;28904437;19613840;11353098;25559998;19528182;21605185;20218876;28149110;18840080",
"title": "Deceptively asymptomatic cryptococcaemia in a renal transplant recipient: the lull before a storm.",
"title_normalized": "deceptively asymptomatic cryptococcaemia in a renal transplant recipient the lull before a storm"
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"abstract": "Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation and destruction of normal tissue architecture. The present study aimed to evaluate the inflammatory signaling cascade by analyzing the cytokines of AAA tissue. Materials and Methods: We analyzed the comprehensive cytokine secretion profiles of 52 cytokines from human AAA in four patients with AAA using fluorescent beads-based multiplex assay. Further, the effect of janus kinase (JAK) inhibition by pyridone 6 on cytokine profiles was also evaluated. Results: Cytokine secretion profiles were found to be similar among the four patients. A high level of JAK/signal transducers and activator of transcription (STAT) pathway activity in AAA tissue in culture was maintained, which may be attributed to the secretion of endogenous JAK-activating cytokines. Inhibition of JAK by pyridone 6 resulted in the suppression of STAT3 phosphorylation and secretion of a subset of chemokines and JAK-activating cytokines. However, the inhibition of JAK had no effect on the secretion of matrix metalloproteinase (MMP)-2, MMP-9, or TGF-β family that is responsible for the metabolism of extracellular matrix. Conclusion: The findings of the present study suggested that AAA tissue exhibits a stereotypical profile of cytokine secretion, where JAK/STAT pathway may play a role in regulating a subset of cytokines. Identification of such a cytokine profile may reveal potential diagnostic markers and therapeutic targets for AAA.",
"affiliations": "Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.;Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.",
"authors": "Ohno|Tomokazu|T|;Aoki|Hiroki|H|;Ohno|Satoko|S|;Nishihara|Michihide|M|;Furusho|Aya|A|;Hiromatsu|Shinichi|S|;Akashi|Hidetoshi|H|;Fukumoto|Yoshihiro|Y|;Tanaka|Hiroyuki|H|",
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"doi": "10.3400/avd.oa.17-00086",
"fulltext": "\n==== Front\nAnn Vasc DisAnn Vasc DisavdAnnals of Vascular Diseases1881-641X1881-6428Japanese College of Angiology / The Japanese Society for Vascular Surgery / Japanese Society of Phlebology Italian Cultural Institute Building 8F, Kudan-Minami 2-1-30, Chiyoda-ku, Tokyo 102-0074, Japan 10.3400/avd.oa.17-00086Original ArticleCytokine Profile of Human Abdominal Aortic Aneurysm: Involvement of JAK/STAT Pathway Ohno Tomokazu 1Aoki Hiroki *2Ohno Satoko 3Nishihara Michihide 3Furusho Aya 3Hiromatsu Shinichi 1Akashi Hidetoshi 1Fukumoto Yoshihiro 3Tanaka Hiroyuki 11 Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan2 Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan3 Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, JapanCorresponding author: Hiroki Aoki, MBA, MD, PhD. Cardiovascular Research Institute, Kurume University, 67 Asahimachi, Kurume, Fukuoka 830-0011, Japan Tel: +81-942-31-7880, Fax: +81-942-31-7707, E-mail: haoki@med.kurume-u.ac.jp25 3 2018 11 1 84 90 16 8 2017 7 10 2017 Copyright © 2018 The Editorial Committee of Annals of Vascular Diseases2018This article is distributed under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided the credit of the original work, a link to the license, and indication of any change are properly given, and the original work is not used for commercial purposes. Remixed or transformed contributions must be distributed under the same license as the original.Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation and destruction of normal tissue architecture. The present study aimed to evaluate the inflammatory signaling cascade by analyzing the cytokines of AAA tissue.\n\nMaterials and Methods: We analyzed the comprehensive cytokine secretion profiles of 52 cytokines from human AAA in four patients with AAA using fluorescent beads-based multiplex assay. Further, the effect of janus kinase (JAK) inhibition by pyridone 6 on cytokine profiles was also evaluated.\n\nResults: Cytokine secretion profiles were found to be similar among the four patients. A high level of JAK/signal transducers and activator of transcription (STAT) pathway activity in AAA tissue in culture was maintained, which may be attributed to the secretion of endogenous JAK-activating cytokines. Inhibition of JAK by pyridone 6 resulted in the suppression of STAT3 phosphorylation and secretion of a subset of chemokines and JAK-activating cytokines. However, the inhibition of JAK had no effect on the secretion of matrix metalloproteinase (MMP)-2, MMP-9, or TGF-β family that is responsible for the metabolism of extracellular matrix.\n\nConclusion: The findings of the present study suggested that AAA tissue exhibits a stereotypical profile of cytokine secretion, where JAK/STAT pathway may play a role in regulating a subset of cytokines. Identification of such a cytokine profile may reveal potential diagnostic markers and therapeutic targets for AAA.\n\nabdominal aortic aneurysmcytokinesJAK/STATpyridone 6\n==== Body\nIntroduction\nAbdominal aortic aneurysm (AAA) is the most prevalent aortic disease in the elderly, with unidentified etiology.1) AAA is primarily characterized by the weakening of aortic walls because of degradation and extensive remodeling of the load-bearing extracellular matrix (ECM), leading to progressive dilatation of the abdominal aorta. Although no symptoms are manifested in most patients, AAA progress over the time and eventually ruptures, leading to high mortality. Presently, the therapeutic strategy for AAA is limited to surgical intervention with open repair or endovascular stent-graft implantation for AAAs >5.5 cm in diameter. However, smaller AAAs are usually managed by “watchful waiting,” as effective non-surgical therapy is unavailable.\n\nRecently, studies have highlighted the significance of inflammatory response in the degradation and remodeling of ECM in AAA lesions.2,3) During vascular remodeling, inflammatory cells secrete proteolytic enzymes including matrix metalloproteinases (MMPs) that are involved in the degradation of ECM in aortic walls.4) Various cell types have been reported to be important in this inflammatory response, including monocytes/macrophages, mast cells, neutrophils, and lymphocytes.2,3) In addition to the secretion of tissue degrading enzymes, these cells secrete a number of cytokines that mediate complex cell–cell interactions and maintain and amplify the inflammation cascade in aortic tissue. Thus, these cytokines regulate migration, proliferation, differentiation, activation, and survival of inflammatory and interstitial cells through interactions with specific receptors on various cell types and activate janus kinase (JAK)/signal transducers and activator of transcription (STAT), nuclear factor-kappa B (NFκB), and mitogen-activated protein kinase (MAP) kinase signaling pathways, thus building a complex network of inflammatory signaling.\n\nDespite the fact that animal studies have identified several potential therapeutic targets in the pathogenesis of AAA, pharmacotherapy for AAA is yet to be established. This is partially because of the complexity of human AAA compared to animal models of AAA.5,6) To overcome the problem, the characterization of inflammatory system in human AAA tissue is necessary. Indeed, previous studies have demonstrated the increased expression of proinflammatory cytokines at the mRNA and protein levels in human AAA tissue.7) However, a number of cytokines secreted from AAA tissue have not yet been analyzed.\n\nTherefore, for better understanding of the inflammatory signaling cascade in human AAA, we examined cytokine secretions from the human AAA tissue in culture. Further, we also studied the effect of pyridone 6, a pan-JAK inhibitor, because JAK/STAT is one of the leading signaling pathways in inflammatory response, reported to be involved in human AAA,8) and hypothesized to have a significant role in the pathogenesis of AAA.9)\n\nMethods\nHuman AAA tissue culture\nThe Institutional Review Board of Kurume University Hospital approved all protocols that involved human specimens, and all the samples were obtained with written informed consent from the patients. Aortic wall specimens were collected from randomly selected four patients (Table 1) during the open aneurysm repair surgery to replace an aneurysm with the artificial graft as described before.10) The anterior aortic wall at the site of transition from the normal diameter to the dilated lesion (approximately 30 mm in length and 15 mm in width) was collected during surgery (Figs. 1A and 1B). The specimens were immediately immersed in ice-cold phosphate buffered saline (PBS, #10010023, Thermo Fisher Scientific, Waltham, MA, USA) containing penicillin/streptomycin (1,000 units/mL each, #15140122, Thermo Fisher Scientific, Waltham, MA, USA) to minimize the proinflammatory effect of microbes, and transported to the laboratory. In the laboratory, the aortic wall specimens were transferred to Dulbecco’s modified Eagle medium (DMEM) supplemented with penicillin and streptomycin (1,000 units/mL each), rinsed and cleaned of the blood clot and loose connective tissue aseptically. Because of heterogeneity in the histopathological features of the aortic aneurysmal walls, the following procedure was performed to minimize variation in tissue content in each well of the 12-well culture plate. The aortic wall was cut into three pieces; proximal, middle, and distal portions of the aortic wall. Each piece was further cut into small pieces (approximately 2 mm×2 mm). Further, the small pieces were transferred to the 12-well tissue culture plate, such that each well received an equal number of pieces from the original proximal, middle and distal portion of the aortic wall. After this preparatory procedure, the specimens were cultured in 2 mL DMEM at 37°C in a humidified incubator with 5% CO2 and 95% room air. After 48 h, the culture media was replaced with fresh DMEM to remove blood clots and tissue debris, and further experiments were conducted. The AAA tissue culture was maintained for 48 h to obtain conditioned media to detect the basal cytokine secretions (PRE group). Furthermore, the culture media was replaced with the fresh DMEM with 0, 1, and 10 µM pyridone 6 (#420099, Millipore, Burlington, MA, USA) or 100 ng/mL IL-6 (#206-IL, R&D Systems, Minneapolis, MN, USA). After 48 h, the conditioned media was collected to measure cytokine secretion (POST group) in the presence or absence of pyridone 6 or IL-6.\n\nTable 1 Patient characteristics\nPatient\tAge\tGender\tMaximal diameter (mm)\tSmoking\tHT\tDL\tDM\tCOPD\tCVD\tOther comorbidities\tMedication\tFamily history of CVD\t\n#1\t76\tM\t53\t+\t−\t−\t−\t+\t−\tAppendicitis, right femur fracture, duodenal ulcer, ocular fundus bleeding\tFamotidine, magnesium oxide\t−\t\n#2\t66\tM\t46\t+\t+\t+\t−\t−\t−\t\tAspirin, doxazosin, nifedipine, ketoprofen, rosuvastatin, probenecid, ifenprodil\t−\t\n#3\t77\tM\t47\t+\t+\t+\t−\t−\tCoronary artery disease\tChronic kidney disease (Stage 4)\tWarfarin, aspirin, methyldigoxin, carvedilol, enalapril, azosemide, spironolactone, pravastatin, ubidecarenone, ethyl icosapentate\tCardiac hypertrophy (father)\t\n#4\t81\tM\t50\t−\t+\t+\t−\t−\t−\tMelanoma, colon cancer, prostate cancer, hepatitis C, cataract, glaucoma\tAmlodipine, allopurinol, distigmine, bicalutamide, tamsulosin, ezetimibe, eviprostat\tCongestive heart failure (father)\t\nCOPD: chronic obstructive pulmonary disease; CVD: cardiovascular disease; DL: dyslipidemia; DM: diabetes mellitus; HT: hypertension\n\nFig. 1 Human AAA tissue culture and cytokine secretion. (A) Depicted is the procedure of human AAA tissue culture. The anterior aortic wall (approximately 30 mm in length and 15 mm in width) was collected during surgery. The aortic wall was cut into three pieces; proximal, middle, and distal portions of the aortic wall. Each piece was further cut into small pieces (approximately 2 mm×2 mm). Further, the small pieces were transferred to a 12-well tissue culture plate, so that each well received an equal number of pieces from the original proximal, middle, and distal portion of the aortic wall. (B) Culture media was replaced with the fresh DMEM to remove blood clots and tissue debris, 48 h after starting the culture, and further experiments were conducted. After another 48 h of incubating the culture with the indicated concentrations of pyridone 6, the culture media was collected to measure the levels of cytokines secreted into the media. (C) Quantitative analysis of the basal secretion in human AAA tissue culture from four patients is demonstrated for a panel of 49 cytokines. Conditioned media was collected after incubating with human AAA tissue in 12-well culture plates for 48 h, and subjected to the beads-based multiplex assay. Data are expressed as means±standard errors from 4–8 wells of a 12-well culture plate with similar culture conditions.\nExpression assays\nWe measured the profiles of 52 cytokines (Table 2) that were secreted into the conditioned media using fluorescent beads-based multiplex assay (Bio-Plex, Bio-Rad, Hercules, CA, USA), using human cytokine 27-plex (#M500KCAF0Y, Bio-Rad), cytokine 21-plex (#MF0005KMII, Bio-Rad), VCAM-1 (#171B6022M, Bio-Rad), ICAM-1 (#171B6009M, Bio-Rad), and human TGF-β 3-plex (#171W4001M, Bio-Rad) assays according to the manufacturer’s protocol. Cytokine secretion was normalized for the wet weight of tissue as measured by the end of culture. The effect of pyridone 6 or IL-6 on cytokine secretion was estimated by calculating the ratio of cytokine secretion in the presence and absence of pyridone 6 or IL-6 (POST) to the basal cytokine secretion (PRE) (Fig. 1). Immunoblotting was performed for phosphorylated STAT3 (Tyr705, #9145, Cell Signaling Technology, Danvers, MA, USA), total STAT3 (#4904, Cell Signaling Technology), and GAPDH (#MAB374, Millipore), which served as the internal reference. Gelatin zymography was performed using the Novex zymogram system (#EC6175BOX, Thermo Fisher Scientific) according to the manufacturer’s instruction.\n\nTable 2 Cytokine panel in this study\nAbbreviations\tCommon names\t\nCTACK\tCutaneous T cell-attracting chemokine (CCL27)\t\nEotaxin\tEotaxin (CCL11)\t\nFGF basic\tFibroblast growth factor basic (FGF2)\t\nG-CSF\tGranulocyte colony-stimulating factor (CSF3)\t\nGM-CSF\tGranulocyte macrophage colony-stimulating factor\t\nGROα\tGrowth-regulated protein alpha (CXCL1)\t\nHGF\tHepatocyte growth factor\t\nICAM-1\tIntercellular adhesion molecule-1\t\nIFN-γ\tInterferon-γ\t\nIL-10\tInterleukin-10\t\nIL-12 p40\tInterleukin-12 p40 subunit\t\nIL-12 p70\tInterleukin-12 p70 subunit\t\nIL-13\tInterleukin-13\t\nIL-15\tInterleukin-15\t\nIL-16\tInterleukin-16\t\nIL-17\tInterleukin-17\t\nIL-18\tInterleukin-18\t\nIL-1ra\tInterleukin-1 receptor antagonist\t\nIL-1α\tInterleukin-1α\t\nIL-1β\tInterleukin-1β\t\nIL-2\tInterleukin-2\t\nIL-2Ra\tInterleukin-2 receptor α chain\t\nIL-3\tInterleukin-3\t\nIL-4\tInterleukin-4\t\nIL-5\tInterleukin-5\t\nIL-6\tInterleukin-6\t\nIL-7\tInterleukin-7\t\nIL-8\tInterleukin-8 (CXCL8)\t\nIL-9\tInterleukin-9\t\nIP-10\tInterferon-γ-induced protein 10 (CXCL10)\t\nLIF\tLeukemia inhibitory factor\t\nM-CSF\tMacrophage colony-stimulating factor (CSF1)\t\nMCP-1\tMonocyte chemoattractant protein-1 (CCL2)\t\nMCP-3\tMonocyte chemoattractant protein-3 (CCL7)\t\nMIF\tMacrophage migration inhibitory factor\t\nMIG\tMonokine induced by γ-interferon (CXCL9)\t\nMIP-1α\tMacrophage inflammatory protein-1α (CCL3)\t\nMIP-1β\tMacrophage inflammatory protein-1β (CCL4)\t\nPDGF-BB\tPlatelet-derived growth factor-BB\t\nRANTES\tRegulated on activation, normal T cell expressed and secreted (CCL5)\t\nSCF\tStem cell factor\t\nSCGF-β\tStem cell growth factor-β (CLEC11A)a\t\nSDF-1α\tStromal cell-derived factor 1alpha (CXCL12)\t\nTGF-β1\tTransforming growth factor-β1\t\nTGF-β2\tTransforming growth factor-β2\t\nTGF-β3\tTransforming growth factor-β3\t\nTNF-α\tTumor necrosis factor-α (TNF)\t\nTNF-β\tTumor necrosis factor-β (lymphotoxin-α) (LTA)\t\nTRAIL\tTNF-related apoptosis-inducing ligand (TNFSF10)\t\nVCAM-1\tVascular cell adhesion molecule-2\t\nVEGF\tVascular endothelial growth factor\t\nβ-NGF\tβ-nerve growth factor\t\nStatistical analyses\nAll the statistical analyses were performed using GraphPad PRISM (Ver. 5, GraphPad Software, La Jolla, CA, USA). The data are expressed as mean±standard errors. Mann–Whitney U test was used to compare the difference between the two groups. Kruskal–Wallis test was used to compare three or more groups with Dunn’s correction for multiple comparisons. A p value ≤0.05 was considered statistically significant.\n\nResults\nCytokine profile in AAA tissue culture\nWe determined the culture media levels for 52 cytokines (soluble mediators) in the cultures of AAA derived from four patients. The cytokine profile revealed minute variation for each cytokine in a set of tissue cultures obtained from a single patient, possibly reflecting the heterogeneity of AAA tissue (Fig. 1C). However, variation among cytokines for a single patient was small as compared to the difference in cytokine levels among the four patients, and the orders of the cytokines were similar among the patients. Functional class of cytokines which had the highest level of secretion were JAK/STAT-activating cytokines: IL-6, MIF, LIF, and IFN-γ, chemokines; MCP-1, IL-8, MIG, IP-10, and GROα, growth factors; SCGF-β, HGF, and VEGF, and cell adhesion molecules; ICAM-1 and VCAM-1. These findings suggested that the intrinsic manifestation of inflammation was similar among the patients.\n\nEffect of JAK inhibition on cytokine secretions\nFurther, we examined the effect of pyridone 6, a pan-JAK inhibitor, on the activation of STAT3 (phosphorylation at Y705) and cytokine secretions. Pyridone 6 suppressed the phosphorylation of STAT3 during the 48 h of culture, without affecting the expression of STAT3 (Figs. 2A–2C).\n\nFig. 2 Effect of pyridone 6 on the activity of STAT3, MMPs, and TGF-β in human AAA tissue culture. Effect of pyridone 6 on STAT3 activity was evaluated by immunoblotting for activated (phosphorylated) STAT3 (P-STAT3) and total STAT3 after incubation of the AAA tissue with the indicated concentration of pyridone 6 for 48 h. (A) Representative images of immunoblotting for P-STAT3 and STAT3 are shown, and GAPDH was used as the internal control. (B) Expression levels of P-STAT3 normalized to that of GAPDH are represented. (C) Expression levels of STAT3 normalized to that of GAPDH are represented. (D) Secretions of MMP-9 and -2 were evaluated by gelatin zymography of the conditioned media. After collecting the basal secretion for 48 h, AAA tissue culture was treated with or without 100 ng/mL IL-6 and the indicated concentrations of pyridone 6. (E) Basal secretions of TGF-β family are shown in the conditioned media after 48 h of culture. (F) The effect of 10 µM pyridone 6 on the secretions of TGF-β family of cytokines is represented. Data are expressed as means±standard errors. The sample without pyridone 6 treatment was assigned a value of 1. * p<0.05.\nMoreover, to evaluate the role of JAK/STAT pathway in ECM degradation, we examined the effect of pyridone 6 on the secretion of MMP-2 and MMP-9 by gelatin zymography (Fig. 2D). Both MMP-2 and MMP-9 were detected at significant levels in the culture supernatant of human AAA tissue. However, the treatment of AAA culture with pyridone 6 exhibited no apparent effect on the secretion of MMP-9 or MMP-2 at 1 µM and may have caused marginal suppression of MMP-2 at 10 µM. Further, the addition of exogenous IL-6 had no significant effect on the secretion of MMP-9 or MMP-2, probably because of high endogenous IL-6 secretion level during tissue culture. These results suggested that JAK/STAT pathway does not play a significant role in the secretion of these MMPs.\n\nWe measured the secretions of TGF-β1, TGF-β2, and TGF-β3 (Fig. 2E), which are important for the regulation of inflammation and ECM metabolism and their sensitivity to pyridone 6 (Fig. 2F) in two sets of human AAA culture from different patients. The secretion of TGF-β isoforms was comparable between the two sets of culture, where TGF-β1 had the highest expression. None of the TGF-β isoforms were sensitive to pyridone 6, indicating that TGF-β secretion was independent of JAK/STAT pathway in this experimental condition.\n\nNext, we evaluated the effect of pyridone 6 (10 µM) on a panel of cytokine secretions. The secretion level of a subset of cytokines decreased; however, treatment with pyridone 6 did not increase the secretion levels of any of the cytokines (Fig. 3A). There was no significant correlation between the pyridone 6 sensitivity and cytokine secretion levels (Fig. 3B). The functional classes of pyridone 6-sensitive cytokines were JAK/STAT-activating interleukins (IL-2, IL-4, IL-9, IL-12p70, IL-15, and IL-18), chemokines (MCP-3, MIP-1β, IL-8, SDF-1α, and Eotaxin), and growth factors (VEGF and PDGF-BB). These results indicated that JAK/STAT pathway promotes the secretion of a subset of cytokines.\n\nFig. 3 Effect of pyridone 6 on cytokine secretions in human AAA tissue culture. Human AAA tissue was cultured for 48 h without any treatment to measure the basal cytokine secretion (basal secretion). AAA tissue was further cultured with or without 10 µM pyridone 6 for another 48 h (secretion after treatment). The effect of pyridone 6 on cytokine secretion was assessed by the P6/Cont ratio as indicated in Fig. 1. Data are expressed as means±standard errors in the order of the P6/Cont ratio. * p<0.05 for the P6/Cont ratio of the corresponding cytokines.\nDiscussion\nIn the present study, we examined the cytokine secretion profile of AAA tissue in culture, which revealed reproducible cytokine profiles among the four sets of tissue culture derived from different patients. The results were largely consistent with previous studies that examined either the relative expression levels of a panel of cytokines using immunoassays, quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), and deoxyribonucleic acid (DNA) microarray or the absolute expression levels of specific cytokines by enzyme-linked immunosorbent assays (ELISAs).7) Furthermore, we also evaluated the effect of pyridone 6, a pan-JAK inhibitor, to determine whether or not JAK/STAT pathway regulates the secretion of a subset of cytokines in AAA tissue culture.\n\nStudies indicate that inflammatory responses may contribute to aortic wall destruction in AAA.2,3) Because inflammatory cells and interstitial cells work in concert through various cytokines to maintain and promote inflammation, cytokines and their signaling pathways represent potential diagnostic markers and therapeutic targets.7) It is noteworthy that cytokine therapy has already been applied in clinical practice as neutralizing antibodies and decoy receptors for TNF-α, IL-6, and other cytokines, which resulted in excellent clinical outcomes in inflammatory disorders, including rheumatoid arthritis, inflammatory bowel syndrome, and psoriasis.11) To identify the significance of cytokine therapy for AAA, it is essential to understand how cytokines are involved in the pathogenesis of AAAs.6,7) Previous studies have demonstrated that cytokine inhibition, including MCP-1,12) IP-10,13) TNF-α,14,15) IL-1β,16) IL-4,17) IL-5,18) IL-17,19) IFN-γ,20) SDF-1,21) GM-CSF,22) and VEGF,23) was effective in suppressing the development of AAA in mice. However, other cytokines, including TGF-β,24,25) IL-10,25) IP-10, and IFN-γ,13) have been reported to exhibit protective effects in experimental AAA. Furthermore, studies have also highlighted the complexity of the inflammatory network and cytokine functions as exemplified by the fact that IFN-γ and IP-10 have been reported to have either promotive or suppressive effects in experimental AAA.13,20) Although animal studies have provided critical knowledge in understanding the mechanism of AAA, no single model recapitulates all the characteristics of human AAA. Besides, owing to the heterogeneity in histopathology1) and clinical courses among patients,26) cytokine profiles may be different among patients. Therefore, in addition to animal models of AAA, the role of cytokines should be characterized in the context of human AAA.6) Notably, while the overall profile of cytokine secretions was similar in the four patients in the present study, some of the highly expressed cytokines, including MCP-1, SCGF-β, LIF, and G-CSF, exhibited a difference of >10-fold among the patients. Whether and how differences secretion profiles of specific cytokines reflect AAA activity and status remains to be elucidated in future research.\n\nOur results indicated that STAT3 was found to be highly activated in human AAA tissue for several days in culture. Moreover, the exogenous addition of IL-6 to the tissue culture did not affect P-STAT3 levels (data not shown); it is possible that JAK/STAT pathway was already activated by the endogenous inflammatory cytokines within the AAA tissue as previously reported.8) Indeed, IL-6 accumulated to approximately 100 ng/mL during 48 h of tissue culture, which would be sufficient to fully activate STAT3. In turn, JAK/STAT pathway in AAA tissue may promote the secretion of a subset of cytokines, as previously reported27,28) and as demonstrated in the present study. However, consistent with previous reports,29,30) JAK/STAT pathway did not appear to regulate the secretion of MMP-2, MMP-9, or TGF-β family.\n\nThe major limitations of the present study are the small number of patients, which precluded thorough characterization of the inflammatory network in human AAA tissue. Also, the role of cytokines that promote cell infiltration in the pathogenesis of AAA may be underestimated, because tissue in culture does not have a continuous supply of inflammatory cells from the bloodstream and surrounding tissue. Another limitation was the absence of normal tissue or tissue with other aortic diseases for comparison in the experimental group, which precluded the identification of AAA-specific cytokines. Because of these limitations, the present study should be observed as an initial screening for cytokines secreted at high levels among a panel of cytokines to characterize the inflammatory network within human AAA tissue. Besides, it should be noted that isolated tissue in culture differs starkly from aortic tissue in patients. For example, the aortic tissue in culture is free from hemodynamic stress, circulating humoral factors, or neuronal stimuli. Future studies are required to test whether cytokines secreted at high levels and their signaling pathways can serve as diagnostic markers or therapeutic targets for AAA.\n\nConclusion\nIn conclusion, we have characterized the profile of the secreted cytokines in AAA tissue, which appeared to be partly maintained by endogenous JAK/STAT pathway. Deciphering such an inflammatory network would lead to the identification of therapeutic targets, including cytokines and signaling molecules, and diagnostic markers for evaluating the activity of chronic inflammation in the pathogenesis of AAA.\n\nDisclosure Statement\nThe authors have no conflict of interest.\n\nAuthor Contributions\nStudy conception: TO, HAo, YF, HT\n\nSample curation: TO, SH, HAk, HT\n\nAnalysis: TO, HA, SO, MN, AF\n\nWriting: TO, HAo\n\nFunding acquisition: HAo, YF, HT\n\nCritical review and revision: all authors\n\nFinal approval of the article: all authors\n\nAccountability for all aspects of the work: all authors\n==== Refs\n1) Curci JA, Baxter BT, Thompson RW. Arterial aneurysms: etiologic considerations. In: Rutherford RB ed. Vascular Surgery. Philadelphia: Saunders, 2005 : 475-92.\n2) Aoki H, Yoshimura K, Matsuzaki M. 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Bone marrow-derived monocyte chemoattractant protein-1 receptor CCR2 is critical in angiotensin II-induced acceleration of atherosclerosis and aneurysm formation in hypercholesterolemic mice. \nArterioscler Thromb Vasc Biol \n2004 ; 24 : e174 -8 .15331433 \n13) King VL, Lin AY, Kristo F, et al. Interferon-gamma and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture. \nCirculation \n2009 ; 119 : 426 -35 .19139386 \n14) Hingorani A, Ascher E, Scheinman M, et al. The effect of tumor necrosis factor binding protein and interleukin-1 receptor antagonist on the development of abdominal aortic aneurysms in a rat model. \nJ Vasc Surg \n1998 ; 28 : 522 -6 .9737463 \n15) Kaneko H, Anzai T, Horiuchi K, et al. Tumor necrosis factor-alpha converting enzyme is a key mediator of abdominal aortic aneurysm development. \nAtherosclerosis \n2011 ; 218 : 470 -8 .21722904 \n16) Johnston WF, Salmon M, Su G, et al. Genetic and pharmacologic disruption of interleukin-1beta signaling inhibits experimental aortic aneurysm formation. \nArterioscler Thromb Vasc Biol \n2013 ; 33 : 294 -304 .23288154 \n17) Shimizu K, Shichiri M, Libby P, et al. Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas. \nJ Clin Invest \n2004 ; 114 : 300 -8 .15254597 \n18) Xu J, Ehrman B, Graham LM, et al. Interleukin-5 is a potential mediator of angiotensin II-induced aneurysm formation in apolipoprotein E knockout mice. \nJ Surg Res \n2012 ; 178 : 512 -8 .22459292 \n19) Sharma AK, Lu G, Jester A, et al. Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment. \nCirculation \n2012 ; 126 Suppl 1: S38 -45 .22965992 \n20) Xiong W, Zhao Y, Prall A, et al. 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TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. \nJ Clin Invest \n2010 ; 120 : 422 -32 .20101093 \n25) Meng X, Yang J, Zhang K, et al. Regulatory T cells prevent angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E knockout mice. \nHypertension \n2014 ; 64 : 875 -82 .25024283 \n26) Brady AR, Thompson SG, Fowkes FG, et al. Abdominal aortic aneurysm expansion: risk factors and time intervals for surveillance. \nCirculation \n2004 ; 110 : 16 -21 .15210603 \n27) Spörri B, Muller KM, Wiesmann U, et al. Soluble IL-6 receptor induces calcium flux and selectively modulates chemokine expression in human dermal fibroblasts. \nInt Immunol \n1999 ; 11 : 1053 -8 .10383937 \n28) Qu T, Yang H, Walston JD, et al. Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty. \nCytokine \n2009 ; 46 : 319 -24 .19342252 \n29) Yoshizaki T, Sato H, Furukawa M, et al. The expression of matrix metalloproteinase 9 is enhanced by Epstein–Barr virus latent membrane protein 1. \nProc Natl Acad Sci USA \n1998 ; 95 : 3621 -6 .9520415 \n30) Araki Y, Tsuzuki Wada T, Aizaki Y, et al. Histone methylation and STAT-3 differentially regulate interleukin-6-induced matrix metalloproteinase gene activation in rheumatoid arthritis synovial fibroblasts. \nArthritis Rheumatol \n2016 ; 68 : 1111 -23 .26713842\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1881-641X",
"issue": "11(1)",
"journal": "Annals of vascular diseases",
"keywords": "JAK/STAT; abdominal aortic aneurysm; cytokines; pyridone 6",
"medline_ta": "Ann Vasc Dis",
"mesh_terms": null,
"nlm_unique_id": "101471467",
"other_id": null,
"pages": "84-90",
"pmc": null,
"pmid": "29682112",
"pubdate": "2018-03-25",
"publication_types": "D016428:Journal Article",
"references": "20036416;17522832;23288154;19139386;20101093;19342252;15331433;22965992;15254597;19729799;25024283;17484978;22833280;25923510;26713842;15210603;17182928;24876351;14764734;9737463;21722904;9520415;10383937;23044097;23111417;16311603;21764069;22459292;21436157",
"title": "Cytokine Profile of Human Abdominal Aortic Aneurysm: Involvement of JAK/STAT Pathway.",
"title_normalized": "cytokine profile of human abdominal aortic aneurysm involvement of jak stat pathway"
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"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-040501",
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"abstract": "Calciphylaxis is commonly associated with end-stage renal disease (ESRD) and renal transplant. We present a rare case of early onset calciphylaxis in a patient presenting with acute kidney injury (AKI) secondary to anti-glomerular basement membrane (anti-GBM) antibody disease. A 65-year-old obese Caucasian woman with type 2 diabetes mellitus and hypertension presented with a 1-month history of painless gross haematuria and worsening lower extremity oedema. Laboratory results indicated AKI and nephrotic-range proteinuria. Anti-glomerular antibodies were elevated. Renal biopsy revealed focal crescentic glomerulonephritis with linear capillary immunoglobulin G staining consistent with anti-GBM antibody disease. She was treated with haemodialysis, plasmapheresis, steroids, bumetanide and cyclophosphamide. Two months later, she developed necrotic lesions on bilateral thighs. Wound biopsy was consistent with calciphylaxis. This case highlights that calciphylaxis, usually seen in patients with chronic kidney disease or ESRD, can manifest in patients with AKI as well.",
"affiliations": "Internal Medicine, Albany Medical Center Hospital, Albany, New York, USA shahzas1@amc.edu.;Nephrology and Hypertension, Albany Medical Center Hospital, Albany, New York, USA.;Pathology, Albany Medical Center Hospital, Albany, New York, USA.;Nephrology and Hypertension, Albany Medical Center Hospital, Albany, New York, USA.",
"authors": "Shahzad|Sheikh Raza|SR|;Alfaris|Faris|F|;Arslan|Mustafa Erdem|ME|http://orcid.org/0000-0002-0683-7421;Mehta|Swati|S|",
"chemical_list": "D001323:Autoantibodies",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-241265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(4)",
"journal": "BMJ case reports",
"keywords": "acute renal failure; calcium and bone; dialysis; nephrotic syndrome; proteinurea",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D019867:Anti-Glomerular Basement Membrane Disease; D001323:Autoantibodies; D002115:Calciphylaxis; D003924:Diabetes Mellitus, Type 2; D005260:Female; D005921:Glomerulonephritis; D006470:Hemorrhage; D006801:Humans; D008171:Lung Diseases",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33827879",
"pubdate": "2021-04-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early onset calciphylaxis following acute kidney injury secondary to anti-glomerular basement membrane antibody disease.",
"title_normalized": "early onset calciphylaxis following acute kidney injury secondary to anti glomerular basement membrane antibody disease"
} | [
{
"companynumb": "US-MLMSERVICE-20220106-3304302-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional":... |
{
"abstract": "A 30-year-old female presented with recurrent opticospinal demyelinating attacks after introduction of nivolumab to treat Hodgkin's lymphoma. Paraneoplastic, neuronal surface, and demyelinating antibodies were negative from the serum and/or cerebrospinal fluid. Oligoclonal bands were negative and she met clinical criteria for NMOSD without AQP4-IgG. She could not tolerate plasmapheresis due to transfusion-related acute lung injury but responded well to corticosteroids and discontinuation of nivolumab. The precipitation of typical NMOSD without AQP4-IgG syndrome by a checkpoint inhibitor suggests a possible T-cell mediated pathogenesis. This may help explain why this patient group lacked response to B-cell therapies in NMOSD clinical trials.",
"affiliations": "Multiple Sclerosis and Neuroimmunology Program, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, 44106, OH, United States. Electronic address: salamnasrallah@gmail.com.;Case Western Reserve University, School of Medicine, Cleveland, OH, United States.",
"authors": "Nasralla|Salam|S|;Abboud|Hesham|H|",
"chemical_list": "D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2020.102451",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "46()",
"journal": "Multiple sclerosis and related disorders",
"keywords": null,
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D051401:Aquaporin 4; D001323:Autoantibodies; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D009471:Neuromyelitis Optica; D013601:T-Lymphocytes",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102451",
"pmc": null,
"pmid": "32835902",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Is neuromyelitis optica without AQP4-IgG a T-cell mediated disease? insights from checkpoint inhibitor immune-related adverse events.",
"title_normalized": "is neuromyelitis optica without aqp4 igg a t cell mediated disease insights from checkpoint inhibitor immune related adverse events"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-072704",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nInitial clinical manifestations of NMOSD may rarely overlap with MS. Fingolimod may trigger severe attacks in patients with NMOSD previously misdiagnosed as MS. These cases are rare and their pathophysiology remains elusive.\n\n\nMETHODS\nWe recruited all NMOSD patients treated by fingolimod in a single-center cohort of Afro-Caribbean neuro-inflammatory patients in Fort-de-France (French West Indies). Six patients were collected from the literature.\n\n\nRESULTS\nAmong 622 patients followed locally for MS, 101 received fingolimod and two suffered severe attacks revealing a typical NMOSD presentation. These two patients were found to have AQP4-IgG. The risk of misdiagnosed NMOSD in MS in our high-risk Afro-Caribbean patients was estimated to be 1.9% (0 to 4.7%). Among the whole cohort, relapses occurred within a month after fingolimod initiation in five patients. All attacks were severe and contrasted with previously benign attacks, suggesting a shift to a more severe disorder. An unusual finding in these patients was large brain lesions.\n\n\nCONCLUSIONS\nAQP4-IgG should be obtained before initiation of fingolimod in high-risk patients, especially in those from areas of high NMOSD prevalence.",
"affiliations": "Service de Neurologie, Centre Hospitalier de Pau, 4 Bd Hauterive, 64000 Pau, France. Electronic address: mickael_bonnan@yahoo.fr.;Service de Neurologie, Hôpital Zobda Quitman, 97261 Fort-de-France, French West Indies.;Service de Neurologie, Hôpital Zobda Quitman, 97261 Fort-de-France, French West Indies.",
"authors": "Bonnan|Mickael|M|;Berthelot|Emeline|E|;Cabre|Philippe|P|",
"chemical_list": "D051401:Aquaporin 4; D001323:Autoantibodies; D000068876:Fingolimod Hydrochloride",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2021.102975",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "52()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Drug side-effect; Fingolimod; Neuromyelitis optica spectrum disorders",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D051401:Aquaporin 4; D001323:Autoantibodies; D000068876:Fingolimod Hydrochloride; D005602:France; D006801:Humans; D009103:Multiple Sclerosis; D009471:Neuromyelitis Optica",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102975",
"pmc": null,
"pmid": "33951589",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Multiple sclerosis-like NMOSD patients suffer severe worsening of status after fingolimod initiation.",
"title_normalized": "multiple sclerosis like nmosd patients suffer severe worsening of status after fingolimod initiation"
} | [
{
"companynumb": "FR-NOVARTISPH-NVSC2021FR198020",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo assess the relative frequency of reporting of adverse events involving ventricular arrhythmia, cardiac arrest, corrected QT interval (QTc) prolongation or torsade de pointes to the US Food and Drug Administration (FDA) between buprenorphine and methadone.\n\n\nMETHODS\nRetrospective pharmacoepidemiological study.\n\n\nMETHODS\nAdverse drug events reported spontaneously to the FDA between 1969 and June 2011 originating in 196 countries (71% events from the United States).\n\n\nMETHODS\nAdverse event cases mentioning methadone (n = 14 915) or buprenorphine (n = 7283) were evaluated against all other adverse event cases (n = 4 796 017).\n\n\nMETHODS\nThe primary outcome was the composite of ventricular arrhythmia or cardiac arrest. The secondary outcome was the composite of QTc prolongation or torsade de pointes. The proportional reporting ratio (PRR) was used to identify disproportionate reporting defined as a PRR > 2, χ(2) error > 4, with ≥ 3 cases.\n\n\nRESULTS\nThere were 132 (1.8%) ventricular arrhythmia/cardiac arrest and 19 (0.3%) QTc prolongation/torsade de pointes cases associated with buprenorphine compared with 1729 (11.6%) ventricular arrhythmia/cardiac arrest and 390 (2.6%) QTc prolongation/torsade de pointes cases involving methadone. PRRs associated with buprenorphine were not significant for ventricular arrhythmia/cardiac arrest (1.10, 95%, confidence interval (0.93-1.31, χ(2) = 1.2) or QTc prolongation/torsade de pointes (1.03, 95% CI = 0.66-1.62, χ(2) = 0.01), but were for methadone (7.20, 95% CI = 6.88-7.52, χ(2) = 8027; 10.7, 95% CI = 9.66-11.8, χ(2) = 1538, respectively).\n\n\nCONCLUSIONS\nIn spontaneously reported adverse events, methadone is associated with disproportionate reporting of cardiac arrhythmias, whereas buprenorphine is not. Although these findings probably reflect clinically relevant differences, a causal connection cannot be presumed and disproportionality analysis cannot quantify absolute risk per treatment episode. Population-based studies to definitively quantify differential incidence rates are warranted.",
"affiliations": "University of Colorado School of Medicine, Aurora, CO,, USA.;Uniformed Services University, Bethesda, MD,, USA.;University of Colorado School of Medicine, Aurora, CO,, USA.;University of Colorado School of Medicine, Aurora, CO,, USA.",
"authors": "Kao|David P|DP|http://orcid.org/0000-0002-2832-9348;Haigney|Mark C P|MC|;Mehler|Philip S|PS|;Krantz|Mori J|MJ|",
"chemical_list": "D009292:Narcotic Antagonists; D002047:Buprenorphine; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1111/add.13013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0965-2140",
"issue": "110(9)",
"journal": "Addiction (Abingdon, England)",
"keywords": "Buprenorphine; QTc prolongation; addiction; methadone; opiate; pharmacotherapy; pharmacovigilance; torsade de pointes",
"medline_ta": "Addiction",
"mesh_terms": "D000328:Adult; D001145:Arrhythmias, Cardiac; D002047:Buprenorphine; D005260:Female; D006323:Heart Arrest; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008691:Methadone; D009292:Narcotic Antagonists; D012189:Retrospective Studies; D016171:Torsades de Pointes; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "9304118",
"other_id": null,
"pages": "1468-75",
"pmc": null,
"pmid": "26075588",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "22026519;15781034;11828828;11347725;11150107;24939555;25130184;24990587;24837755;24500948;23820570;20532839;23689766;23571771;19459718;18071169;17696584;17313907;16507617;22612853;22763888;23007110;23227572;22744806;12388652;12580646;12812006;14558179;3716982;20702049",
"title": "Arrhythmia associated with buprenorphine and methadone reported to the Food and Drug Administration.",
"title_normalized": "arrhythmia associated with buprenorphine and methadone reported to the food and drug administration"
} | [
{
"companynumb": "US-PFIZER INC-2017157133",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe pattern of adjuvant chemotherapy (AC) use, toxicity profile, and survival benefit in elderly patients with colon cancer (CC) is unclear. We sought to (1) determine whether patients ≥ 65 years with stage III CC were offered single-agent or combination AC, (2) evaluate the reason for selecting single-agent versus combination AC, (3) evaluate the toxicity profile of single-agent and combination AC in the elderly, and (4) determine whether a survival benefit exists for elderly patients receiving combination AC.\n\n\nMETHODS\nA retrospective analysis of records of patients ≥ 65 years diagnosed with stage III CC from 2004 to 2010 was performed to identify baseline characteristics, AC protocols, toxicity, dose intensity, and survival.\n\n\nRESULTS\nTwo hundred sixty-eight patients ≥ 65 years were diagnosed and treated with AC from 2004 to 2010. Of these patients, 178 were treated with single-agent AC and 90 were treated with combination AC. The most common reasons for choosing single-agent AC were patient preference, comorbidities, and lack of drug coverage. For each year over 65 years, the odds of receiving combination over single-agent AC decreased by 22%. There were more dose delays, dose reductions, and early chemotherapy discontinuation in the combination AC group because of hematologic toxicity. The 5-year overall survival (OS) was 73% in patients who received single-agent AC compared with 84% in those who received combination AC. There was no difference in cancer-related deaths between the groups.\n\n\nCONCLUSIONS\nIn elderly patients treated with AC for stage III CC, single-agent AC is used more frequently than combination AC, based on age, comorbidities, and patient choice. Toxicity with combination AC in elderly patients is high. No survival benefit was seen with combination AC over single-agent AC.",
"affiliations": "Cross Cancer Institute, Edmonton, Alberta, Canada. Electronic address: christinakim3@gmail.com.;Cross Cancer Institute, Edmonton, Alberta, Canada.;Cross Cancer Institute, Edmonton, Alberta, Canada.;Cross Cancer Institute, Edmonton, Alberta, Canada.;Cross Cancer Institute, Edmonton, Alberta, Canada.",
"authors": "Kim|Christina A K|CA|;Spratlin|Jennifer L|JL|;Armstrong|Dawn E|DE|;Ghosh|Sunita|S|;Mulder|Karen E|KE|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D014803:Vitamin B Complex; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-0028",
"issue": "13(3)",
"journal": "Clinical colorectal cancer",
"keywords": "Adjuvant chemotherapy; Combination therapy; Elderly; Survival; Toxicity",
"medline_ta": "Clin Colorectal Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002170:Canada; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D002755:Choice Behavior; D003110:Colonic Neoplasms; D015897:Comorbidity; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D006801:Humans; D019458:Insurance Coverage; D007356:Insurance, Pharmaceutical Services; D002955:Leucovorin; D008297:Male; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D057240:Patient Preference; D012189:Retrospective Studies; D015996:Survival Rate; D014803:Vitamin B Complex",
"nlm_unique_id": "101120693",
"other_id": null,
"pages": "199-206",
"pmc": null,
"pmid": "25088184",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of single agent or combination adjuvant chemotherapy in elderly patients with colon cancer: a Canadian cancer institute experience.",
"title_normalized": "efficacy and safety of single agent or combination adjuvant chemotherapy in elderly patients with colon cancer a canadian cancer institute experience"
} | [
{
"companynumb": "CA-ROCHE-1437955",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents, and ranges on the spectrum of malignancy from low grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF1,2. However, in approximately 50% of cases no genetic driver has been established2. Clinical whole-genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine-threonine kinase that activates MEK3,4. The patient, who had exhausted all other therapeutic options, was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations of MAP3K8 in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements-uncovered by comprehensive clinical sequencing of a single case-are the most common genetic event in spitzoid melanoma, are present in adult melanomas and could be amenable to MEK inhibition.",
"affiliations": "Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. scott.newman@stjude.org.;Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Departments of Pathology and Translational Research, Institute Curie, Paris, France.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.;Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. jinghui.zhang@stjude.org.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. armita.bahrami@stjude.org.",
"authors": "Newman|Scott|S|http://orcid.org/0000-0001-9309-4752;Fan|Liying|L|;Pribnow|Allison|A|;Silkov|Antonina|A|;Rice|Stephen V|SV|;Lee|Seungjae|S|;Shao|Ying|Y|;Shaner|Bridget|B|;Mulder|Heather|H|;Nakitandwe|Joy|J|;Shurtleff|Sheila|S|;Azzato|Elizabeth M|EM|;Wu|Gang|G|http://orcid.org/0000-0002-1678-5864;Zhou|Xin|X|;Barnhill|Raymond|R|;Easton|John|J|;Nichols|Kim E|KE|;Ellison|David W|DW|;Downing|James R|JR|;Pappo|Alberto|A|;Potter|Philip M|PM|;Zhang|Jinghui|J|http://orcid.org/0000-0003-3350-9682;Bahrami|Armita|A|http://orcid.org/0000-0002-8515-2649",
"chemical_list": "D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1038/s41591-019-0373-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-8956",
"issue": "25(4)",
"journal": "Nature medicine",
"keywords": null,
"medline_ta": "Nat Med",
"mesh_terms": "D000818:Animals; D002648:Child; D005091:Exons; D015894:Genome, Human; D006801:Humans; D020930:MAP Kinase Kinase Kinases; D008297:Male; D008545:Melanoma; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "9502015",
"other_id": null,
"pages": "597-602",
"pmc": null,
"pmid": "30833747",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas.",
"title_normalized": "clinical genome sequencing uncovers potentially targetable truncations and fusions of map3k8 in spitzoid and other melanomas"
} | [
{
"companynumb": "PHHY2019US094683",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRAMETINIB"
},
"drugadditional": null,
"drug... |
{
"abstract": "Six patients with refractory adult-onset Still's disease (AOSD) were treated with tacrolimus (TAC). Patient 1 was pregnant, for whom high-dose corticosteroid (CS) monotherapy did not achieve clinical remission, whereas TAC concomitant with CS was successful, and her baby had no apparent abnormalities. Patient 2 had hemophagocytic syndrome (HPS), for whom high-dose CS monotherapy did not achieve clinical remission, whereas TAC improved HPS, and a complete clinical remission was achieved with concomitant administration of TAC and methotrexate (MTX) with CS. Cases 3-5 could not have reduced CS doses due to repeated recurrences and other disease-modifying antirheumatic drugs, including MTX, Cyclosporine A, and tumor necrosis factor alpha inhibitors, did not control disease activity. TAC administration allowed for reduced CS doses. Case 6 experienced adverse effects, and TAC was discontinued due to elevated serum creatinine and potassium levels. TAC was useful for five of six patients, which suggests it as an option for refractory AOSD.",
"affiliations": "a 3rd Department of Internal medicine , Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital , Obihiro , Hokkaido , Japan.;a 3rd Department of Internal medicine , Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital , Obihiro , Hokkaido , Japan.;a 3rd Department of Internal medicine , Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital , Obihiro , Hokkaido , Japan.;a 3rd Department of Internal medicine , Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital , Obihiro , Hokkaido , Japan.;a 3rd Department of Internal medicine , Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital , Obihiro , Hokkaido , Japan.",
"authors": "Nakamura|Hiroyuki|H|;Odani|Toshio|T|;Shimizu|Yuka|Y|;Takeda|Tsuyoshi|T|;Kikuchi|Hideaki|H|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D018501:Antirheumatic Agents; D016572:Cyclosporine; D016559:Tacrolimus; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.3109/14397595.2014.933997",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "26(6)",
"journal": "Modern rheumatology",
"keywords": "Adult-Onset Still's disease; Hemophagocytic syndrome; Pregnancy; Tacrolimus",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D018501:Antirheumatic Agents; D016572:Cyclosporine; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011247:Pregnancy; D011248:Pregnancy Complications; D016706:Still's Disease, Adult-Onset; D016559:Tacrolimus",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "963-967",
"pmc": null,
"pmid": "25036233",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Usefulness of tacrolimus for refractory adult-onset still's disease: Report of six cases.",
"title_normalized": "usefulness of tacrolimus for refractory adult onset still s disease report of six cases"
} | [
{
"companynumb": "JP-AMGEN-JPNNI2015083318",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nGadolinium-induced encephalopathy is a well documented complication due to the inadvertent entrance of a high dose of gadolinium into the intrathecal compartment. In lab animals, injecting gadolinium into the intrathecal compartment resulted in neurotoxicity and seizures. It is also well recognized that the presence of autologous blood in the intrathecal compartment can cause a broad range of neurological changes that can include seizures and mental status changes. At the time of writing this report, there were no references in the literature of simultaneous injection of gadolinium and blood into the subarachnoid space.\n\n\nMETHODS\nWe present a case of a patient who received a high dose of gadolinium in the epidural space for needle placement confirmation during a fluoroscopically-guided epidural steroid injection for the treatment of lumbar radiculopathy. The injection was complicated by a wet tap necessitating an epidural blood patch for post-dural puncture headache. Shortly after the injection of the autologous blood, the patient developed grand-mal seizures and mental status changes requiring endotracheal intubation and admission to an intensive care unit. We describe the clinical course and management, as well as brain MRI findings and cerebrospinal fluid (CSF) changes. The patient made a complete recovery and was discharged.\n\n\nCONCLUSIONS\nThis case reinforces the need for using a low dose of gadolinium for the confirmation of needle placement in the epidural space, especially in procedures that carry the risk of inadvertent intrathecal injection. We attribute these findings to inadvertent simultaneous intrathecal injection of high dose gadolinium and autologous blood. A literature review of the cases of gadolinium-induced encephalopathy is provided followed by discussion.",
"affiliations": "Penn State Hershey Medical Center, Hershey, PA, USA.",
"authors": "Kapoor|Ravish|R|;Liu|Jiabin|J|;Devasenapathy|Ashok|A|;Gordin|Vitaly|V|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D003287:Contrast Media; D000077555:Methylprednisolone Acetate; D005682:Gadolinium; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-3159",
"issue": "13(5)",
"journal": "Pain physician",
"keywords": null,
"medline_ta": "Pain Physician",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D017217:Blood Patch, Epidural; D001927:Brain Diseases; D003287:Contrast Media; D005260:Female; D005682:Gadolinium; D006801:Humans; D007268:Injections, Epidural; D008775:Methylprednisolone; D000077555:Methylprednisolone Acetate; D008875:Middle Aged; D051299:Post-Dural Puncture Headache; D011843:Radiculopathy",
"nlm_unique_id": "100954394",
"other_id": null,
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"abstract": "Immuno checkpoint inhibitors (ICIs) including anti-PD-L1 antibody have shown certain therapeutic effects on various cancer types. Here, we reported a case of the patient with resectable non-small cell lung cancer (NSCLC) showing a complete response to nivolumab combined with chemotherapy.\nA 66-year-old male was diagnosed with stage IIIA large cell lung cancer, cT2N2M0, who was considered impossible to have a tumor resection due to his right hilar node enlargement. The diameter of the neoplasms was 22mm, and the patient wanted to get the chance of surgery. Light of all, surgery was the only radical treatment option and therefore planned.\nAfter administering 2 cycles of nivolumab combined with paclitaxel and cisplatin, the second chest computed tomography (CT) after the first scanning revealed the tumor apparent shrinking and vascular compression was disappeared than before. We performed a right upper lobectomy and mediastinal lymph node dissection. Pathologically, we confirmed no large cell lung cancer cells in the resected lung specimen.\nThe follow-up showing that patient remains alive without recurrence to these days.\nThis case report may provide a clue to the future development of induction therapy using nivolumab and surgery. The combined treatment of nivolumab and chemotherapy is likely to be considered as an optional management of resectable NSCLC.",
"affiliations": "Department of Oncology, Zhongshan Hospital Affiliated to Guangzhou TCM University, Zhongshan, People's Republic of China.;Department of Oncology, Zhongshan Hospital Affiliated to Guangzhou TCM University, Zhongshan, People's Republic of China.;Department of Oncology, Zhongshan Hospital Affiliated to Guangzhou TCM University, Zhongshan, People's Republic of China.;Department of Oncology, Zhongshan Hospital Affiliated to Guangzhou TCM University, Zhongshan, People's Republic of China.",
"authors": "Zhao|Liangchen|L|;Li|Luzhen|L|;Chen|Ting|T|;Fang|Cantu|C|0000-0003-0984-7067",
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"fulltext": "\n==== Front\nOnco Targets Ther\nOnco Targets Ther\nott\nott\nOncoTargets and therapy\n1178-6930 Dove \n\n266155\n10.2147/OTT.S266155\nCase Report\nEffective Treatment of NSCLC with Surgery After Nivolumab Combined with Chemotherapy: A Case Report and Brief Review of the Literature\nZhao et alZhao et alZhao Liangchen 1 Li Luzhen 1 Chen Ting 1 http://orcid.org/0000-0003-0984-7067Fang Cantu 1 1 Department of Oncology, Zhongshan Hospital Affiliated to Guangzhou TCM University, Zhongshan, People’s Republic of China\nCorrespondence: Cantu Fang Zhongshan Hospital Affiliated to Guangzhou TCM University, Zhongshan, People’s Republic of China Email 3568076269@qq.com\n30 12 2020 \n2020 \n13 13307 13313\n25 6 2020 09 11 2020 © 2020 Zhao et al.2020Zhao 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).Introduction\nImmuno checkpoint inhibitors (ICIs) including anti-PD-L1 antibody have shown certain therapeutic effects on various cancer types. Here, we reported a case of the patient with resectable non-small cell lung cancer (NSCLC) showing a complete response to nivolumab combined with chemotherapy.\n\nPatient Information\nA 66-year-old male was diagnosed with stage IIIA large cell lung cancer, cT2N2M0, who was considered impossible to have a tumor resection due to his right hilar node enlargement. The diameter of the neoplasms was 22mm, and the patient wanted to get the chance of surgery. Light of all, surgery was the only radical treatment option and therefore planned.\n\nInterventions\nAfter administering 2 cycles of nivolumab combined with paclitaxel and cisplatin, the second chest computed tomography (CT) after the first scanning revealed the tumor apparent shrinking and vascular compression was disappeared than before. We performed a right upper lobectomy and mediastinal lymph node dissection. Pathologically, we confirmed no large cell lung cancer cells in the resected lung specimen.\n\nOutcomes\nThe follow-up showing that patient remains alive without recurrence to these days.\n\nConclusion\nThis case report may provide a clue to the future development of induction therapy using nivolumab and surgery. The combined treatment of nivolumab and chemotherapy is likely to be considered as an optional management of resectable NSCLC.\n\nKeywords\nnon-small cell lung cancerneoadjuvant immunotherapynivolumabcase report\n==== Body\nBackground\nLung cancer is the first leading cause of cancer-related death worldwide, with the highest morbidity. Patients with early and locally advanced lung cancer could prolong their lifespan by surgery, but to a certain degree, the effect of surgery is limited. Neoadjuvant therapy gives early and locally advanced lung cancer patients benefits, it helps downgrade tumors and even create surgery opportunities for patients who were initially unable to operate. In recent years, many trials have shown the results that in neoadjuvant therapy, immunotherapy is more effective and safer than chemotherapy, it contributes to prolong patients’ survival. Herein, we reported a case of an elder man with locally advanced lung large cell carcinoma who underwent surgery after receiving neoadjuvant immunotherapy, and reviewed the application of nivolumab in NSCLC briefly.\n\nCase Report\nA 66-year-old male was admitted to our hospital on June 13, 2019, due to “chest tightness and coughing for more than half a month”, with a history of a lung mass on a positron emission tomography (PET) scan performed at another hospital. He had no relevant past medical or family history, nor had he taken any medication. He used to smoke for more than 30 years and had been kicked the habit for more than 10 years. At the time of admission, his physical examination showed that the lung sounds in the right upper lung field were weakened. In order to assess the quality of his lung, he underwent a computed tomography (CT) scan and found that the density of the irregular soft tissue in the anterior segment of the right upper lung lobe was about 22mm×19mm, and there were multiple burr shadows on the edges (Figure 1). It suggested that the right upper lobe lung cancer was complicated by hilar and mediastinal lymph node metastasis. Then, the patient underwent a fine needle aspiration biopsy of the right lung mass, the pathologic diagnosis was large cell carcinoma (Figure 2). Molecular analysis showed no epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene mutations, either. By direct sequencing, retrospective programmed death-ligand 1 (PD-L1) immunostaining showed high PD-L1 expression with a tumor proportion score, more than 50%. Based on the examinations, a tentative diagnosis of lung cancer with T3N2M0 (stage IIIA, according to the seventh edition of TNM) was proposed. Given that the tumor was unresectable, the preferred treatment was sequential immunotherapy after simultaneous radiotherapy and chemotherapy. But the patient requested surgery strongly. After assessment by the multiple disciplinary team (MDT) in our hospital, we considered that the portal lymph nodes were swollen and had obvious adhesion with the right pulmonary artery and the right upper pulmonary vein, which could not be completely removed by surgery. According to the NADIM study updated by the 2019 ASCO annual meeting,1 and his genetic test results, it was feasible to perform neoadjuvant therapy with chemotherapy plus immunotherapy mode, to achieve the purpose of downgrading surgery. Then, he received 2 cycles of neoadjuvant chemotherapy of nivolumab+cisplatin-paclitaxel from July to August 2019 (actual usage: Paclitaxel 210mg +cisplatin 120 mg + nivolumab 360 mg, q21d). During the two cycles of nivolumab treatment, the patient was diagnosed with moderate bone marrow suppression based on blood test. After 2 cycles of neoadjuvant therapy, the chest was rechecked with enhancement CT. We observed that the area of the anterior segment of the right upper lobe of the lung was significantly reduced compared to the previous one. The maximum cross section was about 11mm×7mm. The enlarged lymph nodes in the mediastinum and right hilar were smaller than before, and the compression of the adjacent pulmonary vessels was relieved (Figure 3). At this time, he was diagnosed with right upper lung cancer (large cell carcinoma) with right lung and mediastinal lymph node metastasis, cT2N2M0 stage IIIA. The patient’s general condition was not very bad. He rejected the third cycle of chemotherapy+immunotherapy and requested surgery as soon as possible. After another MDT assessment, considering that the patient responded relatively well to the therapy, according to the response evaluation criteria for solid tumors (RECIST), the longest diameter of the target lesion was reduced by 50%, and the efficacy evaluation was partial response (PR). Moreover, the pressure of blood vessels was relieved more than before, surgical treatment was feasible. Then, he was performed a right upper lobe anterior segmentectomy and mediastinal lymph node dissection. Pathology of the nodule confirmed a diagnosis of stage IIIA NSCLC (T2N2M0). It had been seen from the postoperative pathological section that the patient achieved pathologic complete response (pCR) after treatment, so no subsequent treatment was performed after the operation. After an uneventful recovery from surgery, he has been going to the hospital for checkups regularly. Currently, the patient remains on oncological follow-up visits. At the last follow-up visit, in November 2020, the CT scan showed no disease recurrence.Figure 1 (A) Chest enhanced CT before treatment: an anterior segment of the right upper lobe with an irregular soft tissue density of approximately 22 mm x 19 mm in shape. (B) Multiple burr shadows on the edges, and multiple enlarged lymph nodes in the right hilum.\n\nFigure 2 Right lung tumor biopsy specimen: malignant tumor of epithelial origin, prone to large cell carcinoma. Immunohistochemistry: CK (+), Ki67 (60% +), P63 individual cells (+), TTF-1 (-), Syn (-), CD56 (-), CgA (-).\n\nFigure 3 Chest enhanced CT after neoadjuvant immunotherapy: (A) The area of the anterior segment of the right upper lobe of the lung was significantly smaller than that of the anterior, with a maximum cross-section of about 11 mm × 7 mm. (B) The mediastinal and right hilar swollen lymph nodes were smaller than before, and the adjacent pulmonary vessels were more compressed Before remission.\n\n\n\nDiscussion\nDuring a long time, surgery is usually considered as the treatment option for early disease. However, in stage III diseases, many patients have locally advanced or lymphatic metastasis at diagnosis, in which case, treatment is limited. Historically, patients with stage III NSCLC have poorer clinical outcomes, but recent advances in the treatment of adjuvant immune checkpoint blockade (ICB) have shown survival benefit, and recent data also show the benefit with adjuvant nivolumab. Immune checkpoint inhibitor therapy has changed the standard drug therapy for relapsed or advanced non-small cell lung cancer. With the rapid development of treatment methods, many studies have illustrated that immunotherapy has been extensively used in cancer treatment. Immunotherapy can alleviate the restriction of the immune system (PD-1 inhibitor) or cancer cell defense system (PD-L1 inhibitor), activates the body’s own immune system, and enables tumor-specific T cells to better recognize and eliminate cancer cells and tumor tissue. Compared with chemotherapy and targeted drugs, the biggest feature of immunotherapy is not to blow out the cancer cells themselves, but to kill the cancer cells through the host’s immune response, thereby returning the patient’s own immune function to normal. Herein, we summarize the novel new therapies of nivolumab in NSCLC.\n\nIn many studies of the treatment of NSCLC, nivolumab’s efficacy and safety are exciting. Patients with early, mid-term and partially resectable locally advanced lung cancer can be treated by surgical resection due to the limitations of the lesion. The combination of nivolumab and surgery could reduce the tumor stage, reduce the difficulty of surgery, and maximize the complete removal of tumor tissue, thereby helping to prolong the progression-free survival time of locally advanced patients.\n\nCheckmate 159 study is the first trail to study immunoadjuvant therapy for NSCLC.2 The study included 21 cases of early-stage (I stage of -IIIA) patients, 86% of patients had a history of smoking. Before the operation, they received 2 cycles of nivolumab treatment. Of these 20 patients who received the surgery as scheduled, during the 1-year follow-up, 16 patients were still alive and had no tumor recurrence. At a follow-up of 18 months, the overall progression-free survival (PFS) rate of the patient was 73%. At a follow-up of 30 months, 15 of 20 patients were disease-free and alive. The 24m RFS rate was 69% (95% CI: 51–93).3 In terms of safety, this study showed treatment-related adverse reactions were 23%, only 1 case exceeded grade 3.\n\nThe NADIM study aims to explore the efficacy of immunotherapy combined with chemotherapy for patients with stage IIIA NSCLC.1 The study admitted 46 patients with resectable tumor stage IIIA (N2, T4N0/N1), and EGFR/ALK negative. It was confirmed that 41 patients were performed surgery with r0 resection, 34 patients (83%) achieved major pathological response (MPR), including 24 (59%) of them were pCR, the World Conference on Lung Cancer (WCLC) 2019 reported that the 12-month PFS was 95.7%, the 18-month PFS was 81%, the median follow-up was 13.8 months, OS in the intent-to-treat population was 98% (95% CI, 85–100) at 12 months and 91% (95% CI, 73–97) at 18 months,4 and with 90.2% of patients (37/41) had staged decline.5 No surgical delay occurred.6 At present, other indicators of the study are still under observation. In the NADIM study, the pathological significant remission rate was significantly higher than similar data in chemotherapy and single-agent immunity studies, implementing the value-added benefit of 1 + 1>2.\n\nCheckmate 816, which had met a primary endpoint of pathologic complete response (pCR) in resectable non-small cell lung cancer (NSCLC). In the trial, significantly more patients treated with nivolumab plus chemotherapy before surgery showed no evidence of cancer cells in their resected tissue compared to those treated with chemotherapy alone.\n\nIn addition to monotherapy and combined chemotherapy, dual immunotherapy is another new ideas. NEOSTAR is a Phase II study designed to evaluate the efficacy of nivolumab combined with Ipilimumab or neoadjuvant nivolumab in the treatment for stage-IIIA resectable NSCLC. Results of NEOSTAR showed that the total MPR rate of 37 evaluable patients was 30%, of which the MPR rates of the nivolumab group and the combined group were 19% and 44%, respectively. The objective response rate (ORR) of the intention-to-treat (ITT) population was 20%, and the MPR response rates of the nivolumab group and the combination treatment group were 22% (4/23) and 19% (5/21), respectively. MPR rate was up to 78% among the patient who obtained complete response (CR) or partial response (PR). The study also found that before treatment, the higher the level of PD-L1 expression, the more effective. Compared to the patients whose PD-L1 >1% and PD-L1 ≤1%, the former had the lower survived tumors cells (median 20% vs 80%).7 The results have been showed that the dual immunoadjuvant therapy is better than the single immunotherapy.\n\nThrough Checkmate 159 study, it has been discovered that the use of PD-1 blockers before surgery can enhance the anti-tumor T cells’ response ability, and can also make peripheral blood continuously produce more memory-specific CD8+ T cells. The anti-tumor activity of T cells continues to destroy cancer cells, thereby potentially eliminating micro-metastatic cancer that might cause recurrence after surgery. Data from many other clinical studies show that nivolumab immunoadjuvant therapy will not affect the operation time, which is expected to change the traditional treatment of lung cancer. The application of neoadjuvant immunotherapy+chemotherapy treatment will enable many patients to shrink tumors before surgery, reduce the difficulty of surgery, and even allow some locally advanced patients who could not be operated to obtain the chances for surgery. In addition, immunotherapy helps to establish immune recognition of tumor cells by itself. Post-operative T cells will identify and attack tumor cells, which helps to eliminate micrometastases and reduce the risk of recurrence. These advantages will greatly improve the cure rate and long-term survival rate of lung cancer. It is worth noting that the median age of people diagnosed with NSCLC is 70 years old, and a considerable number of patients have a history of smoking or other basic diseases. Neoadjuvant immunotherapy gives these patients time to quit smoking. Better management of underlying diseases is a key intervention to reduce risks and create opportunities for intraoperative safety and postoperative recovery. Compared with other therapies, after receiving neoadjuvant immunotherapy, clinicians can evaluate the comprehensive treatment effect based on the pathology of the removed tumor, and determine the follow-up treatment plan accordingly.\n\nHowever, there is currently no uniform usage of the neoadjuvant immunotherapy cycle. Most clinical trials use 2–3 cycle before and after operation. The efficacy judgement, the prescription for post-operation, and withdrawal criteria are still under discussion. In view of the above problems, in order to better use nivolumab in clinical practice, a large samples of evidence support is still needed. Fortunately, some large-scale new auxiliary studies of nivolumab-related immunity are currently underway (Table 1). We believe these trials will bring surprises.Table 1 Clinical Researchers of Nivolumab in Neoadjuvant Immunotherapy with NSCLC\n\nTrails\tNCT\tPrimary Outcome Measures\tSecondary Outcome Measure\tEstimated Enrollment\tStage\tEstimated Primary Completion Date\t\nCheckmate816\t02998528\tEFS, pCR\tOS, MPR, TTDM\t350\tIB(T>4cm)-IIIA\t2020/4/8\t\nCheckmate77T\t04025879\tEFS\tOS, pCR, MPR, SAEs, AEs\t452\tIIA(T>4cm)-IIIB (T3N2)\t2023/5/24\t\nANVIL\t02595944\tDFS, OS\tAEs\t903\tIB (T≥4cm) -IIIA\t2024/7/1\t\nNADIM II\t03838159\tpCR\t-\t90\tIIIA-IIIB (T3N2)\t2022/3/15\t\nAbbreviations: NSCLC, non small cell lung cancers; EFS, event-free survival; OS, overall survival; TTDM, time to death or distant metastases; SAEs, incidence of serious adverse events; AEs, incidence of adverse events; DFS, disease-free survival.\n\n\n\n\nIn the safety analysis, nivolumab-related adverse events are common and relatively well tolerated. In a retrospective study,8 scholars found that when using nivolumab in the treatment of NSCLC, patients with immune-related adverse reactions had a better prognosis. That means immune-related adverse reactions may become a predicator of the effect of immunotherapy. Although the incidence of adverse reactions caused by immunotherapy is relatively low, it involves multiple organs and systems throughout the body. Clinicians should inform patients as soon as possible during treatment, only by detecting and treating early, the adverse reactions can be prevented and controlled.\n\nData from some trials and meta-analyses indicated that9,10 there was no significant difference in the perioperative complication rate and postoperative mortality rate between patients receiving neoadjuvant chemotherapy and those undergoing direct surgery.\n\nIn the field of immunotherapy, the PD-1/the PD-L1 expression level, tumor mutation burden (TMB) and other indicators of efficacy are commonly used to predict curative effect. The results of the Checkmate 017 study showed that the expression status of PD-L1 was not significantly correlated with the prognosis of squamous cell carcinoma patients.11 However, in the Checkmate057 study, the benefit of patients with non-squamous carcinoma was related to the expression of PD-L1,11 and the patient’s remission rate was proportional to the level of PD-L1 expression: among patients with tumors expressing PD-L1, patients with PD-L1 >5 had an ORR of 36% and PFS was 18.1 months, while patients with PD-L1<5 had an ORR of 10% and PFS was only 9.7 months. A summary analysis12 showed that patients with high expression of PD-L1 had a higher remission rate (RR:2.19) and a longer progression-free survival (HR:0.69), the overall survival rate was higher (HR:0.77). It is foreseeable that future clinical trials may tend to recruit patients with higher expression levels of PD-1/PD-L1.\n\nConclusions\nIn our report, we demonstrated the efficacy of neoadjuvant nivolumab in a patient with unresectable NSCLC. Due to environmental and tobacco reasons, the number of people suffering from lung cancer is increasing. Clinical studies have shown that compared with the same therapy given in an adjuvant setting, the neoadjuvant drug administration of nivolumab has an improved survival rate and enhanced anti-tumor immune response. In recent years, the rapid progression of immunotherapy has broken through the bottleneck of cytotoxicity-based chemotherapy in wild-type non-small cell lung cancer, and has improved the prognosis and life quality for patients. ICIs have reshaped the management of NSCLC. Tumor immunotherapy represented by nivolumab is an epoch-making revolutionary measure. It has been proven to be superior to chemotherapy in a number of clinical trials. This achievement has breakthrough significance. However, there are still some questions to be resolved. How to choose the best target group? How to combine with other treatment methods to benefit patients more? Are the evaluation criteria consistent after immunotherapy? In our case, the patient had high PD-L1 expression and achieved pCR after treatment. Can pCR be used as an indicator of clinical endpoints? These problems need to be resolved urgently. This is inseparable from the joint participation and dedication of tens of thousands of scientists, medical staff, and patients, and requires a lot of medical evidence. The concerted efforts of all of us have promoted new breakthroughs in the field of anti-cancer. We have reasons to believe that immunotherapy will make more progress in the future, enabling patients to obtain a higher quality of life while prolonging their survival period.\n\nStatement of Ethics\nWritten informed consent was obtained from the patient for the publication of both the case report and its accompanying images. This is a retrospective case report and institutional approval was not needed.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Provencio-Pulla \nM , Nadal-Alforja \nE , Cobo \nM , et al. Neoadjuvant chemo/immunotherapy for the treatment of stages IIIA resectable non-small cell lung cancer (NSCLC): a phase II multicenter exploratory study—NADIM study-SLCG\n. J Clin Oncol . 2018 ;36 (15_suppl ):8521 .\n2. Forde \nPM , Chaft \nJE , Smith \nKN , et al. Neoadjuvant PD-1 blockade in resectable lung cancer\n. N Engl J Med . 2018 ;378 (21 ):1976 –1986\n. doi:10.1056/NEJMoa1716078 29658848 \n3. Reuss \nJE , Smith \nKN , Anagnostou \nV , et al. Neoadjuvant nivolumab in resectable non-small cell lung cancer: extended follow-up and molecular markers of response\n. J Clin Oncol . 2019 ;37 (15_suppl ):8524 . doi:10.1200/JCO.2019.37.15_suppl.8524 \n4. Provencio \nM , Nadal \nE , Insa \nA , et al. OA13.05 NADIM Study: updated clinical research and outcomes\n. J Thorac Oncol . 2019 ;14 (10 ):S241 . doi:10.1016/j.jtho.2019.08.480 \n5. Provencio \nM . ES02. 04 concurrent, sequential and combination immunotherapy regimens in LA-NSCLC\n. J Thorac Oncol . 2019 ;14 (10 ):S17 –S18\n.\n6. Provencio \nM , Nadal \nE , Insa \nA , et al. Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): a phase II multicenter exploratory study—final data of patients who underwent surgical assessment\n. J Clin Oncol . 2019 ;37 (15_suppl ):8509 . doi:10.1200/JCO.2019.37.15_suppl.8509 \n7. Cascone \nT , William \nWN , Weissferdt \nA , et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study\n. J Clin Oncol . 2019 ;37 :8504 .\n8. Haratani \nK , Hayashi \nH , Chiba \nY , et al. Association of immune-related adverse events with nivolumab efficacy in non–small-cell lung cancer\n. JAMA Oncol . 2018 ;4 (3 ):374 .28975219 \n9. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet\n2014 ;383(9928):1561-1571.\n10. Blumenthal \nGM , Bunn \nPA , Chaft \nJE , et al. Current status and future perspectives on neoadjuvant therapy in lung cancer\n. J Thorac Oncol . 2018 ;13 (12 ):1818 –1831\n.30268698 \n11. Borghaei \nH , Paz-Ares \nL , Horn \nL , et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer\n. N Engl J Med . 2015 ;373 (17 ):1627 –1639\n.26412456 \n12. Aguiar \nPN , De Mello \nRA , Hall \nP , et al. PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data\n. Immunotherapy . 2017 ;9 (6 ):499 –506\n. doi:10.2217/imt-2016-0150 28472902\n\n",
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"title": "Effective Treatment of NSCLC with Surgery After Nivolumab Combined with Chemotherapy: A Case Report and Brief Review of the Literature.",
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"abstract": "We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.",
"affiliations": "1Department of Nephrology and Rheumatology, University Medicine Göttingen, Göttingen, Germany.",
"authors": "Fließer|E E|EE|;Korsten|P|P|;Koziolek|M J|MJ|;Niewold|T B|TB|;Patschan|D|D|;Müller|G A|GA|;Patschan|S A|SA|",
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"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D018450:Disease Progression; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D009173:Mycophenolic Acid; D011507:Proteinuria; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Successful treatment of a mycophenolate mofetil-refractory proliferative lupus nephritis with Belimumab in a 19-year-old woman.",
"title_normalized": "successful treatment of a mycophenolate mofetil refractory proliferative lupus nephritis with belimumab in a 19 year old woman"
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"abstract": "Preclinical animal studies have demonstrated an association between maternal use of tyrosine kinase inhibitors and embryofetal toxicity; yet, multiple clinical case series have reported normal pregnancy outcomes and healthy infants in women on these medications during the course of their pregnancy. We describe a case of a woman with chronic myeloid leukemia who had taken the second-generation tyrosine kinase inhibitor dasatinib during the first 12 weeks of her dichorionic diamniotic twin pregnancy and subsequently delivered two low-birth weight infants, one with severe cardiac malformations and the other without apparent birth abnormalities. To our knowledge, this is the first reported case of fetal cardiovascular defects in an infant born to a woman on dasatinib during a twin pregnancy and supports current recommendations to avoid this medication during pregnancy. We also review relevant preclinical and clinical studies of tyrosine kinase inhibitor use during pregnancy and explore alternative therapeutic options for patients with chronic myeloid leukemia during pregnancy to aid clinicians in the appropriate management of these patients so as to minimize both maternal and fetal risks.",
"affiliations": "Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Department Medicine, University of Southern California-Keck School of Medicine.;Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Department Medicine, University of Southern California-Keck School of Medicine.;Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Department Medicine, University of Southern California-Keck School of Medicine.;Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Department Medicine, University of Southern California-Keck School of Medicine.;Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Department Medicine, University of Southern California-Keck School of Medicine.",
"authors": "Hermel|David J|DJ|https://orcid.org/0000-0001-6342-6023;Chiu|Victor|V|;Hermel|Melody H|MH|;Tulpule|Anil|A|;Akhtari|Mojtaba|M|",
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"country": "England",
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"doi": "10.1177/1078155217745710",
"fulltext": null,
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"issn_linking": "1078-1552",
"issue": "25(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Birth defects; chronic myeloid leukemia; dasatinib; pregnancy; tyrosine kinase inhibitors",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000069439:Dasatinib; D004200:Diseases in Twins; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D011247:Pregnancy; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "699-702",
"pmc": null,
"pmid": "29207935",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cardiac birth defects in a twin infant born to a woman with chronic myeloid leukemia on dasatinib.",
"title_normalized": "cardiac birth defects in a twin infant born to a woman with chronic myeloid leukemia on dasatinib"
} | [
{
"companynumb": "US-APOTEX-2019AP010250",
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{
"abstract": "Varicella zoster virus (VZV)-associated meningitis is usually progressive and can be fatal, and early diagnosis and aggressive treatment with intravenous antivirals such as acyclovir (ACV) are required in immunocompromised patients. Patients receiving corticosteroids and immunosuppressive therapy have a significantly higher risk of VZV-associated meningitis. In this report, we describe an unusual case of herpes zoster (HZ) in a young woman who was first diagnosed during tapering of prednisone for dermatomyositis. The skin lesions affected the left L2 and L3 dermatomes, which is unusual in VZV-associated meningitis. Despite showing a good rapid response to antivirals, she developed VZV-associated meningitis immediately after discontinuation of ACV. This phenomenon is often called rebound VZV reactivation disease and occurs after discontinuation of antivirals. This case was notable in that the affected dermatomes were distant from the cranial nerves. Thus, progression of HZ to VZV reactivation-associated meningitis can occur even in appropriately treated HZ patients. Continuation of antivirals beyond 1 week in patients on immunosuppressive therapy may be associated with a decreased risk of severe rebound VZV disease, such as VZV-associated meningitis.",
"affiliations": "Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan.;Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan.;Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan.",
"authors": "Sato|Tetsuko|T|;Yamamoto|Takenobu|T|;Aoyama|Yumi|Y|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000512710",
"fulltext": "\n==== Front\nCase Rep Dermatol\nCase Rep Dermatol\nCDE\nCase Reports in Dermatology\n1662-6567\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000512710\ncde-0013-0148\nSingle Case\nVaricella Zoster Virus-Associated Meningitis as a Rebound Varicella Zoster Disease after Antiviral Discontinuation\nSato Tetsuko a\nYamamoto Takenobu ab\nAoyama Yumi a*\naDepartment of Dermatology, Kawasaki Medical School, Kurashiki, Japan\nbDepartment of Dermatology, Kawasaki Medical School General Medical Center, Kurashiki, Japan\n*Yumi Aoyama, Department of Dermatology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192 (Japan), ymaoyama@med.kawasaki-m.ac.jp\nJan-Apr 2021\n26 2 2021\n26 2 2021\n13 1 148153\n16 8 2020\n29 10 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nThis article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nVaricella zoster virus (VZV)-associated meningitis is usually progressive and can be fatal, and early diagnosis and aggressive treatment with intravenous antivirals such as acyclovir (ACV) are required in immunocompromised patients. Patients receiving corticosteroids and immunosuppressive therapy have a significantly higher risk of VZV-associated meningitis. In this report, we describe an unusual case of herpes zoster (HZ) in a young woman who was first diagnosed during tapering of prednisone for dermatomyositis. The skin lesions affected the left L2 and L3 dermatomes, which is unusual in VZV-associated meningitis. Despite showing a good rapid response to antivirals, she developed VZV-associated meningitis immediately after discontinuation of ACV. This phenomenon is often called rebound VZV reactivation disease and occurs after discontinuation of antivirals. This case was notable in that the affected dermatomes were distant from the cranial nerves. Thus, progression of HZ to VZV reactivation-associated meningitis can occur even in appropriately treated HZ patients. Continuation of antivirals beyond 1 week in patients on immunosuppressive therapy may be associated with a decreased risk of severe rebound VZV disease, such as VZV-associated meningitis.\n\nKeywords\n\nVaricella zoster virus\nHerpes zoster\nMeningitis\nRebound phenomenon\nAcyclovir\n==== Body\nIntroduction\n\nReactivation of latent varicella zoster virus (VZV) typically results in the clinical syndrome of herpes zoster (HZ), but the virus is also responsible for atypical clinical presentations, particularly in immunocompromised patients. HZ has been widely described in the setting of various systemic autoimmune diseases, and a recent nationwide population-based cohort study in Taiwan demonstrated that dermatomyositis (DM)/polymyositis (PM) was associated with an increased risk of subsequent HZ compared with the absence of DM/PM in both women and men [1]. In addition, patients with DM/PM on immunosuppressive therapy had a significantly higher risk of HZ [1]. Although the most common complication of HZ is postherpetic neuralgia, other serious complications that may occur include VZV-associated meningitis, meningoencephalitis, encephalitis, myelopathy, and vasculopathy [2]. These diseases are usually progressive and can be fatal; therefore, early diagnosis and aggressive treatment with intravenous antivirals are required in immunocompromised patients.\n\nIn this report, we describe an unusual case of HZ in a young woman; the diagnosis was first made during tapering of corticosteroids for DM, and the skin lesions affected the left L2 and L3 dermatomes, which is unusual in VZV-associated meningitis. Although she showed a good rapid response in the vesicles to treatment with intravenous acyclovir (ACV), she returned to our hospital 3 days after discharge with acute onset of severe headache and widespread erythematous lesions on her left thigh. The development of these serious complications immediately after withdrawal of ACV while receiving mycophenolate mofetil (MMF) therapy raised suspicion that VZV reactivation triggered by tapering of corticosteroids was exacerbated by the withdrawal of ACV and that rebound VZV reactivation contributed to this classic but serious complication seen in patients on immunosuppressive therapy. There is no consensus on how long antivirals should be given to patients on immunosuppressive therapy because of concerns over rebound VZV disease after the discontinuation of antivirals.\n\nCase Report\n\nA 38-year-old woman with DM presented with a 3-day history of multiple painful grouped vesiculobullous lesions distributed along the left L2 and L3 dermatomes (day 1). She had no past history of diabetes, HIV, or other immunodeficiency. She had received prednisone (20 mg/day) plus MMF (1.5 g/day) for 2 months. The onset of HZ coincided with tapering of the corticosteroids to 10 mg/day. After starting oral famciclovir 30 mg/kg for 1 day following intravenous ACV 750 mg/day for 5 days, the lesions started healing with crusting and postinflammatory pigmentation. She was discharged with a prescription for prednisone and MMF.\n\nTwo days after discontinuation of ACV, she developed severe intermittent headaches with fever, cervical rigidity, and multiple erythematous papules and plaques on the left thigh (day 17; Fig. 1). There was no mucosal involvement or lymphadenopathy. Because the severe headaches did not improve with NSAID use, lumbar puncture was performed to investigate the cause of the headache. Adverse effects of MMF were suspected, and it was discontinued, but the clinical symptoms rapidly deteriorated. The patient reported having fever, but no paresthesia, vision changes, or hearing loss.\n\nLaboratory tests revealed normal white blood cell counts (7,830/µL, 76% lymphocytes) and C-reactive protein levels (0.36 mg/dL). Cerebrospinal fluid (CSF) analysis showed an elevated white blood cell count of 45.3/µL (96.3% mononuclear cells) and elevated protein levels of 109 mg/dL (reference range: 10–40 mg/dL). VZV DNA was detected by PCR in the CSF viral panel. The VZV DNA load on day 17 was 1.9 × 102 copies/mL in saliva, undetectable in blood, and 6.0 × 104 copies/mL in CSF. We diagnosed aseptic meningitis due to VZV reactivation and VZV-induced erythema multiforme (EM).\n\nHistological examination of a skin biopsy showed perivascular lymphocytic infiltrates in the papillary dermis with few histiocytes. VZV immunostaining of the skin tissue was interpreted as positive, with glycoprotein E detected only at crusts formed in the upper epidermis. She was started on intravenous ACV 1,500 mg/day with concurrent prednisone 10 mg/day, and the headaches completely resolved thereafter (Fig. 2). At a follow-up examination 6 months after the episode of meningitis, the patient was completely free of any central nervous system symptoms.\n\nDiscussion\n\nAseptic meningitis is a relatively rare neurologic complication of HZ, occurring in approximately 0.5% of patients diagnosed with recent HZ [3]. According to a retrospective study that investigated potential risk factors for aseptic meningitis in patients with HZ [4], VZV-associated aseptic meningitis occurred more frequently in patients with skin lesions affecting the craniocervical distribution (87.5%) compared with the thoracic (12.5%), lumbar (0%), and sacral (0%) dermatomes. These observations suggest the possibility that a close anatomical distance to the involved nerves could facilitate viral invasion of the brain meninges. In this regard, our patient was notable in that the involved dermatomes were distant from the cranial nerves. She did not have contiguity between the meningitis and dermatomal levels, suggesting that the virus may have arisen at different spiral root ganglia. This appears consistent with previous work suggesting that the virus could spread via blood vessels in the central nervous system [5].\n\nVariable time periods have been reported between the onset of HZ and the symptoms of meningitis, ranging from 1 to 9 days after the initiation of antiviral therapy [6]. Kim et al. [4] reported that the mean interval was 5.3 days and suggested that symptoms of meningitis appeared within 6 days from onset of HZ lesions. Given that patients with HZ are usually treated with ACV at a dose of 5–10 mg/kg body weight 3 times daily for at least 7 days, many patients are likely to develop aseptic meningitis during antiviral therapy. Interestingly, our patient developed aseptic meningitis and EM lesions 2 days after discontinuation of antiviral therapy, unlike in other reported cases. This phenomenon is often called rebound VZV reactivation disease, which occurs after discontinuation of antivirals [7]. Thus, physicians must be aware that VZV-associated meningitis and EM can occur after the end of treatment with an anti-VZV agent as a late complication. The progression of HZ to VZV-associated meningitis occurred even in appropriately treated HZ patients.\n\nThe critical question is what additional factors could be responsible for the development of aseptic meningitis and EM after the end of successful treatment. One possibility is that rebound replication of VZV may have occurred upon discontinuation of antiviral treatment during immunosuppressive therapy. Although discontinuation or reduction of immunosuppressive therapy upon diagnosis of VZV-associated aseptic meningitis seems to be intuitively rational, abrupt reduction of immunosuppressive therapy could paradoxically result in rebound of pathogenic inflammatory responses to VZV, thereby leading to severe meningitis. Thus, maintaining the dose of immunosuppressive agents despite the occurrence of VZV-associated meningitis might be appropriate in the management of these patients to avoid severe meningitis. Although there are no established guidelines for the treatment of HZ in patients on immunosuppressive therapy, these patients may require a higher dose of antivirals (e.g., 10 mg/kg every 8 h) for a prolonged period (up to 2 weeks) [8].\n\nIn conclusion, the progression of HZ to aseptic meningitis may occur more frequently in patients on immunosuppressive therapy than previously thought, even when they are treated with appropriate antiviral therapy. HZ patients with DM on immunosuppressive therapy may be at particularly high risk of progressing to aseptic meningitis. To identify patients at high risk of progressing to meningitis, patients with HZ who develop severe headache should undergo CSF analysis via PCR. Continuation of high-dose antivirals beyond 1 week in patients on immunosuppressive therapy may be associated with a decreased risk of severe rebound VZV reactivation diseases, such as VZV-associated meningitis.\n\nStatement of Ethics\n\nThe study was approved by the Institutional Review Board at Kawasaki Medical University and followed the guidelines for the ethical conduct of human research. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nThe authors report no conflicts of interest.\n\nFunding Sources\n\nThis study was supported by Kawasaki Medical School. This work was partially supported by grants from the Japan Agency for Medical Research and Development (20ek0410068h0001).\n\nAuthor Contributions\n\nAll authors contributed to the design of the study, data collection, and manuscript preparation. All authors have read the manuscript and have approved its submission.\n\nFig. 1 Clinical image showing widespread erythema and follicular papules after the cessation of acyclovir.\n\nFig. 2 Clinical symptoms and laboratory findings in this case with reactivation of VZV in relation to treatment. ACV, acyclovir; CSF, cerebrospinal fluid; FCV, famciclovir; MMF, mycophenolate mofetil; PSL, prednisone; VZV, varicella zoster virus; WBC, white blood cell count.\n==== Refs\nReferences\n\n1 Tsai SY Lin CL Wong YC Yang TY Kuo CF Cheng JM Increased Risk of Herpes Zoster Following Dermatomyositis and Polymyositis: A Nationwide Population-Based Cohort Study Medicine (Baltimore) 2015 7 94 (28) e1138 26181551\n2 Gilden D Nagel M Cohrs R Mahalingam R Baird N Varicella Zoster Virus in the Nervous System F1000 Res 2015 11 4 (1356) 1356\n3 Gupta P Ranjan R Agrawal CS Muralikrishnan K Dave N Rana DS Meningitis with polymerase chain reaction for varicella zoster positivity in cerebrospinal flid of a young immunocompetent adult J Neurosci Rural Pract 2016 Oct-Dec 7 (4) 591 3 27695246\n4 Kim SH Choi SM Kim BC Choi KH Nam TS Kim JT Risk Factors for Aseptic Meningitis in Herpes Zoster Patients Ann Dermatol 2017 6 29 (3) 283 7 28566903\n5 Grahn A Studahl M Varicella-zoster virus infections of the central nervous system − Prognosis, diagnostics and treatment J Infect 2015 9 71 (3) 281 93 26073188\n6 Braun-Falco M Hoffmann M Herpes zoster with progression to acute varicella zoster virus-meningoencephalitis Int J Dermatol 2009 8 48 (8) 834 9 19673047\n7 Boeckh M Kim HW Flowers ME Meyers JD Bowden RA Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation—a randomized double-blind placebo-controlled study Blood 2006 3 107 (5) 1800 5 16282339\n8 Dworkin RH Johnson RW Breuer J Gnann JW Levin MJ Backonja M Recommendations for the management of herpes zoster Clin Infect Dis 2007 44 Suppl 1 S1 S26 17143845\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6567",
"issue": "13(1)",
"journal": "Case reports in dermatology",
"keywords": "Acyclovir; Herpes zoster; Meningitis; Rebound phenomenon; Varicella zoster virus",
"medline_ta": "Case Rep Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101517685",
"other_id": null,
"pages": "148-153",
"pmc": null,
"pmid": "33790759",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26918131;17143845;26073188;19673047;28566903;16282339;27695246;26181551",
"title": "Varicella Zoster Virus-Associated Meningitis as a Rebound Varicella Zoster Disease after Antiviral Discontinuation.",
"title_normalized": "varicella zoster virus associated meningitis as a rebound varicella zoster disease after antiviral discontinuation"
} | [
{
"companynumb": "JP-ACCORD-223201",
"fulfillexpeditecriteria": "1",
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"patient": {
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"activesubstancename": "ACYCLOVIR"
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"drugadditional": "1",
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{
"abstract": "Seizures are common in term infants with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia. Although phenobarbital (PHB) is generally considered first-line therapy, some centers have embraced third-generation antiepileptic drugs (AEDs) such as levetiracetam (LEV) given the impression of comparable efficacy and superior tolerability. We set out to compare the efficacy of PHB and LEV in a large single-center cohort.\n\n\n\nWe retrospectively identified consecutive newborns with HIE who were monitored with continuous video-electroencephalogram (VEEG) for the duration of therapeutic hypothermia. After identification of seizures, infants were treated with PHB or LEV at the discretion of treating physicians. We assessed time to seizure freedom as a function of AED choice, with adjustment for HIE severity and initial seizure frequency using the Kaplan-Meier procedure and multivariate Cox proportional hazards regression.\n\n\n\nWe identified 78 infants with HIE. Among 44 (56%) patients who had VEEG-confirmed seizures, 34 became seizure-free during monitoring, and the remaining 10 died. Initial treatment with LEV, in comparison with PHB, predicted a shorter interval to seizure freedom in a univariate analysis (Hazard ratio (HR) = 2.58, P = 0.007), even after adjustment for initial seizure frequency and an unbiased ad hoc measure of HIE severity (adjusted HR = 2.57, P = 0.010). This effect was recapitulated in an analysis in which patients with treatment crossover were excluded. As expected, severity of HIE was an independent predictor of longer duration to seizure freedom (HR = 0.16, P < 0.001) and remained a significant predictor after adjustment for initial seizure burden and treatment agent.\n\n\n\nDespite a relatively small sample size and retrospective design, this study suggests that LEV is a viable alternative to PHB in the treatment of neonatal seizures associated with HIE. A large-scale randomized controlled trial is needed to confirm these findings.",
"affiliations": "Division of Neurology, Department of Pediatrics, UCLA Mattel Children's Hospital, USA.;Division of Neurology, Department of Pediatrics, UCLA Mattel Children's Hospital, USA. Electronic address: shussain@mednet.ucla.edu.;Division of Neurology, Department of Pediatrics, UCLA Mattel Children's Hospital, USA.;School of Medicine and Health Sciences, George Washington University, USA.;Division of Neonatology, Department of Pediatrics, UCLA Mattel Children's Hospital, USA.;Division of Neonatology, Department of Pediatrics, UCLA Mattel Children's Hospital, USA.;Division of Neurology, Department of Pediatrics, UCLA Mattel Children's Hospital, USA; Department of Neurology, David Geffen School of Medicine at UCLA, USA.",
"authors": "Rao|Lekha M|LM|;Hussain|Shaun A|SA|;Zaki|Timothy|T|;Cho|Alexander|A|;Chanlaw|Teresa|T|;Garg|Meena|M|;Sankar|Raman|R|",
"chemical_list": "D000927:Anticonvulsants; C000717328:PHB protein, human; D000091402:Prohibitins; D000077287:Levetiracetam; D010634:Phenobarbital",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2018.09.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "88()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Apoptosis; Epilepsy; Newborn; Toxicity",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000927:Anticonvulsants; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D000077287:Levetiracetam; D008297:Male; D010634:Phenobarbital; D000091402:Prohibitins; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012640:Seizures; D016896:Treatment Outcome",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "212-217",
"pmc": null,
"pmid": "30296665",
"pubdate": "2018-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A comparison of levetiracetam and phenobarbital for the treatment of neonatal seizures associated with hypoxic-ischemic encephalopathy.",
"title_normalized": "a comparison of levetiracetam and phenobarbital for the treatment of neonatal seizures associated with hypoxic ischemic encephalopathy"
} | [
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"companynumb": "US-UCBSA-2018048738",
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"activesubstancename": "LEVETIRACETAM"
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... |
{
"abstract": "A 63-year-old Japanese male with stomach adenocarcinoma received oral 5-fluorouracil derivative, cisplatin and trastuzumab chemotherapy. On day 8, severe diarrhea and mucositis developed; chemotherapy was stopped. On day 14, the patient developed renal dysfunction and febrile neutropenia. He also suffered from pneumonia due to Candida albicans. Systemic symptoms improved after intensive conservative treatment. Best supportive care was continued until the patient died from gastric cancer. The dihydropyrimidine dehydroge-nase protein level was low at 3.18 U/mg protein. The result of DPYD genotyping revealed three variants at posi-tions 1615 (G > A), 1627 (A > G), and 1896 (T > C) in exons 13, 13, and 14, respectively.",
"affiliations": "Department of Internal Medicine, Tsuyama Chuo Hospital.;Department of Internal Medicine, Tsuyama Chuo Hospital.;Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.;Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.;Department of Internal Medicine, Tsuyama Chuo Hospital.;Department of Internal Medicine, Tsuyama Chuo Hospital.;Department of Internal Medicine, Tsuyama Chuo Hospital.;Department of Internal Medicine, Tsuyama Chuo Hospital.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.",
"authors": "Ishiguro|Mikako|M|;Takenaka|Ryuta|R|;Ogura|Kenichiro|K|;Hiratsuka|Akira|A|;Takeda|Hiromasa|H|;Kawai|Daisuke|D|;Tsugeno|Hirofumi|H|;Fujiki|Shigeatsu|S|;Okada|Hiroyuki|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.18926/AMO/61217",
"fulltext": null,
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"issn_linking": "0386-300X",
"issue": "74(6)",
"journal": "Acta medica Okayama",
"keywords": "5-fluorouracil; DPYD variant; dihydropyrimidine dehydrogenase deficiency; gastric cancer",
"medline_ta": "Acta Med Okayama",
"mesh_terms": "D000230:Adenocarcinoma; D000964:Antimetabolites, Antineoplastic; D000075203:Contraindications, Drug; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D017809:Fatal Outcome; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms",
"nlm_unique_id": "0417611",
"other_id": null,
"pages": "557-562",
"pmc": null,
"pmid": "33361878",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Japanese Patient with Gastric Cancer and Dihydropyrimidine Dehydrogenase Deficiency Presenting with DPYD Variants.",
"title_normalized": "a japanese patient with gastric cancer and dihydropyrimidine dehydrogenase deficiency presenting with dpyd variants"
} | [
{
"companynumb": "JP-ACCORD-213478",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"activesubstance": {
"activesubstancename": "CAPECITABINE"
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"drugadditional": "1",
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{
"abstract": "Psychiatric disorders may complicate the pregnancy and is one of the causes of maternal and fetal morbidity. We report the case of a patient with severe decompensated schizophrenia during her pregnancy that required prolonged hospitalization in psychiatric ward. The psychiatric status of the patient required the realization of a caesarean section at 36 weeks of amenorrhea. In our case, we decided to perform this cesarean section under general anaesthesia, since regional anaesthesia was not feasible in this patient in a state of uncontrolled agitation. Moreover, general anaesthesia permitted to combine cesarean section with a first session of electroconvulsive therapy, which had been declined during pregnancy. Given the huge amount of antipsychotic agents administered to the patient, we also studied their transplacental transfer and found a very high loxapine concentration in the fetus. Finally, this case raised several important ethical issues related to the management of the mother and her fetus in case of severe psychiatric disorders.",
"affiliations": "Département d'anesthésie réanimation, hôpital Cochin, 27, rue Faubourg-Saint-Jacques, 75014 Paris, France.",
"authors": "Vermersch|C|C|;Smadja|S|S|;Amselem|O|O|;Gay|O|O|;Marcellin|L|L|;Gaillard|R|R|;Mignon|A|A|",
"chemical_list": "D014150:Antipsychotic Agents; D008152:Loxapine",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0750-7658",
"issue": "32(10)",
"journal": "Annales francaises d'anesthesie et de reanimation",
"keywords": "Anesthésie locorégionale; Electroconvulsive therapy; Ethics; Grossesse; Pregnancy; Regional anesthesia; Schizophrenia; Schizophrénie; Sismothérapie; Éthique",
"medline_ta": "Ann Fr Anesth Reanim",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D000773:Anesthesia, Obstetrical; D014150:Antipsychotic Agents; D002585:Cesarean Section; D004565:Electroconvulsive Therapy; D005260:Female; D005333:Fetus; D006801:Humans; D008152:Loxapine; D011247:Pregnancy; D011248:Pregnancy Complications; D012559:Schizophrenia; D012565:Schizophrenic Psychology",
"nlm_unique_id": "8213275",
"other_id": null,
"pages": "711-4",
"pmc": null,
"pmid": "24054003",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Cesarean section and sismotherapy in a severe psychotic parturient: A case report.",
"title_normalized": "cesarean section and sismotherapy in a severe psychotic parturient a case report"
} | [
{
"companynumb": "FR-WATSON-2014-15400",
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"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RISPERIDONE"
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"drugadditional": null,
... |
{
"abstract": "The introduction of tumor necrosis factor-alpha (TNF-α)-targeting drugs has given new opportunities in the treatment of various inflammatory rheumatic diseases and has been the most important development in the treatment of spondyloarthritis (SpA). However, the increasing use and longer follow-up periods of treatment also pose risks of developing various adverse effects ranging from common ones including infections to uncommon renal complications. This report describes a case of infliximab-induced focal segmental glomerulosclerosis (FSGS) in a 40-year-old female patient with ankylosing spondylitis (AS) who presented with asymptomatic proteinuria and microscopic hematuria. To the best of our knowledge, this is the second reported case of FSGS attributed to infliximab (IFX). A review of the English literature was conducted for cases of possible IFX-associated renal disorders in patients with SpA and SpA spectrum diseases. In this respect, the reported renal pathologies were IgA nephropathy, crescentic glomerulonephritis, acute renal artery occlusion, acute tubulointerstitial nephritis (ATIN), FSGS, and membranous glomerulopathy. Furthermore, partial or complete resolution was reported after cessation of therapy. In conclusion, although renal complications of TNF inhibitors (TNFi) are uncommon, spot urine evaluation may be recommended in the follow-up of patients treated with TNFi.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Dokuz Eylul University School of Medicine, Izmir, Turkey. drhandanyarkan@gmail.com.;Division of Rheumatology, Department of Internal Medicine, Dokuz Eylul University School of Medicine, Izmir, Turkey.;Division of Rheumatology, Department of Internal Medicine, Dokuz Eylul University School of Medicine, Izmir, Turkey.;Division of Rheumatology, Department of Internal Medicine, Dokuz Eylul University School of Medicine, Izmir, Turkey.;Department of Pathology, Dokuz Eylul University School of Medicine, Izmir, Turkey.;Division of Rheumatology, Department of Internal Medicine, Dokuz Eylul University School of Medicine, Izmir, Turkey.;Division of Rheumatology, Department of Internal Medicine, Dokuz Eylul University School of Medicine, Izmir, Turkey.",
"authors": "Yarkan Tuğsal|Handan|H|http://orcid.org/0000-0003-0633-790X;Zengin|Berrin|B|http://orcid.org/0000-0002-7417-4682;Kenar|Gökçe|G|http://orcid.org/0000-0002-0485-1369;Can|Gerçek|G|http://orcid.org/0000-0001-8347-0873;Ünlü|Mehtat|M|http://orcid.org/0000-0002-7170-7594;Önen|Fatoş|F|http://orcid.org/0000-0002-6341-2622;Birlik|Merih|M|http://orcid.org/0000-0001-5118-9307",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors; D000069285:Infliximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-019-04241-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "39(3)",
"journal": "Rheumatology international",
"keywords": "Ankylosing spondylitis; Focal segmental glomerulosclerosis; Infliximab",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D000328:Adult; D005260:Female; D005922:Glomerulonephritis, IGA; D015433:Glomerulonephritis, Membranous; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D000069285:Infliximab; D007674:Kidney Diseases; D009395:Nephritis, Interstitial; D013167:Spondylitis, Ankylosing; D000079424:Tumor Necrosis Factor Inhibitors",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "561-567",
"pmc": null,
"pmid": "30673815",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "11849393;16204273;18793566;19011506;19028367;19556300;21209465;21448162;22662255;23269570;24255891;24840285;24870303;25515529;26114187;26192790;27181549;29146018;29292692;29973427;3307414;3664158;9890685",
"title": "Infliximab-associated focal segmental glomerulosclerosis in a patient with ankylosing spondylitis.",
"title_normalized": "infliximab associated focal segmental glomerulosclerosis in a patient with ankylosing spondylitis"
} | [
{
"companynumb": "TR-JNJFOC-20190306517",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": "1",
... |
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