article dict | reports listlengths 1 3.97k |
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{
"abstract": "OBJECTIVE\nTo assess the efficacy of peginterferon alpha 2b at doses of 50 microg weekly and 80 microg weekly (based on body weight) plus ribavirin in HCV genotype 2 and genotype 3 chronic hepatitis C patients.\n\n\nMETHODS\nDuring the study period of Jan 2002 to Dec 2003, all patients diagnosed as chronic hepatitis C or HCV related compensated cirrhosis were treated with peginterferon alpha 2b 50 microg S/C weekly (body weight < 60 kg) or 80 microg S/C weekly (body weight > 60 kg) plus ribavirin 800 mg/d for 24 wk.\n\n\nRESULTS\nOverall 28 patients, 14 patients in each group (based on body weight) were treated during the period. Out of 28 patients, 75% were genotype 3, 18% were genotype 2 and 7% were genotype 1. The mean dose of peginterferon alpha 2b was 0.91 microg/kg in group 1 and 1.23 microg/kg in group 2 respectively. The end of treatment and sustained virologic response rates were 82% and 78% respectively. Serious adverse effects were seen in 3.5% patients.\n\n\nCONCLUSIONS\nLow dose peginterferon alpha 2b in combination with ribavirin for 24 wk is effective in HCV genotype 2 and 3 chronic hepatitis C patients.",
"affiliations": "Asian Institute of Gastroenterology, Somajiguda 63661, Hyderabad, India.",
"authors": "Gupta|Rajesh|R|;Ramakrishna|C H|CH|;Lakhtakia|Sandeep|S|;Tandan|Manu|M|;Banerjee|Rupa|R|;Reddy|D Nageshwar|DN|",
"chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v12.i34.5554",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "12(34)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5554-6",
"pmc": null,
"pmid": "17006999",
"pubdate": "2006-09-14",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "10847128;9819446;11439948;11481625;11583749;12324553;12407572;12407575;12407599;12785176;14996676;15158341;15334688;9382365;9807989;11106715",
"title": "Efficacy of low dose peginterferon alpha-2b with ribavirin on chronic hepatitis C.",
"title_normalized": "efficacy of low dose peginterferon alpha 2b with ribavirin on chronic hepatitis c"
} | [
{
"companynumb": "IN-ROCHE-1449276",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Capecitabine-induced hypertriglyceridemia (CIHT) represents an increasingly significant treatment-related adverse event from capecitabine given its potential for both acute complications (acute pancreatitis) and chronic metabolic complications (cardiovascular disease). The incidence of CIHT is relatively rare and the majority of cases thus far reported have been managed with lipid-lowering therapy and/or discontinuation of capecitabine followed by resumption of the drug upon normalization of triglyceride levels. We present among the first U.S. cases of CIHT to be reported in the published literature and highlight management approaches for this rare but clinically relevant adverse event. Further understanding of the mechanisms of CIHT and its long-term adverse effects as well as effective preventive strategies, interventions, and monitoring strategies are prudent given the widespread and often prolonged use of capecitabine-based chemotherapy in gastrointestinal and other cancers.",
"affiliations": "Division of Medical Oncology and Hematology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA.;Division of Medical Oncology and Hematology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA.;Division of Medical Oncology and Hematology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA.;Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.;Division of Medical Oncology and Hematology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA.;Division of Medical Oncology and Hematology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA.;Division of Medical Oncology and Hematology, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA.",
"authors": "Uche|An|A|;Vankina|Ritika|R|;Gong|Jun|J|;Cho|May|M|;Yeh|James J|JJ|;Kim|Phyllis|P|;Pan|Kathy|K|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo.2018.07.07",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "9(6)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "Capecitabine; adverse event (AE); breast cancer; colorectal cancer; hypertriglyceridemia",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "1213-1219",
"pmc": null,
"pmid": "30603144",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "16391007;16821596;17595791;18421053;18641989;20002489;20100161;20431291;20664584;21386842;21968696;22418760;23038659;23223655;23627980;23783143;24172179;24595094;24781450",
"title": "Capecitabine-induced hypertriglyceridemia: a rare but clinically relevant treatment-related adverse event.",
"title_normalized": "capecitabine induced hypertriglyceridemia a rare but clinically relevant treatment related adverse event"
} | [
{
"companynumb": "US-ACCORD-098987",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "A 30-year-old woman presented with severe headache, dysarthria and right hemiparesis. She was treated for suspected viral encephalopathy and recovered over the following weeks although the headaches persisted. Two months later she was treated in-hospital for pulmonary embolism. The following year she was readmitted for increased frequency of headaches and was given a diagnosis of migraine. A subsequent MRI head scan was suggestive of longstanding venous sinus infarcts and neuroradiology review concluded that encephalitis had been the incorrect initial diagnosis. Subsequent investigations for an underlying cause of the two episodes of venous thrombosis revealed a total homocysteine level of >350 μmol/L (<15 μmol/L). An underlying diagnosis of homocystinuria secondary to cystathionine β-synthase deficiency was made although this metabolic condition is normally recognised in childhood. Treatment with pyridoxine and betaine normalised her homocysteine levels and she has had no further thrombotic event since.",
"affiliations": "QE Hospital Birmingham, Birmingham, UK.;QE Hospital Birmingham, Birmingham, UK.;Department of Radiology, University of Birmingham, Birmingham, West Midlands, UK.;Department of Endocrinology, University Hospital of Birmingham, Birmingham, UK.",
"authors": "Woods|Emily|E|http://orcid.org/0000-0003-2349-2688;Dawson|Charlotte|C|;Senthil|Latha|L|;Geberhiwot|Tarekegn|T|",
"chemical_list": "D008082:Lipotropic Agents; D014803:Vitamin B Complex; D001622:Betaine; D011736:Pyridoxine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-217477",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001622:Betaine; D002533:Cerebral Angiography; D000072226:Computed Tomography Angiography; D003951:Diagnostic Errors; D004401:Dysarthria; D018792:Encephalitis, Viral; D005260:Female; D006261:Headache; D006712:Homocystinuria; D006801:Humans; D008082:Lipotropic Agents; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008881:Migraine Disorders; D010291:Paresis; D010690:Phlebography; D011655:Pulmonary Embolism; D011736:Pyridoxine; D012851:Sinus Thrombosis, Intracranial; D014803:Vitamin B Complex",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28137899",
"pubdate": "2017-01-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11254663;11480268;15475638;15858188;16702350;3872065",
"title": "Cerebral venous thrombosis as the first presentation of classical homocystinuria in an adult patient.",
"title_normalized": "cerebral venous thrombosis as the first presentation of classical homocystinuria in an adult patient"
} | [
{
"companynumb": "GB-UCBSA-2017009628",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "Background. Anaphylaxis is a potentially fatal medical emergency. The frequency of hospital admissions for anaphylaxis seems to be increasing in the recent decades. Objective. Characterize the patients admitted for anaphylaxis to the adult emergency department (ED) of a tertiary care hospital over a 10-year period, discriminating aetiologies, clinical features and therapy administered. Methods. Retrospective, descriptive and inferential study, evaluating age, sex, Manchester triage system, suspected allergen, site of allergen exposure, comorbidities, cofactors, clinical findings and symptoms, treatment and management. Patients admitted between January 2007 and December 2016 were included. Results. Forty-three patients were enrolled: 23 males, mean age 54.3 ± 16.2 years, n = 22 had history of allergic disease. Two patients were triaged as non-urgent. The most frequently suspected causes of anaphylaxis were: drugs (33%, n = 14), Hymenoptera venoms (23%, n = 10), foods (21%, n = 9) and iodinated contrast products (12%, n = 5). Adrenaline was used in 88% of the episodes (n = 38), 55% of which (n = 21) intramuscularly. Mortality was registered in one case. At discharge, adrenaline auto-injector was prescribed in 7% (n = 3) of the patients, and Allergy and Clinical Immunology consultation (ACIC) was requested in 65% of the episodes (n = 28). Statistically significant associations (p minor 0.05) were established: a, anaphylaxis to drugs associated with a low intramuscular adrenaline use and with frequent oxygen therapy; b, anaphylaxis to food associated with intramuscular adrenaline administration; c, anaphylaxis to Hymenoptera venom associated with male sex; and d, anaphylaxis to iodinated contrasts associated with referral to ACIC and with shock. All obese patients developed shock. Conclusions. Anaphylaxis is a life-threatening condition that requires early recognition. Although most patients received adrenaline, administration was not always performed by the recommended route and only a few patients were prescribed adrenaline auto-injector.",
"affiliations": "Serviço de Imunoalergologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Serviço de Medicina Interna, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Serviço de Imunoalergologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Serviço de Imunoalergologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Serviço de Medicina Interna, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Serviço de Medicina Intensiva, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Serviço de Urgência, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Serviço de Imunoalergologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Serviço de Imunoalergologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.",
"authors": "Alen Coutinho|I|I|;Ferreira|D|D|;Regateiro|F S|FS|;Pita|J|J|;Ferreira|M|M|;Martins|J F|JF|;Fonseca|I A|IA|;Loureiro|C|C|;Todo-Bom|A|A|",
"chemical_list": "D000485:Allergens; D001180:Arthropod Venoms; D004364:Pharmaceutical Preparations; D004837:Epinephrine",
"country": "Italy",
"delete": false,
"doi": "10.23822/EurAnnACI.1764-1489.98",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1764-1489",
"issue": "52(1)",
"journal": "European annals of allergy and clinical immunology",
"keywords": "adrenaline; adults; anaphylaxis; complementary treatment; drug; food; insect venom; iodinated contrast products; obesity; treatment",
"medline_ta": "Eur Ann Allergy Clin Immunol",
"mesh_terms": "D000328:Adult; D000485:Allergens; D000707:Anaphylaxis; D000818:Animals; D001180:Arthropod Venoms; D004636:Emergency Service, Hospital; D004837:Epinephrine; D005260:Female; D005502:Food; D006801:Humans; D006927:Hymenoptera; D006967:Hypersensitivity; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D011174:Portugal; D012189:Retrospective Studies; D062606:Tertiary Care Centers",
"nlm_unique_id": "101466614",
"other_id": null,
"pages": "23-34",
"pmc": null,
"pmid": "31287264",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anaphylaxis in an emergency department: a retrospective 10-year study in a tertiary hospital.",
"title_normalized": "anaphylaxis in an emergency department a retrospective 10 year study in a tertiary hospital"
} | [
{
"companynumb": "PT-TEVA-2020-PT-1193301",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nProgel Pleural Air Leak Sealant (Progel) is currently the only sealant approved by the FDA for the treatment of air leaks during lung surgery. This study was performed to determine whether Progel use improves hospital length of stay (LOS) and hospitalization costs compared with other synthetic/fibrin sealants in patients undergoing lung surgery.\n\n\nMETHODS\nThe US Premier hospital database was used to identify lung surgery discharges from January 1, 2010 to June 30, 2015. Eligible discharges were categorized as \"Progel Sealant\" or \"other sealants\" using hospital billing data. Propensity score matching (PSM) was performed to control for hospital and patient differences between study groups. Primary outcomes were hospital LOS and all-cause hospitalization costs. Clinical outcomes, hospital re-admissions, and sealant product use were also described.\n\n\nRESULTS\nAfter PSM, a total of 2,670 discharges were included in each study group; baseline characteristics were balanced between groups. The hospital LOS (mean days ± standard deviation, median) was significantly shorter for the Progel group (9.9 ± 9.6, 7.0) compared with the other sealants group (11.3 ± 12.8, 8.0; p < .001). Patients receiving Progel incurred significantly lower all-cause hospitalization costs ($31,954 ± $29,696, $23,904) compared with patients receiving other sealants ($36,147 ± $42,888, $24,702; p < .001).\n\n\nCONCLUSIONS\nIt is not possible to say that sealant type alone was responsible for the findings of this study, and analysis was restricted to the data available in the Premier database.\n\n\nCONCLUSIONS\nAmong hospital discharges for lung surgery, Progel use was associated with significantly shorter hospital LOS and lower hospitalization costs compared with other synthetic/fibrin sealants, without compromising clinical outcomes.",
"affiliations": "a Division of Thoracic Surgery , The George Washington University Hospital , Washington , DC , USA.;b Becton Dickinson , Murray Hill , NJ , USA.;b Becton Dickinson , Murray Hill , NJ , USA.;b Becton Dickinson , Murray Hill , NJ , USA.;c Cornerstone Research Group Inc. , Burlington , ON , Canada.;c Cornerstone Research Group Inc. , Burlington , ON , Canada.",
"authors": "Mortman|Keith D|KD|;Corral|Mitra|M|;Zhang|Xiaohong|X|;Berhane|Indrias|I|;Soleas|Ireena M|IM|;Ferko|Nicole C|NC|",
"chemical_list": "D014014:Tissue Adhesives",
"country": "England",
"delete": false,
"doi": "10.1080/13696998.2018.1499519",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1369-6998",
"issue": "21(10)",
"journal": "Journal of medical economics",
"keywords": "I10; O30; Pleural air leak; database; health economics; outcomes; surgery complications",
"medline_ta": "J Med Econ",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D017722:Hospital Charges; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D061646:Operative Time; D010359:Patient Readmission; D013510:Pulmonary Surgical Procedures; D012189:Retrospective Studies; D012959:Socioeconomic Factors; D014014:Tissue Adhesives; D055815:Young Adult",
"nlm_unique_id": "9892255",
"other_id": null,
"pages": "1016-1022",
"pmc": null,
"pmid": "29999435",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Length of stay and hospitalization costs for patients undergoing lung surgery with Progel pleural air leak sealant.",
"title_normalized": "length of stay and hospitalization costs for patients undergoing lung surgery with progel pleural air leak sealant"
} | [
{
"companynumb": "US-JNJFOC-20181019024",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN\\THROMBIN HUMAN"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nThere exist several reports of atopy and allergen-specific IgE-mediated hypersensitivity transferred by bone marrow transplantation, and it has been concluded that the transfer of allergic reactivity results from adoptive transfer of IgE-producing donor-derived B- and/or plasma cells. To the best of our knowledge we report the first case of peanut allergy after PBSCT.\n\n\nMETHODS\nA 55-year-old anciently non allergic man with secondary acute myeloid leukemia (AML) received an allogeneic peripheral blood stem cell transplantation from a matched unrelated donor following reduced-intensity conditioning. On day 32 after PBSCT, while still on prophylactic systemic immunosuppression, the patient noticed a first episode of angioedema with swelling of the nasal and oral mucosa 30 min after consuming peanut puffs. In a second episode, eight months after PBSCT, he again developed angioedema, generalized pruritus and nausea within minutes after eating biscuits containing hazelnut and peanut. Moreover, after topical application of a peanut oil-containing ointment, the patient experienced facial erythema and angioedema. Nine months after PBSCT an evaluation for peanut allergy revealed a highly increased specific IgE to peanut of 75.9 kU/l. Accordingly, skin prick tests for peanut extract were also positive. In consequence, the patient was counseled to strictly avoid peanut-related products, and provided with an emergency set. No adverse allergic events have occurred since for an observation time of 15 months after PBSCT. The stem cell donor was contacted and confirmed intolerance to peanuts. His specific serum IgE pattern nine month after PBSCT harvest was analysed and showed similar sensitization profiles compared to those of the transplant recipient.\n\n\nCONCLUSIONS\nBecause of the close temporal association between the onset of allergic symptoms in the PBSC recipient it is reasonable to assume that the acquired peanut allergy had been transferred from the donor to the recipient by the PBSC graft.",
"affiliations": "Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University Göttingen, Göttingen, Germany ; Department of Dermatology and Venereology, University Medical Center, Rostock, Germany.;Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University Göttingen, Göttingen, Germany ; Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen and University of Osnabrück, Osnabrück, Germany.;Department for Hematology and Oncology, University Medical Center, Georg August University, Göttingen, Germany.;Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University Göttingen, Göttingen, Germany ; Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen and University of Osnabrück, Osnabrück, Germany ; Dermatology Office, Elmshorn, Germany.",
"authors": "Brauns|Birka|B|;Schön|Michael P|MP|;Wulf|Gerald|G|;Mempel|Martin|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1186/s40413-016-0093-4",
"fulltext": "\n==== Front\nWorld Allergy Organ JWorld Allergy Organ JThe World Allergy Organization Journal1939-4551BioMed Central London 9310.1186/s40413-016-0093-4Case ReportA lurking threat: transfer of peanut allergy through peripheral blood stem cell transplantation Brauns Birka 0049-381-494 9797birka.brauns@med.uni-rostock.de Schön Michael P. michael.schoen@med.uni-goettingen.de Wulf Gerald gerald.wulf@med.uni-goettingen.de Mempel Martin martin.mempel@gmx.de Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University Göttingen, Göttingen, Germany Lower Saxony Institute of Occupational Dermatology, University Medical Center Göttingen and University of Osnabrück, Osnabrück, Germany Department for Hematology and Oncology, University Medical Center, Georg August University, Göttingen, Germany Dermatology Office, Elmshorn, Germany Department of Dermatology and Venereology, University Medical Center, Rostock, Germany 8 2 2016 8 2 2016 2016 9 310 7 2015 4 1 2016 © Brauns et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThere exist several reports of atopy and allergen-specific IgE-mediated hypersensitivity transferred by bone marrow transplantation, and it has been concluded that the transfer of allergic reactivity results from adoptive transfer of IgE-producing donor-derived B- and/or plasma cells. To the best of our knowledge we report the first case of peanut allergy after PBSCT.\n\nCase Presentation\nA 55-year-old anciently non allergic man with secondary acute myeloid leukemia (AML) received an allogeneic peripheral blood stem cell transplantation from a matched unrelated donor following reduced-intensity conditioning. On day 32 after PBSCT, while still on prophylactic systemic immunosuppression, the patient noticed a first episode of angioedema with swelling of the nasal and oral mucosa 30 min after consuming peanut puffs. In a second episode, eight months after PBSCT, he again developed angioedema, generalized pruritus and nausea within minutes after eating biscuits containing hazelnut and peanut. Moreover, after topical application of a peanut oil-containing ointment, the patient experienced facial erythema and angioedema. Nine months after PBSCT an evaluation for peanut allergy revealed a highly increased specific IgE to peanut of 75.9 kU/l. Accordingly, skin prick tests for peanut extract were also positive. In consequence, the patient was counseled to strictly avoid peanut-related products, and provided with an emergency set. No adverse allergic events have occurred since for an observation time of 15 months after PBSCT. The stem cell donor was contacted and confirmed intolerance to peanuts. His specific serum IgE pattern nine month after PBSCT harvest was analysed and showed similar sensitization profiles compared to those of the transplant recipient.\n\nConclusions\nBecause of the close temporal association between the onset of allergic symptoms in the PBSC recipient it is reasonable to assume that the acquired peanut allergy had been transferred from the donor to the recipient by the PBSC graft.\n\nKeywords\nPeanut allergyStem cell transplantationAllergy transferIgE-mediated hypersensitivityNoneNoneBrauns Birka issue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nAtopy and food sensitization following solid-organ or bone marrow transplantation has previously been reported [1–6]. One theorised mechanism is the sensitization by passive transfer of donor IgE [7]. Another concept is the allergy transfer via mature specific T and/or B lymphocytes leading to active production of allergen-spezific IgE in the transplant recipient [1, 2]. The relevance of the immunosuppressive therapy (particularly of tacrolimus) for post-transplant allergies has also been previously discussed [8, 9].\n\nHere, we present the case of a male patient who unexpectedly developed anaphylactic peanut allergy after he received peripheral blood stem cell transplantation (PBSCT) for acute myeloid leukaemia.\n\nCase presentation\nA 55-year-old male patient who received peripheral blood stem cell transplantation (PBSCT) for acute myeloid leukaemia unexpectedly developed anaphylactic peanut allergy.\n\nIn his past medical history, the index patient had not experienced any allergic food reactions or atopy, and in particular he had regularly ingested peanut products without any problems. There was no atopic dermatitis, asthma or pollinosis in the family. The patient’s further medical history included a colon adenocarcinoma stage II treated by hemicolectomy followed by adjuvant chemotherapy in 2002 and partial nephrectomy for renal cell carcinoma stage 1a in 2006. In 2010, the diagnosis of secondary acute myeloid leukemia (AML) with NPM1-mutation and normal karyotype was established, and he received intensive induction and consolidation chemotherapy with AraC and anthracyclin-based regimens. In 2011, his AML relapsed. After achieving a second remission by salvage chemotherapy, the patient received an allogeneic peripheral blood stem cell transplantation from a matched unrelated donor following reduced-intensity conditioning. Immunosuppression for the prevention of graft-versus-host disease (GvHD) comprised pre-transplant antithymoglobulin (ATG), as well as cyclosporine (CsA) from day 0 through 120 and mycophenolate mofetil (MMF) from day 0 through 28. Hematological engraftment occurred on day 10, with complete donor chimerism in the peripheral blood achieved from day 14 on. Immune reconstitution mirrored by CD4-T-cell counts >200/μl were documented from day 120 on. The patient then developed extensive chronic GvHD of the skin, necessitating local and systemic steroids as well as tacrolimus at trough levels (5–10 ng/ml) starting at 6 months after transplantation.\n\nOn day 32 after PBSCT, while still on prophylactic systemic immunosuppression and receiving an otherwise defined low-bacteria lactose-free diet, the patient noticed a first episode of angioedema with swelling of the nasal and oral mucosa 30 min after consuming peanut puffs. In a second episode, eight months after PBSCT while on normal nutrition, he again developed angioedema, generalized pruritus and nausea within minutes after eating biscuits containing hazelnut and peanut. There have been no cardiovascular symptoms. The patient was successfully treated intravenous with 250 mg methylprednisolone and 2 mg clemastine.\n\nMoreover, between 2nd and 4th week after PBSCT occasional topical application of a refined peanut oil-containing lipid replenishing cream induced skin erythema and pruritus within minutes.\n\nThese events prompted an evaluation for peanut allergy nine months after PBSCT, revealing a total IgE of 202 kU/l and a highly increased specific IgE to peanut of 75.9 kU/l. In detail, we found high specific IgE to the major recombinant peanut allergens Ara h1, Ara h2 and Ara h3 (Table 1). Accordingly, skin prick tests for peanut extract were also positive (>6 mm). In consequence, the patient was counseled to strictly avoid peanut-related products, and provided with an emergency set (containing self-injectable epinephrine, liquid oral antihistamines and steroid). The patient strictly avoided further exposition to peanut products, and no further adverse allergic events occurred. Unfortunately, the patient succumbed to progressive leukemia 36 months after PBSCT.Table 1 Specific IgE and skin prick test in the transplant recipient and the transplant donor\n\nTest\tAllergen\tResults 9 months after PBSCT\t\nTransplant recipient\tTransplant donor\t\nsIgE\tTotal IgE\t202 kU/l\t361 kU/l\t\n\tPeanut\t75.9 kU/l\t>100 kU/l\t\n\t rArah1\t7.02 kU/l\t45.3 kU/l\t\n\t rArah2\t7.73 kU/l\t30.9 kU/l\t\n\t rArah3\t36.50 kU/l\t31.70 kU/l\t\n\t rArah8\t<0.35 kU/l\t0.68 kU/l\t\n\t rArah9\t<0.35 kU/l\t<0.35 kU/l\t\nSkin prick test\tPeanut (1:10)\t++++ (>6 mm)\tNot performed\t\n\nsIgE serum IgE, PBSCT peripheral blood stem cell transplantation\n\n\n\nThe stem cell donor was contacted and confirmed clinical allergy to peanuts and negated any other allergies. His specific serum IgE pattern nine month after PBSCT harvest was analysed and showed similar sensitization profiles compared to those of the transplant recipient with increased specific IgE to peanut and high specific IgE to the major recombinant peanut allergens Ara h1, Ara h2 and Ara h3 (Table 1).\n\nAlthough the sensitization profiles of donor and recipient (reactions against Ara h1, Ara h2 and Ara h3) can be found in a large proportion of true peanut allergic patients it is reasonable to assume that the acquired peanut allergy had been transferred from the donor to the recipient by the PBSC graft.\n\nThere exist several reports of atopy and allergen-specific IgE-mediated hypersensitivity other than peanut transferred by bone marrow transplantation, and it has been concluded that the transfer of allergic reactivity results from adoptive transfer of IgE-producing donor-derived B- and/or plasma cells [1, 2]. The case of the index patient presented here is compatible with this concept of allergy transfer via mature specific memory B-cells, eliciting a reactivity pattern almost identical to that of the donor. To the best of our knowledge it is the first case of peanut allergy after PBSCT. Numbers of transplanted cells were generally higher in PBSC than BM grafts (e. g. G-CSF-primed peripheral blood grafts contain approximately 10-fold more T-cells) and are associated with better engraftment but increased risk of (chronic) GvHD. The mature specific memory B-cells in the index patient must have been either circulating blood B-cells or they had been mobilized from the marrow into the blood by the G-CSF pre-treatment of the PBSC donor. An additional pro-allergenic influence of progenitor cell mobilization with G-CSF is conceivable.\n\nIn addition to the late reaction to peanut products attributable to the engraftment of specific B-cells, the index patient had also experienced mild reactions to peanut products between 2nd and 4th week after transplantation. While assuming that this reaction already was a symptom of the peanut reactivity, it appears unlikely that the B-cells transferred with the graft might have produced the amounts of IgE responsible for the reaction at that early time point. Yet, because the graft had been transplanted in a volume of 300 ml, it is conceivable that passive transfer of IgE itself in the PBSC-bag or of cell-bound IgE contributed to the reaction. Such passive and transient transfer of peanut allergy has been described in solid-organ transplants for patients having received liver [3], lung [4], combined liver-kidney transplants [5] or combined pancreas-kidney transplants [6]. While the transfer of IgE-mediated allergy in BMT can be explained by the transfer of long-living plasma cells in the bone marrow [10], solid organs such as the lungs have not been described to harbor such long-living plasma cells. Alternatively, IgE itself has been described a carrier of IgE-mediated memory [7] and might therefore be responsible for persisting allergic reactions.\n\nThe relevance of the immunosuppressive therapy with CsA, MMF and tacrolimus for post-transplant allergies was previously discussed. In particular tacrolimus seems to be a potential risk factor, as it may lead to a Th1/Th2 imbalance towards Th2 and also inhibited the regulatory T cells by suppression of interleukin 2 [8, 9]. Thus in our case an additional effect of tacrolimus on the occurrence of posttransplant peanut sensitization appears conceivable. Especially in patients with altered skin barrier function the cutaneous exposure to food protein can induce allergic sensitization [11]. Refined topical peanut oil products as applied by our patient are considered to be safe and the risk to induce type I allergy very low [12]. However an additional effect with sensitization via the peanut containing ointment is therefore unlikely in our case in our opinion, but might principally also be possible.\n\nConclusion\nThis case documents a probable stable transfer of IgE-memory cells by peripheral stem cell transplantation, which elicitied significant clinical symptoms. Although uncommon, the consequences of transplant-conveyed allergies can be life-threateningly severe. Thus, exclusion of significant type-I allergies prior to performing PBSCT appears to be a worthwhile investment. In case of known hypersensitivity in the donor, we recommend adequate testing and counselling of the PBSC recipient.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nBMTbone marrow transplantation\n\ncGvHDchronic graft versus host disease\n\nCsACyclosporine\n\nMMFmycophenolate mofetil\n\nPBSCTperipheral blood stem cell transplantation\n\nsIGEserum IGE\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nBB, GW, MM treated the index patient and collected the clinical data. BB and MM drafted the manuscript. MPS and MD helped to draft the manuscript. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Saarinen UM Transfer of latent atopy by bone marrow transplantation? A case report J Allergy Clin Immunol 1984 74 196 200 10.1016/0091-6749(84)90286-0 6379019 \n2. Tucker J Barnetson RS Eden OB Atopy after bone marrow transplantation Br Med J (Clin Res Ed) 1985 290 116 7 10.1136/bmj.290.6462.116 \n3. Dewachter P Vézinet C Nicaise-Roland P Chollet-Martin S Eyraud D Creusvaux H Passive transient transfer of peanut allergy by liver transplantation Am J Trans 2011 11 1531 1534 10.1111/j.1600-6143.2011.03576.x \n4. Khalid I Zoratti E Stagner L Betensley AD Nemeh H Allenspach L Transfer of peanut allergy from the donor to a lung transplant recipient J Heart Lung Transplant 2008 27 1162 4 10.1016/j.healun.2008.07.015 18926410 \n5. Legendre C Caillat-Zucman S Samuel D Morelon S Bismuth H Bach JF Transfer of symptomatic peanut allergy to the recipient of a combined liver-and-kidney transplant N Engl J Med 1997 337 822 4 10.1056/NEJM199709183371204 9297112 \n6. Berry A Campsen J Shihab F Firszt R Transfer of peanut IgE sensitization after combined pancreas-kidney transplant Clin Exp Allergy. 2014 44 1020 1022 10.1111/cea.12355 24919754 \n7. Griffith QK Liang Y Onguru DO Mwinzi PN Ganley-Leal LM CD23-bound IgE augments and dominates recall responses through human naive B cells J Immunol 2011 186 2 1060 7 10.4049/jimmunol.1002709 21160045 \n8. Gruber S Tiringer K Dehlink E Eiwegger T Mayer E Konstantin H Allergic sensitiziation in kidney-transplanted patients prevails under tacrolimus treatment Clin Exp Allergy. 2011 41 1125 32 10.1111/j.1365-2222.2011.03761.x 21545550 \n9. Ozdemir O New developments in transplant-acquired allgergies World J Transplant. 2013 3 30 5 10.5500/wjt.v3.i3.30 24255880 \n10. Luger EO Fokuhl V Wegmann M Abram M Tillack K Achatz G Induction of long-lived allergen-specific plasma cells by mucosal allergen challenge J Allergy Clin Immunol 2009 124 819 26 10.1016/j.jaci.2009.06.047 19815119 \n11. Lack G Update on risk factors for food allergy J Allergy Clin Immunol. 2012 129 1187 97 10.1016/j.jaci.2012.02.036 22464642 \n12. Ring J Möhrenschlager M Allergy to peanut oil – clinically relevant? J Eur Acad Dermatol Venereol. 2007 21 452 455 17373969\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1939-4551",
"issue": "9()",
"journal": "The World Allergy Organization journal",
"keywords": "Allergy transfer; IgE-mediated hypersensitivity; Peanut allergy; Stem cell transplantation",
"medline_ta": "World Allergy Organ J",
"mesh_terms": null,
"nlm_unique_id": "101481283",
"other_id": null,
"pages": "3",
"pmc": null,
"pmid": "26904156",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "21160045;21545550;9297112;6379019;3917707;18926410;19815119;24255880;21668638;22464642;24919754;17373969",
"title": "A lurking threat: transfer of peanut allergy through peripheral blood stem cell transplantation.",
"title_normalized": "a lurking threat transfer of peanut allergy through peripheral blood stem cell transplantation"
} | [
{
"companynumb": "DE-WATSON-2016-04987",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"... |
{
"abstract": "Leptomeningeal carcinomatosis (MC) represents an uncommon, but devasting manifestation of metastatic breast cancer. This is the first systematic review/pooled analysis to synthesize all available data evaluating the efficacy and safety of intrathecal (IT) administration of trastuzumab for the treatment of MC in HER2-positive breast cancer patients. This study was performed in accordance with the PRISMA guidelines. A total of 13 articles (17 patients) were eligible. The mean age of patients at IT trastuzumab administration was 48.2 years (SD 8.4, range 38-66). The mean total dose was 399.8 mg (SD 325.4, range 35-1,110 mg). IT trastuzumab alone or as part of combination therapies seemed to be safe; no serious adverse events were reported in 88.2 % of cases. In 68.8 % of cases, a significant clinical improvement was observed, while stabilization or progression of the disease was noticed in 31.2 % of cases. Cerebrospinal fluid (CSF) response was noted in 66.7 % of cases. The median overall survival was 13.5 months, whereas the median central nervous system progression-free survival (CNS-PFS) was 7.5 months. In 23.5 % of cases, IT trastuzumab was administered beyond CNS progression with a response noticed in 75 % of cases and a CNS-PFS of 9.4 months. The cumulative dose of IT trastuzumab given was 1,040 mg (SD 697.9, median 1,215, range 55-1,675). The protective effect of prior radio- or neurosurgery upon CNS-PFS was sizeable but did not reach formal statistical significance (HR 0.28, 95 % CI 0.06-1.37). Clinical improvement (HR 0.14, 95 % CI 0.02-0.91) and CSF response (HR 0.09, 95 % CI 0.01-0.89) were associated with longer CNS-PFS. IT trastuzumab administration seems to represent a safe and in some cases effective option for the treatment of HER2-positive breast cancer patients with leptomeningeal involvement. However, clinical trials are urgently needed to establish the definite role of IT trastuzumab in HER2-positive metastatic breast cancer patients with MC.",
"affiliations": "Department of Clinical Therapeutics, Alexandra Hospital, Medical School, University of Athens, Athens, Greece. florazagouri@yahoo.co.uk",
"authors": "Zagouri|Flora|F|;Sergentanis|Theodoros N|TN|;Bartsch|Rupert|R|;Berghoff|Anna S|AS|;Chrysikos|Dimosthenis|D|;de Azambuja|Evandro|E|;Dimopoulos|Meletios-Athanassios|MA|;Preusser|Matthias|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10549-013-2525-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6806",
"issue": "139(1)",
"journal": "Breast cancer research and treatment",
"keywords": null,
"medline_ta": "Breast Cancer Res Treat",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D007278:Injections, Spinal; D055756:Meningeal Carcinomatosis; D000068878:Trastuzumab",
"nlm_unique_id": "8111104",
"other_id": null,
"pages": "13-22",
"pmc": null,
"pmid": "23588955",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis.",
"title_normalized": "intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in her2 positive metastatic breast cancer a systematic review and pooled analysis"
} | [
{
"companynumb": "PT-PFIZER INC-2019520002",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe efficacy and tolerability of M-TIP was evaluated as first-line treatment for patients with poor-risk germ cell tumors (GCT), according to International Germ Cell Cancer Collaborative Group (IGCCCG) criteria.\n\n\nMETHODS\nThirty patients with poor-risk GCT were treated with M-TIP (methotrexate 250 mg/m(2) given as a 4-hour infusion with folinic acid rescue on day 1, paclitaxel 175 mg/m(2) given as a 3-hour infusion on day 1, followed by ifosfamide 1.2 g/m(2) given as a 2-hour infusion and cisplatin 20 mg/m(2) given as a 2-hour infusion on days 2 to 6) regimen for four cycles.\n\n\nRESULTS\nFive (16.6%, 95% confidence interval [CI]: 2%-31%) patients achieved clinical complete response (cCR) with chemotherapy only, 15 (50%, 95% CI: 31-69%) patients pathologic complete response (pCR) (11 had necrosis/fibrosis and 4 had mature teratoma) and 3 (10%) patients surgical complete response (sCR) for an overall favorable response of 76.6%. Twenty-one patients are continuously disease-free at a median follow-up of 5.3 years (range 0.9-8.4+ years), resulting in a 5-year progression-free survival (PFS) rate of 66.6% (95% CI = 49%-85%) and a 5-year survival rate of 70% (95% CI = 53%-87%). Toxicity was generally mild except for myelotoxicity. Patients with febrile neutropenia were successfully treated with broad spectrum antibiotics and G-CSF support. Hematologic toxicity in this trial was ameliorated with the use of G-CSF. Neurotoxicity and nephrotoxicity were not a problem, since only 6.6% and 3.3% of patients developed sensory neuropathy and renal toxicity, respectively.\n\n\nCONCLUSIONS\nM-TIP is a highly effective (high proportion of patients achieved long-term disease-free status, lack of relapses) and well tolerated regimen for first-line treatment of poor-risk GCT patients. These results have to be compared with the standard BEP chemotherapy or more intensive regimens in multicentre randomized trials.",
"affiliations": "Second Department of Internal Medicine, Propaedeutic, Oncology Section, University of Athens, Attikon University Hospital, Athens, Greece. pectasid@otenet.gr",
"authors": "Pectasides|Dimitrios|D|;Pectasides|Eirini|E|;Papaxoinis|George|G|;Xiros|Nikolaos|N|;Kamposioras|Konstantinos|K|;Tountas|Nikolaos|N|;Economopoulos|Theofanis|T|",
"chemical_list": "D017239:Paclitaxel; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.urolonc.2008.10.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1439",
"issue": "28(6)",
"journal": "Urologic oncology",
"keywords": null,
"medline_ta": "Urol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D018572:Disease-Free Survival; D006801:Humans; D007069:Ifosfamide; D053208:Kaplan-Meier Estimate; D008297:Male; D008479:Mediastinal Neoplasms; D008727:Methotrexate; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal; D017239:Paclitaxel; D013736:Testicular Neoplasms; D055815:Young Adult",
"nlm_unique_id": "9805460",
"other_id": null,
"pages": "617-23",
"pmc": null,
"pmid": "19110454",
"pubdate": "2010",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Methotrexate, paclitaxel, ifosfamide, and cisplatin in poor-risk nonseminomatous germ cell tumors.",
"title_normalized": "methotrexate paclitaxel ifosfamide and cisplatin in poor risk nonseminomatous germ cell tumors"
} | [
{
"companynumb": "GR-SA-2020SA155572",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nPathological complete response (pCR) and clinical outcomes [overall survival (OS), disease-free survival (DFS), locoregional control (LC)] were evaluated in a single-institution experience of different schedules of neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC).\n\n\nMETHODS\nData for 322 patients with LARC were retrospectively analyzed. pCR was evaluated according to Mandard tumor regression grade (TRG). The Kaplan-Meier method was used to estimate OS, DFS and LC.\n\n\nRESULTS\nThree hundred and three (94.1%) patients underwent surgery. pCR was observed in 81 patients (26.7%), with TRG1-2 rate of 41.8%. The 5- and 10-year OS, DFS and LC rates were 82.5%±2.5% and 65.5%±3.8%, 81.2%±2.4% and 79.3%±2.9%, 93.1%±1.7% and 90.5%±2.1%, respectively.\n\n\nCONCLUSIONS\nNeoadjuvant CRT in LARC patients resulted in favorable long-term oncological outcomes, with a high pCR rate and acceptable toxicity.",
"affiliations": "Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy.;Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy.;Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy lcaravatta@hotmail.com.;Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy.;Department of Radiation Therapy, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.;Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy.;Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy.;Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy.;Department of Radiology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy.;Division of Surgery, Villa Serena Clinic, Città S. Angelo, Italy.;Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University, Chieti, Italy.;Division of Pathology, SS. Annunziata Hospital, Chieti, Italy.;Division of Pathology, SS. Annunziata Hospital, Chieti, Italy.;Division of Surgery III, Santo Spirito Hospital, Pescara, Italy.;Division of Pathology, Santo Spirito Hospital, Pescara, Italy.;Division of Surgery, Renzetti Hospital, Lanciano, Italy.;Division of Pathology, Villa Serena Clinic, Città S. Angelo, Italy.;Division of Surgery, Villa Serena Clinic, Città S. Angelo, Italy.;Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, G. D'Annunzio University, Chieti, Italy.;Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, G. D'Annunzio University, Chieti, Italy.;Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy.",
"authors": "DI Tommaso|Monica|M|;Rosa|Consuelo|C|;Caravatta|Luciana|L|;Augurio|Antonietta|A|;Borzillo|Valentina|V|;DI Santo|Sara|S|;Perrotti|Francesca|F|;Taraborrelli|Maria|M|;Cianci|Roberta|R|;Innocenti|Paolo|P|;DI Sebastiano|Pierluigi|P|;Colasante|Antonella|A|;Angelucci|Domenico|D|;Basti|Massimo|M|;Sindici|Giulia|G|;Mazzola|Lorenzo|L|;Pizzicannella|Giuseppe|G|;DI Bartolomeo|Nicola|N|;Marchioni|Michele|M|;DI Nicola|Marta|M|;Genovesi|Domenico|D|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.21873/invivo.11896",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0258-851X",
"issue": "34(3)",
"journal": "In vivo (Athens, Greece)",
"keywords": "Chemoradiotherapy; late toxicities; long-term results; pathological complete response; rectal cancer",
"medline_ta": "In Vivo",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D012004:Rectal Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8806809",
"other_id": null,
"pages": "1223-1233",
"pmc": null,
"pmid": "32354913",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "26374429;7713792;24276776;26189067;15936556;17762432;20194850;17557563;16246976;16750329;21606427;21851185;8194005;12680168;15496622;17919844;18407433;22503032;15856263;15337549;18418009;25281582;20692872;16971718;21555930;22763027;17008704;11547717;11920483;31005204;17497093",
"title": "Treatment Intensification for Locally Advanced Rectal Cancer: Impact on Pathological Complete Response and Outcomes.",
"title_normalized": "treatment intensification for locally advanced rectal cancer impact on pathological complete response and outcomes"
} | [
{
"companynumb": "IT-ROCHE-2653826",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "The purpose of this study is to develop a standard for monitoring outpatients starting bone-modifying agents (BMAs) at a community cancer center. The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines recommend the monitoring of serum magnesium and phosphorus during BMA therapy but do not define a standard interval. The risk of hypomagnesemia and hypophosphatemia was assessed for the BMAs denosumab, pamidronate, and zoledronic acid. Compliance with dental clearance was also evaluated. Adult cancer outpatients newly started on BMAs between January 1, 2016, to December 31, 2016, were evaluated. Patients with hypercalcemia of malignancy were excluded. Primary endpoints were the composite rates of grade 3 and 4 hypomagnesemia and hypophosphatemia. Secondary endpoints included all-grade hypomagnesemia, all-grade hypophosphatemia, charges for laboratory draws, rate of dental clearance, and rate of osteonecrosis of the jaw (ONJ). Among 61 patients, 4.3% experienced grade 3 and 4 hypophosphatemia. No cases of grade 3 and 4 hypomagnesemia occurred. The annual cost for serum magnesium and phosphorus lab draws totaled $9,144.80. Dental clearance was obtained in 100% of patients, with 67% of clearances obtained from a dentist. No patients developed ONJ. Composite rates of grade 3 and 4 hypomagnesemia and hypophosphatemia were lower than reported in the literature. We propose to monitor magnesium and phosphorus levels at baseline, and then every 6 months. More frequent laboratory draws may be indicated based on clinical judgment. This recommendation will reduce laboratory draws and provide cost savings for patients. Compliance with dental clearance was fully achieved.",
"affiliations": "Pharmacy Department, University of Colorado Health Memorial Hospital, Colorado Springs, Colorado.;Cancer Care and Hematology, University of Colorado Health Memorial Hospital, Colorado Springs, Colorado.;Pharmacy Department, University of Colorado Health Memorial Hospital, Colorado Springs, Colorado.;Cancer Care and Hematology, University of Colorado Health Memorial Hospital, Colorado Springs, Colorado.",
"authors": "Nguyen|Anton|A|;Kalis|Joseph A|JA|;Sutz|Theresa R|TR|;Jeffers|Kate D|KD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nJ Adv Pract OncolJ Adv Pract OncolJADPROJournal of the Advanced Practitioner in Oncology2150-08782150-0886Harborside Press jadpro.v09.i06.pg601Review ArticleOncologyDevelopment of a Practice Standard for Monitoring Adult Patients Receiving Bone-Modifying Agents at a Community Cancer Center Nguyen Anton PharmD1Kalis Joseph A. PharmD, BCOP2Sutz Theresa R. PharmD1Jeffers Kate D. PharmD, BCOP2\n1 \nPharmacy Department, University of Colorado Health Memorial Hospital, Colorado Springs, Colorado;\n\n2 \nCancer Care and Hematology, University of Colorado Health Memorial Hospital, Colorado Springs, Colorado\nCorrespondence to: Anton Nguyen, PharmD, 170 N. 1100 E., American Fork, UT 84003. E-mail: slc.anton.n@gmail.com\n\nSep-Oct 2018 1 9 2018 9 6 601 607 Copyright © 2018, Harborside Press2018This article is distributed under the terms of the\nCreative Commons Attribution Non-Commercial License, which permits\nunrestricted non-commercial use, distribution, and reproduction in any\nmedium, provided the original work is properly cited.The purpose of this study is to develop a standard for monitoring outpatients starting bone-modifying agents (BMAs) at a community cancer center. The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines recommend the monitoring of serum magnesium and phosphorus during BMA therapy but do not define a standard interval. The risk of hypomagnesemia and hypophosphatemia was assessed for the BMAs denosumab, pamidronate, and zoledronic acid. Compliance with dental clearance was also evaluated. Adult cancer outpatients newly started on BMAs between January 1, 2016, to December 31, 2016, were evaluated. Patients with hypercalcemia of malignancy were excluded. Primary endpoints were the composite rates of grade 3 and 4 hypomagnesemia and hypophosphatemia. Secondary endpoints included all-grade hypomagnesemia, all-grade hypophosphatemia, charges for laboratory draws, rate of dental clearance, and rate of osteonecrosis of the jaw (ONJ). Among 61 patients, 4.3% experienced grade 3 and 4 hypophosphatemia. No cases of grade 3 and 4 hypomagnesemia occurred. The annual cost for serum magnesium and phosphorus lab draws totaled $9,144.80. Dental clearance was obtained in 100% of patients, with 67% of clearances obtained from a dentist. No patients developed ONJ. Composite rates of grade 3 and 4 hypomagnesemia and hypophosphatemia were lower than reported in the literature. We propose to monitor magnesium and phosphorus levels at baseline, and then every 6 months. More frequent laboratory draws may be indicated based on clinical judgment. This recommendation will reduce laboratory draws and provide cost savings for patients. Compliance with dental clearance was fully achieved.\n==== Body\nBone health is a critical aspect of cancer management, as bone complications can significantly reduce patients’ quality of life and survival (Hernandez et al., 2015). Cancer treatments such as hormonal therapy, chemotherapy, glucocorticoids, and radiation can decrease bone mineral density (Guise, 2006). Additionally, bone complications often occur as a result of metastases and multiple myeloma. Significant morbidity and skeletal-related events (SREs) can occur, including pathologic fractures, spinal cord compression, severe pain, impaired mobility, and declining performance status. Risk factors for SREs include endocrine therapy, low bone mineral density (T-score of -1 or lower on a bone mineral density test), older age, chronic corticosteroid use, low body mass index (body mass index less than 18.5 kg/m²), prior history of fracture, family history of fracture, smoking, excessive alcohol intake, inadequate weight-bearing exercise, low calcium intake, and vitamin D deficiency (Centers for Disease Control and Prevention, 2016; Gralow et al., 2013; National Institutes of Health Osteoporosis and Related Bone Diseases National Resource Center, 2015).\n\nEffective prevention and treatment of bone loss can delay complications, relieve symptoms, and improve patients’ quality of life. Injectable pharmacologic options, known as bone-modifying agents (BMAs), include denosumab (Prolia, Xgeva), pamidronate (Aredia), and zoledronic acid (Reclast, Zometa). Pamidronate and zoledronic acid are bisphosphonates, which inhibit bone resorption and decrease mineralization by disrupting osteoclast activity (Ben Venue Laboratories, Inc., 1991; Novartis Pharmaceutical Corporation, 2001). Denosumab is a monoclonal antibody to receptor activator of nuclear factor κB ligand (RANKL). It inhibits osteoclast differentiation, proliferation, and function (Amgen, Inc., 2010). The risks of BMAs include acute-phase response, hypocalcemia, atypical femur fracture, nephrotoxicity with bisphosphonates, hypomagnesemia, hypophosphatemia, and osteonecrosis of the jaw (ONJ).\n\nOsteonecrosis of the jaw is a rare, serious side effect of BMA use (Gralow et al., 2013). Risk factors include increasing duration of BMA use, dental extractions, invasive procedures, periodontitis, and poor oral hygiene. Signs and symptoms involve tooth pain, jaw pain, feeling of loose teeth, swelling of the jaw, ongoing and recurrent dental infections, and exposure of jaw bone on physical examination. The American Association of Oral and Maxillofacial Surgeons and the US Food and Drug Administration labeling recommends all patients with cancer receive a dental examination and necessary preventive dental care prior to starting BMA therapy, unless factors exist which preclude dental assessment (Ruggiero et al., 2014). Our institution requests dental clearance prior to the initiation of BMAs.\n\nThe National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines recommend regular monitoring of serum magnesium and phosphorus during BMA therapy but do not specify a standard interval (Gralow et al., 2013; Van Poznak et al., 2011). At our community cancer center, serum magnesium and phosphorus labs are built into treatment plans for each injectable BMA. These labs are routinely monitored with each treatment cycle. Grade severity is based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Definitions can be found in Table 1 (National Institutes of Health, 2009). The reported incidences from the literature of grade 3 and 4 hypomagnesemia and hypophosphatemia for each BMA can be found in Table 2 (Amgen, Inc., 2010; Ben Venue Laboratories, Inc., 1991; Novartis Pharmaceutical Corporation, 2001). No evidence is currently available to guide the interval for monitoring serum magnesium and phosphorus with BMAs.\n\nTable 1 \nDefinitions of Grade 3 and 4 Hypomagnesemia and Hypophosphatemia Based on CTCAE Version 4.0\n\n\nTable 2 \nReported Incidences of Grade 3 and 4 Hypomagnesemia and Hypophosphatemia for Each Injectable Bone-Modifying Agent From the Literature\n\n\nThe purpose of this study is to develop a standard for monitoring serum magnesium and phosphorus in adult outpatients newly initiated on denosumab, pamidronate, and zoledronic acid at a community cancer center. Patients’ laboratory charges for serum magnesium and phosphorus were tracked. Compliance with dental clearance and incidence of ONJ were also evaluated.\n\nMETHODS\nA retrospective, descriptive study was conducted from January 1, 2016, to December 31, 2016, at a community cancer center. The study was reviewed and approved by the institutional review board. Patient data were collected from electronic chart reviews. Patient demographics collected included age, sex, use of active chemotherapy at baseline, presence of bone metastases at baseline, height, weight, serum creatinine, creatinine clearance based on the Cockcroft-Gault equation, chronic kidney disease diagnosis, oncologic diagnoses, and number of BMA cycles received. Inclusion criteria were cancer outpatients 18 years of age or older newly initiated on denosumab, pamidronate, or zoledronic acid. Figure 1 illustrates patients screened and included. Patients were excluded for the following reasons: treatment of hypercalcemia of malignancy (HCM), treatment use prior to the study period, or treatment administered at another institution.\n\nFigure 1 \nScreening, inclusion, and exclusion of patients by treatment group. HCM = hypercalcemia of malignancy.\n\n\nThe primary endpoints are composite rates of grade 3 and 4 hypomagnesemia and grade 3 and 4 hypophosphatemia. Secondary endpoints include rate of all-grade hypomagnesemia, rate of all-grade hypophosphatemia, patient charge for serum magnesium and phosphorus levels, proportion of cycles with serum magnesium and phosphorus draws, dental clearance rate by a dentist, and ONJ incidence. Descriptive statistics were used to describe patient characteristics.\n\nRESULTS\nBaseline patient characteristics are reported in Table 3. A total of 61 patients were included for final analysis. One patient on pamidronate was screened but then excluded due to BMA use for HCM. Eighteen patients were excluded for treatment not being started pending insurance authorization and/or dental clearance. Patients’ ages ranged between 32 to 85 years of age. The median age was 67, with the majority of the population being female. A higher rate of patients were receiving concomitant active chemotherapy at baseline in the zoledronic acid group compared to the denosumab group. Similarly, there was a higher rate of bone metastases in the zoledronic acid group. Most patients had normal renal function based on creatinine clearance calculations. Seventy-two percent of patients received hormonal cancer therapy at baseline. Table 4 shows rates of oncologic diagnoses. The most frequently encountered oncologic diagnosis was breast cancer followed by lung cancer. One patient was diagnosed with both multiple myeloma and breast cancer.\n\nTable 3 \nBaseline Patient Characteristics\n\n\nTable 4 \nCancer Diagnoses\n\n\nTable 5 illustrates primary and secondary outcomes related to hypomagnesemia and hypophosphatemia. Magnesium and phosphorus levels were drawn 115 times each for the entire study population with approximately half of levels drawn for each group. There were no cases of grade 3 and 4 hypomagnesemia. Compared to the zoledronic acid group, the denosumab group had a slightly higher rate of composite grade 3 and 4 hypophosphatemia (5% vs. 3.6%, respectively). The denosumab group also had slightly higher rates of all-grade hypomagnesemia (6.7% vs. 5.5%) and all-grade hypophosphatemia (13.3% vs. 10.9%) compared to the zoledronic acid group.\n\nTable 5 \nPrimary and Secondary Outcomes Related to Hypomagnesemia and Hypophosphatemia\n\n\nTable 6 shows BMA cycles with laboratory draws and annualized patient charge for levels. Approximately 79% of all treatment cycles included serum magnesium and phosphorus laboratory draws. There was a higher rate of cycles with laboratory draws in the denosumab group compared to the zoledronic acid group (89.6% vs. 70.5%). At the study site, patient charge per serum magnesium level was $46.29 and patient charge per serum phosphorus level was $33.23. The annual patient charge for serum magnesium and phosphorus laboratory draws was slightly greater in the denosumab group since this group had 5 more cycles with draws compared to the zoledronic acid group.\n\nTable 6 \nBone-Modifying Agent Cycles and Patients’ Charges for Magnesium and Phosphorus Levels\n\n\nTable 7 shows dental clearance by a dentist and incidence of ONJ. Rates of dental clearance by a dentist were similar between both treatment groups with a total rate of 67.2% for all patients. Compliance with dental clearance was achieved in 100% of patients based on oncologist documentation and dentist letters. No patients were diagnosed with ONJ over the 1-year period.\n\nTable 7 \nDental Clearance by a Dentist and Incidence of Osteonecrosis of the Jaw\n\n\nDISCUSSION\nStudy limitations are a small sample size, single-center study, descriptive design, and short study duration. Most patients are treated for longer than 1 year or indefinitely, which underestimates actual cost savings. In addition, ONJ has a mean onset of 1 to 3 years after initiating an injectable BMA (Rasmusson & Abtahi, 2014). No patients on pamidronate were included in the study. Data was unavailable for patients treated at another institution, although they were followed by the oncologists at the study site.\n\nStudy strengths are exclusion of patients treated for HCM, use of CTCAE version 4.0, and evaluation of patients newly initiated on BMAs. Hypercalcemia of malignancy is an oncologic emergency and precludes dental clearance. It may also overestimate the incidence of hypophosphatemia. CTCAE version 4.0 provides severity grades with grade 3 indicating the need for hospitalization and grade 4 indicating a life-threatening risk (National Institutes of Health, 2009). Evaluation of new starts allows for better validation of risks.\n\nComposite rates of grade 3 and 4 hypomagnesemia and hypophosphatemia in the study were lower than the rates reported in the package inserts (Amgen, Inc., 2010; Novartis Pharmaceutical Corporation, 2001). These low incidences support a change in the monitoring interval of magnesium and phosphorus levels at our cancer center, where these levels are routinely monitored with each BMA cycle. For this 1-year study, the approximate number of BMA doses administered per patient was 2 cycles. The billed charge for 2 cycles of serum magnesium and phosphorus laboratory draws was $159.04.\n\nDespite our current practice of drawing magnesium and phosphorus levels with each cycle, laboratory orders were not drawn in approximately 20% of the cycles. Magnesium and phosphorus labs were not released from the treatment orders in these cases, and no explanation was provided in the documentation. There was a greater proportion of cycles with serum magnesium and phosphorus draws in the denosumab group, indicating greater provider awareness for risk of hypomagnesemia and hypophosphatemia associated with the use of this medication. The annual charge for drawing both levels totaled $9,144.80 in the study. If levels were drawn for every cycle based on our current practice, the annual cost would be approximately $11,500. \n\nBased upon our findings, we recommend the following: Serum magnesium and phosphorus levels should be drawn at baseline and then every 6 months for cancer outpatients on injectable BMAs. Clinical judgment should be used if more frequent laboratory draws are needed, such as in patients with renal insufficiency, symptoms suggestive of hypomagnesemia and hypophosphatemia, and baseline hypomagnesemia and hypophosphatemia. The proposed change will lead to cost savings and reduce the amount of serum magnesium and phosphorus draws.\n\nCONCLUSION\nComposite rates of grade 3 and 4 hypomagnesemia and hypophosphatemia were lower than the rates reported in the literature for denosumab and zoledronic acid. No patients on pamidronate were included in the data analysis. Based on the low incidences of grade 3 and 4 hypomagnesemia and hypophosphatemia in both the literature and this study, we propose to monitor serum magnesium and phosphorus levels at baseline, and then every 6 months. More frequent draws may be considered based on clinical judgment. Dental clearance was obtained in all patients, with dental letters acquired for 67% of patients. No cases of ONJ were reported.\n\n\nDr. Jeffers has served on advisory boards for Takeda Oncology, Tesaro, and Oncology Reimbursement Management, and served on the speakers bureau for Amgen.\n==== Refs\n1 Amgen, Inc. Xgeva (denosumab) package insert. 2010 Retrieved from\nhttp://pi.amgen.com/united_states/xgeva/xgeva_pi.pdf \n2 Ben Venue Laboratories, Inc. Pamidronate package insert. 1991 \n3 Centers for Disease Control and Prevention. Defining adult overweight and obesity. 2016 Retrieved from\nhttps://www.cdc.gov/obesity/adult/defining.html \n4 Gralow J R Biermann J S Farooki A Fornier M N Gagel R F Kumar R Van Poznak C H NCCN Task Force Report: Bone health in cancer care. Journal of the National Comprehensive Cancer Network 2013 11 S1 S50 Retrieved from\n 10.6004/jnccn.2013.0215 \n5 Guise T A Bone loss and fracture risk associated with cancer therapy. Oncologist 2006 11 10 1121 1131 10.1634/theoncologist.11-10-1121 17110632 \n6 Hernandez Rohini K Adhia Avanti Wade Sally W O’Connor Emily Arellano Jorge Francis Kevin Alvrtsyan Hasmik Million Ryan P Liede Alexander Prevalence of bone metastases and bone-targeting agent use among solid tumor patients in the United States. Clinical epidemiology 2015 7 335 345 26229504 \n7 National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 2009 Retrieved from\nhttps://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm \n8 National Institutes of Health Osteoporosis and Related Bone Diseases National Resource Center. Bone mass measurement: What the numbers mean (NIH Publication No. 15-7877-E). 2015 Retrieved from\nhttps://www.bones.nih.gov/health-info/bone/bone-health/bone-mass-measurement-what-numbers-mean \n9 Novartis Pharmaceutical Corporation. Reclast (zoledronic acid) package insert. 2001 Retrieved from\nhttp://www.pharma.us.novartis.com/product/pi/pdf/reclast.pdf \n10 Rasmusson L Abtahi J Bisphosphonate associated osteonecrosis of the jaw: An update on pathophysiology, risk factors, and treatment. International Journal of Dentistry, 2014, Article ID 471035. 2014 10.1155/2014/471035 \n11 Ruggiero Salvatore L Dodson Thomas B Fantasia John Goodday Reginald Aghaloo Tara Mehrotra Bhoomi O’Ryan Felice American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 2014 72 1938 1956 \n12 Van Poznak Catherine H Temin Sarah Yee Gary C Janjan Nora A Barlow William E Biermann J Sybil Bosserman Linda D Geoghegan Cindy Hillner Bruce E Theriault Richard L Zuckerman Dan S Von Roenn Jamie H American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011 29 1221 1227 21343561\n\n",
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"title": "Development of a Practice Standard for Monitoring Adult Patients Receiving Bone-Modifying Agents at a Community Cancer Center.",
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"abstract": "Phase III studies have demonstrated the efficacy of FOLFOXIRI regimens (5-fluorouracil/leucovorin, oxaliplatin, irinotecan) with/without bevacizumab in metastatic colorectal cancer (mCRC). Capecitabine is an orally administered fluoropyrimidine that may be used instead of 5-fluorouracil/leucovorin. We evaluated a triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab in 53 patients with mCRC. A Phase I study identified the maximum tolerated dose of irinotecan as 150 mg/m². Median follow-up in a subsequent Phase II study using this dose was 28 months (74% progressed). For all patients, a complete response was achieved in 4% and a partial response in 60%; median progression-free survival (PFS) was 16 months and median overall survival (OS) was 28 months. Median PFS was longer for patients with an early treatment response (28 vs. 9 months for others; P = 0.024), or early tumor shrinkage (25 vs. 9 months for others; P = 0.006), or for patients suitable for surgical removal of metastases with curative intent (median not reached vs. 9 months for others; P = 0.001). Median OS was longer for patients with early tumor shrinkage (median not reached vs. 22 months for others; P = 0.006) or surgery (median not reached vs. 22 months for others, P = 0.002). K-ras mutations status did not influence PFS (P = 0.88) or OS (P = 0.82). Considerable Grade 3/4 toxicity was encountered (36% for diarrhea, 21% for vomiting and 17% for fatigue). In conclusion, the 3-weekly triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab, was active in the first-line treatment of mCRC, although at the expense of a high level of toxicity.",
"affiliations": "Oncology Center, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh, 11211, Saudi Arabia.;Oncology Center, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh, 11211, Saudi Arabia.;Oncology Center, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh, 11211, Saudi Arabia.;Oncology Center, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh, 11211, Saudi Arabia.;Oncology Center, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh, 11211, Saudi Arabia.;Department of Biostatistics, Epidemiology and Scientific Computing, Research Center, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh, 11211, Saudi Arabia.",
"authors": "Bazarbashi|Shouki|S|;Aljubran|Ali|A|;Alzahrani|Ahmad|A|;Mohieldin|Ahmed|A|;Soudy|Hussein|H|;Shoukri|Mohammed|M|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000069287:Capecitabine; D000077146:Irinotecan; D002166:Camptothecin",
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"fulltext": "\n==== Front\nCancer MedCancer Medcam4Cancer Medicine2045-76342045-7634John Wiley & Sons, Ltd Chichester, UK 2620761410.1002/cam4.497Clinical Cancer ResearchPhase I/II trial of capecitabine, oxaliplatin, and irinotecan in combination with bevacizumab in first line treatment of metastatic colorectal cancer Bazarbashi Shouki 1Aljubran Ali 1Alzahrani Ahmad 1Mohieldin Ahmed 12Soudy Hussein 13Shoukri Mohammed 41 Oncology Center, King Faisal Specialist Hospital and Research CenterPO Box 3354, Riyadh, 11211, Saudi Arabia2 Medical Oncology Department, Zagazig UniversityAl-Gamaá Road, Zagazig, Sharkia Governorate, 44519, Egypt3 Faculty of medicine, Cairo UniversityKasr Al-Ainy Street, Cairo, 11562, Egypt4 Department of Biostatistics, Epidemiology and Scientific Computing Research Center, King Faisal Specialist Hospital and Research CenterPO Box 3354, Riyadh, 11211, Saudi ArabiaCorrespondence Shouki Bazarbashi, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Tel: +966114423935; Fax: +966114423941; E-mail: Bazarbashi@gmail.comFunding Information Funded by King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.\n\n10 2015 24 7 2015 4 10 1505 1513 13 1 2015 03 6 2015 09 6 2015 © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.2015This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Phase III studies have demonstrated the efficacy of FOLFOXIRI regimens (5-fluorouracil/leucovorin, oxaliplatin, irinotecan) with/without bevacizumab in metastatic colorectal cancer (mCRC). Capecitabine is an orally administered fluoropyrimidine that may be used instead of 5-fluorouracil/leucovorin. We evaluated a triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab in 53 patients with mCRC. A Phase I study identified the maximum tolerated dose of irinotecan as 150 mg/m2. Median follow-up in a subsequent Phase II study using this dose was 28 months (74% progressed). For all patients, a complete response was achieved in 4% and a partial response in 60%; median progression-free survival (PFS) was 16 months and median overall survival (OS) was 28 months. Median PFS was longer for patients with an early treatment response (28 vs. 9 months for others; P = 0.024), or early tumor shrinkage (25 vs. 9 months for others; P = 0.006), or for patients suitable for surgical removal of metastases with curative intent (median not reached vs. 9 months for others; P = 0.001). Median OS was longer for patients with early tumor shrinkage (median not reached vs. 22 months for others; P = 0.006) or surgery (median not reached vs. 22 months for others, P = 0.002). K-ras mutations status did not influence PFS (P = 0.88) or OS (P = 0.82). Considerable Grade 3/4 toxicity was encountered (36% for diarrhea, 21% for vomiting and 17% for fatigue). In conclusion, the 3-weekly triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, plus bevacizumab, was active in the first-line treatment of mCRC, although at the expense of a high level of toxicity.\n\nBevacizumabcapecitabineirinotecanmetastatic colorectal canceroxaliplatin\n==== Body\nIntroduction\nColorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second most common in females; more than 1.2 million new cases and 608,700 deaths have occurred worldwide in 2008. 1 Chemotherapy remains the primary therapeutic option for patients with metastatic CRC (mCRC). Combinations of fluoropyrimidines, irinotecan, and oxaliplatin have been shown to be effective in this setting, along with the more recent introduction of targeted chemotherapy with monoclonal antibodies against the vascular endothelial growth factor (bevacizumab) or the epidermal growth factor receptor (cetuximab and panitumumab). The addition of a targeted agent to first line chemotherapy has improved progression free survival (PFS) and overall survival (OS) in randomized trials 2–6 and is now considered to represent the standard of care for mCRC.\n\nPhase III trials have shown the FOLFOXIRI (5-flourouracil [5-FU]/leucovorin, oxaliplatin, irinotecan) to be superior to the FOLFIRI (5-FU/leucovorin, irinotecan) regimen, in terms of improvements in response rate, PFS, and OS, with or without addition of bevacizumab 7,8. This improved efficacy was at the expense of increased toxicity which was manageable, as the incidence of grade 3 or 4 toxicity did not exceed 20% 7–9. Nevertheless, infusional chemotherapy requires a central venous catheter with its associated complications, frequent hospital visits (every 2 weeks) and the need to carry a pump. Capecitabine, an oral fluoropyrimidine, was at least as active and effective as 5-FU in the first-line treatment of mCRC in Phase III trials, with a superior safety profile 10–12. Similarly, a combination of capecitabine and oxaliplatin (Xelox or Capox) but not irinotecan (Xeliri/Capiri) was at least as effective as its infusional counterpart, FOLFOX 13–19.\n\nIt is therefore of interest to study the therapeutic profile of capecitabine within a triple-therapy regimen, with the addition of targeted chemotherapy in mCRC. Accordingly, we have evaluated the combination of capecitabine, oxaliplatin, and irinotecan with bevacizumab in the first-line management of mCRC in a Phase I/II trial.\n\nMaterials and Methods\nPatients\nThe study was conducted at a single institution. Patients eligible for inclusion in the study were men or women aged ≥18 years with histologically confirmed colorectal adenocarcinoma presenting as unresectable metastatic or locally advanced disease; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2; measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST); no previous chemotherapy or bevacizumab for metastatic disease; and adequate hematological, renal, and hepatic function (absolute neutrophil count ≥1.5 × 109/L, platelet count ≥100 × 109/L, normal serum creatinine, normal serum bilirubin, serum transaminases ≤2.5 times the upper limit of normal [UNL; ≤5.0 times UNL if elevated secondary to liver metastases]); and urine dipstick for protinuria <2+. Patients who had received prior adjuvant 5-FU or oxaliplatin chemotherapy were eligible if they had remained free of disease for at least 12 months after the completion of adjuvant therapy.\n\nExclusion criteria included patients with known or suspected dihydropyrimidine deficiency; the presence of central nervous system metastasis; previous malignancy within the last 5 years (except adequately treated nonmelanomatous skin cancer or in situ cervical cancer); severe cardiovascular disease; major bleeding disorder; significant traumatic injury or major surgery within 28 days of starting therapy; minor surgery within 7 days of starting therapy; recent significant hemoptysis; active uncontrolled infection; uncontrolled hypertension; pregnancy or breastfeeding; any other serious medical condition (in the judgment of the investigator); treatment with other experimental drugs within 30 days of entry into the trial; treatment with other anticancer therapy; known hypersensitivity to any of the study drugs; any psychological, familial, geographic, or social circumstances which could impair the patient's ability to participate in the trial and comply with follow-up, including legal incapacity.\n\nTreatment\nPretreatment baseline evaluation included a complete medical history and physical examination, full blood count and chemistry profile including carcinoembryonic antigen, and a CT scan of the chest, abdomen, and pelvis.\n\nThe Phase I trial was designed to find the maximum tolerated dose of irinotecan, with a design based on the standard 3-week Xelox/Capox regimen, in order to minimize the requirements for hospital attendance while maintaining efficacy. All patients received oral capecitabine 1000 mg/m2 twice-daily on days 1–14, with intravenous oxaliplatin 130 mg/m2, and bevacizumab 7.5 mg/kg body weight on day 1.\n\nThe prespecified dose levels for irinotecan were 150, 200, and 250 mg/m2, given intravenously on day one of each cycle. The starting dose was based on previous clinical experience with the use of irinotecan within three-drug combinations, which involved administration of this agent at starting doses of 150–180 mg/m2 given every 2 weeks 20,21. Accordingly, we adopted the dose of 150 mg/m2 as a starting dose to explore the maximum tolerated dose within the more standard three-weekly administration regimen employed here.\n\nAt least three patients were included sequentially in each dose level, and no intrapatient dose-escalation was allowed. Dose escalation was permitted if no dose limiting toxicity (any grade 4 hematological toxicity and/or grade 3 or 4 nonhematological toxicity) was encountered by the end of the first cycle. If one of three patients experienced dose-limiting toxicity, three additional patients were enrolled at the same dose level. The maximum tolerated dose was defined according to the occurrence of dose-limiting toxicity in least 2/3 or at least 4/6 patients.\n\nThe recommended dose for the Phase II study was the dose level immediately below the maximum tolerated dose. Additional patients were then enrolled to confirm the safety profile of the combination 22. Treatment was administered every 21 days. A total of 5–8 cycles of the four drug combination was planned, followed by maintenance capecitabine and bevacizumab at the same dose level until disease progression.\n\nDuring either phase, the feasibility of surgical resection of metastatic sites was assessed every 2 months and strongly recommended when feasible. Treatment was withdrawn in the event of disease progression, unacceptable toxicity, or withdrawal of patient consent.\n\nDose modification\nDose modifications were made according to the most serious toxicity observed during the previous cycle, graded according to the National Cancer Institute Common Terminology Criteria (version 3) 23. Only the capecitabine dose was modified for hand-foot syndrome and mucositis, the capecitabine, and irinotecan doses could be modified for diarrhea, and the oxaliplatin was modified for neuropathy. Bevacizumab doses were not modified. Chemotherapy treatment was delayed until neutrophil count was ≥1.0 × 109/L and platelet count was ≥100 × 109/L prior to start of the next cycle. Patients were withdrawn from the trial if toxicity required treatment to be delayed by more than 2 weeks.\n\nStudy endpoints\nThe primary endpoint for the Phase I study was to identify the maximum tolerated dose of irinotecan. Primary outcomes for the Phase II study were the response rate and toxicity profile in patients with mCRC. Secondary endpoints were PFS and OS. PFS was calculated from the day of treatment start to the first observation of disease progression or death from any cause. OS was calculated from the day of treatment start until death from any cause, censoring patients where necessary at the last date known to be alive.\n\nEvaluation of response\nAssessment of response was done according to RECIST criteria, version 1.1 24 A CT scan or MRI scan of the chest, abdomen, and pelvis were done after the second, fifth and eighth cycle of chemotherapy and then every 2 months. This schedule facilitated detection of early tumor shrinkage after the first 6 weeks, followed by subsequent regular, two-monthly evaluation. Deepness of response (DpR) was defined as the percentage of tumor shrinkage observed (if shrinkage occurred) at the nadir (best response) using the longest diameter based on RECIST criteria 25. Early tumor shrinkage was defined as ≥20% decrease in the maximum tumor dimension by RECIST criteria at the time of first evaluation of response 26.\n\nFollow-up and end of study visits\nAll patients underwent measurement of complete blood count with differential, renal, and hepatic profile, carcino-emberyonic antigen (CEA), and urine for proteinuria on day one of each cycle. Blood count was also done on the day 10–14 for the first two cycles. Toxicity evaluation was recorded prior to starting treatment and on day 1 of each cycle of chemotherapy. Patients were followed up until the study was closed upon reaching the planned number of events.\n\nStatistics\nThe number of patients to be recruited in the Phase I trial was depended on the maximum tolerated dose of irinotecan. The number of patients for the Phase II trial followed a two-stage Simon optima design to include the patient recruited in Phase I. For a lower activity level of 40% (P0=0.40, percentage of patients free of progression at 10 months in the null hypothesis) and higher activity level of 60% (P1=0.60, percentage of patients free of progression at 10 months in the alternative hypothesis), and with α and β error of 0.05 and 0.20, the Phase I trial was planned to recruit 16 patients. If fewer than seven patients achieved an objective response, the trial would close as the study treatment was not more effective than standard chemotherapy. If more than seven patients in Phase I achieved an objective response then a total of 46 patients would be recruited.\n\nKaplan–Meier survival curves were compared using log-rank tests. Statistical analyses were performed using SPSS version 17.0 (IBM corporation, Armonk, NY, USA). The efficacy analysis was performed on the intention-to-treat population, which comprised all patients who received at least two cycles of study treatment.\n\nEthics\nThe study was carried out fully in accordance with the requirements of Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the ethics committees of our institution. Patients were informed of the investigational nature of the study and provided written informed consent before registration. The trial was registered at clinicaltrials.gov (NCT01311050).\n\nResults\nPatients\nFifty-four patients were entered into the Phase I and Phase II studies between 24 January 2009 and 14 December 2011. One patient was found at a later stage to have a concurrent chaolangiocarcinoma, rather than metastatic colon cancer and was excluded from analyses other than the Phase I toxicity evaluation. All other analyses included the remaining 53 patients.\n\nThe study population was roughly equally divided between men and women (Table1). The majority of patients had ECOG PS 2, with tumors in the colon or rectosigmoid. About half had undergone surgery, a minority had previously received adjuvant chemotherapy, but none had received radiotherapy. Similar numbers of patients had single or multiple metastases, most commonly in the liver. Wild-type K-ras or K-ras mutations were also found in similar numbers of patients.\n\nTable 1 Patients at baseline (n = 53)\n\nMedian age (range), years\t52 (23–74)\t\nMale/female, n (%)\t29 (55)/24 (45)\t\nECOG performance status, n (%)\t\n 0\t7 (13)\t\n 1\t35 (66)\t\n 2\t11 (21)\t\nPrimary tumor site, n (%)\t\n Colon\t23 (40)\t\n Rectosigmoid\t21 (36)\t\n Rectum\t9 (15)\t\nPrior surgery for primary tumor, n (%)\t29 (55)\t\nPrior adjuvant chemotherapy, n (%)\t6 (11)\t\nPrior radiotherapy, n (%)\t0\t\nNumber of metastasis sites, n (%)\t\n Single\t22 (42)\t\n Multiple sites\t31 (58)\t\nMetastasis sites, n (%)\t\n Liver\t35 (66.0)\t\n Lung\t22 (41.5)\t\n Lymph nodes\t21 (39.6)\t\n Peritoneum\t14 (26.4)\t\nK-ras, n (%)\t\n Wild-type\t20 (37.0)\t\n Mutated\t20 (37.0)\t\n Unknown\t13 (26.0)\t\nAll data are given as n (%), except where indicated. ECOG, Eastern Cooperative Oncology Group.\n\nMaximum tolerated dose of irinotecan in the Phase I study\nThree patients were received irinotecan at a dose of 150 mg/m2, of whom one developed Grade 4 diarrhea and fatigue in cycle 2. Three further patients received irinotecan 200 mg/m2, of whom one developed Grade 3 diarrhea and neutropenia and one developed Grade 3 vomiting. The maximum tolerated dose of irinotecan was therefore 150 mg/m2. Recruitment commenced for the Phase II trial using this dose level and an additional 47 patients were enrolled. However, a high incidence of Grade 3 and 4 toxicity (mainly diarrhea) led to a reduction in the capecitabine dose to 800 mg/m2 twice daily after 30 patients had been enrolled.\n\nTreatments\nA total of 230 cycles of treatment were administered, with a median of five cycles per patient (range 1–8). Six patients received only one cycle of chemotherapy, either due to withdrawal of consent or Grade 4 toxicity. Thirty-four patients received the planned 5–8 cycles of induction triplet chemotherapy. Reasons for receipt of less than five cycles included toxicity in 11 patients, progression in four patients, withdrawn consent in three patients, and temporary loss of follow-up in a further patient. The relative dose intensity was 92% of that planned for irinotecan and oxaliplatin, and 79% of that planned for capecitabine. Maintenance treatment with capecitabine and bevacizumab was administered to 32 patients (60%).\n\nSurgical resection of metastatic disease (Table2) was attempted with a curative intent in 13 patients (24.5%): four (7.5%) had surgical resection of the primary tumor, three (11.3%) had liver resection only, and six (11.3%) underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Radical (R0) resection was achieved in 10 patients (18.9%) with a pathological complete response (pCR) in two of these patients (each had pCR of the primary tumor and of the metastasis in the liver or peritoneum).\n\nTable 2 Surgery of metastases\n\n\tN (%)\t\nSurgical resection\t\n Yes/no\t13 (25)/40 (75)\t\n Margin: R0/R1\t10 (19)/3 (6)\t\nType of surgery\t\n Liver resection\t3 (6)\t\n CRS and HIPEC\t5 (9)\t\n Primary tumor resection and liver resection\t3 (6)\t\n Primary + CRS and HIPEC1\t1 (28)\t\n Lung resection\t1 (2)\t\n1 Primary: primary tumour resection, CRS and HIPEC: cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.\n\nEfficacy\nOf the 53 patients included in efficacy analyses, 45 were evaluable for response evaluation (four patients withdrew consent, two were discontinued for Grade 4 toxicity and two died). Two patients (4.4%) had a complete response and 27 patients (60%) had a partial response, for an overall response rate of 64.4%. Stable disease was observed in 31.1% and progressive disease in 4.4%. Fifteen patients (33.3%) achieved a response at the first evaluation (early treatment response) and 27 (60%) achieved early tumor shrinkage. The time to best response was 48 days (range 18–1041) and the median DpR was 33% (range −12 to 100).\n\nThe median follow-up duration was 28 months (range 1–50; 95% CI 23–33), at which time 39 patients (74%) had progressed. Median PFS was 16 months and median OS was 28 months in the overall population (Table3, Fig.1). Median PFS was significantly longer in patients with early treatment response or early tumor shrinkage, or in subjects who underwent surgery with curative intent (Table3, Fig.2). OS was significantly prolonged in subjects with early tumor shrinkage or surgical resection. K-ras mutations did not influence PFS or OS (Table3, Fig.2).\n\nTable 3 Median survival in selected subgroups\n\nPatients\tPFS (months)\tP\tOS (months)\tP\t\nAll (n = 53)\t16 (10.6–21.4)\t–\t28 (23.2–32.7)\t–\t\nEarly response (n = 15)\t28 (16–41)\t0.024\t28 (18.7–37.3)\t0.55\t\nNo early response (n = 38)\t9 (6–12)\t28 (22.6–33.3)\t\nEarly tumor shrinkage (n = 27)\t25 (12–38)\t0.006\tMedian not reached\t0.006\t\nNo early tumor shrinkage (n = 26)\t9 (4–14)\t22 (20–24)\t\nMutated K-ras (n = 20)\t13.7 (2.6–24.8)\t0.88\t24.7 (17.0–32.4)\t0.82\t\nWild-type K-ras (n = 20)\t15.8 (6.8–24.8)\t27.7 (23–32.6)\t\nSurgical resection (n = 13)\tMedian not reached\t0.001\tMedian not reached\t0.002\t\nNo surgical resection (n = 40)\t9 (5–19)\t23 (18–28)\t\nFigures in parentheses are 95% CI. PFS, progression-free survival; OS, overall survival.\n\nFigure 1 Kaplan–Meier estimates of survival in 53 patients.\n\nFigure 2 Kaplan–Meier estimates of progression-free survival and overall survival in subgroups of patients defined according to early tumor shrinkage (in 43 patients), surgical resection (in 53 patients), or K-ras mutation status (in 40 evaluable patients).\n\nToxicity\nAll 53 patients were evaluable for toxicity (Table4). Diarrhea was the most common Grade 3/4 toxicity was of diarrhea (36%), which was complicated by dehydration and renal impairment in one patient, and by neutropenia (32%), which was complicated by fever in nine patients. Other grade 3/4 adverse events were nausea/vomiting (21%), fatigue (17%), anemia (6%), thrombocytopenia (4%), and allergic reaction (4%). Grade 4 arterial thrombosis was reported in one patient who developed cerebrovascular thrombosis. Grade 3 peripheral neurotoxicity was reported in one patient.\n\nTable 4 Toxicity (n = 53)\n\n\tNumber with toxicity (%)\t\n\tGrade 1\tGrade 2\tGrade 3\tGrade 4\t\nAnemia\t8 (15)\t9 (17)\t3 (6)\t0\t\nNeutropenia\t0\t7 (13)\t16 (30)\t1 (2)\t\nThrombocytopenia\t2 (4)\t0\t0\t2 (4)\t\nFebrile neutropenia\t0\t0\t9 (17)\t0\t\nHand and foot syndrome\t17 (32)\t8 (15)\t0\t0\t\nNausea/vomiting\t11 (21)\t24 (45)\t10 (19)\t1 (2)\t\nAnorexia\t0\t7 (13)\t3 (6)\t0\t\nFatigue\t4 (8)\t12 (23)\t7 (13)\t2 (4)\t\nMucositis\t21 (40)\t3 (6)\t0\t0\t\nDiarrhea\t2 (4)\t23 (43)\t18 (34)\t1 (2)\t\nPeripheral neuropathy\t20 (38)\t24 (45)\t1 (2)\t0\t\nAllergic reaction\t1 (2)\t1 (2)\t2 (4)\t0\t\nSkin reaction\t1 (2)\t0\t0\t0\t\nHypertension\t0\t4 (8)\t0\t0\t\nArterial thrombosis\t0\t0\t0\t1 (2)\t\nVenous thrombosis\t0\t0\t0\t0\t\nBowel perforation\t0\t0\t0\t0\t\nOthers\t1 (2)\t9 (17)\t8 (15)\t2 (4)\t\nToxic death occurred in three patients, two after the first cycle and one after fifth the cycle of chemotherapy. All deaths occurred outside our institution; one developed fever at home and refused to go to a hospital, one death was secondary to cerebrovascular accident and one died from non-neutropenic septic shock. There was no significant difference in toxicity between patients who received capecitabine at a dose of 1000 or 800 mg/m2.\n\nDiscussion\nThe result of this trial are consistent with the results of previous randomized trials that demonstrated enhanced efficacy of the ripple-therapy regimens in mCRC 7,8. The response rate in our trial of 60% is similar to the roughly 60–80% response rates observed with other triple-therapy regimens 7,8,20,21,27,28. The PFS obtained in our regimen (16 months) represents one of the best reported results so far in mCRC, although this did not translate to a similarly high OS (28 months). Receipt of no more than five cycles by half of the patients and the high toxicity of the regimen may account for this finding.\n\nWe observed marked toxicity, with Grade 3 and 4 diarrhea (35%) requiring frequent dose reduction, especially of capecitabine, resulting in a low relative dose intensity for capecitabine of 79%, although the dose reduction did not translate into a reduced frequency of Grade 3/4 diarrhea. Febrile neutropenia was also common (17%), compared with other evaluations of triple regimens in mCRC 7,8,20,21,27,28. It is apparent that the planned dose intensity of both bi-weekly triplet regimens reported for capecitabine (5000 mg/m2 per week 20 and 7000 mg/m2 per week 21) was lower than in our trial, even after the capecitabine dose was reduced to 800 mg/m2 twice-daily (7466 mg/m2 per week). This probably explains the difference in toxicity between our study and these earlier trials. In addition, clinical experience in the Middle East suggests that the tolerance of Saudi patients to standard doses of capecitabine may be lower than that reported for Western populations. The toxicity encountered with our regimen might also be explained in part by 87% of our patients having PS 1–2. Nevertheless, other regimens combining capecitabine and irinotecan have yielded similar high rates of toxicity, with incidence rates for diarrhea approaching 40% 18,19. These regimens maintained activity with decreased toxicity by lowering the doses of both irinotecan and capecitabine 29,30.\n\nWe also demonstrated that the concept of early tumor shrinkage, reported previously, is not limited to anti-epidermal growth factor receptors (EGFR) regimens 26,31,32. Patients who achieved ≥20% tumor shrinkage at the first evaluation (after two cycles of induction therapy) had improved PFS and OS compared with patients who did not. Our study also confirmed the lack of influence of K-ras mutation status on prognosis in patients treated with a bevacizumab-containing triple-chemotherapy regimen, as reported elsewhere 27,33,34.\n\nIt has been reported that surgery for resectable metastasis improves survival in patients with mCRC 35–37, and our data provide further confirmation of this benefit. In addition, our study confirms the high rate of R0 resection (approaching 19%) in patients treated with triple-chemotherapy regimens. The high percentage of surgical resection confirms the feasibility of such procedures in patients receiving bevacizumab containing regimens.\n\nThe main limitations of our study were that it was a Phase I/II noncomparative trial, conducted at a single institution, and in a relatively small patient population. On the other hand, our trial enrolled an unselected patient population who were similar to the patients we see in daily practice, as shown by the relatively high percentage of patients with PS 2 (20%) and multiple organ involvement (58%).\n\nIn conclusion, the three weekly triple-chemotherapy regimen of capecitabine, oxaliplatin, and irinotecan, combined with bevacizumab, was active in the first line treatment of mCRC, although at the expense of a high level of toxicity. We do not recommend further application of this regimen at the doses described above. Further evaluation of this regimen in a more selected group of patients with mCRC with better PS and an adjusted dose of capecitabine and irinotecan may yield lower toxicity while maintaining therapeutic activity.\n\nThe study was funded by King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. A medical writer (Dr Mike Gwilt, GT Communications, funded by the same institution) edited the manuscript drafted by the authors for English and style.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\nJemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics CA Cancer J. Clin 2011 61 69 21296855 \nHurwitz H Fehrenbacher L Novotny W Cartwright T Hainsworth J Heim W Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N. Engl. J. Med 2004 350 2335 2342 15175435 \nSaltz LB Clarke S Díaz-Rubio E Scheithauer W Figer A Wong R Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study J. Clin. 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Oncol 2014 25 1346 1355 24718886 \nFalcone A Ricci S Brunetti I Pfanner E Allegrini G Barbara C Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest J. Clin. Oncol 2007 25 1670 1676 17470860 \nLoupakis F Cremolini C Masi G Lonardi S Zagonel V Trenta P FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): results of the phase III randomized TRIBE trial J. Clin. Oncol 2013 31 Suppl. 4 336 ): abstract \nSouglakos J Androulakis N Syrigos K Polyzos A Ziras N Athanasiadis A FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG) Br. J. Cancer 2006 94 798 805 16508637 \nHoff PM Ansari R Batist G Cox J Kocha W Kuperminc M Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study J. Clin. Oncol 2001 19 2282 2292 11304782 \nVan Cutsem E Twelves C Cassidy J Allman D Bajetta E Boyer M Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study J. Clin. Oncol 2001 19 4097 4106 11689577 \nCassidy J Twelves C Van Cutsem E Hoff P Bajetta E Boyer M First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin Ann. Oncol 2002 13 566 575 12056707 \nCassidy J Clarke S Díaz-Rubio E Scheithauer W Figer A Wong R Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer J. Clin. Oncol 2008 26 2006 2012 18421053 \nRothenberg ML Cox JV Butts C Navarro M Bang YJ Goel R Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study Ann. Oncol 2008 19 1720 1726 18550577 \nDucreux M Bennouna J Hebbar M Ychou M Lledo G Conroy T Capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer Int. J. Cancer 2011 128 682 690 20473862 \nPorschen R Arkenau HT Kubicka S Greil R Seufferlein T Freier W Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group J. Clin. Oncol 2007 25 4217 4223 17548840 \nDíaz-Rubio E Tabernero J Gómez-España A Massu tí B Sastre J Chaves M Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial J. Clin. 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Oncol 2014 25 ii105 ii117 \nInce WL Jubb AM Holden SN Holmgren EB Tobin P Sridhar M Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab J. Natl. Cancer Inst 2005 97 981 989 15998951 \nHurwitz HI Yi J Ince W Novotny WF Rosen O The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer Oncologist 2009 14 22 28 19144677 \nKanas GP Taylor A Primrose JN Langeberg WJ Kelsh MA Mowat FS Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors Clin. Epidemiol 2012 4 283 301 23152705 \nAdam R De Gramont A Figueras J Guthrie A Kokudo N Kunstlinger F The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus Oncologist 2012 17 1225 1239 22962059 \nVerwaal VJ van Ruth S de Bree E van Sloothen GW van Tinteren H Boot H Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer J. Clin. Oncol 2003 21 3737 3743 14551293\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "4(10)",
"journal": "Cancer medicine",
"keywords": "Bevacizumab; capecitabine; irinotecan; metastatic colorectal cancer; oxaliplatin",
"medline_ta": "Cancer Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D055815:Young Adult",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "1505-13",
"pmc": null,
"pmid": "26207614",
"pubdate": "2015-10",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15175435;19144677;18065406;17823385;11689577;17548839;18421054;24043732;21502544;20702138;11304782;19114683;17470860;17548840;18421053;14551293;12056707;19097774;16508637;15998951;24718886;19436300;9262252;23152705;21296855;23169296;18398161;17947725;22962059;20473862;18550577",
"title": "Phase I/II trial of capecitabine, oxaliplatin, and irinotecan in combination with bevacizumab in first line treatment of metastatic colorectal cancer.",
"title_normalized": "phase i ii trial of capecitabine oxaliplatin and irinotecan in combination with bevacizumab in first line treatment of metastatic colorectal cancer"
} | [
{
"companynumb": "SA-ROCHE-1618536",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
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"drugadditional": null,
"dr... |
{
"abstract": "Burning Mouth Syndrome (BMS) is defined as a chronic orofacial pain syndrome, without evidence of mucosal lesions and other clinical signs of disease or laboratory abnormalities. Patients with BMS complain of burning pain in the mouth, xerostomia and taste disturbances. It is more common among women and the median age of occurrence is about 60 years. BMS may be primary or secondary to other diseases. The mainstay in the treatment of BMS includes antidepressants, benzodiazepines, and anticonvulsants. A few cases of BMS caused due to medication have been reported. The causative drugs include angiotensin-converting enzyme inhibitors, anticoagulants, antipsychotics, antiretrovirals, and benzodiazepines. This is a case report of a patient on antidepressants who developed symptoms of BMS thereby causing a dilemma in management.",
"affiliations": "Department of Oral Medicine and Radiology, KLE Society's Institute of Dental Sciences, Bangalore, India.;Department of Oral Medicine and Radiology, Vokkaligara Sangha Dental College and Hospital, Bangalore, India.;Department of Oral Medicine and Radiology, KLE Society's Institute of Dental Sciences, Bangalore, India.;Department of Oral Medicine and Radiology, KLE Society's Institute of Dental Sciences, Bangalore, India.;Department of Oral Medicine and Radiology, KLE Society's Institute of Dental Sciences, Bangalore, India.",
"authors": "Raghavan|Shubhasini Attavar|SA|;Puttaswamiah|Rajiv Nidasale|RN|;Birur|Praveen N|PN|;Ramaswamy|Bhanushree|B|;Sunny|Sumsum P|SP|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3344/kjp.2014.27.3.294",
"fulltext": "\n==== Front\nKorean J PainKorean J PainKJPThe Korean Journal of Pain2005-91592093-0569The Korean Pain Society 10.3344/kjp.2014.27.3.294Case ReportAntidepressant-induced Burning Mouth Syndrome: A Unique Case Raghavan Shubhasini Attavar Puttaswamiah Rajiv Nidasale *Birur Praveen N Ramaswamy Bhanushree Sunny Sumsum P Department of Oral Medicine and Radiology, KLE Society's Institute of Dental Sciences, Bangalore, India.* Department of Oral Medicine and Radiology, Vokkaligara Sangha Dental College and Hospital, Bangalore, India.Correspondence to: Shubhasini Attavar Raghavan. Department of Oral Medicine and Radiology, KLE Society's Institute of Dental Sciences, No. 20, Yeshwanthpur Suburb, Tumk 560022, India. Tel: +91-9448519271, Fax: +08023474305, subhashiniar@gmail.com7 2014 30 6 2014 27 3 294 296 10 1 2014 21 3 2014 29 3 2014 Copyright © The Korean Pain Society, 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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Burning Mouth Syndrome (BMS) is defined as a chronic orofacial pain syndrome, without evidence of mucosal lesions and other clinical signs of disease or laboratory abnormalities. Patients with BMS complain of burning pain in the mouth, xerostomia and taste disturbances. It is more common among women and the median age of occurrence is about 60 years. BMS may be primary or secondary to other diseases. The mainstay in the treatment of BMS includes antidepressants, benzodiazepines, and anticonvulsants. A few cases of BMS caused due to medication have been reported. The causative drugs include angiotensin-converting enzyme inhibitors, anticoagulants, antipsychotics, antiretrovirals, and benzodiazepines. This is a case report of a patient on antidepressants who developed symptoms of BMS thereby causing a dilemma in management.\n\nantidepressantsburning mouth syndromedrug-induced BMSfluoxetinSSRI\n==== Body\nBurning mouth syndrome (BMS) is characterized by a burning sensation of the oral mucosa without accompanying abnormal clinical or laboratory findings. It mainly affects post-menopausal women [1].\n\nBMS is classified as primary or idiopathic BMS, for which a neuropathological cause is likely, and secondary BMS, which results from local factors or systemic conditions [2]. Antidepressants are the main therapeutic regimen for the management of primary BMS [3]. This article describes an unusual case of a patient who developed symptoms of BMS as a result of antidepressant treatment.\n\nCASE REPORT\nA 55-year-old female patient presented with a four-month history of a continuous burning sensation of the oral mucosa. It was initially present only on the tongue but gradually involved the entire mouth. The burning sensation was not associated with an altered taste sensation or dry mouth. It developed in the morning and progressively increased in intensity throughout the day. It was aggravated by spicy food and not relieved when taking analgesics.\n\nHer medical history revealed that the patient had been in menopause for four years. The patient had witnessed an accident and suffered from major depression 3 years prior to visiting our clinic. The patient had been on the following medication for 3 years: Monoprolol 40 mg, Benzhexol (Parkin) 2 mg, Sodium valproate (Valprol) 50 mg, Haloperidol (Trancodol) 5 mg and Fluoxetin 100 mg.\n\nIn the course of managing her depression, the dosage of the drug fluoxetin was briefly increased one year prior to her visit from 100 to 200 mg per day for a month. During this period, the patient experienced a mild burning sensation in her mouth, which returned to normal when the dosage was decreased. The dosage of the same drug was again increased from 100 to 200 mg six months prior to her visit, and the patient had been experiencing symptoms of burning mouth for the last four months.\n\nOn examination, the patient was apparently healthy, conscious, co-operative, well-oriented, well-built and nourished. Her vital signs were within the normal range. Intraoral examination revealed that the oral mucosa appeared normal and healthy; there were no mucosal lesions to explain the pain. Salivary secretion appeared adequate, and saliva was thin and copious.\n\nThe intensity of the burning sensation was rated on a visual analogue scale, with a score of 8. Laboratory analysis of her bloodwork revealed that all parameters were within the normal range.\n\nThe patient was referred to her psychiatrist with a request to alter or reduce the dosage of the drug fluoxetin. The drug was discontinued, and her depression was managed instead with the drug Colostrinin (Cognate). Following this change, the patient's glossodynia disappeared completely within one month.\n\nBased on her history, clinical features and response after drug cessation, a final diagnosis of selective serotonin reuptake inhibiter (SSRI) antidepressant-induced BMS was arrived upon. The patient is under constant follow-up and remains pain-free.\n\nDISCUSSION\nBurning mouth syndrome is defined by the International Association for the Study of Pain as burning pain in the tongue or other oral mucous membrane associated with normal signs and laboratory findings, lasting for at least 4 to 6 months [3]. One of the most commonly affected sites is the tip and anterior two thirds of the tongue, which are the areas of greatest movement in the oral cavity [4]. The prevalence of burning mouth symptoms reported by international studies ranges from 0.6% to 15% [5]. Patients are around 60 years of age, and females are more commonly affected than males [6].\n\nLamey and Lewis [7] have suggested classifying BMS into three patterns: types 1, 2, and 3. Type 1 includes symptom-free waking, with sensations developing in the morning and progressively rising to a severe level by evening. Type 2 involves continuous symptoms throughout the day; whereas type 3 features intermittent symptom-free periods throughout the day. Nonpsychologic causative factors, such as nutritional deficiencies, have been linked to type 1, chronic anxiety to type 2, and food allergies to type 3.\n\nAnother approach in classifying BMS is to divide patients into either primary or secondary groups. While primary BMS is idiopathic, secondary BMS may be caused by local factors or systemic conditions. Local factors associated with BMS include mucosal diseases, fungal infections, bacterial invasion, allergies, temporomandibular joint dysfunctions, and salivary gland abnormalities. Deficiency diseases, hormonal and immunologic disturbances, and pharmacotherapeutic side effects are included in the systemic conditions [8].\n\nSecondary BMS requires appropriate diagnosis and treatment of the underlying condition to manage symptoms. In primary BMS, the cause is unclear and counselling and medication remain the mainstay of treatment [9].\n\nPatton et al. [10] set out the guidelines for the management of primary BMS based on a systematic review of randomized controlled trials, and recommended the following drugs: SSRI, clonazepam, alphalipolic acid, amisulpride and cognitive behavioral therapy.\n\nHowever, several medications have been reported to induce BMS. These include the following: efavirenz, clonazepam, hormonal replacement therapies, fluoxetine, sertraline and a broad range of antihypertensive agents such as captopril, enalapril, and lisinopril [11]. Thirty-three percent of drug-induced BMS have been seen to be dose-dependent phenomena, because the burning sensation appears after elevating the drug dose in search of increased therapeutic efficacy [12].\n\nLevenson [13] reported a case of a patient with major depression who developed BMS after an increase in the dosage of SSRI (fluoxetine, sertraline) and whose burning sensation was completely relieved after discontinuation of the medication.\n\nThe pathogenesis of BMS has been described in terms of local factors or conditions that alter the peripheral nerves, resulting in a decreased threshold of burning sensation and peripheral sensitization. If the peripheral sensitization continues for a long period of time, it adversely affects the central nervous system and results in neuroplasticity and central sensitization [14]. Antidepressants decrease the delay in neurotransmission by increasing neurotransmitters in the synapses. SSRIs block the reabsorption of serotonin by nerve cells in the brain. This leaves more serotonin available, which enhances neurotransmission. This improves the depressive state of the patient [15].\n\nHowever, serotonin has a central analgesic effect but acts as an algogenic peripherally. Our patient was on SSRI for the management of depression. The dose of her medication was increased to improve the efficacy of treatment for her depression. However, this resulted in the symptoms of a burning mouth. This probably occurred because of the peripheral algogenic action of serotonin.\n\nThis is a case report of a patient who developed BMS while on antidepressants. The purpose of this article is to bring to light this rare occurrence. Cessation of the drug is the best way to manage such patients after obtaining physician consultation for the medical management of depression.\n==== Refs\n1 Grushka M Epstein JB Gorsky M Burning mouth syndrome Am Fam Physician 2002 65 615 620 11871678 \n2 Scala A Checchi L Montevecchi M Marini I Giamberardino MA Update on burning mouth syndrome: overview and patient management Crit Rev Oral Biol Med 2003 14 275 291 12907696 \n3 Merskey H Bogduk N Task Force on Taxonomy of the International Association for the Study of Pain Lesions of the ear, nose, and oral cavity Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms 2nd ed Seattle (WA) IASP Press 1994 74 75 \n4 Grushka M Clinical features of burning mouth syndrome Oral Surg Oral Med Oral Pathol 1987 63 30 36 3468464 \n5 Zakrzewska JM Hamlyn PJ Facial pain Crombie IK Croft PR Linton SJ LeResche L Von Korff M Epidemiology of pain: a report of the Task Force on Epidemiology of the International Association for the Study of Pain Seattle (WA) IASP Press 1999 175 182 \n6 Lamey PJ Burning mouth syndrome: approach to successful management Dent Update 1998 25 298 300 10478025 \n7 Lamey PJ Lewis MA Oral medicine in practice: burning mouth syndrome Br Dent J 1989 167 197 200 2789896 \n8 Cibirka RM Nelson SK Lefebvre CA Burning mouth syndrome: a review of etiologies J Prosthet Dent 1997 78 93 97 9237148 \n9 Klasser GD Fischer DJ Epstein JB Burning mouth syndrome: recognition, understanding, and management Oral Maxillofac Surg Clin North Am 2008 20 255 271 vii 18343329 \n10 Patton LL Siegel MA Benoliel R De Laat A Management of burning mouth syndrome: systematic review and management recommendations Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007 103 S39.e1 S39.e13 17379153 \n11 Lauria G Majorana A Borgna M Lombardi R Penza P Padovani A Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome Pain 2005 115 332 337 15911160 \n12 Salort-Llorca C Mínguez-Serra MP Silvestre FJ Druginduced burning mouth syndrome: a new etiological diagnosis Med Oral Patol Oral Cir Bucal 2008 13 E167 E170 18305436 \n13 Levenson JL Burning mouth syndrome as a side effect of SSRIs J Clin Psychiatry 2003 64 336 337 12716278 \n14 Okeson JP The various presentations of pain Bell's orofacial pains: the clinical management of orofacial pain 6th ed Chicago (CA) Quintessence 2005 107 128 \n15 Rang HP Dale MM Ritter JM Flower RJ Henderson G Antidepressant drugs Rang and Dale's pharmacology 7th ed Edinburgh Elsevier/Churchill Livingstone 2012 564 583\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2005-9159",
"issue": "27(3)",
"journal": "The Korean journal of pain",
"keywords": "SSRI; antidepressants; burning mouth syndrome; drug-induced BMS; fluoxetin",
"medline_ta": "Korean J Pain",
"mesh_terms": null,
"nlm_unique_id": "101528125",
"other_id": null,
"pages": "294-6",
"pmc": null,
"pmid": "25031818",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports",
"references": "9237148;10478025;12907696;17379153;2789896;11871678;18305436;18343329;12716278;15911160;3468464",
"title": "Antidepressant-induced Burning Mouth Syndrome: A Unique Case.",
"title_normalized": "antidepressant induced burning mouth syndrome a unique case"
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"abstract": "The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Multiple clinical trials have demonstrated that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment-free remission. TKI discontinuation is now offered to select patients in routine clinical care. In order to better support patient decision making, we explored patients' views on TKI discontinuation and the factors patients consider when making this decision.\n\n\n\nPatients were recruited from three U.S. academic cancer centers. Qualitative interviews were recorded, transcribed, and content analyzed.\n\n\n\nWe interviewed 22 patients, half of whom wanted to try TKI discontinuation. Eleven factors relevant to the decision emerged, and patients weighed these factors differently. Commonly mentioned factors included perceived risk of relapse, TKI side effects, financial considerations, polypharmacy, and willingness to change something that was working (status quo). There were notable differences in patients' understanding of the likelihood of achieving a treatment-free remission, with patients who did not want to stop TKIs more accurately reporting the risk of relapse than patients who wanted to stop.\n\n\n\nThis is a novel decision that will become more common as the prevalence of patients with well-controlled CML continues to increase. These results highlight the need for patient education and decision support so that patients and providers can make shared decisions that are informed and values based.\n\n\n\nThe standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Clinical trials have shown that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment-free remission. TKI discontinuation is now being offered to patients outside of clinical trials. This study explored factors that patients who are eligible to try TKI discontinuation considered when making this decision. Factors relevant to the decision included risk of relapse, side effects, financial considerations, polypharmacy, and willingness to change something that was working. This is a novel decision that will become more common as the prevalence of patients with well-controlled CML continues to increase. These results highlight the need for decision support and outline the factors that should be included so that patients and providers can make shared decisions that are informed and values based.",
"affiliations": "Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA kflynn@mcw.edu.;Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA.;Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.",
"authors": "Flynn|Kathryn E|KE|0000-0002-4427-3583;Myers|Judith M|JM|;D'Souza|Anita|A|;Schiffer|Charles A|CA|;Thompson|James E|JE|;Atallah|Ehab|E|",
"chemical_list": "D047428:Protein Kinase Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0831",
"fulltext": null,
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"issn_linking": "1083-7159",
"issue": "24(9)",
"journal": "The oncologist",
"keywords": "Chronic phase; Decision making; Goals; Leukemia; Myeloid; Polypharmacy",
"medline_ta": "Oncologist",
"mesh_terms": "D000328:Adult; D003657:Decision Making; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D019338:Polypharmacy; D047428:Protein Kinase Inhibitors; D014481:United States",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1253-1258",
"pmc": null,
"pmid": "30944185",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12775739;16204405;17151364;22616642;23620577;24764709;26282944;26837842;27085529;27217448;28095277;28218239;28561719;29735299;29937585",
"title": "Exploring Patient Decision Making Regarding Discontinuation of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.",
"title_normalized": "exploring patient decision making regarding discontinuation of tyrosine kinase inhibitors for chronic myeloid leukemia"
} | [
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"abstract": "BACKGROUND\nEPP is characterized by photosensitivity and by liver disease. When LT is performed in EPP, recurrence often occurs in the allograft due to ongoing protoporphyrin production in bone marrow. Therefore, curative treatment requires allogeneic HSCT after LT. Long-term immunosuppression could be spared by using the same donor for both transplants.\n\n\nMETHODS\nA 2-year-old girl with EPP in liver failure underwent liver transplant from her father. Transfusion and apheresis therapy were used to lower protoporphyrin levels before and after liver transplant. Ten weeks after liver transplant, she underwent HSCT, using the same donor. Conditioning was with treosulfan, fludarabine, cyclophosphamide, and ATG. GVHD prophylaxis was with abatacept, methotrexate, MMF, and tacrolimus. We followed the patient's erythrocyte protoporphyrin and liver and skin health for 2 years after transplant.\n\n\nRESULTS\nAfter hematopoietic stem cell engraftment, a decline in protoporphyrin levels was observed, with clinical resolution of photosensitivity. Liver biopsies showed no evidence of EPP. Mild ACR occurred and responded to steroid pulse. Two years post-HSCT, the patient has been weaned off all immunosuppression and remains GVHD and liver rejection free.\n\n\nCONCLUSIONS\nSequential liver and HSCT from the same haploidentical donor are feasible in EPP. This strategy can allow for discontinuation of immune suppression.",
"affiliations": "Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.;Division of General and Thoracic Surgery, Hospital for Sick Children Toronto, ON, Canada.;Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.;Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.;Division of Oncology, Hematology and BMT, Department of Pediatrics, BC Children's Hospital/University of British Columbia, Vancouver, BC, Canada.;Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.;Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.;Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada.;Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.;Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.",
"authors": "Malkiel|Sarah|S|https://orcid.org/0000-0001-5465-6169;Sayed|Blayne A|BA|;Ng|Vicky|V|https://orcid.org/0000-0002-9998-5692;Wall|Donna A|DA|;Rozmus|Jacob|J|;Schreiber|Richard A|RA|;Faytrouni|Farah|F|;Siddiqui|Iram|I|;Chiang|Kuang-Yueh|KY|;Avitzur|Yaron|Y|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.14040",
"fulltext": null,
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"issn_linking": "1397-3142",
"issue": "25(6)",
"journal": "Pediatric transplantation",
"keywords": "EPP; HSCT; LT; sequential transplant",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e14040",
"pmc": null,
"pmid": "34076929",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Sequential paternal haploidentical donor liver and HSCT in EPP allow discontinuation of immunosuppression post-organ transplant.",
"title_normalized": "sequential paternal haploidentical donor liver and hsct in epp allow discontinuation of immunosuppression post organ transplant"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-329903",
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"activesubstancename": "TACROLIMUS"
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"abstract": "BACKGROUND\nNonseminomatous germ cell tumors (NSGCTs) represent one of the main groups of germ cell tumors (GCTs), and they have a more invasive course than seminomatous GCTs. Human immunodeficiency virus (HIV) positivity is considered to be a risk factor for testicular seminoma patients, but reports about HIV-infected individuals with NSGCTs are rare.\n\n\nMETHODS\nWe report a case of a retroperitoneal mixed extragonadal germ cell tumor in an HIV-infected man who has been diagnosed with bilateral cryptorchidism since birth. A 30-year-old man presented with a large heterogeneously mixed echo mass located in the right lower abdomen according to an abdominal ultrasound; he was HIV-positive and had a low CD4 count of 70 cells/ml in the followed test, which suggested severe immunosuppression, and ultrasound-guided biopsy histology revealed a malignant yolk sac tumor of the testis. First, the patient received combination antiretroviral therapy; then, to relieve his symptoms, an exploratory laparotomy and retroperitoneal neoplasm resection under general anesthesia were performed for subsequent treatment. The postoperative histopathological examination indicated that the patient exhibited malignant mixed GCTs of the undescended testis that were composed predominantly of yolk sac tumors with foci of embryonal cell carcinoma and seminoma; It is a rare type in various GCTs, especially in HIV-infected patients. After the operation, the patient underwent computed tomography follow-up scans at 1 week and 2 weeks, and the results showed that the size of the right inguinal mass gradually increased, which suggested a poor outcome. To limit the growth of the tumors, right inguinal mass resection under local anesthesia was performed 17 days after the initial operation, and pathological examination revealed mixed GCT metastasis. Subsequently, the patient received salvage chemotherapy with a regimen of cisplatin, etoposide, and ifosfamide. Unfortunately, the patient died 1 week after the first cycle of chemotherapy because of severe immunosuppression, a low platelet count and cancer cachexia.\n\n\nCONCLUSIONS\nBecause of severe immunosuppression, the treatment of advanced extragonadal NSGCTs in an HIV-infected patient resulted in a poor prognosis. This outcome should be considered in further research, and appropriate management for achieving long-term survival needs to be established.",
"affiliations": "Department of Radiology, Beijing Youan Hospital, Capital Medical University, No. 8, Xi Tou Tiao, Youanmen Wai, Fengtai District, Beijing, 100069, China.;Department of Radiology, Beijing Youan Hospital, Capital Medical University, No. 8, Xi Tou Tiao, Youanmen Wai, Fengtai District, Beijing, 100069, China. lihongjun00113@126.com.",
"authors": "Li|Ruili|R|;Li|Hongjun|H|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-019-5456-0",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 545610.1186/s12885-019-5456-0Case ReportPoor prognosis of retroperitoneal mixed extragonadal germ cell tumors in an HIV-infected man with severe immunosuppression and bilateral cryptorchidism: a case report Li Ruili 1985lrli@sina.com Li Hongjun lihongjun00113@126.com grid.414379.cDepartment of Radiology, Beijing Youan Hospital, Capital Medical University, No. 8, Xi Tou Tiao, Youanmen Wai, Fengtai District, Beijing, 100069 China 18 3 2019 18 3 2019 2019 19 2444 12 2018 12 3 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\nNonseminomatous germ cell tumors (NSGCTs) represent one of the main groups of germ cell tumors (GCTs), and they have a more invasive course than seminomatous GCTs. Human immunodeficiency virus (HIV) positivity is considered to be a risk factor for testicular seminoma patients, but reports about HIV-infected individuals with NSGCTs are rare.\n\nCase presentation\nWe report a case of a retroperitoneal mixed extragonadal germ cell tumor in an HIV-infected man who has been diagnosed with bilateral cryptorchidism since birth. A 30-year-old man presented with a large heterogeneously mixed echo mass located in the right lower abdomen according to an abdominal ultrasound; he was HIV-positive and had a low CD4 count of 70 cells/ml in the followed test, which suggested severe immunosuppression, and ultrasound-guided biopsy histology revealed a malignant yolk sac tumor of the testis. First, the patient received combination antiretroviral therapy; then, to relieve his symptoms, an exploratory laparotomy and retroperitoneal neoplasm resection under general anesthesia were performed for subsequent treatment. The postoperative histopathological examination indicated that the patient exhibited malignant mixed GCTs of the undescended testis that were composed predominantly of yolk sac tumors with foci of embryonal cell carcinoma and seminoma; It is a rare type in various GCTs, especially in HIV-infected patients. After the operation, the patient underwent computed tomography follow-up scans at 1 week and 2 weeks, and the results showed that the size of the right inguinal mass gradually increased, which suggested a poor outcome. To limit the growth of the tumors, right inguinal mass resection under local anesthesia was performed 17 days after the initial operation, and pathological examination revealed mixed GCT metastasis. Subsequently, the patient received salvage chemotherapy with a regimen of cisplatin, etoposide, and ifosfamide. Unfortunately, the patient died 1 week after the first cycle of chemotherapy because of severe immunosuppression, a low platelet count and cancer cachexia.\n\nConclusions\nBecause of severe immunosuppression, the treatment of advanced extragonadal NSGCTs in an HIV-infected patient resulted in a poor prognosis. This outcome should be considered in further research, and appropriate management for achieving long-term survival needs to be established.\n\nKeywords\nNonseminomatous germ cell tumorExtragonadalHIVImmunosuppressionPoor prognosishttp://dx.doi.org/10.13039/501100001809National Natural Science Foundation of China81771806Li Hongjun Capital medical university research and incubation funding (CN)PYZ2017124Li Ruili Beijing Municipal Administration of Hospitals Incubating Program (CN)PX2016036Li Ruili issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nGerm cell tumors (GCTs) in males mainly develop in testicular tissue; 1–5% of GCTs occur in extragonadal sites and are defined as extragonadal germ cell tumors (EGGCTs) [1]. GCTs include seminomas (35–71%) and nonseminomatous germ cell tumors (NSGCTs) [2]. Cryptorchidism is a certain risk factor for testicular GCTs [3]. With the worldwide human immunodeficiency virus (HIV) pandemic, seminoma appears to be more common among HIV-infected subjects, but NSGCTs are rare [4]. The standardized treatment guidelines for non-HIV-infected GCT patients may not be applicable to HIV-infected patients, especially those with severe immunosuppression. Here, we describe a rare case of retroperitoneal mixed EGGCTs in an HIV-infected man with severe immunosuppression and bilateral cryptorchidism, and the clinical manifestations, treatment, and prognosis are reported.\n\nCase presentation\nA 30-year-old man complained of a gradually enlarged mass in the right lower abdomen. The results of an abdominal ultrasound taken at the local hospital 3 months prior showed a heterogeneously mixed echo mass located in the right lower abdomen, and the size of the mass was approximately 8.6 cm × 7.3 cm. He had no family history of malignancy but had a history of bilateral undescended testis since birth. The local medical officer suspected a testicular tumor according to the history of cryptorchidism. At the same time, his rapid HIV-1 antibody test showed positive results, and the baseline CD4 count was 70 cells/ml (normal: 404–1612 cells/ml) upon further testing, which suggested severe immunosuppression. The patient initially received combination antiretroviral therapy (cART) but refused treatment for the abdominal mass. As the mass rapidly grew for 3 months, he came to our hospital for treatment of abdominal neoplasm. Upon examination, an immobile and nontender mass was visibly noticeable and palpable in the right lower abdomen. The bilateral testis was not visualized and could not be palpated. The patient had significantly elevated levels of alpha-fetoprotein (AFP), slightly elevated levels of beta-human chorionic gonadotropin (β-HCG), moderately decreased levels of hemoglobin and a low CD4 count (Table 1). Further evaluation revealed a low viral load, which was less than 40 copy/ml. Computed tomography (CT) images showed a large, lobulated, ill-defined heterogeneous retroperitoneal mass measuring 17 cm × 16 cm × 24 cm without fat or calcifications and with marked inhomogeneous enhancement due to the presence of necrotic-colliquative areas (Fig. 1a). The lesion displaced the bilateral lower ureters, resulting in bilateral hydronephrosis. The lesion also compressed the surrounding small intestine, with possible infiltrating signs. Around the mass, ascites was detected, but no enlarged lymph nodes were found. Cystic-solid masses (5 cm × 5 cm) were detected in the bilateral inguinal regions, and their density and enhanced characteristics were similar to those of the retroperitoneal neoplasm (Fig. 1a, b). A diagnosis of testicular tumors with bilateral inguinal region metastases was suspected. The patient underwent routine clinical staging and prognosis evaluations according to the results of radiological and laboratory examinations. Clinical staging and risk group categorization were classified as stage IIIC and poor prognosis using the American Joint Committee on Cancer staging system (AJCC) [5] and the International Germ Cell Cancer Collaboration Group (IGCCCG) prognostic scoring scheme (IGCCCG, 1997), respectively [6].Table 1 The pre- and postoperative hematological and tumor parameters of the patient\n\n\tPre\tPost (2 days later)\tNormal range\t\nAFP (ng/ml)\t34,222\t8145\t0–7\t\nβ-HCG (IU/L)\t9.2\t1.8\t0–2\t\nHemoglobin (g/L)\t77\t64\t130–175\t\nCD4+ count (cells/ml)\t86\t78\t404–1612\t\nFig. 1 CT imaging findings of the case. a Coronal contrast-enhanced CT scan showed a retroperitoneal heterogeneous enhancement mass with multiple large necrotic areas (long arrow) and cystic-solid masses in the bilateral inguinal regions (short arrow). b-d The right inguinal region mass gradually increased (short arrow) (5 days, 18 days, 25 days after admission)\n\n\n\nAn ultrasound-guided biopsy was performed on the 5th day after admission, and histology revealed a malignant yolk sac tumor of the testis. Then, the patient underwent exploratory laparotomy, retroperitoneal neoplasm resection, partial ileum resection, ileal anastomosis, and double J ureteral stent implantation under general anesthesia on the 11th day after admission. Histopathological examination revealed the lesion as a malignant mixed GCT of the undescended testis composed predominantly of yolk sac tumors with foci of embryonal cell carcinoma and seminoma (Fig. 2a, b). The repeated hematological and tumor markers 2 days after the operation are listed in Table 1. Hemoglobin level was still low; then, 4 Units of suspended red blood cells were transfused to correct anemia with no obvious transfusion reaction. The level of AFP was still high, and the follow-up CT scan showed a gradually enlarged right inguinal mass (Fig. 1c, d) 1 week and 2 weeks after the surgery, respectively. On the 17th day after the operation, the patient underwent right inguinal mass resection under local anesthesia. Pathological examination revealed mixed GCT metastasis (Fig. 2c), accompanied by hemorrhage and necrosis. Subsequently, the patient received salvage chemotherapy with a regimen of cisplatin, etoposide, and ifosfamide. Hematology was closely monitored during the treatment. After the first cycle of chemotherapy, the full blood counts remained within the normal range. CD4 count did not decrease during the course of treatment and remained at 118 cells/ml. Then, the patient was discharged and waited for the next cycle chemotherapy. Unfortunately, on the 4th day after discharge, he showed several symptoms of cancer cachexia including fever, progressive weight loss, pain, and severe weakness. Moreover, a low platelet count, which is a side effect of chemotherapy, was found (20 × 109/L, normal 125–350 × 109/L). Therefore, IL-11 was administered subcutaneously at a dosage of 50 μg/kg/day for thrombocytopenia. Two days later, the platelet count was still low (23 × 109/L); on the next day, the patient died because of severe immunosuppression, a low platelet count and cancer cachexia.Fig. 2 Pathology findings of the case. a, b Hematoxylin and eosin (H&E) staining (× 200). Embryonal carcinoma component and yolk sac tumor component (retroperitoneal mass). c H&E staining (× 200). Yolk sac tumor component (inguinal mass)\n\n\n\nDiscussion\nTesticular GCTs are relatively uncommon and account for 1% of male tumors [7]. The incidence of testicular GCTs in China is approximately 1/100,000, accounting for 1–1.5% of male tumors and 3–9% of urinary tumors [8], which are similar results to global statistics [7]. GCTs account for 90–95% of all testicular tumors and include seminomas (35–71%) and NSGCTs [2]. NSGCTs usually have a more invasive course than seminomas [9], and they can be classified as follows: teratoma, embryonal carcinoma, endodermal sinus tumor/yolk sac tumors [10], choriocarcinoma and mixed GCTs. Mixed GCTs are relatively rare in China. A retrospective analysis of the clinical data of 133 patients with testicular tumors at Peking University Third Hospital (Beijing, China) from May 1994 to November 2016 was conducted [11]. The results showed that mixed GCTs accounted for only 16% (22/133) of testicular tumors. To date, no research on HIV-infected GCT patients has been reported in China because of the rarity of this tumor type. EGGCTs account for 1–5% of all GCTs [1] and typically occur at or near the midline [12]. In adults, the most common sites of EGGCTs are the mediastinum, retroperitoneum, and cranium in descending order. Primary retroperitoneal GCTs account for approximately 30% of EGGCTs [9]. Usually, the most general components of mixed GCTs are embryonal carcinoma and teratoma [13], followed by the presence of yolk sac tumors. However, our patient developed a retroperitoneal testicular malignant mixed GCT consisting of yolk sac tumors as the major components and seminoma and embryonal carcinoma as the minor components. As it rarely occurs, the exact incidence of histopathology is unknown. To the best of our knowledge, only two cases have been reported [14, 15]. Furthermore, cryptorchidism is a certain risk factor for testicular cancer [3]. It has been reported that cryptorchidism is associated with a 5- to 10-fold increase in testicular malignancy [16]. Approximately 10% of all cases of GCTs occur in men with a history of cryptorchidism [17]. The relationship between cryptorchidism and GCTs is still unclear. Several explanations have been reported, and one of them indicated that androgen signaling, which is a common regulatory pathway, might be a possible reason for the relationship [18]. Another explanation is that infertility and germ cell tumorigenesis are directly related to the abnormal portion of the testis itself [19].\n\nAcquired immune deficiency syndrome (AIDS)-defining cancers, including non-Hodgkin’s lymphoma, Kaposi’s sarcoma, and invasive cervical cancer, occur more frequently in HIV-infected individuals. However, with the advancement and introduction of cART, the prognosis and survival for patients with HIV have been improved, and the incidence of AIDS-defining cancers has decreased substantially [20–23]. At the same time, the incidence of certain non-AIDS-defining malignancies, such as lung cancer, head and neck cancers, GCTs, anal cancer, hepatocellular carcinoma, and Hodgkin’s lymphoma, has increased significantly, and it has become a considerable factor of mortality in HIV-infected individuals [24, 25]. Compared to the general population, HIV-infected men are 1.4 to 8.2 times more likely to develop testicular tumors [26], particularly seminomas [4]. The mechanisms by which HIV-induced immunodeficiency could increase the risk for GCTs are complex and unclear, and they may involve a combination of factors, including oncogenic viral infection, immunosuppression, impairment of tumor immune surveillance, and an imbalance between cellular proliferation and differentiation [26]. A report showed that two HIV patients developed mixed GCTs subsequent to starting hepatitis C virus (HCV) treatment. In contrast, our patient was not coinfected with HCV. The roles that pegylated-interferon and ribavirin play in carcinogenesis merit further investigation [27].\n\nAFP and β-HCG are serum tumor markers of testicular neoplasia that play important roles in diagnosis, treatment, prognosis, and follow-up [28]. AFP is produced by endodermal sinus tumors, either alone or in association with other types of GCTs, and β-HCG is only produced by syncytiotrophoblasts, which are components of choriocarcinoma. In our case, the serum marker AFP was highly elevated, i.e., 34,222 ng/ml, predominantly indicating the presence of a yolk sac tumor.\n\nThe CT performance of primary extragonadal mixed GCTs is nonspecific; these GCTs are depicted as heterogeneous tumors with areas of hemorrhage, necrosis, and heterogeneous enhancement. However, CT can characterize the mass and its relationship to adjacent structures and can identify benign or malignant tumors as well as detect lymph node metastasis and distant metastasis, providing important evidence for tumor staging before treatment and surveillance after therapy.\n\nThe diagnosis of GCTs is not very difficult according to the results of serum tumor markers, imaging examinations, and histological evaluations. However, the optimal management of GCTs in HIV-infected patients, especially those with severe immunosuppression, remains uncertain and challenging. There are three possible reasons for the poor outcome of HIV-infected patients with GCTs. First, there are high levels of HIV-related mortality due to opportunistic infections [29]. Second, HIV-infected patients poorly tolerate chemotherapy, resulting in a reduction in the drug dose and patient response rate. Researchers found a similar rate of response to chemotherapy in GCTs between HIV-infected patients and the general population, but they noted that 43% of HIV patients received reduced doses of chemotherapy because of toxicity or poor compliance [30]. Third, due to severe immunosuppression and impairment of tumor immune surveillance, HIV-infected individuals may have a more aggressive clinical course. Our patient presented with bilateral inguinal region metastases and rapid growth of a right inguinal mass, which demonstrated aggressive disease in this HIV patient.\n\nOur patient had a poor outcome and died 1.5 months after exact diagnosis. This case was categorized as stage IIIC and was composed of a variety of germ cell tumor components (including yolk sac tumors, embryonal cell carcinoma and seminoma). The later clinical stage and complicated histological pattern suggested a poor prognosis. Extragonadal primary disease and extremely high levels of AFP are validated prognostic factors of poor disease-free survival [31]. Due to a retroperitoneal primary mass with bilateral inguinal metastases and extremely high levels of AFP (34,222 ng/ml), the patient was classified as poor risk. The initial bulky disease (17 cm × 16 cm × 24 cm) and aggressive nature of the lesion in this HIV-infected individual with severe immunosuppression may be further contributing factors. Patients with retroperitoneal NSGCTs greater than 10 cm in size usually have significantly worse survival rates [32]. Our patient failed to be diagnosed as HIV positive promptly and did not receive cART until admission because of an abdominal mass. Therefore, the patient showed a very low CD4 count of 70 cells/ml, which suggested severe immunosuppression. Another reason for the poor prognosis could be due to delayed and improper management. When the abdominal lump was found in a local hospital and a testicular tumor was suspected, the patient initially refused active treatment at that time. It was not until the tumor had grown rapidly for 3 months and the volume had increases 2–3-fold that the patient returned to the hospital for treatment. Although optimal treatment strategies for NSGCTs in HIV-infected patients have not been established, previous studies have suggested that HIV-infected patients can tolerate standard treatment remarkably well and should be treated with similar strategies used for HIV-negative individuals with GCTs [26, 33–35]. According to the NCCN Guidelines: Testicular Cancer (Version 1.2019), the treatment strategies for NSGCTs among healthy individuals should be based on histology, clinical staging and prognosis evaluations [36]. For poor prognosis and advanced metastatic (stage IIIC) NSGCT patients without HIV infection, standard chemotherapy is the initial treatment option. EGGCT patients are also treated with initial chemotherapy [36]. A BEP (bleomycin, etoposide, and cisplatin) regimen is well tolerated and effective, and it offers good survival and prognosis. Four cycles of BEP with 3-week intervals is the standard [36, 37]. Alternatively, patients who cannot tolerate bleomycin can be treated with 4 cycles of a VIP (etoposide, ifosfamide, and cisplatin) regimen [36, 38]. Studies have demonstrated that conventional-dose chemotherapy is recommended, and first-line high-dose chemotherapy failed to improve the outcome [39, 40]. Enhanced CT scans and serum tumor markers are indicated to assess the response after chemotherapy. If a complete response is found according to the results of imaging and tumor markers, close surveillance is recommended [36]. Patients who experience a partial response to chemotherapy (detection of a residual mass on imaging and/or persistently elevated serum tumor makers) are treated with surgical resection of all residual masses [1, 36, 41]. If only natural teratoma or necrosis is found in the resected tissue, surveillance is recommended. If yolk sac, choriocarcinoma, embryonal, or seminoma elements are encountered in the residual mass, patients should be treated with 2 cycles of chemotherapy [EP (etoposide and cisplatin), TIP (paclitaxel, ifosfamide, and cisplatin), or VIP/VeIP (vinblastine, mesna, ifosfamide, and cisplatin)] [36]. Moreover, one case showed that it was safe to give chemotherapy and HAART simultaneously [26]. Since EGGCTs are rare, HIV-infected patients with EGGCTs are even more rare. Additionally, there is no standardized treatment for HIV-infected EGGCT patients with severe immunosuppression. For the purpose of relieving the patient’s symptoms, radical surgical resection of the retroperitoneal mass and the inguinal metastases was performed, followed by chemotherapy, which was inconsistent with the treatment guidelines for HIV-negative individuals with advanced NSGCTs.\n\nGenerally, the outcome of non-HIV-infected extragonadal NSGCT patients is satisfactory. A non-HIV-infected man with unilateral cryptorchidism presented with a rapidly growing mass for 6 months and large (17 cm × 19 cm × 35 cm) mixed GCTs (mostly yolk sac tumors: 90–95%) in the retroperitoneum with elevated levels of AFP (120,000 ng/mL). He then underwent excision of the mass and postoperative chemotherapy. Histology, clinical staging, prognosis evaluations, and treatments were similar in our case, but the patient had a successful short-term survival; a one-year follow-up showed no recurrence, and AFP levels were normalized [15]. Häcker et al. reported a primary retroperitoneal EGGCT patient without HIV infection who received chemotherapy and surgical resection of the residual mass and developed metachronous testicular cancer 10 months later [41]. A prospective trial of chemotherapy in non-HIV-infected patients with EGGCTs demonstrated a significant response in patients with retroperitoneal tumors and a 4-year survival rate of more than 70% [42]. Furthermore, 3-year progression-free survival was achieved in 48 to 54% of HIV-negative patients with EGGCTs by using chemotherapy followed by surgical consolidation [43, 44]. Hashimoto et al. reported that among HIV-negative patients with retroperitoneal NSGCTs, the 5-year survival rate was 94.7% with the use of chemotherapy, and 76.9% of poor-risk patients (10/13) survived for 2 years without evidence of disease [45].\n\nHowever, the treatment outcome of HIV-positive patients with progressive NSGCTs is uncertain. One HIV-infected patient with advanced mixed GCTs (clinical stage IIC) received chemotherapy at onset but died 1.5 months after tumor diagnosis [46]. A report documented that a BEP regimen offered an initially remarkable response in a cART-naïve HIV patient with bulky abdominal yolk sac tumors and lung metastasis; however, the response did not last, as the patient suffered lung recurrence 5 months after completing chemotherapy [47]. These studies show that NSGCTs in HIV-infected patients were more likely to progress and recur after treatment. Some studies have demonstrated inconsistent results. Fizazi et al. retrospectively analyzed the results of chemotherapy in 34 HIV-infected men with GCTs (18 of them had NSGCTs), and 50% of patients were alive with a median follow-up of 27 months (range, 3–150) [30]. Powles et al. demonstrated that HIV patients with stage II or stage III GCTs treated with standard therapy had similar favorable outcomes compared to the HIV-negative population, and only two of the 14 patients died from the progressive disease at a median follow-up of approximately 4.5 years [26]. Another study found that HIV patients with metastatic GCTs who underwent chemotherapy had a similar disease-free survival compared with the general population [48]. The optimal treatment strategy and therapeutic guidelines for achieving long-term survival in HIV-positive patients with severe immunosuppression and advanced NSGCTs remain to be defined, and more prospective clinical trials should be conducted in the future.\n\nConclusions\nThis case report demonstrated the challenges that pertain to the management of HIV-infected patients with primary EGGCTs due to their aggressive nature, and it evaluated the poor treatment outcome. The standard treatment guidelines for non-HIV-infected GCT patients are important treatment principles for various types of GCTs, but HIV-infected GCT patients with severe immunosuppression need special consideration. The appropriate management of advanced GCTs in HIV-infected patients with severe immunosuppression needs to be established in the future, and collaboration among oncologists, surgeons and HIV physicians is key.\n\nAbbreviations\nAFPAlpha-fetoprotein\n\nAIDSAcquired immune deficiency syndrome\n\ncARTCombination antiretroviral therapy\n\nCTComputed tomography\n\nEGGCTsExtragonadal germ cell tumors\n\nGCTsGerm cell tumors\n\nHCVHepatitis C virus\n\nHIVHuman immunodeficiency virus\n\nNSGCTsNonseminomatous germ cell tumors\n\nβ-HCGBeta-human chorionic gonadotropin\n\nAcknowledgements\nNot applicable.\n\nFunding\nThis research was supported by the National Natural Science Foundation of China (No: 81771806), Capital Medical University Research and Incubation Funding (No: PYZ2017124), and Beijing Municipal Administration of Hospitals Incubating Program (No: PX2016036). The funding bodies had no roles in the study design, data collection and analysis, and preparation of the manuscript.\n\nAvailability of data and materials\nThe material supporting the conclusion of this study has been included in the manuscript.\n\nAuthors’ contributions\nRLL and HJL were directly involved in the clinical management of this case and offered expert radiological opinions on the case as well as the presentation of the results for publication. RLL designed the study and drafted the original manuscript under the guidance of HJL. Both authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis research was approved by the ethics committee of Beijing Youan Hospital.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s brother for publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Oldenburg J Fossa SD Nuver J Heidenreich A Schmoll HJ Bokemeyer C Horwich A Beyer J Kataja V Group EGW Testicular seminoma and non-seminoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2013 24 Suppl 6 vi125 vi132 10.1093/annonc/mdt304 24078656 \n2. Bahrami A Ro JY Ayala AG An overview of testicular germ cell tumors Arch Pathol Lab Med 2007 131 8 1267 1280 17683189 \n3. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "19(1)",
"journal": "BMC cancer",
"keywords": "Extragonadal; HIV; Immunosuppression; Nonseminomatous germ cell tumor; Poor prognosis",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D003456:Cryptorchidism; D017809:Fatal Outcome; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D011379:Prognosis; D012186:Retroperitoneal Neoplasms; D016879:Salvage Therapy; D013736:Testicular Neoplasms; D013737:Testis",
"nlm_unique_id": "100967800",
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"pages": "244",
"pmc": null,
"pmid": "30885154",
"pubdate": "2019-03-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11423738;11745223;11919246;12218392;12232845;12455069;12590788;12743144;12853764;14579191;14971360;15034740;15083180;1552581;15847726;17084512;17235042;17390054;17683189;20471872;20858789;20933444;21098858;21128977;21768233;21986225;22343384;23316184;23448004;24078656;24176649;25948949;27042527;28120701;28816282;29313949;29804238;3008176;7538557;7595728;7627853;7680950;9053482;9552027",
"title": "Poor prognosis of retroperitoneal mixed extragonadal germ cell tumors in an HIV-infected man with severe immunosuppression and bilateral cryptorchidism: a case report.",
"title_normalized": "poor prognosis of retroperitoneal mixed extragonadal germ cell tumors in an hiv infected man with severe immunosuppression and bilateral cryptorchidism a case report"
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"abstract": "Lung lesions of Hodgkin's lymphoma (HL) are rare and difficult to diagnose by nonsurgical biopsy. We herein present the case of a 72-year-old Japanese male who presented with accumulation of lung infiltrates and masses bilaterally on the lungs for 3 years. Although transbronchial lung biopsy (TBB) and computed tomography-guided biopsy were conducted several times, his diagnosis remained inconclusive. On further deterioration of lung lesions, the patient was transferred to our hospital. Positron emission tomography revealed increased accumulation in the bilateral lungs and right supraclavicular lymph nodes. Surgical biopsy of the lymph node was performed. He was finally diagnosed with HL and underwent chemotherapy with doxorubicin, vinblastine, dacarbazine, and brentuximab vedotin. After chemotherapy, the lung lesion showed significant regression. A literature review indicated that the diagnostic success rate of TBB was low (18.5%) in cases of lung lesions in HL.",
"affiliations": "Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Hematology and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.",
"authors": "Hoshi|Miki|M|;Kobayashi|Nobuaki|N|https://orcid.org/0000-0002-7064-320X;Tanaka|Katsushi|K|;Somekawa|Kohei|K|;Kaneko|Ayami|A|;Izawa|Ami|A|;Seki|Kenichi|K|;Tagami|Yoichi|Y|;Aoki|Ayako|A|;Fujii|Hiroaki|H|;Watanabe|Keisuke|K|https://orcid.org/0000-0001-9623-1492;Horita|Nobuyuki|N|https://orcid.org/0000-0002-8200-0340;Hara|Yu|Y|https://orcid.org/0000-0002-2574-2516;Matsumura|Mai|M|;Enaka|Makiko|M|;Hagihara|Maki|M|;Kaneko|Takeshi|T|",
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"country": "Singapore",
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"doi": "10.1111/1759-7714.14190",
"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\n34698453\n10.1111/1759-7714.14190\nTCA14190\nCase Report\nCase Reports\nDiagnostic utility of transbronchial biopsy for Hodgkin's lymphoma: A case study\nHoshi et al.\nHoshi Miki 1\nKobayashi Nobuaki https://orcid.org/0000-0002-7064-320X\n1 nkobayas@yokohama-cu.ac.jp\n\nTanaka Katsushi 1\nSomekawa Kohei 1\nKaneko Ayami 1\nIzawa Ami 1\nSeki Kenichi 1\nTagami Yoichi 1\nAoki Ayako 1\nFujii Hiroaki 1\nWatanabe Keisuke https://orcid.org/0000-0001-9623-1492\n1\nHorita Nobuyuki https://orcid.org/0000-0002-8200-0340\n1\nHara Yu https://orcid.org/0000-0002-2574-2516\n1\nMatsumura Mai 2\nEnaka Makiko 3\nHagihara Maki 4\nKaneko Takeshi 1\n1 Department of Pulmonology Yokohama City University Graduate School of Medicine Yokohama Japan\n2 Department of Pathology Yokohama City University Graduate School of Medicine Yokohama Japan\n3 Department of Molecular Pathology Yokohama City University Graduate School of Medicine Yokohama Japan\n4 Department of Hematology and Clinical Immunology Yokohama City University Graduate School of Medicine Yokohama Japan\n* Correspondence\nNobuaki Kobayashi, Department of Pulmonology, Yokohama City University Graduate School of Medicine, 3‐9 Fukuura, Kanazawaku, Yokohama, Kanagawa 236‐0004, Japan.\nEmail: nkobayas@yokohama-cu.ac.jp\n\n25 10 2021\n12 2021\n12 23 10.1111/tca.v12.23 32813285\n29 9 2021\n31 8 2021\n01 10 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nLung lesions of Hodgkin's lymphoma (HL) are rare and difficult to diagnose by nonsurgical biopsy. We herein present the case of a 72‐year‐old Japanese male who presented with accumulation of lung infiltrates and masses bilaterally on the lungs for 3 years. Although transbronchial lung biopsy (TBB) and computed tomography‐guided biopsy were conducted several times, his diagnosis remained inconclusive. On further deterioration of lung lesions, the patient was transferred to our hospital. Positron emission tomography revealed increased accumulation in the bilateral lungs and right supraclavicular lymph nodes. Surgical biopsy of the lymph node was performed. He was finally diagnosed with HL and underwent chemotherapy with doxorubicin, vinblastine, dacarbazine, and brentuximab vedotin. After chemotherapy, the lung lesion showed significant regression. A literature review indicated that the diagnostic success rate of TBB was low (18.5%) in cases of lung lesions in HL.\n\nHere, we report a case of undiagnosed HL with lung lesions despite multiple TBBs. Our literature review indicated that the diagnostic success rate of TBB was low (18.5%) in cases of lung lesions in HL. Surgical biopsy should be considered early to avoid a delay in diagnosis because the diagnostic ability of TBB for HL patients with lung lesions is limited.\n\nbiopsy\nchemotherapy\nlymphoma\nsource-schema-version-number2.0\ncover-dateDecember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:01.12.2021\nHoshi M , Kobayashi N , Tanaka K , Somekawa K , Kaneko A , Izawa A , et al. Diagnostic utility of transbronchial biopsy for Hodgkin's lymphoma: A case study. Thorac Cancer. 2021;12 :3281–3285. 10.1111/1759-7714.14190\n==== Body\npmcINTRODUCTION\n\nLung lesions are rare in Hodgkin's lymphoma (HL) and are diagnosed based on pathological findings from samples taken during lung biopsy. Although several methods are available to obtain pathological samples for the diagnosis of HL with lung lesions, their diagnostic utilities differ. Herein, we report on a patient diagnosed with HL with lung lesions by lymph node biopsy after diagnostic failure following several attempts at transbronchial biopsy (TBB) and provide a literature review on the diagnostic utility of TBB among patients with similar clinical presentations.\n\nCASE REPORT\n\nA 72‐year‐old Japanese male with a smoking history of 40 cigarettes per day until 2011 was diagnosed with smoking‐related interstitial pneumonia in 2017 which was followed up with chest radiography and computed tomography (CT) (Figure 1a,b). In 2018, follow‐up radiography showed consolidation in bilateral lungs (Figure 1c,d). Although TBB and CT‐guided biopsy of the lung lesions were conducted on three occasions between 2018 and 2019, pathological findings revealed that nonspecific inflammatory cells only invaded the lung. During the TBBs, biopsy sites were confirmed with endobronchial ultrasound (EBUS) using EBUS‐guided sheath methods. On further lung involvement and deterioration, he was referred to our hospital for examination.\n\nFIGURE 1 (a, b) Chest radiography and CT images obtained in 2017. Reticular and ground‐glass opacities are visible in the bilateral lungs. (c, d) Chest radiography and CT images obtained in 2018. Multiple masses are seen in the bilateral lungs. (e, f) Chest radiography and CT images obtained in 2019. Masses are enlarged and developed in consolidation. (g) Positron emission tomography performed in 2020 revealed accumulation of fluorodeoxyglucose in the lungs and right supraclavicular lymph nodes are detected. (h–k) Immunohistochemistry (IHC) of the supraclavicular lymph node biopsy. IHC is positive in CD30 (h), negative in CD15 (i), negative in CD20 (j), and positive in PAX5 (k)\n\nOn physical examination, his vital signs and physical findings were unremarkable, respiratory rate was 16/min, SpO2 was 97%, and there was no palpable lymphadenopathy. Routine laboratory tests were normal, except for slightly elevated KL‐6 (783 U/ml), C‐reactive protein (8.70 mg/l), and soluble interleukin‐2 receptor (798 U/ml) levels. Lung cancer‐related tumor markers were negative. Chest radiography and CT revealed accumulation of multiple nodules in bilateral lungs (Figure 1e,f). Positron emission tomography(PET)‐CT revealed increased fluorodeoxyglucose accumulation in the right supraclavicular lymph nodes and bilateral lung lesions (Figure 1g). Surgical biopsy of these lymph nodes showed an eosinophilic granulomatous region with scattered binuclear large cells between follicles. Immunohistochemistry (IHC) was positive for cluster of differentiation (CD) 30 (Figure 1h) and negative for CD15 (Figure 1i), organic anion transporter (Oct) 1, B‐cell Oct‐binding protein (BOB) 1, and programmed cell death protein (PD) 1. CD20 and paired box 5 (PAX5) was dim. Typically, Epstein–Barr virus‐encoded small RNA (EBER) is positive in large hodgkinoid cells; however, EBER was positive only in the small cells in this patient. Although it is atypical for Hodgkin's lymphoma to have numerous CD20+ cells (Figure 1j) and negative PD‐1 in all cells, the positive IHC in PAX5 (Figure 1k) and CD30 and negative IHC in BOB‐1 and Oct‐2 were consistent with the features of Hodgkin's cells. Based on these findings, the patient was diagnosed with HL following careful pathological examination and subsequently underwent treatment with doxorubicin, vinblastine, dacarbazine, and brentuximab vedotin (A + AVD)‐based chemotherapy. Although peripheral neuropathy and febrile neutropenia emerged as chemotherapy‐related adverse events and the amount of therapy had to be reduced, six courses were completed. Following treatment, lesions on both the lungs and lymph nodes had significantly regressed (Figure 2a–f).\n\nFIGURE 2 Interval changes of clinical images after chemotherapy. (a, b) Chest radiography and chest CT are performed just before the induction of chemotherapy. (c, d) Clinical images after two cycles of chemotherapy. (e, f) Clinical images after four cycles of chemotherapy\n\nTo explore the diagnostic utility of several biopsy methods for HL with lung lesions, a literature review was performed. A database search identified 101 cases between 1990 and 2020 (Table 1). 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 Most cases were diagnosed by surgical biopsy (85 cases), followed by CT‐guided biopsy (eight cases) and TBB (four cases).\n\nTABLE 1 Summary of lung biopsy used for the diagnosis of Hodgkin's lymphoma with lung lesions\n\nReference\tYear\tNumber of cases\tBiopsy method for final diagnosis\t\nTransbronchial biopsy\tCT‐guided biopsy\tSurgical biopsy\tOthers\t\nRadin a\t1990 1\t47\t1\t0\t46\t\t\nSchee et al.\t1990 2\t2\t0\t0\t2\t\t\nPinson et al.\t1992 3\t1\t0 (1)\t0\t1\t\t\nChetty et al.\t1995 4\t3\t0\t0\t3\t\t\nCartier et al.\t1999 5\t3\t1 (1)\t1\t1\t\t\nBoshnakova et al.\t2000 6\t2\t0 (2)\t0\t2\t\t\nStachura et al.\t2003 7\t1\t0 (1)\t0\t1\t\t\nHosoi et al.\t2005 8\t1\t0\t1\t0\t\t\nRodriguez et al.\t2006 9\t5\t1\t0\t4\t\t\nCodrich et al\t2006 10\t1\t0 (1)\t0\t1\t\t\nUrasinski et al.\t2010 11\t3\t0 (1)\t0\t3\t\t\nHonda et al.\t2013 12\t1\t0 (1)\t0\t1\t\t\nCooksley et al. b\t2014 13\t15\t0 (8)\t0 (3)\t15\t\t\nSchild et al.\t2014 14\t1\t0\t1\t0\t\t\nTanveer\t2015 15\t1\t0\t0\t1\t\t\nWatanabe et al.\t2015 16\t1\t0\t1\t0\t\t\nEl Hage et al.\t2017 17\t1\t0 (1)\t1\t0\t\t\nLowenthal et al.\t2017 18\t2\t2\t0\t0\t\t\nSinha et al.\t2017 19\t1\t0\t1\t0\t\t\nTahara et al.\t2017 20\t2\t0 (2)\t1\t1\t\t\nAljehani et al.\t2018 21\t3\t0 (1)\t2 (1)\t1\t\t\nConti et al.\t2018 22\t1\t0 (1)\t1\t0\t\t\nChowdhary et al.\t2020 23\t1\t0\t0\t1\t\t\nParente et al.\t2020 24\t1\t0\t0\t0\tUS‐guided aspiration: 1\t\nTakumi et al.\t2020 25\t1\t0 (1)\t0\t1\t\t\nNote: ( ): Biopsy was performed but undiagnostic.\n\na Radin reported 61 cases, but only 47 of them underwent lung biopsy evaluation.\n\nb Cooksley reported 20 cases, but two of them were diagnosed by lymph node biopsy and two of them did not mention the biopsy method, and one case was not identified.\n\nBased on our case and the literature review, TBB and CT‐guided biopsies seem less effective for diagnosing HL with lung lesions than surgical biopsy; therefore, the diagnostic utility of those methods was analyzed using data from Table 1. The success rate for arriving at the final diagnosis via TBB was only 18.5%, which was higher for CT‐guided biopsy (71.4%).\n\nDISCUSSION\n\nHere, we report a case of undiagnosed HL with lung lesions despite multiple TBBs. HL is a relatively rare malignant lymphoma (ML) in Japan (5%–10% of ML cases). 26 Furthermore, lung parenchyma involvement in HL is uncommon and difficult to diagnose via TBB. 27 Yao et al. reported that the median duration to arrive at the final diagnosis was 6 months and the longest duration was 2 years in 19 cases of HL with lung lesions. 28 Smoking increases the risk of HL and may contribute to the development of cancer cells, as in our case study. 29 Our literature review revealed that TBB is inappropriate for most cases of HL with lung lesions.\n\nReasons for the poor diagnostic performance of TBB and CT‐guided biopsy might be the small volume of samples obtained by both methods. The presence of Hodgkin's or Reed‐Sternberg cells in the specimen is a histological feature of HL, but these cells are few and scattered in the background of small lymphocyte infiltration. Kogawara et al. diagnosed 67% of diffuse large B cell lymphoma (DLBCL) and 33% of mucosa‐associated lymphoid tissue lymphoma by TBB or endobronchial biopsy, which is higher than the diagnostic utility of TBB for HL. 30 Although it is more invasive for patients, with the possibility of complications especially for patients with interstitial lung disease, a surgical biopsy can solve these issues, especially in HL cases. 31\n\nAs a tool to overcome this dilemma, transbronchial cryobiopsy (TBCB) has recently gained attention. It is transbronchial and less invasive than the surgical approach and can obtain a sample large enough to diagnose at the first instance (maximum diameter: 5–7 mm). 32 Its usefulness in diagnosing ML has been previously reported. Bianchi et al. reported that in 12 of 13 cases of ML, diagnosis was reached via TBCB, with two cases being HL. Dante et al. diagnosed DLBCL via TBCB after failure with TBB. Successfully diagnosed cases of TBCB in HL are few and TBCB is unavailable at most facilities. Our case had a history of smoking‐related interstitial pneumonia with concerns regarding exacerbation of respiratory function; therefore, a surgical biopsy was avoided for many years. One cause of HL is smoking. Cancer cells can migrate to the lungs as a result of smoking. Imaging features of HL of the lung include solitary or multiple nodules and alveolar consolidation. 33 There is also predilection of the upper lobes in cases of primary pulmonary HL. 15 , 27 Differential diagnosis of HL includes lung cancer, metastasis, lymphocytic interstitial pneumonia, and cryptogenic organizing pneumonia. In our case, chest CT showed multiple nodules and consolidation in bilateral lungs and TBB was not diagnostic. Thus, we could not rule out HL and decided to perform surgical biopsy of the right supraclavicular lymph nodes. This case study demonstrates that surgical biopsy should be conducted for suspicious lesions.\n\nIn conclusion, TBB or CT‐guided biopsy remains a common diagnostic tool for HL patients with lung lesions, but its diagnostic ability is limited. Surgical biopsy or TBCB should be considered early to avoid a delay in diagnosis.\n\nCONFLICT OF INTEREST\n\nOn behalf of the co‐authors, the corresponding author declares no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Radin I . Primary pulmonary Hodgkin's disease. Cancer. 1990;65 :550–63.2404558\n2 Schee AC , Dinkla BA , Knapen A . Primary pulmonary manifestation of Hodgkin's disease. Respiration. 1990;57 :127–8.2236933\n3 Pinson P , Joos G , Praet M , Pauwels R . Primary pulmonary Hodgkin's disease. Respiration. 1992;59 :314–6.1488566\n4 Chetty R , Slavin JL , O'Leary JJ , Ansari NA , Gatter KC . Primary Hodgkin's disease of the lung. Pathology. 1995;27 :111–4.7567133\n5 Cartier Y , Johkoh T , Honda O , Müller NL . Primary pulmonary Hodgkin's disease: CT findings in three patients. Clin Radiol. 1999;54 :182–4.10201869\n6 Boshnakova T , Michailova V , Koss M , Georgiev C , Todorov T , Sarbinova M . Primary pulmonary Hodgkin's disease—report of two cases. Respir Med. 2000;94 :830–1.10955762\n7 Stachura T , Malinowski E . Primary pulmonary Hodgkin's lymphoma with Epstein‐Barr and cytomegaly virus infections. A case report and differential diagnosis. Pol J Pathol. 2003;54 :79–83.12817885\n8 Hosoi K , Chikuie N , Min KY , Satoh T , Tokumine Y , Ishikawa K , et al. [Primary pulmonary Hodgkin's disease]. Nippon Naika Gakkai Zasshi. 2005;94 :1399–401.16097597\n9 Rodriguez J , Tirabosco R , Pizzolitto S , Rocco M , Falconieri G . Hodgkin lymphoma presenting with exclusive or preponderant pulmonary involvement: a clinicopathologic study of 5 new cases. Ann Diagn Pathol. 2006;10 :83–8.16546042\n10 Codrich D , Monai M , Pelizzo G , Bussani R , Rabusin M , Guastalla P , et al. Primary pulmonary Hodgkin's disease and tuberculosis in an 11‐year‐old boy: case report and review of the literature. Pediatr Pulmonol. 2006;41 :694–8.16703583\n11 Urasinski T , Kamienska E , Gawlikowska‐Sroka A , et al. Pediatric pulmonary Hodgkin lymphoma: analysis of 10 years data from a single center. Eur J Med Res. 2010;15 (Suppl 2 ):206–10.21147653\n12 Honda A , Nakamura F , Nannya Y , Shintani Y , Fukayama M , Ichikawa M , et al. Pulmonary lymphocyte‐rich classical Hodgkin lymphoma with early response to ABVD therapy. Ann Hematol. 2014;93 :1073–4.24173088\n13 Cooksley N , Judge DJ , Brown J . Primary pulmonary Hodgkin's lymphoma and a review of the literature since 2006. BMJ Case Rep. 2014;2014 :bcr2014204020.\n14 Schild MH , Wong WW , Valdez R , Leis JF . Primary pulmonary classical Hodgkin lymphoma: a case report. J Surg Oncol. 2014;110 :341–4.24777934\n15 Tanveer S , El Damati A , El Baz A , Alsayyah A , ElSharkawy T , Regal M . Primary pulmonary Hodgkin lymphoma. Rare Tumors. 2015;7 :5968.26788271\n16 Watanabe N , Fujioka I , Aota Y , Ando J , Tanaka M , Ohta Y , et al. Primary pulmonary Hodgkin lymphoma diagnosed by CT‐guided percutaneous biopsy. Rinsho Ketsueki. 2015;56 :41–3.25745968\n17 El Hage H , Hossri S , Samra B , El‐Sayegh D . Primary pulmonary Hodgkin's lymphoma: a rare etiology of a cavitary lung mass. Cureus. 2017;9 :e1620.29098130\n18 Lowenthal BM , Xu X , Subash M , Jih LJ . Hodgkin's lymphoma with unusual pulmonary presentations: reporting two cases. Indian J Pathol Microbiol. 2017;60 :272–4.28631653\n19 Sinha A , Patti R , Singh P , Solomon W , Kupfer Y . A diagnostic surprise: primary Hodgkin's lymphoma of the lung. J Investig Med High Impact Case Rep. 2017;5 :2324709617734247.\n20 Tahara M , Maekura T , Kasai T , Akira M . Primary pulmonary MALT lymphoma with ground‐glass nodule. Intern Med. 2017;56 :3119–20.28943582\n21 Aljehani Y , Al‐Saif H , Al‐Osail A , Al‐Osail E . Multiloculated cavitary primary pulmonary Hodgkin lymphoma: case series. Case Rep Oncol. 2018;11 :90–7.29606947\n22 Conti L , Pisani D , Gatt A , Montefort S . Unusual case of primary pulmonary Hodgkin's lymphoma presenting with a continuous murmur. BMJ Case Rep. 2018;2018 :bcr2018225674.\n23 Chowdhary GS , Mehta R , Tyagi R . Primary pulmonary Hodgkin's lymphoma with pulmonary histoplasmosis. Med J Armed Forces India. 2020;76 :462–5.33162658\n24 Parente P , Zanelli M , Zizzo M , Carosi I , Di Candia L , Sperandeo M , et al. Primary pulmonary Hodgkin lymphoma presenting as multiple cystic lung lesions: diagnostic usefulness of cell block. Cytopathology. 2020;31 :236–9.32112490\n25 Takumi Y , Karashima T , Abe M , Miyawaki M , Daa T , Sugio K . A case of primary pulmonary classical Hodgkin lymphoma. Jpn J Lung Cancer. 2020;60 :43–7.\n26 Japanese Society of Hematology , Guidelines for Hematopoietic in 2018 (in Japanese). http://www.jshem.or.jp/gui-hemali/table.html\n27 Guermazi A , Brice P , de Kerviler EE , Fermé C , Hennequin C , Meignin V , et al. Extranodal Hodgkin disease: spectrum of disease. Radiographics. 2001;21 :161–79.11158651\n28 Yao D , Zhang L , Wu PL , Gu XL , Chen YF , Wang LX , et al. Clinical and misdiagnosed analysis of primary pulmonary lymphoma: a retrospective study. BMC Cancer. 2018;18 :281.29530011\n29 Pezzuto A , Citarella F , Croghan I , Tonini G . The effects of cigarette smoking extracts on cell cycle and timer spread: novel evidence. Future Sci OA. 2019;5 :FSO394.31205749\n30 Kogawara H , Mato N , Fujiki Y , Takigami A , Nakayama M , Yamasawa H , et al. Factors influencing bronchoscopic approaches to pulmonary malignant lymphoma. J Jpn Soc Respir Endoscopy. 2018;40 :293–9.\n31 Bianchi R , Dubini A , Asioli S , Ravaglia C , Tomassetti S , Puglisi S , et al. Transbronchial cryobiopsy: an effective tool in the diagnosis of lymphoproliferative disorders of the lung. ERJ Open Res. 2020;6 :00260‐2019.\n32 Yap E , Low I . Bronchoscopic transbronchial cryobiopsy diagnosis of recurrent diffuse large B‐cell lymphoma in the lung: a promising new tool? J Bronchology Interv Pulmonol. 2017;24 :e22–3.28323739\n33 Baccari‐Ezzine S , Bouzaidi K , Chelbi E , Ali MB , Ghrairi H . Unusual radiologic and histologic manifestations of primary pulmonary lymphoma. Asian Cardiovasc Thorac Ann. 2014;22 :362–4.24585921\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1759-7706",
"issue": "12(23)",
"journal": "Thoracic cancer",
"keywords": "biopsy; chemotherapy; lymphoma",
"medline_ta": "Thorac Cancer",
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"nlm_unique_id": "101531441",
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"pages": "3281-3285",
"pmc": null,
"pmid": "34698453",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
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"title": "Diagnostic utility of transbronchial biopsy for Hodgkin's lymphoma: A case study.",
"title_normalized": "diagnostic utility of transbronchial biopsy for hodgkin s lymphoma a case study"
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"abstract": "Embryonal tumor with multilayer rosettes (ETMR) is a rare CNS malignancy affecting young children that carries a very poor prognosis. Treatment with intensive surgical resection, radiotherapy, and high-dose chemotherapy is insufficient treatment in the vast majority of cases. Effective, biologically based therapies for this tumor are therefore desperately needed. The Dana-Farber Cancer Institute-modified IRS-III protocol incorporates preclinically active agents, such as doxorubicin and actinomycin D, into the treatment regimen for ETMR and may improve patient outcomes.\nThe authors present a case series of 5 children with ETMR treated with an IRS-III-based chemotherapy backbone.\nAll 5 patients received a gross-total tumor resection. Patients received between 12 and 51 weeks of IRS-III therapy at the discretion of their treating physician. Four patients received focal radiation therapy, with the fifth patient instead receiving a cycle of high-dose chemotherapy with autologous stem cell rescue. Four patients have progression-free survival of more than 18 months. Chemotherapy treatment was reasonably tolerated by all 5 patients with one case of mild sinusoidal obstructive syndrome and one case of Grade 3 peripheral neuropathy.\nThe patient outcomes in this small cohort are far better than would be expected based on the historical survival for this tumor. Given the tremendous need for effective therapy for ETMR, further investigation of this approach is warranted. An international consensus protocol based on the IRS-III regimen has been developed and will be available through a multicenter clinical trial and a global treatment registry.",
"affiliations": "Department of Pediatrics, Hackensack Meridian School of Medicine at Seton Hall University, Nutley, New Jersey, USA.;Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.;Sydney Children's Hospital, Randwick, New South Wales, Australia.;Trombo Protea, Inc., Weston, Massachusetts, USA.;Department of Neurosurgery, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.;Department of Neurosurgery, Hackensack University Medical Center, Hackensack, New Jersey, USA.;Dana-Farber Cancer Institute, Boston, Massachusetts, USA.",
"authors": "Hanson|Derek|D|;Hoffman|Lindsey M|LM|;Nagabushan|Sumanth|S|;Goumnerova|Liliana C|LC|;Rathmann|Allison|A|;Vogel|Timothy|T|;Ziegler|David S|DS|;Chi|Susan|S|",
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"doi": "10.1093/noajnl/vdaa120",
"fulltext": "\n==== Front\nNeurooncol Adv\nNeurooncol Adv\nnoa\nNeuro-oncology Advances\n2632-2498 Oxford University Press US \n\n10.1093/noajnl/vdaa120\nvdaa120\nClinical Investigations\nAcademicSubjects/MED00300\nAcademicSubjects/MED00310\nA modified IRS-III chemotherapy regimen leads to prolonged survival in children with embryonal tumor with multilayer rosettes\nHanson Derek 123 Hoffman Lindsey M 4 Nagabushan Sumanth 56 Goumnerova Liliana C 12 Rathmann Allison 789 Vogel Timothy 3 Ziegler David S 7 Chi Susan 1011 1 \nDepartment of Pediatrics, Hackensack Meridian School of Medicine at Seton Hall University, Nutley, New Jersey, USA\n2 \nDepartment of Pediatrics, Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, New Jersey, USA\n3 \nCenter for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA\n4 \nCenter for Cancer and Blood Disorders, Phoenix Children’s Hospital, Phoenix, Arizona, USA\n5 \nSydney Children’s Hospital, Randwick, New South Wales, Australia\n6 \nUniversity of New South Wales, Sydney, New South Wales, Australia\n7 \nDepartment of Neurosurgery, Hackensack University Medical Center, Hackensack, New Jersey, USA\n8 \nMorristown Medical Center, Morristown, New Jersey, USA\n9 \nSaint Peters University Hospital, New Brunswick, New Jersey, USA\n10 \nDana-Farber Cancer Institute, Boston, Massachusetts, USA\n11 \nHarvard Medical School, Boston, Massachusetts, USA\n12 \nTrombo Protea, Inc., Weston, Massachusetts, USA\nCorresponding Author: Derek Hanson, MD, Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, NJ 07601, USA (Derek.Hanson@hackensackmeridian.org).\nJan-Dec 2020 \n18 9 2020 \n18 9 2020 \n2 1 vdaa12007 11 2020 © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nEmbryonal tumor with multilayer rosettes (ETMR) is a rare CNS malignancy affecting young children that carries a very poor prognosis. Treatment with intensive surgical resection, radiotherapy, and high-dose chemotherapy is insufficient treatment in the vast majority of cases. Effective, biologically based therapies for this tumor are therefore desperately needed. The Dana-Farber Cancer Institute–modified IRS-III protocol incorporates preclinically active agents, such as doxorubicin and actinomycin D, into the treatment regimen for ETMR and may improve patient outcomes.\n\nMethods\nThe authors present a case series of 5 children with ETMR treated with an IRS-III-based chemotherapy backbone.\n\nResults\nAll 5 patients received a gross-total tumor resection. Patients received between 12 and 51 weeks of IRS-III therapy at the discretion of their treating physician. Four patients received focal radiation therapy, with the fifth patient instead receiving a cycle of high-dose chemotherapy with autologous stem cell rescue. Four patients have progression-free survival of more than 18 months. Chemotherapy treatment was reasonably tolerated by all 5 patients with one case of mild sinusoidal obstructive syndrome and one case of Grade 3 peripheral neuropathy.\n\nConclusions\nThe patient outcomes in this small cohort are far better than would be expected based on the historical survival for this tumor. Given the tremendous need for effective therapy for ETMR, further investigation of this approach is warranted. An international consensus protocol based on the IRS-III regimen has been developed and will be available through a multicenter clinical trial and a global treatment registry.\n\nbrain tumorchemotherapyembryonal tumor with multilayer rosettespediatric\n==== Body\nKey Points\nChemotherapy with preclinically active agents may improve outcomes for ETMR.\n\nIRS-III-based treatment led to progression-free survival of more than 18 months in 4 of 5 patients with ETMR.\n\nImportance of the Study\nETMR is an aggressive pediatric CNS tumor for which there is currently no standard of care. Traditional approaches for infant brain tumors have been largely ineffective, and improved treatments incorporating the known biology of ETMR must be pursued. The Dana-Farber Cancer Institute–modified IRS-III protocol provides an avenue for incorporating preclinically active agents into therapy. A series of 5 children treated with this regimen demonstrates promising results with 4 patients achieving progression-free survival of more than 18 months. Based on the available preclinical data and these encouraging clinical outcomes, a global clinical investigation for ETMR has been developed.\n\nEmbryonal tumor with multilayer rosettes (ETMR) is a rare and highly aggressive CNS neoplasm that occurs almost exclusively in young children and is associated with an extremely poor prognosis. There is no current standard therapy for the tumor and survival is historically dismal even with intensive therapy. The Dana-Farber Cancer Institute–modified IRS-III protocol (DFCI-IRS-III) provides an avenue for incorporating preclinically active agents into therapy and may improve outcomes for ETMR. Preliminary efficacy of the regimen has been demonstrated in a small cohort of patients with long-term survival and will be explored further in a larger clinical investigation.\n\nETMR almost always arises in children under 4 years of age, with a median age of diagnosis of approximately 2.5 years.1,2 Two thirds of tumors are located supratentorially and have predilection for the fronto-parietal region. The remainder occur in the cerebellum, brainstem, and rarely, the spinal cord.1–3 The majority of patients with ETMR present with localized disease, though approximately 20% are metastatic at diagnosis.1,2 Clinically, ETMR follows an extremely aggressive course with many patients experiencing tumor progression during therapy or shortly after completing treatment. Korshunov et al. published a series of 55 children with ETMR, which underscored the dismal prognosis of this tumor. Fifty of the described patients experienced disease recurrence with a median progression-free survival (PFS) of 8 months. Median overall survival (OS) was 12.3 months, and 84% (46/55) of patients died within 3 years after their initial diagnosis.1\n\nClassification of ETMR as a distinct clinical entity has been an evolving process. In 2009, Li et al. reported the amplification of C19MC in a variety of tumors including not only embryonal tumor with abundant neuropil and true rosettes but also medulloepithelioma, and ependymoblastoma, suggesting that these tumors may represent different manifestations of a single biologic entity.4 The 2016 WHO classification of CNS tumors unified this group of C19MC-amplified tumors under the nomenclature of ETMR.5 While C19MC amplification is present in approximately 90% of ETMR, a small subset exists without this distinctive molecular signature. The WHO classifies these non-C19MC–amplified tumors as ETMR NOS.\n\nDue to the rarity of ETMR and its recent classification, no large clinical investigations have been conducted to determine optimal therapy for these tumors. Horwitz et al. published a case series describing the French experience with ETMR and provided analysis of 30 patients treated according to the primitive neuroectodermal tumors of high risk (PNET-HR) protocol.2 On multivariate analysis, gross-total resection (GTR), radiotherapy (RT), and high-dose chemotherapy with autologous stem cell rescue (HDCT/SCR) were associated with improved outcomes. However, even with these interventions, patients had a 1-year event-free survival (EFS) and OS of only 36% and 45%, respectively.\n\nData from the French series suggest that our most aggressive standard therapies for pediatric brain tumors are not sufficient for cure in the vast majority of ETMR cases. New treatment approaches harnessing genomic and preclinical data defining certain therapeutic susceptibilities are therefore urgently needed. Recently, Schmidt et al. published findings from a preclinical drug screen aimed at developing novel treatment regimens for children with ETMR.6 An in vitro and in vivo drug screen using patient-derived ETMR cell line BT183 and its xenograft defined susceptibility to both topotecan and doxorubicin. In xenograft mice, monotherapy with topotecan or actinomycin D led to a temporary tumor response and significantly prolonged survival. Multiagent therapy with topotecan or doxorubicin in combination with methotrexate and vincristine further increased tumor responses.\n\nA variety of infant brain tumor regimens are commonly used in the treatment of ETMR as there is no current standard of care. These approaches include the aforementioned PNET-HR protocol, the German HIT protocols, U.S. cooperative group protocols CCG99703 and ACNS0334, as well as the Head Start protocols. While there is some variability between these individual protocols, they similarly incorporate platinum and etoposide-based induction therapy with or without cyclophosphamide, vincristine, and high-dose methotrexate. Of note, none of the above infant brain tumor protocols utilize the most active agents discovered in the German drug screen. The DFCI-IRS-III for atypical teratoid rhabdoid tumor (AT/RT), however, does incorporate the use of both doxorubicin and actinomycin D into a platinum-based induction backbone. The IRS-III regimen has been investigated for use in AT/RT in a phase II study of 20 patients which included intrathecal treatments and focal radiation for children under 3 years of age. The reported 2-year PFS and OS outcomes from this study were 53% and 70%, respectively.7\n\nMaterials and Methods\nIn this case series, we present 5 children with ETMR who received treatment using an IRS-III-based chemotherapy backbone (Table 1). The children were treated consecutively by the authors as they presented across their 4 respective institutions over a period of 6 years. No other children with newly diagnosed ETMR were treated by the authors during this period and through data closure. Patients received individualized therapy at the discretion of their primary oncologist. Caregivers gave informed consent for clinical treatment described in the series. The retrospective chart review of these cases received institutional review board approval with a waiver of informed consent.\n\nTable 1. Summary of Case Series\n\nCase\tAge\tSex\tTumor Location\tM Stage\tC19MC\tSurgery\tIRS-III Treatment\tHDC + ASCT\tRT\tAdditional Therapy\tEFS\tOS\tStatus\t\n1\t32 months\tF\tR Parietal\tM0\tPositive\tGTR\t51 weeks\tNo\tFocal RT\tNone\t7 years 6 months\t7 years 6 months\tAlive, NED\t\n2\t39 months\tF\tR Parietal\tM0\tPositive\tGTR\t19 weeks\tNo\tFocal Proton\tOmburtamab \n\nDFMO\t3 years 3 months\t3 years 3 months\tAlive, NED\t\n3\t5 months\tF\tR Posterior Fossa\tM0\tNegative\tSTR, then GTR\t12 weeks\tYes\tNone\tDFMO Everolimus IT Topotecan\t3 years 2 months\t3 years 2 months\tAlive, NED\t\n4\t22 months\tM\tR Parietal\tM0\tPositive\tGTR\t12 weeks\tNo\tFocal Proton\tDFMO Vorinostat \n\nTopotecan Lorlatinib Irinotecan Olaparib \n\nVeliparib \n\nRT × 2\t4 months\t1 years 10 months\tAlive, NED\t\n5\t26 months\tF\tR Frontal/Parietal\tM0\tPositive\tGTR\t50 weeks\tNo\tFocal Proton\tNone\t1 year 7 months\t1 year 7 months\tAlive, NED\t\nDFMO, difluromethylornithine; F, female; GTR, gross-total resection; HDC + ASCT, high-dose chemotherapy plus autologous stem cell rescue; M, Male; NED, no evidence of disease; RT, radiotherapy; STR, subtotal resection.\n\nResults\nCase 1\nCase 1 is a 32-month-old female who presented with a left focal seizure. An MRI of the brain revealed a 17-mm nonenhancing, T2 hyperintense mass in the right parietal cortex (Figure 1). The MRI of the spine was negative for metastatic disease. The tumor was completely resected, and pathologic examination revealed areas of closely packed embryonal cells with hyperchromatic nuclei, vesicular chromatin, and prominent nucleoli arranged around blood vessels with occasional rosettes identified. Cells were admixed with neuropil, with cortical and leptomeningeal infiltration. The tumor was negative for GFAP, LCA, CD3, and CD20. Neuropil swathes were strongly neurofilament and weakly synaptophysin positive. Ki-67 staining was 80%–90%. The tumor tissue demonstrated C19MC amplification by fluorescence in situ hybridization (FISH) (5–10 copies). CSF cytology was negative for malignant cells.\n\nFigure 1. Representative MRI studies of patients. (A) A T2-weighted image of the brain from Case 1, demonstrating a hyperintense mass in the right parietal cortex. (B) A T2-weighted image of the brain from Case 2, demonstrating a lesion in the right superior parietal lobe. (C) A T2-weighted image of the brain from Case 3, demonstrating a large mass of the right posterior fossa. (D) A T2-weighted image of the brain from Case 4, demonstrating mass involving the right posterior parietal lobe. (E) A T2-weighted image of the brain from Case 5, demonstrating a large right fronto-parietal mass with midline shift.\n\nThe patient began chemotherapy according to the DFCI-IRS-III chemotherapy regimen. She received 6 weeks of induction chemotherapy, followed by 6 weeks of chemoradiotherapy that included focal RT to the primary tumor bed. After finishing 6 weeks of postradiotherapy induction treatment, the patient completed an additional 26 weeks of maintenance therapy, concluding with 7 weeks of doxorubicin-containing continuation therapy.\n\nThe patient is currently 7 years and 6 months from diagnosis without evidence of tumor recurrence. She is healthy with normal vision, hearing, renal, and cardiac function. Neuropsychological evaluations reveal low average to average nonverbal measures of intellectual functioning. She is demonstrating average academic performance in school and does not require additional assistance.\n\nCase 2\nCase 2 is a female who presented at 39 months of age with a seizure. An MRI of the brain revealed a well-circumscribed, diffusion-restricted lesion in the right superior parietal lobe (Figure 1), and the MRI of the spine was negative for metastatic disease. The patient underwent a GTR of the mass. Histological evaluation of the tumor revealed a primitive high-grade neoplasm, with LIN28A overexpression in the majority of cells by immunohistochemistry, consistent with the diagnosis of ETMR. FISH analysis confirmed amplification of the C19M/MIR-371–373 region. CSF cytology was negative for malignant cells.\n\nThe patient received 19 weeks of chemotherapy, including focal irradiation as per the DFCI-IRS-III chemotherapy regimen. Following completion of up-front chemotherapy, the patient received experimental treatment with omburtamab (8H9 monoclonal antibody linked to I131).8 Additional maintenance therapy with difluoromethylornithine (DFMO) was initiated and continued for 2 years.\n\nThe patient is currently 39 months from diagnosis without evidence of tumor recurrence. She is clinically well with normal vision, hearing, renal, and cardiac function. She is performing well academically in the first grade.\n\nCase 3\nCase 3 is a female who presented at 5 months of age with vomiting and somnolence. An MRI of the brain revealed a large calcified and heterogeneously enhancing mass of the right posterior fossa measuring 6.5 × 6.5 × 4.4 cm (Figure 1). The MRI of the spine did not reveal any metastatic disease. The patient underwent a subtotal resection, with residual tumor measuring 4.9 × 4.2 × 4.3 cm, causing mass effect upon the right posterior thalamus and midbrain. Histopathology was consistent with ETMR and was confirmed by a second opinion. The tumor tissue tested positive for LIN28A by immunohistochemistry, and the 19q13.42 locus was negative for amplification by FISH. The tumor did, however, cluster with other ETMR on methylation profiling, confirming the diagnosis. Genomic sequencing of the tumor was negative for a DICER1 mutation. CSF cytology was negative for malignant cells.\n\nThe patient received 4 cycles of induction chemotherapy as per the DFCI-IRS-III regimen. The second cycle of chemotherapy was complicated by the development of sinusoidal obstructive syndrome, which responded quickly to defibrotide therapy. An MRI following the fourth chemotherapy cycle showed a 72% decrease in the size of the tumor to 4.5 × 2.4 × 2.3 cm. The patient underwent a GTR of her remaining tumor. Pathology demonstrated a significant change from the initial specimen with areas of extensive maturation and advanced neuronal/ganglionic differentiation.\n\nThe patient then received HDCT/SCR with a carboplatin and thiotepa conditioning regimen. Due to the patient’s young age, radiotherapy was deferred. She then received maintenance chemotherapy for 18 months with DFMO, everolimus, and intrathecal topotecan.\n\nThe patient is currently 38 months from diagnosis and 12 months from completion of therapy without evidence of tumor recurrence. The child is healthy with normal vision, renal, and cardiac function. She has bilateral hearing loss requiring hearing aids. She is receiving early intervention for motor and speech delays and is attending preschool.\n\nCase 4\nCase 4 is a male who presented at 2 years of age with a left-sided seizure and hemiparesis. Brain MRI revealed a 2-cm T2 FLAIR hyperintense focus with decreased diffusivity in the right posterior parietal lobe. The MRI of the spine was negative for metastatic disease (Figure 1). The patient underwent a GTR of the tumor. Pathology revealed an embryonal tumor with neurocytic differentiation. Microarray analysis showed C19MC alteration, consistent with ETMR. CSF cytology was negative for malignant cells.\n\nThe patient began therapy according to the DFCI-IRSIII regimen, with substitution of intrathecal topotecan in place of methotrexate, hydrocortisone, and cytarabine. After 4 cycles of induction chemotherapy, disease recurrence was noted in the primary surgical cavity on surveillance imaging. He underwent a second complete resection followed by focal proton beam RT and experimental therapy with DFMO and vorinostat. After 2 months, the patient experienced a second local recurrence after which he underwent repeat GTR and was treated with focal re-irradiation and molecularly guided chemotherapy with lorlatinib and topotecan. Six months later, a third recurrence with a metastatic frontal lobe lesion was discovered and was treated with additional radiation followed by targeted therapy. He is now 22 months from diagnosis and 4 months from his last radiotherapy. He is receiving therapy with irinotecan and a PARP inhibitor and has no evidence of disease.\n\nCase 5\nCase 5 is a female who presented at 26 months of age with progressive lethargy and vomiting. An MRI of the brain revealed a nonenhancing 8 × 6 cm right fronto-parietal mass with midline shift (Figure 1). The MRI of the spine and CSF cytology showed no evidence of metastatic spread. The patient underwent GTR of the tumor. Pathology was consistent with ETMR, including LIN28 overexpression by immunohistochemistry and C19MC (19q13.42) amplification by FISH.\n\nThe patient received therapy as per the DFCI-IRS-III chemotherapy regimen, including 6 weeks of induction chemotherapy. The patient received 6 weeks of chemoradiotherapy including focal proton beam RT to the tumor bed (54 Gy). Due to concern for toxicity, intrathecal chemotherapy was not given on Day 1 of the chemoradiotherapy cycle, as prescribed. Additionally, vincristine was held after Week 13 of therapy due to Grade 3 peripheral sensory and motor neuropathy that did not improve with 50% dose reduction in Week 10.\n\nThe patient completed an additional 26 weeks of maintenance therapy followed by 6 weeks of doxorubicin-containing continuation therapy. The final cycle of doxorubicin continuation was held due to delayed count recovery and parental preference. She received initial intrathecal treatment with methotrexate, hydrocortisone, and cytarabine but intrathecal therapy was changed to topotecan after cycle 1. The patient is currently disease-free 19 months from diagnosis and 8 months from completion of therapy.\n\nDiscussion\nETMR is a highly aggressive, poor-prognosis pediatric CNS tumor for which there is no current standard therapy. To date, medical literature pertaining to ETMR is comprised entirely of retrospective data from patients who have received a heterogeneous group of therapies. These series suggest that GTR, RT, and HDCT/SCR may improve outcomes.1,2,9 However, survival for patients remains very poor even with these interventions. New biologically based approaches to the treatment of ETMR must be explored to change the trajectory of this deadly tumor.\n\nThe presented case series details the treatment of 5 children with ETMR treated according to the DFCI-IRS-III-based approach (Table 2). Four patients (80%) have PFS of more than 18 months, more than double the 8-month median survival described in the Korshunov series.1 These results also appear promising when compared with the French series, which described a 1-year EFS of 36%.2 While no definitive conclusions regarding the efficacy of the IRS-III-based chemotherapy backbone can be drawn from this small cohort, the outcomes of these patients are far better than would be expected based on historical outcomes for this tumor, and further investigation of this approach is warranted.\n\nTable 2. Schematic of IRS-III Induction Chemotherapy\n\nWeek 1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t13\t14\t15\t16\t17\t18\t\nV\tV\tV\tV\tV\tV\tV\tV\tV\tV\tV\tV\tV\t\t\tV\t\t\t\nP\t\t\tP\t\t\tP\t\t\tP\t\t\t\t\t\t\t\t\t\nD\t\t\tD\t\t\t\t\t\t\t\t\tD\t\t\t\t\t\t\nC\t\t\t\t\t\tC*\t\t\tC*\t\t\tC\t\t\tC\t\t\t\n\t\t\tE\t\t\tE\t\t\tE\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\tA\t\t\t\nI\tI\t\tI\t\t\tI\t\t\t\t\t\tI\t\t\t\t\t\t\nV = Vincristine 2 mg/m2 i.v. on Day 1; P = Cisplatin 90 mg/m2 i.v. on Day 1; D = Doxorubicin 30 mg/m2/day infused continuously over 48 h on Days 2 and 3; C = Cylophosphamide 300 mg/m2/day infused continuously over 72 h on Days 2, 3, and 4; C* = Cylophosphamide 600 mg/m2 i.v. on Day 2; E = Etoposide 100 mg/m2 i.v. on Days 1, 2, and 3; A = Actinomycin D 1.2 mg/m2 i.v. on Days 1, 2, 3, 4, and 5; I = Methotrexate 15 mg/m2, Hydrocortisone 30 mg/m2, Cytarabine 60 mg/m2 intrathecally on Day 1.\n\nThe age at presentation for the children in this series ranges from 5 to 39 months, consistent with the published median age at presentation of 2 years.2,6 Four patients were female, also consistent with the 2:1 female predominance noted for the tumor.2,6,10 Four patients’ tumors were positive for C19MC amplification, while Case 3 was negative by FISH but confirmed as ETMR by methylation profiling. Approximately 10% of ETMR are C19MC nonamplified.11,12 These tumors have a predisposition for the posterior fossa, consistent with the tumor location of Case 3 (Figure 1). Molecular analysis has shown that ETMRs without C19MC amplification display a similar miRNA pattern to those with C19MC amplification, including expression of C19MC miRNA, and there is no evidence to suggest that these tumors exhibit a different clinical behavior.12\n\nGTR was achieved for all patients, including GTR for 4 at diagnosis and GTR for 1 after second-look surgery. None of the patients had metastatic disease at presentation. Four patients received focal RT early in the course of their treatment, with the youngest patient instead receiving consolidation with HDCT/SCR to avoid the severe cognitive effects of RT in infants. Chemotherapy was reasonably tolerated by all 5 patients with expected side effects of cytopenias and mucositis noted in all patients, some requiring transient dose reduction or chemotherapy delay. Notable adverse events included the development of mild sinusoidal obstructive syndrome in Case 3, which reversed quickly with defibrotide intervention, and the development of Grade 3 peripheral sensory and motor neuropathy in Case 5, which lead to eventual discontinuation of vincristine. The patients are exhibiting good functional status and quality of life following completion of their therapy. They are attending school and receiving supportive services as needed.\n\nPatients in the series received interventions other than the modified IRS-III backbone, and thus their positive outcomes cannot be solely attributed to the chemotherapy agents that were administered. Assessing the specific role of preclinically active chemotherapy in these patients is somewhat challenging. Doxorubicin and actinomycin D are very large molecules with limited blood–brain barrier penetration. We hypothesize that abnormal vasculature in these high-grade tumors and disruption of the blood–brain barrier from neurosurgical resection may allow these agents to penetrate tumor tissue.13 This concept is supported by the successful use of these agents for the treatment of AT/RT, another aggressive infant brain tumor.7 Cases 1, 2, and 5 all underwent an initial GTR with no postoperative evidence of disease, preventing an assessment of objective response to treatment. Case 3, however, had a relatively large residual mass that responded to 4 cycles of DFCI-IRS-III chemotherapy with a 72% tumor reduction, enabling an eventual complete resection.\n\nLimitations of this case series include small patient numbers as well as heterogeneity in the overall treatments administered. Cases 2 and 3 received maintenance therapy following IRS-III chemotherapy, and it is unclear how these additional agents may have contributed to these patients’ positive outcomes. Both received 18 months of treatment with DFMO, an enzyme-activated inhibitor of ornithine decarboxylase (ODC), which is the rate-limiting enzyme for polyamine biosynthesis. Polyamines, regulated by ODC, modulate eIF-5A, which is a direct regulator of the LIN28/let-7 axis.14 Case 2 received omburtamab, a murine IgG1 monoclonal antibody, in an attempt to deliver radioimmunotherapy through the CSF and avoid craniospinal irradiation, and Case 3 received intrathecal topotecan for CSF prophylaxis and everolimus as a targeted approach to downregulate mTOR signaling.8,15\n\nTo date, no prospective clinical trials specific to ETMR have been performed. Rarity of this tumor presents a significant challenge for patient accrual, and the paucity of clinical data limits the institution of a best practice. In 2019, an international panel of pediatric neuro-oncologists, neurosurgeons, and researchers met with the goal of advancing therapy for ETMR. Based on the review of retrospective series, the panel deemed that the following approaches to therapy should be adopted to improve outcomes: aggressive surgical resection with the goal of achieving a GTR during either initial or second-look surgery, judicious use of RT early in treatment for age-appropriate patients with no evidence of disease, and the use of HDCT/SCR for consolidation treatment. In light of the poor outcomes with conventional infant brain tumor regimens, the antitumor activity of doxorubicin, topotecan, and actinomycin D in preclinical models, and the positive outcomes of the children in this case series, the consensus was that a chemotherapy backbone containing preclinically active agents should be incorporated into the overall strategy for a prospective trial in ETMR.\n\nAn international consensus protocol has been developed incorporating maximal safe surgical resection, induction chemotherapy with active preclinical agents, intrathecal chemotherapy, RT, and HDCT/SCR. This protocol represents the first prospective clinical investigation specific to ETMR. In addition to the primary trial centers, the consensus protocol will be made available through a global treatment registry, providing access to the regimen for all patients. This study aims to improve survival by providing aggressive, optimized therapy for ETMR and will serve as a platform to procure tumor specimens for further preclinical endeavors and to explore new biologically promising agents. The investigation will also provide valuable prospective outcome data and correlative biological studies to serve as baseline comparators for future clinical trials.\n\nFunding\nThere is no funding for this study.\n\n\nConflict of interest statement. None of the authors have any conflicts of interest to disclose.\n\nAuthorship Statement.\nPrimary author: D.H. Secondary authors: L.M.H., S.N., and S.C. Manuscript editing: L.M.H., S.N., L.C.G., A.R., T.V., D.S.Z., and S.C. Series design: D.H., D.S.Z., and S.C. Care of patients: D.H., L.M.H., L.C.G., A.R., T.V., D.S.Z., and S.C. All authors have read and approved the manuscript.\n==== Refs\nReferences\n1. \nKorshunov A , Sturm D , Ryzhova M , et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity\n. Acta Neuropathol. 2014 ;128 (2 ):279 –289\n.24337497 \n2. \nHorwitz M , Dufour C , Leblond P , et al. Embryonal tumors with multilayered rosettes in children: the SFCE experience\n. Childs Nerv Syst. 2016 ;32 (2 ):299 –305\n.26438544 \n3. \nWang B , Gogia B , Fuller GN , Ketonen LM \nEmbryonal tumor with multilayered rosettes, C19MC-Altered: clinical, pathological, and neuroimaging findings\n. J Neuroimaging. 2018 ;28 (5 ):483 –489\n.29797626 \n4. \nLi M , Lee KF , Lu Y , et al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors\n. Cancer Cell. 2009 ;16 (6 ):533 –546\n.19962671 \n5. \nLouis DN , Perry A , Reifenberger G , et al. The 2016 World health organization classification of tumors of the central nervous system: a summary\n. Acta Neuropathol. 2016 ;131 (6 ):803 –820\n.27157931 \n6. \nSchmidt C , Schubert NA , Brabetz S , et al. Pre-clinical drug screen reveals topotecan, actinomycin D and volasertib as potential new therapeutic candidates for ETMR brain tumor patients\n. Neuro Oncol . 2017 ;19 (12 ):1607 –1617\n.28482026 \n7. \nChi SN , Zimmerman MA , Yao X , et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor\n. J Clin Oncol. 2009 ;27 (3 ):385 –389\n.19064966 \n8. \nBailey K , Pandit-Taskar N , Humm JL , et al. Targeted radioimmunotherapy for embryonal tumor with multilayered rosettes\n. J Neurooncol. 2019 ;143 (1 ):101 –106\n.30879172 \n9. \nJaramillo S , Grosshans DR , Philip N , et al. Radiation for ETMR: literature review and case series of patients treated with proton therapy\n. Clin Transl Radiat Oncol. 2019 ;15 :31 –37\n.30582019 \n10. \nGessi M , Giangaspero F , Lauriola L , et al. Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor\n. Am J Surg Pathol. 2009 ;33 (2 ):211 –217\n.18987548 \n11. \nKorshunov A , Remke M , Gessi M , et al. Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes\n. Acta Neuropathol. 2010 ;120 (2 ):253 –260\n.20407781 \n12. \nLambo S , Gröbner SN , Rausch T , et al. The molecular landscape of ETMR at diagnosis and relapse\n. Nature. 2019 ;576 (7786 ):274 –280\n.31802000 \n13. \nArvanitis CD , Ferraro GB , Jain RK \nThe blood-brain barrier and blood-tumour barrier in brain tumours and metastases\n. Nat Rev Cancer. 2020 ;20 (1 ):26 –41\n.31601988 \n14. \nMitchell D , Durston M , Nagulapally A , et al. Targeting LIN28 with DFMO in patients with ETMR suggests clinical benefit\n. Neuro-Oncol . 2019 ;21 (suppl. ):ii118 .\n15. \nSpence T , Perotti C , Sin-Chan P , et al. 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"fulltext_license": "CC BY",
"issn_linking": "2632-2498",
"issue": "2(1)",
"journal": "Neuro-oncology advances",
"keywords": "brain tumor; chemotherapy; embryonal tumor with multilayer rosettes; pediatric",
"medline_ta": "Neurooncol Adv",
"mesh_terms": null,
"nlm_unique_id": "101755003",
"other_id": null,
"pages": "vdaa120",
"pmc": null,
"pmid": "33196040",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "30582019;19064966;31802000;29797626;24337497;30879172;28482026;18987548;27157931;26438544;19962671;20407781;24311633;31601988",
"title": "A modified IRS-III chemotherapy regimen leads to prolonged survival in children with embryonal tumor with multilayer rosettes.",
"title_normalized": "a modified irs iii chemotherapy regimen leads to prolonged survival in children with embryonal tumor with multilayer rosettes"
} | [
{
"companynumb": "US-ALVOGEN-2020-ALVOGEN-115351",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "A 77-year-old man presented with a chronic lesion located in the left penoscrotal area. Apart from pruritus, bleeding and an occasional discharge from this area, he also reported reduced appetite and weight loss. Examination revealed an ulcerated skin lesion attached to a firm subcutaneous mass. Wide local excision of the lesion revealed invasive adenocarcinoma on a background of extramammary Paget's disease. Staging studies showed disseminated metastatic disease within the lymph nodes, and liver and bone metastases. He was treated with carboplatin and paclitaxel chemotherapy initially, but then continued only on Carboplatin chemotherapy due to side effects from Paclitaxel. Eleven weeks after the start of his chemotherapy, his restaging imaging showed reduced lymphadenopathy, unchanged liver metastasis and sclerosis of bone metastasis. With completion of chemotherapy, repeat imaging showed stable disease. The patient is currently on follow-up.",
"affiliations": "Department of Urology, University College London Hospital, London, UK.;Department of Histopathology, University College London Hospital, London, UK.;Department of Oncology, University College London Hospital, London, UK.;Department of Urology, University College London Hospital, London, UK.",
"authors": "Christodoulidou|Michelle|M|;Khetrapal|Pramit|P|;Mitra|Anita|A|;Muneer|Asif|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D001859:Bone Neoplasms; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D005834:Genital Neoplasms, Male; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010145:Paget Disease, Extramammary; D035583:Rare Diseases",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26424821",
"pubdate": "2015-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25089091;17447970;23904770;19837650;14692806;19126202;22135629;15801657;19862365",
"title": "A case of metastatic adenocarcinoma on a background of penoscrotal extramammary Paget's disease.",
"title_normalized": "a case of metastatic adenocarcinoma on a background of penoscrotal extramammary paget s disease"
} | [
{
"companynumb": "GB-CORDEN PHARMA LATINA S.P.A.-GB-2015COR000444",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS"
... |
{
"abstract": "CytoSorb® hemadsorption is an adjunctive therapy in order to reduce elevated cytokine levels of interleukin-6, interleukin-1, and tumor necrosis factor alpha. Here we present a successful administration of CytoSorb® hemadsorption in an immunocompromised pediatric patient with collapsing glomerulopathy, acute respiratory distress syndrome, and sepsis.\nClinical observations of one patient.\nCase report.\nData sources are clinical observation during patient management and patient's medical records if needed. The patient's consent was obtained prior to the study.\nA 17-year-old male with diarrhea was admitted to the hospital and was later found to have elevated creatinine levels and proteinuria. The renal biopsy was consistent with collapsing glomerulopathy and treatment with multi immunosuppressive agents including corticosteroids, mycophenolate mofetil, and rituximab coupled with several courses of hemodialysis and plasmapheresis were administered. During the hospital stay, Stenotrophomonas maltophilia bacteremia from the blood and the catheter cultures were identified. No clinical response was achieved, and patient developed severe sepsis despite antibiotics, intravenous immunoglobulin, and supportive management including albumin, platelet and erythrocyte concentrations, and fresh frozen plasma. CytoSorb® hemadsorption was then added to the ongoing treatment for three consecutive days. Subsequent to CytoSorb® hemadsorption, immediate laboratory and clinical response were observed.\nThis is the successful clinical report of an immunocompromised teenager with collapsing nephropathy, sepsis, and multi-organ dysfunction syndrome treated with a combination of renal replacement therapy and CytoSorb® hemadsorption. The usage of CytoSorb® hemadsorption represents a novel approach to improve survival of the patients with multiple organ dysfunction and sepsis.",
"affiliations": "Department of Pediatrics, Gazi University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Hematology, Gazi University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Critical Care, Gazi University Faculty of Medicine, Ankara, Turkey.",
"authors": "Keles|Elif|E|;Fidan|Kibriya|K|;Yenicesu|Idil|I|;Kalkan|Gokhan|G|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1177/0391398819858174",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-3988",
"issue": "42(12)",
"journal": "The International journal of artificial organs",
"keywords": "Cytosorb hemadsorption; collapsing glomerulopathy; immunocompromised; sepsis; therapeutic apheresis",
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D016905:Gram-Negative Bacterial Infections; D006464:Hemoperfusion; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008297:Male; D009102:Multiple Organ Failure; D006435:Renal Dialysis; D051437:Renal Insufficiency; D018805:Sepsis; D020615:Stenotrophomonas maltophilia; D016896:Treatment Outcome",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "765-769",
"pmc": null,
"pmid": "31277560",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful application of CytoSorb® hemadsorption in an immunocompromised teenager with collapsing glomerulopathy, acute respiratory distress syndrome, and sepsis.",
"title_normalized": "successful application of cytosorb hemadsorption in an immunocompromised teenager with collapsing glomerulopathy acute respiratory distress syndrome and sepsis"
} | [
{
"companynumb": "TR-ACCORD-138515",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nThere is no consensus regarding treatment for drug reaction with eosinophilia and systemic symptoms (DRESS).\n\n\nOBJECTIVE\nWe report a single-center observational series of therapeutic management of DRESS.\n\n\nMETHODS\nWe examined data for 50 consecutive patients admitted from March 2005 to June 2009 with a discharge diagnosis of DRESS (RegiSCAR score).\n\n\nRESULTS\nFor the 38 patients with a DRESS score of 4 or more, topical steroid treatment alone was initiated in 66% of cases. On admission, 13 patients received systemic steroids; in 7 of them, systemic steroid treatment was initiated or maintained for life-threatening organ failure, with kidney, lung, and/or nervous system involvement. Complications of DRESS, such as relapse, viral reactivation, and sepsis, were less frequent with topical steroid than with systemic steroids. None of the patients died during their stay in hospital.\n\n\nCONCLUSIONS\nRetrospective nonblinded design and dermatologic recruitment are limitations. The variables underlying the choice of treatment study were not analyzed.\n\n\nCONCLUSIONS\nSystemic steroids may not be required for the management of mild forms of DRESS, and may thus be reserved for more severe cases. Prospective studies are required to evaluate strategies for treating DRESS.",
"affiliations": "Dermatology Department, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France; Referral Center for Toxic and Autoimmune Diseases, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France.;Dermatology Department, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France; Referral Center for Toxic and Autoimmune Diseases, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France.;Dermatology Department, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France.;Department of Dermatology, Hôpital Saint Louis, Assistance Publique-Hõpitaux de Paris (AP-HP), Université Paris VII, Sorbonne Paris Cité, Paris, France.;Dermatology Department, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France; Referral Center for Toxic and Autoimmune Diseases, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France.;Dermatology Department, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France; Referral Center for Toxic and Autoimmune Diseases, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France.;Dermatology Department, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France; Referral Center for Toxic and Autoimmune Diseases, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France.;Dermatology Department, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France; Referral Center for Toxic and Autoimmune Diseases, Assistance Publique-Hõpitaux de Paris (AP-HP), Hôpital Henri-Mondor, Université Paris Est Créteil (UPEC), Créteil, France. Electronic address: laurence.allanore@hmn.aphp.fr.",
"authors": "Funck-Brentano|Elisa|E|;Duong|Tu-Anh|TA|;Bouvresse|Sophie|S|;Bagot|Martine|M|;Wolkenstein|Pierre|P|;Roujeau|Jean-Claude|JC|;Chosidow|Olivier|O|;Valeyrie-Allanore|Laurence|L|",
"chemical_list": "D013256:Steroids",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "72(2)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "drug reaction with eosinophilia and systemic symptoms; drug-induced hypersensitivity syndrome; severe cutaneous adverse reactions; systemic corticosteroids treatment; therapeutic management; topical steroids",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000287:Administration, Topical; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013256:Steroids; D055815:Young Adult",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "246-52",
"pmc": null,
"pmid": "25592341",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Therapeutic management of DRESS: a retrospective study of 38 cases.",
"title_normalized": "therapeutic management of dress a retrospective study of 38 cases"
} | [
{
"companynumb": "FR-PFIZER INC-2015085353",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN"
},
"drugadditional": null,
... |
{
"abstract": "Due to advances in obstetric and transplant medicine, women with a history of liver transplantation can have successful pregnancies. However, data on pregnancy outcomes is still limited, especially for women who have had a repeat liver transplant following graft rejection. This retrospective study compares pregnancy outcomes in women with single and repeat liver transplants managed at 2 tertiary hospitals in Toronto, Canada and Leuven, Belgium. We identified 41 pregnancies in 28 transplanted women, 6 of whom conceived following a second liver transplant after the first was rejected. Mean maternal age at delivery was 30 ± 7 years, and transplant-to-pregnancy interval was 8.5 ± 5.1 years. All women had normal liver function upon conception. Immunosuppressants included tacrolimus ± azathioprine (n = 26), cyclosporine (n = 4), and prednisone with immunosuppressants (n = 11). There were no maternal deaths. Maternal complications included hypertensive disorders of pregnancy (n = 10), deterioration in renal function (n = 6), gestational diabetes (n = 4), graft deterioration (n = 2), and anemia requiring blood transfusion (n = 1). Fetal/neonatal adverse outcomes included 2 miscarriages, 3 stillbirths, 1 neonatal death, 5 small-for-gestational-age infants, and 1 minor congenital anomaly. Mean gestational age at delivery was 36.7 ± 4.2 weeks. There were 14 (38.9%) preterm births. Outcomes in women with a second transplant were similar to those with a single transplant, except for a higher incidence of hypertensive disorders. In conclusion, with appropriate multidisciplinary care, stable graft function at pregnancy onset, and adherence to immunosuppressive regimens, women with single and repeat liver transplants have low rates of graft complications but remain at increased risk for pregnancy complications. Immunosuppressants and high-dose glucocorticoids can be safely used for maintenance of graft function and management of graft deterioration in pregnancy. Liver Transplantation 24 769-778 2018 AASLD.",
"affiliations": "Division of Maternal and Fetal Medicine, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, University of Toronto, Canada.;Department of Obstetrics and Gynecology, University Hospital Leuven, Leuven, Belgium.;Division of Obstetric Medicine, Department of Internal Medicine, Mount Sinai Hospital, University of Toronto, Canada.;Division of Maternal and Fetal Medicine, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, University of Toronto, Canada.;Division of Maternal and Fetal Medicine, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, University of Toronto, Canada.;Division of Maternal and Fetal Medicine, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, University of Toronto, Canada.",
"authors": "Zaffar|Nusrat|N|;Soete|Elisabeth|E|;Gandhi|Shital|S|;Sayyar|Parastoo|P|;Van Mieghem|Tim|T|;D'Souza|Rohan|R|0000-0002-4049-2017",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.25071",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "24(6)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000328:Adult; D001530:Belgium; D002170:Canada; D058625:End Stage Liver Disease; D005260:Female; D005865:Gestational Age; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D016031:Liver Transplantation; D008423:Maternal Age; D055118:Medication Adherence; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012086:Reoperation; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "769-778",
"pmc": null,
"pmid": "29655314",
"pubdate": "2018-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Pregnancy outcomes following single and repeat liver transplantation: An international 2-center cohort.",
"title_normalized": "pregnancy outcomes following single and repeat liver transplantation an international 2 center cohort"
} | [
{
"companynumb": "CA-MYLANLABS-2018M1049389",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "1",
... |
{
"abstract": "We present a case of severe diuretic resistance and edema from acute cardiorenal syndrome complicating heart failure with preserved ejection fraction (HFpEF) and mild alcoholic liver disease. High doses of intravenous (iv) furosemide plus iv doses of chlorothiazide failed to increase the daily urine output (UV) above 1,500 mL or the fractional excretion of sodium (FENa) above 2%. The addition of a relatively low dose of hydralazine (10 mg thrice daily PO) during 5 days of constant iv infusion of furosemide plus iv bolus chlorothiazide doubled the UV and FENa while reducing the serum creatinine concentration from 3.3 to 2.0 mg/dL. Hydralazine may have restored a response to the diuretics by increasing the renal blood flow and thereby the renal diuretic delivery, or by reducing the filtration fraction or reducing the renal congestion and thereby reducing the proximal reabsorption during blockade of distal reabsorption with diuretics. Further mechanistic studies of low-dose hydralazine for diuretic resistance are warranted.",
"affiliations": "Division of Nephrology and Hypertension Center, Georgetown University, Washington, District of Columbia, USA.;Division of Nephrology and Hypertension Center, Georgetown University, Washington, District of Columbia, USA.",
"authors": "Alshehri|Mohammed|M|;Wilcox|Christopher|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000515387",
"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\n10.1159/000515387\ncnd-0011-0254\nCase and Review\nDiuretic Resistance Treated with Low-Dose Hydralazine: A Case Report and Review of the Literature\nAlshehri Mohammed a b *\nWilcox Christopher a\naDivision of Nephrology and Hypertension Center, Georgetown University, Washington, District of Columbia, USA\nbDivision of Nephrology and Hypertension, Georgetown University, Washington, District of Columbia, USA\n*Mohammed Alshehri, mohd.shehri@gmail.com\nMay-Aug 2021\n12 8 2021\n12 8 2021\n11 2 254260\n7 12 2020\n23 2 2021\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.\nWe present a case of severe diuretic resistance and edema from acute cardiorenal syndrome complicating heart failure with preserved ejection fraction (HFpEF) and mild alcoholic liver disease. High doses of intravenous (iv) furosemide plus iv doses of chlorothiazide failed to increase the daily urine output (UV) above 1,500 mL or the fractional excretion of sodium (FE<sub>Na</sub>) above 2%. The addition of a relatively low dose of hydralazine (10 mg thrice daily PO) during 5 days of constant iv infusion of furosemide plus iv bolus chlorothiazide doubled the UV and FE<sub>Na</sub> while reducing the serum creatinine concentration from 3.3 to 2.0 mg/dL. Hydralazine may have restored a response to the diuretics by increasing the renal blood flow and thereby the renal diuretic delivery, or by reducing the filtration fraction or reducing the renal congestion and thereby reducing the proximal reabsorption during blockade of distal reabsorption with diuretics. Further mechanistic studies of low-dose hydralazine for diuretic resistance are warranted.\n\nKeywords\n\nFurosemide\nChlorothiazide\nHeart failure with preserved ejection fraction\nCardiorenal syndrome\n==== Body\npmcIntroduction\n\nDiuretic resistance is a failure to clear congestion or edema despite a full diuretic dosage. It is associated with worse short- and long-term outcomes [1]. Here, we present a case of diuretic-resistant volume overload where the addition of a low dose of hydralazine restored the responsiveness to diuretics and relieved the congestion. We discuss a potential role of low-dose hydralazine in diuretic-resistant heart failure, review the literature, and propose physiological mechanisms.\n\nCase Report\n\nThe patient was a 52-year-old female with a past medical history of hypertension, obesity, heart failure with preserved ejection fraction (HFpEF), and mild alcoholic liver disease. She was admitted to the hospital with a 3-day history of altered mental status. She was afebrile. Her BP was 109/59 mm Hg, O2 saturation 98% on room air, and weight 134 kg. Her serum creatinine concentration (Scr) had increased from 0.8 to 3.6 mg/dL over 1 month, and she had gained 30 kg of weight over 5 months. Other investigations included BUN 41 mg/dL, serum sodium 131 mmol/L, and serum potassium 6.7 mmol/L. Hyperkalemia was treated successfully with iv furosemide plus insulin with glucose. She was managed initially for presumed hepatorenal syndrome (HRS) with infusions of human salt-poor albumin, midodrine, and octreotide but had no significant improvement. The nephrology team was consulted on the third hospital day.\n\nPhysical examination revealed jugular venous distention of >5–8 cm H2O, decreased breath sounds at the lung bases, and 2+ pitting edema of the lower extremities up to the lower abdomen. Laboratory values included a hemoglobin of 8.7 g/dL, platelet count of 109,000/µL, serum sodium 140 mmol/L, serum potassium 3.8 mmol/L, serum chloride 106 mmol/L, serum total CO2 23 mmol/L, BUN 47 mg/dL, Scr 3.47 mg/dL, and proBNP 1,170 pg/mL with normal values for blood glucose, calcium, and liver enzymes but a reduced plasma albumin of 2.5 g/dL. Urinalysis revealed a specific gravity of 1.017 without proteinuria or casts. Urine sodium and chloride concentrations were <10 mmol/L, and fractional excretion of Na+ (FENa) was 0.1%. The preserved renal concentrating ability, low FENa, and absence of proteinuria or casts suggested a hemodynamic basis for her increase in Scr.\n\nA chest X-ray revealed signs of pulmonary edema. An echocardiogram from 2 weeks prior revealed a preserved ejection fraction of 60–65% but diastolic dysfunction. Abdominal sonography was negative for ascites.\n\nThe patient was diagnosed with an exacerbation of HFpEF. Acute tubular necrosis was considered unlikely because of the absence of a specific cause for acute tubular necrosis, the urine studies, and the significant volume overload. HRS also was considered unlikely because of the lack of ascites, the failure to respond to the specific HRS therapy, and the high level of proBNP that favored the primary diagnosis of HF. Therefore, diuretic therapy was intensified to furosemide 80 mg plus chlorothiazide 250 mg, both given iv twice daily. Her urine output (UV) increased modestly from 350 to 550 mL, and diuretics were escalated to a continuous iv infusion of furosemide (20 mg/h) plus iv bolus doses of chlorothiazide (500 mg twice daily), but this failed to increase UV above 1,500 mL or FENa above 2% and did not improve her symptoms or change her Scr (shown in Fig. 1). During stable diuretic therapy on hospital day 6, hydralazine (10 mg thrice daily PO) was added. Within 24 h, her Scr began to decrease to a nadir after 5 days of 1.98 mg/dL, and her UV and FENa doubled. Her clinical state improved sufficiently on day 11 to begin an oral regimen of furosemide (80 mg twice daily) plus spironolactone (200 mg daily) and hydralazine (20 mg three times daily). Over the hospital course of 19 days, the patient lost 23 kg in weight, and her Scr improved to 1.3 mg/dL. At follow-up after 3 months while she was prescribed furosemide 80 mg twice daily plus spironolactone 200 mg daily, her symptoms remained well controlled, her weight was reduced by a further 10 kg, and her Scr was at baseline at 0.9 mg/dL. Her SBP remained stable at 110–120 mm Hg.\n\nDiscussion\n\nThe renal blood flow (RBF) and the glomerular filtration rate (GFR) are reduced in many patients with congestive heart failure (CHF) and may contribute to diuretic resistance [1]. Hydralazine leads to prostaglandin-dependent renal vasodilation [2]. There are several studies of the efficacy of hydralazine in improving renal hemodynamics, UV, or sodium excretion (UNaV) that are summarized in Table 1. When measured, hydralazine has increased the RBF more than the GFR and thereby has reduced the filtration fraction (FF). It also has increased the cardiac output (CO). The increase in the RBF is likely a consequence of renal vasodilation [3], increased CO, and decreased systemic vascular resistance. Providing that any reductions in BP are not severe, hydralazine generally has increased the UV and the UNaV.\n\nOur patient had an increase in FENa and diuresis with hydralazine during blockade of Na+ reabsorption in the loop of Henle and the distal tubule. This indicates that hydralazine was principally reducing reabsorption in the proximal tubule (PT). Although the reduction in Scr and the increase in the GFR with hydralazine might have contributed to Na+ losses, the doubling of FENa indicates that it had reduced tubular Na+ reabsorption.\n\nWe considered 3 mechanisms to account for the increased UV and UNaV (Fig. 2). First, an increase in RBF will increase the delivery of the diuretic to the renal tubules [4, 5]. Since diuretics bind to albumin and it is required for diuretic delivery to the renal tubules, the hypoalbuminemia in our patient may have contributed to the diuretic resistance [1]. Indeed, hydralazine increases the renal clearance of furosemide [6]. However, this seems an inadequate explanation since both diuretics were being given iv at doses that are generally considered to be supramaximal [1], and an increase in diuretic dose on day 4 increased UV only marginally (Fig. 1).\n\nSecond, PT reabsorption is dependent on the oncotic pressure in the peritubular capillaries [7] that itself is dependent on the degree to which plasma water is filtered at the glomerulus that is quantitated by the FF. Hemodynamic studies with hydralazine report a consistently greater rise in RBF than in GFR, with a consequent fall in the FF [5, 8, 9, 10, 11, 12, 13] (Table 1).\n\nThird, since an increase in CO with hydralazine (Table 1) reduces preload, hydralazine should reduce renal venous pressure and renal congestion. Increased renal turgor in patients with CHF can contribute to increased PT reabsorption [14, 15, 16] and reduced RBF and GFR [17, 18].\n\nThus, hydralazine may have reduced the FF and the renal congestion and thereby reduced the PT reabsorption. Angiotensin-converting enzyme inhibitors have generally similar hemodynamic effects of increased RBF and reduced FF [19] that will increase the delivery of filtrate to the loop of Henle and distal nephron and thereby enhance diuretic responsiveness. However, many physicians are reluctant to use angiotensin-converting enzyme inhibitors in patients with an acute increase in Scr, as in this patient, but might select a renal vasodilatory drug such as hydralazine.\n\nHydralazine therapy requires care. Its variable and short half-life mandates 3 times daily dosing. Accurate therapy requires genotyping for N-acetyltransferase 2 status to determine whether the patient is a slow or fast acetylator [20]. Moreover, renin increases dose dependently with hydralazine [21]. Careful monitoring of the MAP and heart rate is required, since the desired effects can be compromised by sympathetic system overactivity and activation of the renin-angiotensin-aldosterone system.\n\nThe MAP should not be reduced by >25% in patients with CHF since this prevents the diuretic response [22]. Moreover, patients with HFpEF can be sensitive to blood volume depletion that requires careful use of diuretics [23]. However, the contribution of reduction in before and after load with hydralazine in patients with HFpEF should be preferable to escalating diuretic therapy since that may increase after load and thereby increase the cardiac oxygen usage [24, 25].\n\nAlthough the use of vasodilator therapy to relieve systemic congestion has been reported previously, this approach has not been widely applied given the lack of a clear physiological explanation [26]. This case illustrates the potential of low-dose hydralazine to reduce reabsorption of Na+ in the PT and to relieve diuretic resistance. It suggests the need for further studies to establish the mechanisms involved and the general utility.\n\nStatement of Ethics\n\nThe authors have complied with ethical standards for this case report involving a human participant. Written informed consent for publication of this case report was obtained from the patient.\n\nConflict of Interest Statement\n\nThe authors have no relevant financial or nonfinancial interests to disclose.\n\nFunding Sources\n\nNo funds, grants, or other support was received.\n\nAuthor Contributions\n\nM.A. was responsible for the patient care and wrote the initial draft. C.W. revised manuscript including the data, literature review, and results.\n\nFig. 1 Diuretic and natriuretic responses to hydralazine in a patient with resistance to a loop diuretic + a thiazide. Day 1 is the first day of nephrology consult. FENA, fractional excretion of sodium; Scr, serum creatinine; MAP, mean arterial pressure; bid, twice daily; tid, thrice daily.\n\nFig. 2 Proposed mechanisms for the enhanced diuresis with hydralazine. RBF, renal blood flow; FF, filtration fraction; GFR, glomerular filtration rate.\n\nTable 1 Summary of published clinical reports of the response to hydralazine in human subjects\n\nAuthor (ref)\tN\tDiagnosis\tHydralazine dose, mg, and route\tΔ MAP, %\tΔ UV, %\tΔ UNa V,%\tΔ GFR, %\tΔ RBF, %\tΔ FF, %\tΔ CO, %\t\nReubi [9]\t12\t7 HTN\n2 GN\n4 NL\t8–20, sc\t−19\tIncreased markedly\tna\tns\t+39\t−22\tna\t\nWilkinson et al. [27]\t12\tHealthy, HTN, CP, rheumatic heart disease\t0.25–0.5 mg/kg iv\t−30\tDiuretic action was frequent but inconstant\tna\tNot consistent\t+38*\t−23\t+110\t\nFreis et al. [28]\t6\tHTN\t0.25 mg/kg iv\t−28\tna\tna\tna\tna\t\t+128\t\nVanderkolk et al. [10]\t7\tHTN\t75 mg orally\t−22*\tna\tna\tns\t+36*\t−22*\tna\t\nGjorup and Hilden [5]\t6\tHTN\t0.1–0.3 mg/kg iv\t−14\t+9\t+15\t+6\tna\t−24\tna\t\nHollander et al. [8]\t18\tHTN, CHF, CP\t14–50 mg iv\t−17\t+36\t+400\t+11\t+36\tReduced\t+37\t\nCogan et al. [12]\t9\tCHF (III-IV)\t10–60 mg iv (5 mg every 20 min]\t−11*\t+26\t+161\t+13\t+127*\t−46*\t+70*\t\nElkayam et al. [13]\t9\tCHF\t2.5 mg iv every 20 min until SVR decreased by 25% (mean 10 ± 5 mg]\t−5*\tna\tna\t+3\t+13*\t−5\t+39*\t\nN, number reported; NL, normal; FF, filtration fraction; ?, mean changes from before; sc, subcutaneous; CO, cardiac output; a, receiving maintenance diuretics; iv, intravenous; na, not available; HTN, hypertension; MAP, mean arterial pressure; GN, glomerulonephritis; UV, urine output; CHF, congestive heart failure; GFR, glomerular filtration rate; CP, cor pulmonale; RBF, renal blood flow.\n\n* Statistically significant change.\n==== Refs\nReferences\n\n1 Wilcox CS Testani JM Pitt B Pathophysiology of diuretic resistance and its implications for the management of chronic heart failure Hypertension 2020 76 (4) 1045 54 32829662\n2 Rubin LJ Lazar JD Influence of prostaglandin synthesis inhibitors on pulmonary vasodilatory effects of hydralazine in dogs with hypoxic pulmonary vasoconstriction J Clin Invest 1981 67 (1) 193 200 7451649\n3 Chelly JE Doursout MF Begaud B Tsao CC Hartley CJ Effects of hydralazine on regional blood flow in conscious dogs J Pharmacol Exp Ther 1986 238 (2) 665 9 3735136\n4 Testani JM Brisco MA Turner JM Spatz ES Bellumkonda L Parikh CR Loop diuretic efficiency: a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure Circ Heart Fail 2014 7 (2) 261 70 24379278\n5 Gjorup S Hilden T The effect of hydralazine (apresolin) on kidney function and sodium excretion Scand J Clin Lab Invest 1956 8 (4) 273 7 13390827\n6 Nomura A Yasuda H Katoh K Akimoto T Miyazaki K Arita T Hydralazine and furosemide kinetics Clin Pharmacol Ther 1982 32 (3) 303 6 7105621\n7 Brenner BM Troy JL Postglomerular vascular protein concentration: evidence for a causal role in governing fluid reabsorption and glomerulotublar balance by the renal proximal tubule J Clin Invest 1971 50 (2) 336 49 5540173\n8 Hollander W Judson WE Wilkins RW The effects of intravenous apresoline (hydralazine) on cardiovascular and renal function in patients with and without congestive heart failure Circulation 1956 13 (5) 664 74 13356423\n9 Reubi FC Renal hyperemia induced in man by a new phthalazine derivative Proc Soc Exp Biol Med 1950 73 (1) 102 15402536\n10 Vanderkolk K Dontas AS Hoobler SW Renal and hypotensive effects of acute and chronic oral treatment with 1-hydrazinophthalazine (apresoline) in hypertension Am Heart J 1954 48 (1) 95 101 13171330\n11 Moyer JH Hydrallazine (apresoline) hydrochloride; pharmacological observations and clinical results in the therapy of hypertension AMA Arch Intern Med 1953 91 (4) 419 39 13039601\n12 Cogan JJ Humphreys MH Carlson CJ Rapaport E Renal effects of nitroprusside and hydralazine in patients with congestive heart failure Circulation 1980 61 (2) 316 23 7351056\n13 Elkayam U Weber L Campese VM Massry SG Rahimtoola SH Renal hemodynamic effects of vasodilation with nifedipine and hydralazine in patients with heart failure J Am Coll Cardiol 1984 4 (6) 1261 7 6501724\n14 Bank N Yarger WE Aynedjian HS A microperfusion study of sucrose movement across the rat proximal tubule during renal vein constriction J Clin Invest 1971 50 (2) 294 302 5540167\n15 Carlstrom M Wilcox CS Arendshorst WJ Renal autoregulation in health and disease Physiol Rev 2015 95 (2) 405 511 25834230\n16 Kaloyanides GJ Cacciaguida RJ Pablo NC Porush JG Increased sodium reabsorption in the proximal and distal tubule of caval dogs J Clin Invest 1969 48 (8) 1543 51 5796363\n17 Araujo M Solis G Welch WJ Wilcox CS Renal nerve deafferentation attenuates the fall in GFR during intravenous infusion of furosemide in anesthetized rats Kidney Blood Press Res 2020 45 (1) 70 83 31896111\n18 Mullens W Abrahams Z Francis GS Sokos G Taylor DO Starling RC Importance of venous congestion for worsening of renal function in advanced decompensated heart failure J Am Coll Cardiol 2009 53 (7) 589 96 19215833\n19 Creager M Halperin J Bernard D Faxon D Melidossian C Gavras H Acute regional circulatory and renal hemodynamic effects of converting-enzyme inhibition in patients with congestive heart failure Circulation 1981 64 (3) 483 9 6266691\n20 Collins KS Raviele AL Elchynski AL Woodcock AM Zhao Y Cooper-DeHoff RM Genotype-guided hydralazine therapy Am J Nephrol 2020 51 764 76 32927458\n21 Pettinger WA Campbell WB Keeton K Adrenergic component of renin release induced by vasodilating antihypertensive drugs in the rat Circ Res 1973 33 (1) 82 6 4765702\n22 Kitai T Tang WHW Xanthopoulos A Murai R Yamane T Kim K Impact of early treatment with intravenous vasodilators and blood pressure reduction in acute heart failure Open Heart 2018 5 (2) e000845 30018782\n23 Mullens W Damman K Harjola VP Mebazaa A Brunner‐La Rocca HP Martens P The use of diuretics in heart failure with congestion: a position statement from the Heart Failure Association of the European Society of Cardiology Eur J Heart Fail 2019 21 (2) 137 55 30600580\n24 Palazzuoli A Ruocco G Ronco C McCullough PA Loop diuretics in acute heart failure: beyond the decongestive relief for the kidney Crit Care 2015 19 (1) 296 26335137\n25 Pfeffer MA Shah AM Borlaug BA Heart failure with preserved ejection fraction in perspective Circ Res 2019 124 (11) 1598 617 31120821\n26 Cohn JN Mathew KJ Franciosa JA Snow JA Chronic vasodilator therapy in the management of cardiogenic shock and intractable left ventricular failure Ann Intern Med 1974 81 (6) 777 80 4433083\n27 Wilkinson EL Backman H Hecht HH Cardiovascular and renal adjustments to a hypotensive agent (l'hydrazinophthalazine: Ciba BA-5968: apresoline) J Clin Invest 1952 31 (10) 872 9 12990658\n28 Freis ED Rose JC Higgins TF Finnerty FA Jr Kelley RT Partenope EA The hemodynamic effects of hypotensive drugs in man. IV. 1-hydrazinophthalazine Circulation 1953 8 (2) 199 204 13067200\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "11(2)",
"journal": "Case reports in nephrology and dialysis",
"keywords": "Cardiorenal syndrome; Chlorothiazide; Furosemide; Heart failure with preserved ejection fraction",
"medline_ta": "Case Rep Nephrol Dial",
"mesh_terms": null,
"nlm_unique_id": "101636294",
"other_id": null,
"pages": "254-260",
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"pmid": "34595213",
"pubdate": "2021",
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"title": "Diuretic Resistance Treated with Low-Dose Hydralazine: A Case Report and Review of the Literature.",
"title_normalized": "diuretic resistance treated with low dose hydralazine a case report and review of the literature"
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"abstract": "To investigate the association between psychotropic agents (including antipsychotics, antidepressants and mood stabilizers) and risk of stroke among patients with bipolar disorders.\n\n\n\nWe conducted a disease risk score-matched nested case-control study and identified patients with bipolar disorders (ICD-9 codes: 296.0x, 296.1x, 296.4x, 296.5x, 296.6x, 296.7x, 296.80, 296.81 or 296.89) from the National Health Insurance Research Database in Taiwan. Among them, we identified 1232 cases (981 were ischemic stroke and 251 were hemorrhagic stroke) and 5314 disease risk score-matched controls. Conditional logistic regression model equations were applied to determine the effect of psychotropic agents on stroke risk among patients with bipolar disorders.\n\n\n\nThe results indicated that overall use of psychotropic agents was associated with an increased risk of stroke (adjusted odds ratio [AOR] = 1.82; 95% confidence interval [CI]: 1.56-2.13). When classifying psychotropic agents into antipsychotics, antidepressants and mood stabilizers, respectively, a significant positive association was found for users of antipsychotics (AOR = 1.98; 95% CI = 1.53-2.56), antidepressants (AOR = 1.44; 95% CI = 1.16-1.79), and mood stabilizers (AOR = 1.89; 95% CI = 1.22-2.93). Combined use of psychotropic agents was associated with higher risk of stroke than monotherapy (AOR = 2.62; 95% CI = 1.98-3.45).\n\n\n\nThe results support our hypothesis that psychotropic use is associated with increased risk of stroke among patients with bipolar disorders. The stroke risks are higher among patients with polypharmacy than those with monotherapy. These findings warrant further investigation to confirm and replicate the findings using different methodologies and populations, and to mitigate residual confounding.",
"affiliations": "Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan; Department of Psychiatry, Far Eastern Memorial Hospital, New Taipei City, Taiwan.;Department of Psychiatry, Chang Gung Memorial Hospital, Lin-Kou & Chang Gung University, Lin-Kou, Taiwan.;Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.;Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.;Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.;Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.;Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: tsaihj@nhri.org.tw.",
"authors": "Wu|Chi-Shin|CS|;Wu|Kuan-Yi|KY|;Lo|Yu-Ru|YR|;Huang|Ya-Wen|YW|;Tsai|Yu-Ting|YT|;Li|Yashiun|Y|;Tsai|Hui-Ju|HJ|",
"chemical_list": "D000927:Anticonvulsants; D000928:Antidepressive Agents; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D011619:Psychotropic Drugs",
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"issue": "226()",
"journal": "Journal of affective disorders",
"keywords": "Antidepressants; Antipsychotics; Bipolar disorders; Mood stabilizers; Stroke",
"medline_ta": "J Affect Disord",
"mesh_terms": "D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D000928:Antidepressive Agents; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D002545:Brain Ischemia; D016022:Case-Control Studies; D016208:Databases, Factual; D005260:Female; D006801:Humans; D038801:International Classification of Diseases; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011619:Psychotropic Drugs; D012107:Research Design; D020521:Stroke; D013624:Taiwan",
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"pages": "77-84",
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"pubdate": "2018-01-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Psychotropic use and risk of stroke among patients with bipolar disorders: 10-year nationwide population based study.",
"title_normalized": "psychotropic use and risk of stroke among patients with bipolar disorders 10 year nationwide population based study"
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"abstract": "BACKGROUND\nIsolated acute foot drop due to traumatic brain injury is exceedingly rare and is often misdiagnosed during initial evaluation. Here, we present the case of a patient who presented with left foot drop after falling off a bicycle.\n\n\nMETHODS\nThe patient is a 55-year-old male who was mountain biking when he fell, hit his head, and lost consciousness. Neurologic examination of the left leg revealed foot drop, no sensory deficits, and 3+ reflexes at the knee and ankle with clonus. Electroencephalography, computed tomography (CT) of the head, magnetic resonance imaging (MRI) of the lumbar spine, and CT of the lower extremities were all negative. Only MRI of the brain with a gradient echo sequence revealed microhemorrhages focused around the right precentral gyrus. The patient underwent physical therapy, and by 3 months had regained full strength in his left leg.\n\n\nCONCLUSIONS\nCentral causes of foot drop are exceptionally rare, however, they should be considered in all cases of post-traumatic dorsiflexion paresis. The key to the accurate diagnosis is a high index of suspicion as well as thorough and careful physical examination including reflex and sensory testing. Selective imaging modalities such as MRI or CT can then be used to verify the diagnosis.",
"affiliations": "Department of Neurosurgery, University of California-Los Angeles, Los Angeles, California, USA.;Department of Neurosurgery, University of California-Los Angeles, Los Angeles, California, USA.;Department of Neurosurgery, University of California-Los Angeles, Los Angeles, California, USA.;Department of Neurosurgery, University of California-Los Angeles, Los Angeles, California, USA.;Department of Neurosurgery, University of California-Los Angeles, Los Angeles, California, USA.;Department of Neurosurgery, University of California-Los Angeles, Los Angeles, California, USA.",
"authors": "Tucker|Alexander M|AM|;Niu|Tianyi|T|;Nagasawa|Daniel T|DT|;Everson|Richard|R|;Sedighim|Shaina|S|;Buitrago Blanco|Manuel M|MM|",
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"doi": "10.4103/2152-7806.193727",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-7-75610.4103/2152-7806.193727Case ReportCT-negative, MRI GRE-positive primary motor cortex contusion causing isolated foot drop Tucker Alexander M. ATucker@mednet.ucla.edu*Niu Tianyi TNiu@mednet.ucla.eduNagasawa Daniel T. DNagasawa@mednet.ucla.eduEverson Richard REverson@mednet.ucla.eduSedighim Shaina ssedighim@gmail.comBuitrago Blanco Manuel M. mblanco@mednet.ucla.eduDepartment of Neurosurgery, University of California-Los Angeles, Los Angeles, California, USA* \nCorresponding author\n2016 09 11 2016 7 Suppl 28 SNI: Trauma, a supplement to Surgical Neurology InternationalS756 S758 09 6 2016 24 6 2016 Copyright: © 2016 Surgical Neurology International2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nIsolated acute foot drop due to traumatic brain injury is exceedingly rare and is often misdiagnosed during initial evaluation. Here, we present the case of a patient who presented with left foot drop after falling off a bicycle.\n\nCase Description:\nThe patient is a 55-year-old male who was mountain biking when he fell, hit his head, and lost consciousness. Neurologic examination of the left leg revealed foot drop, no sensory deficits, and 3+ reflexes at the knee and ankle with clonus. Electroencephalography, computed tomography (CT) of the head, magnetic resonance imaging (MRI) of the lumbar spine, and CT of the lower extremities were all negative. Only MRI of the brain with a gradient echo sequence revealed microhemorrhages focused around the right precentral gyrus. The patient underwent physical therapy, and by 3 months had regained full strength in his left leg.\n\nConclusion:\nCentral causes of foot drop are exceptionally rare, however, they should be considered in all cases of post-traumatic dorsiflexion paresis. The key to the accurate diagnosis is a high index of suspicion as well as thorough and careful physical examination including reflex and sensory testing. Selective imaging modalities such as MRI or CT can then be used to verify the diagnosis.\n\nComputed tomographycontusionfoot dropmotor cortexmagnetic resonance imagingtraumatic brain injury\n==== Body\nINTRODUCTION\nPost-traumatic acute foot drop is most commonly the result of direct peripheral nerve injury at the level of the fibular head or secondary to intervertebral disc herniation causing L5 nerve root compression.[811] Traumatic injuries that involve the brain parenchyma of primary motor cortex often extend to adjacent areas and result in hemiplegia or paresis. Cases of isolated motor weakness in a distal extremity due to a concussive traumatic brain injury are rare and often misdiagnosed during initial evaluation.[1] Other central causes of foot drop have been described, including indolent cerebral and spinal tumors, penetrating injuries to the brain or spine, infection, metastases, and post-traumatic diffuse axonal injury.[312]\n\nHere, we present a patient who presented with left lower extremity weakness and isolated foot drop after falling off a bicycle. Work-up included a computerized tomography (CT) of the brain which was negative for acute injury and magnetic resonance imaging (MRI) of the brain which revealed a localized area of hemorrhagic contusion in the right precentral gyrus.\n\nCASE HISTORY\nA 55-year-old male was mountain biking and fell 15 feet, hitting his head and losing consciousness. Neurologic examination of the left leg revealed MRC grade 2/5 strength of dorsiflexion (tibialis anterior), MRC grade 1/5 strength distally (extensor digitorum longus, extensor hallucis), no sensory deficits were noted (normal light touch, two-point discrimination, temperature and vibratory sensation modalities), 3+ tendon reflexes at the knee and ankle, and positive sustained clonus. He reported a headache, but was oriented to name, place, and date. Upon work-up, electroencephalogram (EEG) showed no evidence seizures, CT of the head showed no ischemia or hemorrhage, and MRI of the lumbar spine was negative for acute pathology [Figure 1]. However, a gradient echo sequence (GRE) of MRI of the brain revealed a discrete area of microhemorrhage centered in the right precentral gyrus [Figure 2]. The patient received a 1 week course of levetiracetam (Keppra) for seizure prophylaxis and underwent 3 weeks of targeted physical therapy, both during his acute hospitalization and after discharge. At the 3 month follow-up, he regained complete, MRC grade 5/5, strength throughout all left lower extremity muscle groups.\n\nFigure 1 (a) Sagittal T2-weighted magnetic resonance imaging (MRI) showing degenerative spondylosis without significant cord compression. (b) Computed tomography scout image of left leg demonstrating fibular head without evidence of fracture. (c) Axial proton-density-weighted turbospin echo MRI showing the L5 nerve roots exiting the spinal canal, no foraminal stenosis, or disc herniation\n\nFigure 2 (a) Computed tomography showing chronic left frontal encephalomalacia, but no acute intracranial blood. (b) T1-magnetization prepared rapid gradient echo unremarkable. (c) Fluid-attenuated inversion recovery revealing right frontoparietal hyperintensity. (d) T2-gradient recall echo showing punctate pre and post-central intraparenchymal hemorrhage (white arrow)\n\nDISCUSSION\nFoot drop or dorsiflexion paresis is typically the result of a lower motor neuron injury, such as a lumbar 4-5 disc herniation or a common peroneal nerve injury at the fibular head.[2] In cases of discogenic foot drop, patients often report additional pain in their back, posterior thigh, calf, and foot (L5 radiculopathy). Similarly, common peroneal neuropathy can result in referred pain to the hip or ankle and mimic radiculopathy; although a detailed history and physical exam can generally reveal the pain to be nondermatomal. Those patients, however, generally do not possess exam findings including hyperreflexia or clonus. Isolated unilateral dorsiflexion weaknesses secondary to an intracranial lesion is exceeding rare and has only been reported in a small number of case reports.[3101213]\n\nDespite a low prevalence, we believe that central etiologies of foot drop must be included in the differential diagnosis of all patients presenting with head trauma and unilateral lower extremity weakness. When examining such patients, particular attention should be paid to upper motor neuron signs; Babinski’s sign, hyper-reflexia, and clonus. A detailed sensory exam should also be carefully conducted to determine the existence of sensory changes within a dermatomal distribution. In individuals with clear discogenic or peroneal etiology, MRI of the lumbar spine or CT of the lower extremity in question should be readily obtained to establish the correct diagnosis and treatment. If these imaging studies are nondiagnostic, electrophysiologic studies and cranial evaluation should be considered.\n\nAlthough the quality of CT imaging of the brain continues to advance, MRI remains the most sensitive neurodiagnostic imaging modality for the evaluation of intracranial hemorrhage.[79] MRI, particularly GRE/susceptibility weighted imaging (SWI) sequences, is more sensitive to heme-products than CT and often necessary to accurately diagnose discrete traumatic parenchymal injuries.[5] However, the speed, relative lower cost, and availability of CT makes it the ideal screening tool for traumatic injury. In patients for whom the etiology of symptoms remains dubious following appropriate neuroimaging, electromyography and nerve conduction studies can be of valuable assistance [Figure 3].\n\nFigure 3 Diagnostic workup algorithm for patients with acute unilateral isolated foot drop. Decisions regarding the appropriate imaging/testing modality are guided primarily by physical examination findings (second row)\n\nOther rare causes of foot drop include deep venous thrombosis, rapid weight loss after bariatric surgery, severe diabetic neuropathy, Hansen’s disease, nerve compression during sleep, surgery, or while in stirrups during gynecologic procedures, as well as orthopedic injuries such as hip dislocation, acetabular fractures, proximal fibular fractures, or tight plaster casts.[46]\n\nCONCLUSION\nWhile central causes of foot drop are exceptionally rare,[14] it is important for all clinicians to include them in the differential diagnosis of lower extremity weakness. Here, we present a case of unilateral foot drop in a traumatic brain injury patient, as well as our recommended diagnostic algorithm. In trauma cases, where the etiology of lower extremity weakness is unclear, MRI with a GRE/SWI sequence should be considered because it may provide greater visualization of small hemorrhages than CT alone.[9]\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nhttp://surgicalneurologyint.com/CT-negative,-MRI-GRE-positive-primary-motor-cortex-contusion-causing-isolated-foot-drop/\n==== Refs\nREFERENCES\n1 Atac K Ulas UH Erdogan E Gokcil Z Foot drop due to cranial gunshot wound Mil Med 2004 169 568 9 15291193 \n2 Baima J Krivickas L Evaluation and treatment of peroneal neuropathy Curr Rev Musculoskelet Med 2008 1 147 53 19468889 \n3 Djekidel M Harb W A case of foot drop as an expression of brain metastases? Neurologist 2006 12 274 5 16990742 \n4 Elias WJ Nader P Oskouisan RJ Schirmer B Burns T Peroneal neuropathy following successful bariatric surgery J Neurosurg 2006 105 631 5 17044570 \n5 Fazekas F Kleinert R Roob G Kleinert G Kapeller P Schmidt R Histopathologic analysis of foci of signal loss on gradient-Echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: Evidence of microangiopathy-related microbleeds AJNR Am J Neuroradiol 1999 20 637 42 10319975 \n6 Fukada H Bilateral peroneal nerve palsy caused by intermittent pneumatic compression Int Med 2006 45 93 4 \n7 Gentry LR Godersky JC Thompson B MR imaging of head trauma: Review of the distribution and radiopathologic features of traumatic lesions AJR Am J Roentgenol 988 50 663 72 \n8 Katirji MB Wilbourn AJ Common peroneal mononeuropathy: A clinical and electrophysiologic study of 116 lesions Neurology 1988 38 1723 8 2847078 \n9 Kidwell CS Chalela JA Saver JL Starkman S Hill MD Demchuk AM Comparison of MRI and CT for detection of acute intracerebral hemorrhage JAMA 2004 292 1823 30 15494579 \n10 Oktem NB Tari R Kotil K Bilge T Cerebral contusion as a rare cause of foot drop: Case report Turk Neurosurg 2012 22 99 101 22274979 \n11 Ozdemir N Citak G Acar UD Spastic foot drop caused by a brain tumour: A case report Br J Neurosurg 2004 18 314 5 15327242 \n12 Ozdemir N Gelal MF Oguzoglu S Minoglu M Unilateral acute foot drop due to diffuse axonal injury after head trauma J Clin Neurosci 2008 15 1051 3 18617400 \n13 Ricarte IF Figueiredo MM Fukuda TG Pedroso JL Silva GS Acute foot drop syndrome mimicking peroneal nerve injury: An atypical presentation of ischemic stroke J Stroke Cerebrovasc Dis 2014 23 1229 31 24103672 \n14 Westhout FD Pare LS Linskey ME Central causes of foot drop: Rare and underappreciated differential diagnoses J Spinal Cord Med 2007 30 62 6 17385271\n\n",
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"issue": "7(Suppl 28)",
"journal": "Surgical neurology international",
"keywords": "Computed tomography; contusion; foot drop; magnetic resonance imaging; motor cortex; traumatic brain injury",
"medline_ta": "Surg Neurol Int",
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"nlm_unique_id": "101535836",
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"pages": "S756-S758",
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"pubdate": "2016",
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"title": "CT-negative, MRI GRE-positive primary motor cortex contusion causing isolated foot drop.",
"title_normalized": "ct negative mri gre positive primary motor cortex contusion causing isolated foot drop"
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"abstract": "Obstructive sleep apnea (OSA) is a highly prevalent sleep-disordered breathing (SDB).\nTwo 53- and 51-year-old male cases with daytime sleepiness and opium abuse and severe sleep apnea and long respiratory events duration (200 and 275 seconds respectively) noted in polysomnography were reported at Ebn-e-Sina and Razavi hospitals, in Mashhad, Iran. After positive airway pressure (PAP) therapy respiratory events resolved and patients' daytime alertness improved.\nThe long duration of sleep apnea could be the result of opium abuse. Therefore, drug history should be carefully considered in the evaluation of SDB patients. The PAP device was effective in the management of sleep respiratory events and the improvement of patient's complications.",
"affiliations": "Fellowship of Sleep Medicine, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.;Psychiatrist, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.;Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran, and Department of Pharmacology, Medical University Innsbruck, Innsbruck, Austria.;Department of Medicine at Baylor College of Medicine, VAMC Sleep Center, Houston, TX.;Occupational Medicine, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.;Department of Neurological Diseases, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.;Lung Disease Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.;Psychiatrist, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.",
"authors": "Asadpour|Hadi|H|;Naghibi|Seyede Maryam|SM|;Rahimi|Sadegh|S|;Sharafkhaneh|Amir|A|;Afshari Saleh|Lahya|L|;Rezaee Talab|Fariborz|F|;Amini|Mahnaz|M|;Nikzad|Faezeh|F|",
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"doi": "10.22038/ijorl.2020.41832.2365",
"fulltext": "\n==== Front\nIran J Otorhinolaryngol\nIran J Otorhinolaryngol\nIJO\nIranian Journal of Otorhinolaryngology\n2251-7251 2251-726X Mashhad University of Medical Sciences Mashhad, Iran \n\n10.22038/ijorl.2020.41832.2365\nCase Report\nProlonged Sleep Apnea in Two Patients with a History of Opium Abuse -A Case Report\nAsadpour Hadi MD1 Naghibi Seyede Maryam MD2 Rahimi Sadegh MD3 Sharafkhaneh Amir MD4 Afshari Saleh Lahya MD5 Rezaee Talab Fariborz MD6 Amini Mahnaz MD7 Nikzad Faezeh MD*2 \n1 \nFellowship of Sleep Medicine, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.\n\n\n2 \nPsychiatrist, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.\n\n\n3 \nNeuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran, and Department of Pharmacology, Medical University Innsbruck, Innsbruck, Austria.\n\n\n4 \nDepartment of Medicine at Baylor College of Medicine, VAMC Sleep Center, Houston, TX.\n\n\n5 \nOccupational Medicine, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. \n\n\n6 \nDepartment of Neurological Diseases, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.\n\n\n7 \nLung Disease Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.\n\n* Corresponding Author: Psychiatrist, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail: Faeze.nikzad@gmail.com\n3 2020 \n32 109 127 131\n29 7 2019 15 1 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction:\nObstructive sleep apnea (OSA) is a highly prevalent sleep-disordered breathing (SDB).\n\nCase Report:\nTwo 53- and 51-year-old male cases with daytime sleepiness and opium abuse and severe sleep apnea and long respiratory events duration (200 and 275 seconds respectively) noted in polysomnography were reported at Ebn-e-Sina and Razavi hospitals, in Mashhad, Iran. After positive airway pressure (PAP) therapy respiratory events resolved and patients’ daytime alertness improved. \n\nConclusion:\nThe long duration of sleep apnea could be the result of opium abuse. Therefore, drug history should be carefully considered in the evaluation of SDB patients. The PAP device was effective in the management of sleep respiratory events and the improvement of patient’s complications.\n\nKey Words\nMicroarousalOpiumObstructive sleep apnea (OSA)Sleep ApneaSleep-disordered breathing (SDB)\n==== Body\nIntroduction\nObstructive sleep apnea (OSA) is a highly prevalent sleep-disordered breathing (SDB). The OSA is characterized by recurring episodes of upper airway obstruction during sleep. It may result in reduced airflow followed by a drop in oxygen saturation (i.e. hypopnea) or total cessation of breathing at least 10 sec (i.e. apnea) and lead to periodic arousal (i.e. short-time wakefulness during sleep) during sleep (1). The OSA is almost twice as prevalent in males compared to that reported for females (1). In addition, obesity has been known to be associated with OSA, and body mass index (BMI) positively correlates with the severity of the disease (1). Untimely diagnosis and proper treatment can lead to a range of serious complications, including increased systemic blood pressure, cardiovascular disease, cognitive impairment and psychiatric symptoms, such as depression, irritability, and anxiety (2). While daytime sleepiness and loud snoring are the main symptoms, a variety of complaints, including drowsiness, impaired cognition, fatigue and impatience, loss of attention and energy, morning headaches, and depressive symptoms, often constitute the clinical manifestations (2-4). Polysomnography (PSG) is the gold standard test for the diagnosis of SDB (5, 6). The main finding in PSG is the apnea-hypopnea index (AHI). The AHI is an index used to indicate the severity of sleep apnea, represented by the number of apnea and hypopnea events per hour of sleep. It is categorized as normal for the AHI <5, mild sleep apnea for 5 < AHI <15, moderate sleep apnea for 15 < AHI <30, and severe sleep apnea for AHI > 30 (3,4). \n\nIt can be hypothesized that a higher number of respiratory events per hour of sleep is related to more complications. In a study conducted by Mediano et al., this hypothesis was supported that the patients with extreme daytime sleepiness experience a longer period of apnea and less oxygenation at the night (5); however, the role of the duration of apnea and depth of respiratory desaturation were neglected in the literature. The longer cessation of breathing coud cause a further decline in oxygenation, which leads to extreme stress to different organs of the human body; as a result, fatigue and daytime sleepiness also intensify. This study reported two cases of severe sleep apnea with a long duration of respiratory events, daytime sleepiness, and opium abuse.\n\nCase Report\n\nCase 1\n: A 53-year-old man with progressive daytime sleepiness and disrupted sleep underwent split-night PSG at the sleep laboratory of Ebn-e-Sina hospital, in Mashhad, Iran. He was treated with lorazepam 2 mg at night in the last 3 months with no improvement in sleep patterns. Over the last 2 years, he complained of vague headaches, as well as feeling depressed and impatient. The patient was overweight (BMI: 28.4). He was also diagnosed with hypertension and hypercholesterolemia since 2 years ago. The drug history included the administration of atorvastatin 20 mg daily and captopril 25 mg twice a day. In the clinical examination, blood pressure was 140/85 mmHg. He was heavy smoker (120 packs/year) and reported a history of opium abuse for 10 years. He smoked 3-4 gr traditional opium at home every day. The Epworth Sleepiness Scale (ESS) was 20 (out of maximum 24) indicating severe subjective daytime sleepiness. The STOP-BANG score was 7 (out of 8) indicative of a severe respiratory interruption during sleep. The Min-Mental Status Examination score was 29. On the Hamilton Depression Rating Scale (HAM-D), he had a score of 30 consistent with major depression. During the previous 5 months, he was under treatment for depression with sertraline 150 mg twice a day with no improvement in his mood. \n\nThe patient’s demographic characteristics and questionnaire scores is described in (Table.1). \n\nTable 1 Demographic characteristics and the questionnaires scores of two patients\n\n\t\nAge\n\t\nBMI\n\t\nESS\n\t\nSTOP-BANG\n\t\nneck circumference\n\t\n\t53\t28.4\t20\t7\t45\t\n\t51\t35.3\t12\t8\t48\t\nAI: Arousal index, AHI: Apnea-hypopnea index, BMI: Body mass index, ESS: Epworth Sleepiness Scale,\n\nHe underwent an attended Split-Night PSG (by Harmonia software version 7) with concomitant video recording that was performed according to the guidelines of the American Academy of Sleep Medicine (AASM) with simultaneous monitoring of electroencephalography (EEG), electrooculo- graphy (EOG), Chin electromyography (EMG), airflow and respiratory efforts, pulse oximetry, electrocardiography (EKG), and limb EMG. The scoring manual (version 2.2) of the AASM was used for scoring the sleep study (6).\n\nOvernight PSG demonstrated an AHI of 110.8 per hour of sleep compatible with severe sleep apnea. The notable finding was an obstructive apnea episode lasted for 3 minutes and 20 seconds during the rapid eye movement (REM) period accompanied by electrocardiography(EKG) abnormality and cyanosis, and it was terminated by an awakening.\n\nThe mean oxygen saturation was 88.2%. The minimum oxygen concentration was lower than 55.9%. The desaturation index was 146 per hour of sleep. Arousal occurred with a total arousal index of 88.1, mainly due to respiratory events. ECG demonstrated frequent transient ST elevation and arrhythmia during oxygen desaturation. The patient underwent titration through Bilevel Positive Airway Pressure (BPAP) with the optimal response at BPAP of EPAP=13 cmH2O and IPAP=17 cmH2O. After 1 month of OSA management by BPAP, sleep indices improved which is summarized (Table.2).\n\nTable 2 Polysomnography indices of two patients before titration study\n\n\t\nN1%\n\t\nN2%\n\t\nN3%\n\t\nREM%\n\t\nSleep period (min)\n\t\nSleep efficiency%\n\t\nAI\n\t\nAHI\n\t\nMean duration (sec)\n\t\nLongest duration (sec)\n\t\nODI\n\t\nDs< 90%\n\t\nMean SpO2 (%)\n\t\nLowest Sp O2 (%)\n\t\nPLMI\n\t\n\t18\t78\t0\t4\t72\t49\t88\t111\t15.8\t200.4\t36\t59.3\t94\t< 50\t9 \t\n\t32\t58\t0\t10\t226\t90.6\t42\t62.7\t22.1\t275.6\t89\t99.2\t79.6\t50\t4.4\t\nAI: Arousal index, AHI: Apnea-hypopnea index, , REM: Rapid eye movement, ODI: Oxygen desaturation events index, Ds: Desaturation, PLMI: Periodic leg movement index \n\nIn the following months, he was visited several times. He was satisfied with the permanent application of BPAP.\n\nIn addition, he was reported with less daytime sleepiness and depression-related symptoms (The HAM-D score decreased to 14). \n\n\nCase 2\n: A 51-year-old man complained of nightly snoring and daytime tiredness, exacerbated by gaining weight since 12 years ago, breathing pauses, and waking up gasping for air. The sleep was reported as restless and unrefreshing. In the last month, he tried several sedative drugs, such as diphenhydramine 10 mg or lorazepam 1 mg, through the mouth with no improvement. Morning headaches, feeling sad, boredom, drowsiness, and attention deficit were his complaints throughout the day.\n\n The patient’s demographic characteristics and questionnaire scores is described in Table 1. In the past medical history, he had elevated blood pressure; however, he was not on any pharmacotherapy. He smoked cigarette (50 packs/year) and used opium in the form of buprenorphine (B2). He also had polycythemia (Hct: 62%). Venous blood gas prior to PSG showed hypercapnia with PCO2 of 62 mmHg and HCO3 of 31 mg/dl. He was admitted to the sleep center of Razavi Hospital and underwent split-night PSG (by Remlogic software version 3.2) for 8 h at night. The sleep time during this study was 5 h and 15 min during which 216 occasions of respiratory disturbances, including apneas and hypopneas, occurred with an AHI of 62.7 indicative of severe OSA. The results of the study showed several prolonged obstructive apnea episodes during the REM with a maximum duration of 4 min and 35 seconds. The event was terminated with patient awakening. The oxygen saturation was 79.6% on average. \n\nThe minimum oxygen saturation was 50%. The blood oxygen desaturation index was 89.4 during sleep. In 45.2% of sleep duration, he had loud snoring. The EKG demonstrated arrhythmias, including wide narrow complex tachycardia and bradycardia (as low as 34 beats per minute) and tachycardia (up to 132 beats per minute). \n\n\nTable 3 shows the main PSG indices of the two patients. The patient was titrated with BPAP (IPAP of 22 and EPAP: 18 cm H2O). Sleep indices (including oxygen saturation and arousal index) improved which is summarized in table 2. He was recommended to be evaluated regarding other possible omorbidities, especially through phlebotomy; however, he refused and left the study.\n\nTable 3 Polysomnography indices of two patients after titration study\n\n\t\nN1 %\n\t\nN2 %\n\t\nN3 %\n\t\nREM %\n\t\nSleep period (min)\n\t\nSleep efficiency%\n\t\nAI\n\t\nAHI\n\t\nMean duration (sec)\n\t\nLongest duration (sec)\n\t\nODI\n\t\nDs< 90%\n\t\nMean SpO2 (%)\n\t\nLowest Sp O2 (%)\n\t\n\t17\t39\t13\t31\t259\t64\t22\t25\t34\t173.2\t21\t59.3\t90\t60\t\n\t7.5\t37\t15\t45\t239\t98\t 9\t3.8\t30\t174\t15\t99.2\t85.4\t51\t\nAI: Arousal index, AHI: Apnea-hypopnea index, REM: Rapid eye movement, ODI: Oxygen desaturation events index Ds: Desaturation\n\nCase 1 4 min. epoch N2 REM stage sleep with Snoring, Obstructive Apnea (3 minutes and 20 seconds), with Arousal, Desaturation & RRLM\n\nCase 2 Pretreatment 5 min. epoch REM sleep stage with snoring, Obstructive Apnea (4 minutes and 35 seconds) with Arousal, Desaturation, wide complex tachycardia and Respiratory related leg movements\n\nConclusion\nThe authors noticed long sleep apnea events in two patients complaining of snoring, daytime sleepiness, tiredness, and sleep disturbance. On PSG, the duration of two respiratory events were 200 and 275 seconds. The apnea durations observed for the two cases are the longest reported in Iran and among the longest in the world (7). The AHI were 110.8 and 62.7 for the first and second cases, respectively, which revealed very severe sleep apnea in the patients. Due to the extreme duration of the single apnea event and very high AHI, these cases were worthwhile to report. \n\nThe unusual duration of the single apnea event, as well as the AHI, might be caused by various risk factors, including obesity or depression. However, these factors are frequently observed in patients, suffering from mild to severe OSA, no similar studies found such remarkable figures. In addition, these reported cases had no central apnea, and neurologic examination was normal. Accordingly, opium abuse was considered the root of this notable sleep disturbance in both patients. The opioid-specific receptor, μ (mu), is widespread at various neuronal sites controlling the human breathing. Opioids descend intracellular cyclic AMP levels and suppress respiratory neuronal function via μ receptors (8). Nevertheless, most studies identified central sleep apnea, mixed sleep apnea, and OSA in patients with opium abuse, some studies reported that OSA is more prevalent in chronic opium abuse (9). Opioids can reduce genioglossus muscle activity, which can predispose the patient to upper airway closure and severe OSA (8). \n\nAll the respiratory events were of obstructive type and the majority occurred during REM sleep stage. During REM period, the oropharyngial muscles’ tone decreased and simultaneously the arousal threshold increased. These physiologic changes would be exacerbated with opium use. (8,9) This is the probable mechanism explains the prolonged sleep apnea in our patients. Micro-arousals, preventing longer hypoxia during sleep, might be suppressed by the central effect of opium. Therefore, chronic opium abuse can cause a longer duration of single apnea events in due to lack of arousal. Despite opium abuse, resulting in significant apnea duration, both patients who benefited from PAP therapy revealed its effective role in the management of the diverse range of OSA. However, the impact of opium withdrawal on sleep architecture should be precisely evaluated in further studies. \n\nPAP device is undoubtedly the gold standard treatment for OSA. The PAP is highly effective in controlling symptoms, improving quality of life, and decreasing the clinical complications of sleep apnea similar to the number of nocturnal obstructive events and nocturnal arousals, improving sleep parameters and nocturnal oxygen saturation from the start of treatment (10).\n\n In fact, effective treatment requires long-term management. The careful monitoring of the subject and increased patient adherence to treatment, providing a variety of therapeutic alternatives, as well as the appropriate treatment for comorbidities and associated disorders, will help to achieve the best results. It seems that the efficacy of PAP might be limited by suboptimal adherence. \n\nThe long duration of sleep apnea could be the result of opium abuse; therefore, drug and habitual history should be carefully considered in the SDB approach. The PAP device was effective in the management of sleep apnea, despite the high AHI and concomitant depression, obesity, and drug abuse.\n==== Refs\nReferences\n1 Guven SF Dursun AB Ciftci B Erkekol FO Kurt OK The prevalence of obstructive sleep apnea in patients with difficult-to-treat asthma Asian Pac J Allergy Immunol 2014 32 2 153 9 25003729 \n2 Kielb SA Ancoli-Israel S Rebok GW Spira AP Cognition in obstructive sleep apnea-hypopnea syndrome (OSAS): current clinical knowledge and the impact of treatment Neuromolecular Med 2012 14 3 180 –93 22569877 \n3 Ruehland WR Rochford PD O'Donoghue FJ Pierce RJ Singh P Thornton AT \"The new AASM criteria for scoring hypopneas: impact on the apnea hypopnea index\" [sleep] 2009 32 2 150 7 \n4 Harvard Medical School \"Understanding the Results: Sleep Apnea\" Harvard University 5 septemner 2014 5 septemner 2014 \n5 Mediano O Barcelo A La Pena M de Gozal D Agusti A Barbe F Daytime sleepiness and polysomnographic variables in sleep apnoea patients Eur Respir J 2007 30 1 110 3 17360730 \n6 Richard B Berry, Charlene E Gamaldo, Susan M. Harding, Rita Brooks, Robin M. Lloyd, Bradley V. Vaughn. AASM Scoring Manual Version 2.2 Updates: New Chapters for Scoring Infant Sleep Staging and Home Sleep Apnea Testing. Available from: URL: J Clin Sleep Med. 2015 11 11 11 1253 4 \n7 Aulakh PK Westerman DE Dedhia RC The Longest Obstructive Apnea You Have Ever Seen: A Patient With New-Onset Autonomic Dysfunction J Clin Sleep Med 2018 14 5 893 5 29734980 \n8 Chowdhuri S Javaheri S Sleep Disordered Breathing Caused by Chronic Opioid Use: Diverse Manifestations and Their Management Sleep Med Clin 2017 12 4 573 86 29108612 \n9 Sharkey KM Kurth ME Anderson BJ Corso RP Millman RP Stein MD Obstructive sleep apnea is more common than central sleep apnea in methadone maintenance patients with subjective sleep complaints Drug Alcohol Depend 2010 108 1-2 77 83 20079978 \n10 Lurie A Cardiovascular disorders associated with obstructive sleep apnea Adv Cardiol 2011 46 197 266 22005193\n\n",
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"issue": "32(109)",
"journal": "Iranian journal of otorhinolaryngology",
"keywords": "Microarousal; Obstructive sleep apnea (OSA); Opium; Sleep Apnea; Sleep-disordered breathing (SDB)",
"medline_ta": "Iran J Otorhinolaryngol",
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"pages": "127-131",
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"title": "Prolonged Sleep Apnea in Two Patients with a History of Opium Abuse -A Case Report.",
"title_normalized": "prolonged sleep apnea in two patients with a history of opium abuse a case report"
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"abstract": "Neonatal seizures represent a significant health burden on the term and preterm neonatal population and are linked to poor long-term neurodevelopmental outcomes. Currently, there are no US Food and Drug Administration-approved antiepileptic drugs for neonates, and authors of the medical literature have yet to reach a consensus on the most adequate approach to neonatal seizures. Topiramate is readily used in the adult and older pediatric population for the management of migraines and partial-onset seizures. Topiramate continues to gain favor among pediatric neurologists who often recommend this medication as a third-line treatment of neonatal seizures. We report our recent experience with 4 preterm neonates, born between 2015 and 2017, who developed radiographic signs of necrotizing enterocolitis after receiving topiramate for seizures. Each was given oral topiramate for the treatment of electrographic and clinical seizures and developed the subsequent diagnosis of necrotizing enterocolitis, with abdominal distention, hemoccult-positive stools, and radiographic signs of intestinal distention and pneumatosis. More research regarding the risk factors of topiramate use in premature infants is needed.",
"affiliations": "Divisions of Neonatology and benjamin.courchia@jhsmiami.org.;Divisions of Neonatology and.;Pediatric Neurology, Department of Pediatrics, Miller School of Medicine, University of Miami and Jackson Memorial Hospital, Miami, Florida.;Divisions of Neonatology and.;Divisions of Neonatology and.",
"authors": "Courchia|Benjamin|B|;Kurtom|Waleed|W|;Pensirikul|Alyssa|A|;Del-Moral|Teresa|T|;Buch|Maria|M|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate",
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"mesh_terms": "D000927:Anticonvulsants; D020345:Enterocolitis, Necrotizing; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D012640:Seizures; D000077236:Topiramate",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Topiramate for Seizures in Preterm Infants and the Development of Necrotizing Enterocolitis.",
"title_normalized": "topiramate for seizures in preterm infants and the development of necrotizing enterocolitis"
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"abstract": "Diffuse carcinomatosis of the bone marrow (DCBM) is a rare clinical condition characterized by diffuse bone marrow involvement with hematological changes. This case study concerns a patient who presented with DCBM secondary to colon cancer with diffuse intravascular coagulation. This is a rare presentation of DCBM in colon cancer. The case study also elaborates on clinical features, pathogenesis, and therapy of this unique presentation.",
"affiliations": "White River Health Systems, Batesville, AR, USA.;White River Health Systems, Batesville, AR, USA.;White River Health Systems, Batesville, AR, USA.;White River Health Systems, Batesville, AR, USA.",
"authors": "Desikan|Sai Prasad|SP|0000-0003-1157-6489;Mclaughlin|Nathan|N|;McClain|Charles|C|;Desikan|Raman|R|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n33966469\n10.1177/23247096211012224\n10.1177_23247096211012224\nCase Report\nRecurrent Colon Cancer: Presentation With Disseminated Intravascular Coagulation From Disseminated Carcinomatosis of the Bone Marrow\nhttps://orcid.org/0000-0003-1157-6489\nDesikan Sai Prasad MD 1\nMclaughlin Nathan MD 1\nMcClain Charles MD 1\nDesikan Raman MD 1\n1 White River Health Systems, Batesville, AR, USA\nSai Prasad Desikan, White River Medical Center, 1710 Harrison Street, Batesville, AR 72501, USA. Email: sdesikan1@wrmc.com\n8 5 2021\nJan-Dec 2021\n9 2324709621101222419 1 2021\n9 3 2021\n19 3 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nDiffuse carcinomatosis of the bone marrow (DCBM) is a rare clinical condition characterized by diffuse bone marrow involvement with hematological changes. This case study concerns a patient who presented with DCBM secondary to colon cancer with diffuse intravascular coagulation. This is a rare presentation of DCBM in colon cancer. The case study also elaborates on clinical features, pathogenesis, and therapy of this unique presentation.\n\ndiffuse carcinomatosis of the bone marrow\ndisseminated intravascular coagulation\ncolorectal cancer\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nDisseminated carcinomatosis of the bone marrow (DCBM) is a unique clinical condition distinct from bone and bone marrow metastasis. It is characterized by diffuse infiltrative growth with hematological abnormalities, including cytopenias, disseminated intravascular coagulation (DIC), or microangiopathic hemolytic anemia. DCBM is a rare occurrence. Common cancers that present as DCBM include stomach, breast, prostate, and lung cancers. Other cancers also reported include pancreatic, esophageal, neuroblastoma, and unknown primary. However, DCBM is a very rare occurrence in colon cancer. DIC, while infrequent in solid tumors, is a frequent but not universal occurrence in DCBM. Pathogenesis and clinical correlations associated with DIC in the setting of DCBM are not well defined. DCBM is often associated with evident bone metastasis on imaging; however, this may not be present in all cases.1,2 This case study highlights the pathogenesis, clinical presentation, and therapeutic challenges posed by this presentation.\n\nCase Presentation\n\nA 75-year-old White female with history of stage IIIB (PT4a,PN2b,M0; 25/26 lymph nodes positive) poorly differentiated mucinous colon cancer (Figure 1) was admitted for back pain. Six months prior, she had a colectomy, followed by one cycle of adjuvant chemotherapy. She refused further chemotherapy on account of toxicities encountered with first cycle. She presented with back pain, which had worsened over 2 weeks along with hematuria, increased bruising, nausea, and vomiting. She was evaluated in emergency department 10 days earlier and treated for an urinary tract infection with ciprofloxacin and azithromycin added on account of ground-glass changes in lung bases. Her oncologist evaluated her 2 days later with persistent back pain and resolving hematuria. Examination revealed bruising in the right flank. Computed tomography (CT) scans did not reveal any progression; however, CEA level was increased at 143 ng/mL. Examination was notable for extensive ecchymosis noted in both the upper extremities and abdomen, but less prominent in the lower limbs.\n\nFigure 1. Poorly differentiated mucinous adenocarcinoma (black arrows) invading through the muscularis propria.\n\nLaboratory Evaluation\n\nComplete blood count revealed mild leukocytosis and neutrophilia (11.4 × 103/µL and 8.0 × 103/µL), normocytic anemia (10.3g/dL), and low platelets (120 × 103/µL). The metabolic panel was normal except for mildly elevated alkaline phosphatase (ALP; 143 U/L; range 38-126). Lactate dehydrogenase (LDH) level was not obtained. Peripheral smear revealed neither significant red cell fragmentation, nor any leucoerythroblastic features. Mild poikilocytosis and increased polychromasia were reported. Coagulation abnormalities noted included prolonged prothrombin time (23.6 seconds; 11.4-14.8) and partial thromboplastin time (45.1 seconds; 22.6-37), increased D-dimer (>20 µg/mL FEU [fibrinogen equivalent units; 0-0.48]) and low fibrinogen (60 mg/dL [207-442]), all consistent with DIC.\n\nBone Marrow Aspirate and Biopsy\n\nMetastatic carcinoma was noted on bone marrow biopsy involving approximately 30% of the marrow space. The malignant epithelioid infiltrate showed expression of CK20 and CDX2 and lack of CK7 expression, consistent with metastatic colorectal carcinoma (Figure 2).\n\nFigure 2. Cytokeratin staining of the bone marrow, positive for CK20 as well as CDX2 and negative for CK7 suggesting metastatic carcinoma.\n\nTreatment\n\nAfter the diagnosis of disseminated colorectal carcinoma of bone marrow with associated DIC was confirmed by bone marrow evaluation, the patient was initiated on 5-flurouracil, leucovorin, and oxaliplatin (modified FOLFOX6 regimen) for colorectal cancer along with supportive therapy for DIC with fresh frozen plasma and cryoprecipitate.\n\nThe patient had significant improvement in pain. Her hematuria resolved and coagulation abnormalities showed improvement; international normalized ratio improved from 2.5 to 1.4 and fibrinogen from 60 mg/dL to 143 mg/dL. Unfortunately, the patient refused further therapy and died in hospice care 2 months later.\n\nDiscussion\n\nSkeletal metastasis is rare in patients with colorectal cancer (1% to 10%). In addition, bone marrow metastases occur in only a fraction (around 1%), and DCBM is also exceedingly rare.3,4 Increasing back pain in conjunction with hematological changes (DIC and cytopenias), increasing ALP, and increasing LDH should increase suspicion for DCBM. DIC was noted early on in the presentation of the patients as suggested by the easy bruising, thrombocyotpenia, elevated D-dimer, and low fibrinogen. Elevated ALP reflects bone metastases, which often accompany DCBM. The patient did not show a significantly elevated ALP level due to lack of skeletal metastasis. LDH level was not evaluated in our patient, though LDH level may have been a better reflection of bone marrow involvement. The CT scan was normal in our patient, despite significant back pain being the prominent symptom. Positron emission tomography-CT may be a better study for evaluating bone marrow involvement.1\n\nGastric cancer is the leading cause of DCBM, and thus, the most studied. In a gastric cancer study involving a series of 27 patients, signet-ring cell carcinoma and poorly differentiated carcinoma predominated (25/26). The distribution of histology was similar in a smaller number of colorectal cancer patients, and rectal cancers accounted for more than half of the patients compiled in the study.3 The subject of this case study was reported to have poorly differentiated, mucinous type cancer in the cecum. On bone marrow biopsy during admission, signet ring cells were noted suggesting a correlation between this histology and DCBM.\n\nDIC is a very common occurrence in DCBM, although not universal. Twenty-three of 27 patients with DCBM from the gastric cancer study had laboratory features of DIC. Increased incidence of DIC in DCBM may be secondary to mucinous histology, which is known to be associated with increased incidence of thrombosis, and also with increase in circulating tumor cells associated with DCBM. Tissue factor (TF) expression by tumor cells plays a central role in tumor-induced thrombosis; moreover, TF contributes to tumor growth, metastasis, and angiogenesis. Incidence of thrombosis correlates with the level of TF expression. TF expression on microparticles in addition to tumor cells also contributes to DIC. Independent of TF, mucinous adenocarcinomas can also predispose to thrombosis via mucin-selectin interactions with leukocytes and platelets.1,5-7\n\nTreatment of DIC is mainly based on reversing the underlying process. Outcomes are dependent on the response of the underlying cancer to the proposed therapy. Prompt initiation of chemotherapy in conjunction with other supportive measures can reverse DIC and cytopenias. In addition to reversing DIC, chemotherapy also decreases mortality. Advancements in chemotherapy have been associated with improved survival.1,8\n\nTreatment of underlying cancer may not effectively improve DIC immediately, and supportive care with blood products and antithrombotic measures may be necessary. It is important to utilize blood products only when clinically necessary on account of active bleeding, and not based on coagulation parameters alone. In addition to guidelines-based administration of blood products (platelets, fresh frozen plasma, and cyroprecipitate), patients should be started on unfractionated or low molecular weight heparin to address excessive thrombin production.1,9,10 Thrombomodulin, a glycoprotein expressed on the luminal surface of vascular endothelium, is a multifaceted anticoagulant protein. In addition to anticoagulant action, it exhibits cytoprotective and anti-inflammatory properties. Recombinant thrombomodulin has been approved in Japan for treatment of DIC from sepsis. Thrombomodulin has also been used in treatment of DIC from hematologic malignancies and DIC observed in solid tumors.8\n\nDespite DCBM exhibiting diffuse infiltration, osteoclast activation is thought to be important in the pathogenesis. RANKL expression has been demonstrated by immunostaining on infiltrating gastric cancer cells. Denusomab, a human monoclonal antibody, which binds to RANKL and is commonly used to treat bone metastasis from solid tumors, is also used in treatment of DCBM. However, the utility in DCBM has not been proven through clinical studies.8\n\nDCBM is a rare diagnosis in colorectal cancer that imparts poor prognosis. Reversal of DIC and cytopenia is accomplished by prompt treatment of the underlying malignancy with chemotherapy. Case reports indicate that chemotherapy also improves survival.8 At this time, chemotherapy and supportive care are the mainstays of treatment. It has yet to be seen what role other modalities, including targeted therapy or immunotherapy, will have in the treatment of DCBM with DIC.\n\nWe would like to acknowledge our pathologist Dr Deborah Johnson for her help and guidance in the diagnosis of our patient.\n\nAuthor Contributions: Sai Prasad Desikan (guarantor) wrote the initial draft and submitted the report. Raman Desikan (guarantor) edited the draft and provided oncology input. Nathan Mclaughlin participated in the care of the patient and provided input in the case presentation. Charles McClain provided radiology input.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases.\n\nInformed Consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: Sai Prasad Desikan https://orcid.org/0000-0003-1157-6489\n==== Refs\nReferences\n\n1 Iguchi H. Recent aspects for disseminated carcinomatosis of the bone marrow associated with gastric cancer: what has been done for the past, and what will be needed in future? World J Gastroenterol. 2015;21 :12249-12260.26604634\n2 Konstantinidis C Varsos P Kympouris S. Disseminated carcinomatosis of bone marrow due to sigmoid colon cancer. Am J Med Case Rep. 2015;3 :102-104.\n3 Assi R Mukherji D Haydar A Saroufim M Temraz S Shamseddine A. Metastatic colorectal cancer presenting with bone marrow metastasis: a case series and review of literature. J Gastrointest Oncol. 2016;7 :284-297.27034798\n4 Kim B Lee KT. A report of bone marrow metastasis of colon cancer as a primary diagnosis, supported by cytokeratin immunohistochemical staining. Lab Med Online. 2019;9 :103-106.\n5 Nakashima Y Takeishi K Guntani A , et al . Rectal cancer with disseminated carcinomatosis of the bone marrow: report of a case. Int Surg. 2014;99 :518-522.25216414\n6 Shimazu K Fukuda K Yoshida T Inoue M Shibata H. High circulating tumor cell concentrations in a specific subtype of gastric cancer with diffuse bone metastasis at diagnosis. World J Gastroenterol. 2016;22 :6083-6088.27468200\n7 Wahrenbrock M Borsig L Le D Varki N Varki A. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Investig. 2003;112 :853-862.12975470\n8 Tkaeyama H Sakiyama T Wkasa T , et al . Disseminated carcinomatosis of the bone marrow with disseminated intravascular coagulation as the first symptom of recurrent colon cancer successfully treated with chemotherapy: a case report and review of the literature. Oncol Lett. 2017;13 :4290-4294.28599429\n9 Thachil J Falangs A Levi M Liebman H Di Nisio M. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost. 2015;13 :671-675.25556711\n10 Vitale FV Longo-Sorbello GS Rotondo S Ferrau F. Understanding and treating solid tumor-related disseminated intravascular coagulation in the “era” of targeted cancer therapies. SAGE Open Med. 2017;5 :2050312117749133.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "colorectal cancer; diffuse carcinomatosis of the bone marrow; disseminated intravascular coagulation",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D001853:Bone Marrow; D019046:Bone Marrow Neoplasms; D003110:Colonic Neoplasms; D004211:Disseminated Intravascular Coagulation; D006801:Humans; D009364:Neoplasm Recurrence, Local; D010534:Peritoneal Neoplasms",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "23247096211012224",
"pmc": null,
"pmid": "33966469",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28599429;12975470;25556711;29318012;25216414;27468200;26604634;27034798",
"title": "Recurrent Colon Cancer: Presentation With Disseminated Intravascular Coagulation From Disseminated Carcinomatosis of the Bone Marrow.",
"title_normalized": "recurrent colon cancer presentation with disseminated intravascular coagulation from disseminated carcinomatosis of the bone marrow"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-03226",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"d... |
{
"abstract": "OBJECTIVE\nPreterm infants weighing less than 1500 g routinely undergo a series of eye examinations to screen for retinopathy of prematurity (ROP). While these examinations are important for the prevention of blindness, infants may suffer adverse physiologic events during and after the examination. The procedure includes administration of mydriatic eye drops that may be absorbed systemically and physical manipulation of the eye that is accompanied by stress and pain. The purpose of the study was to monitor changes in infant health status and adverse physiologic events in the 2 days after ROP eye screening.\n\n\nMETHODS\nThe study used 50 preterm infants with a mean gestational age of 32 weeks, undergoing their first ROP examination in a NICU located in a university medical center.\n\n\nMETHODS\nThis pilot study used a prospective, descriptive design.\n\n\nMETHODS\nPhysiologic changes and illness events were recorded before and for 2 days after the eye examination, using tools that tracked parameters of respiratory, cardiovascular, gastrointestinal, and neurological status. Data were collected directly from daily audits of medical records. McNemar's test for comparing paired proportions and the signed rank test were used for comparing significance of physiologic changes before and after the ROP eye examination.\n\n\nRESULTS\nApnea events increased significantly (P = .04) in the 24- to 48-hour period after the eye examination compared with apnea events before the eye examination. These results were based on 39 infants who were not receiving ventilator support. There was a significant difference in the frequency of oxygen desaturation events between infants with and without apnea (0-24 hours after examination, P < .002; 25-48 hours after examination, P < .001). There were no significant differences in heart rate, cyanosis, gastric residuals, or seizures after the eye examinations.\n\n\nCONCLUSIONS\nThe ROP examinations may be associated with increased apnea, a clinically significant problem. Nursing implications include careful monitoring of infants during and after ROP eye examinations, discharge teaching for caregivers, and continued research on nursing interventions to prevent adverse physiologic events.",
"affiliations": "Department of Biostatistics, College of Nursing, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. AMitchell@uams.edu",
"authors": "Mitchell|Anita J|AJ|;Green|Angela|A|;Jeffs|Debra A|DA|;Roberson|Paula K|PK|",
"chemical_list": "D009184:Mydriatics",
"country": "United States",
"delete": false,
"doi": "10.1097/ANC.0b013e318225a332",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1536-0903",
"issue": "11(4)",
"journal": "Advances in neonatal care : official journal of the National Association of Neonatal Nurses",
"keywords": null,
"medline_ta": "Adv Neonatal Care",
"mesh_terms": "D000046:Academic Medical Centers; D001049:Apnea; D001131:Arkansas; D005260:Female; D006304:Health Status; D006801:Humans; D007231:Infant, Newborn; D015931:Intensive Care, Neonatal; D008297:Male; D009184:Mydriatics; D010865:Pilot Projects; D047928:Premature Birth; D011446:Prospective Studies; D012178:Retinopathy of Prematurity; D012720:Severity of Illness Index; D014787:Vision Tests",
"nlm_unique_id": "101125644",
"other_id": null,
"pages": "291-7",
"pmc": null,
"pmid": "22123352",
"pubdate": "2011-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15855243;17079623;18069428;1408510;19482499;9197568;15797982;16428355;15655442;20876596;15616486;18450869;19262437;17435431;10969255;16452383;17967152;15240989;15097885;15226730;15343351;19542771;15977870;11177093;8473525",
"title": "Physiologic effects of retinopathy of prematurity screening examinations.",
"title_normalized": "physiologic effects of retinopathy of prematurity screening examinations"
} | [
{
"companynumb": "NVSC2020US088852",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPARACAINE HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nSingle-agent carboplatin at area under the curve 10 (AUC10) is an effective treatment for metastatic seminoma. As far as we are aware of, there have been no studies reporting its effects on short-term quality of life. The objective was to study the efficacy, safety and tolerability, using health-related quality of life, of carboplatin AUC10 chemotherapy in patients with metastatic seminoma.\n\n\nMETHODS\nForty-four patients with metastatic seminoma treated at Mount Vernon Cancer Centre with carboplatin AUC10 were included in this study. Response to treatment was determined by radiological imaging (Response Evaluation Criteria in Solid Tumors v 1.1) and serum tumour markers. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events Version 4.0. Quality of life treatment-related toxicities were assessed during treatment at pre-chemotherapy assessments. After treatment, toxicity was assessed using a defined telephone questionnaire consisting of four questions relating to hair loss, hearing impairment, days absent from work, and neuropathy.\n\n\nRESULTS\nAt a median follow-up of 27.5 (range=4-84) months, no patient had experienced relapse. Grade 3/4 neutropenia was seen in 15 (35%) patients, nine (21%) required prophylactic granulocyte colony-stimulating factor, 13 (30%) patients had grade 3/4 thrombocytopenia. Commonest non-haematological toxicities were fatigue in 28 (65%) and nausea 14 (33%) patients. They were grade 1 in 82% and 92% of cases, respectively. Six out of 44 (14%) had residual tinnitus. One patient had residual grade 1 peripheral neuropathy. Ten patients continued to work throughout treatment and two patients were retired. Of the remaining patients, 16 (37%), took fewer than 5 days off work.\n\n\nCONCLUSIONS\nCarboplatin AUC10 is a safe and effective treatment for stage II/III seminoma with better health-related quality of life than experienced with combination cisplatin-based chemotherapy.",
"affiliations": "Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, U.K.;Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, U.K.;Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, U.K.;Department of Radiology, Mount Vernon Cancer Centre, Paul Strickland Scanner Centre, Northwood, U.K.;Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, U.K.;Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, U.K. anand.sharma3@nhs.net.",
"authors": "Milic|Marina|M|;Hall|Marcia|M|;Hawkins|Annette|A|;Gogbashian|Andrew|A|;Rustin|Gordon|G|;Sharma|Anand|A|",
"chemical_list": "D016190:Carboplatin; D002945:Cisplatin",
"country": "Greece",
"delete": false,
"doi": "10.21873/invivo.11465",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0258-851X",
"issue": "33(1)",
"journal": "In vivo (Athens, Greece)",
"keywords": "Seminoma; bone marrow; carboplatin; toxicity; work functioning",
"medline_ta": "In Vivo",
"mesh_terms": "D000328:Adult; D000368:Aged; D001853:Bone Marrow; D016190:Carboplatin; D002945:Cisplatin; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009503:Neutropenia; D011788:Quality of Life; D018239:Seminoma; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "8806809",
"other_id": null,
"pages": "233-237",
"pmc": null,
"pmid": "30587629",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "10460406;10597202;11104556;12407434;12431967;12910518;14726503;1515239;15266169;15266338;16254023;17916870;18936476;19097774;20180029;20530199;20638003;20878864;21665493;22943385;24263066;25265940;27189322;27242529;28866371;3398663;7198012;7505805;8558663;9164193;9469360;9579846",
"title": "A Qualitative Analysis of the Impact of Carboplatin AUC 10 on Physical, Work Functioning and Bone Marrow Toxicity Among Seminoma Patients - A Single-centre Experience.",
"title_normalized": "a qualitative analysis of the impact of carboplatin auc 10 on physical work functioning and bone marrow toxicity among seminoma patients a single centre experience"
} | [
{
"companynumb": "GB-ACCORD-100610",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Acute generalised exanthematous pustulosis (AGEP) is a rare but serious cutaneous adverse drug reaction, often related to antibiotics such as beta-lactams or macrolides. However, it is rarely associated with clindamycin which belongs to the lincosamide antibiotics. The Netherlands Pharmacovigilance Centre Lareb received five reports of AGEP associated with the use of clindamycin. We present these five cases and provide support for this association from the Lareb database, the database of the WHO Collaborating Centre for International Drug Monitoring (Vigibase™), the database of the European Medicine Agency (Eudravigilance), and from a mini review of the literature.",
"affiliations": "1Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch, the Netherlands.",
"authors": "Smeets|T J L|TJ|;Jessurun|N|N|;Härmark|L|L|;Kardaun|S H|SH|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002981:Clindamycin",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "74(10)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000038:Abscess; D056150:Acute Generalized Exanthematous Pustulosis; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002981:Clindamycin; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010304:Paronychia; D018805:Sepsis; D012852:Sinusitis; D014069:Tonsillitis",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "421-428",
"pmc": null,
"pmid": "27966434",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clindamycin-induced acute generalised exanthematous pustulosis: five cases and a review of the literature.",
"title_normalized": "clindamycin induced acute generalised exanthematous pustulosis five cases and a review of the literature"
} | [
{
"companynumb": "NL-MYLANLABS-2017M1003940",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLINDAMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective.\n\n\n\nBoth 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double-blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20-50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children's Depression Rating Scale-Revised (CDRS-R).\n\n\n\nA total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26.\n\n\n\nDesvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study.",
"affiliations": "Finger Lakes Clinical Research, Rochester, New York.;IPS Research, Oklahoma City, Oklahoma.;Pfizer Inc., Collegeville, Pennsylvania.;Pfizer Inc., Collegeville, Pennsylvania.;Pfizer Inc., Collegeville, Pennsylvania.;Pfizer Inc., Groton, Connecticut.;Pfizer Inc., New York, New York.",
"authors": "Atkinson|Sarah|S|0000-0001-6971-7112;Thurman|Louise|L|;Ramaker|Sara|S|;Buckley|Gina|G|;Jones|Sarah Ruta|SR|;England|Richard|R|;Wajsbrot|Dalia|D|",
"chemical_list": "D000928:Antidepressive Agents; D000069468:Desvenlafaxine Succinate",
"country": "United States",
"delete": false,
"doi": "10.1017/S1092852918001128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-8529",
"issue": "24(5)",
"journal": "CNS spectrums",
"keywords": "Adolescents; antidepressant; children; clinical trial; safety",
"medline_ta": "CNS Spectr",
"mesh_terms": "D000293:Adolescent; D000928:Antidepressive Agents; D002648:Child; D003865:Depressive Disorder, Major; D000069468:Desvenlafaxine Succinate; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D000069451:Long Term Adverse Effects; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "9702877",
"other_id": null,
"pages": "496-506",
"pmc": null,
"pmid": "30419989",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety, Tolerability, and Efficacy of Desvenlafaxine in Children and Adolescents with Major Depressive Disorder: Results from Two Open-Label Extension Trials.",
"title_normalized": "safety tolerability and efficacy of desvenlafaxine in children and adolescents with major depressive disorder results from two open label extension trials"
} | [
{
"companynumb": "US-PFIZER INC-2016156354",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DESVENLAFAXINE SUCCINATE"
},
"drugadditional":... |
{
"abstract": "A 26-year-old man undergoing therapy with 45 mg ustekinumab (Stelara) for chronic psoriasis vulgaris was referred by his general practitioner to an infectious diseases department for fatigue, fever, night sweating, generalised lymphadenomegaly and unexplained weight loss. Physical examination revealed bilateral occipital, cervical, axillary and inguinal lymphadenomegalies in addition to splenomegaly. Preliminary investigation revealed elevated Plasmodium lactate dehydrogenase and an inversion of the CD4/CD8 ratio. Whole-body spiral CT scanning with and without contrast showed splenomegaly and highlighted supradiaphragmatic and subdiaphragmatic lymphadenopathies. A complete Infectious Disease Test Panel revealed high levels of anti-Toxoplasma gondii antibodies. Immunoglobulin G avidity was negative. Peripheral blood lymphocyte phenotyping was performed to exclude underlying lymphatic neoplasia. The diagnosis of severe acute toxoplasmosis infection in the setting of immune response modifiers was made. Ustekinumab was suspended indefinitely and the patient underwent monthly serological tests to monitor the immune response until all symptoms resolved and the serological testing was negative for Toxoplasma.",
"affiliations": "Facolta di Medicina, Universita degli Studi di Pavia Facolta di Medicina e Chirurgia, Pavia, Lombardia, Italy.;Facolta di Medicina, Universita degli Studi di Pavia Facolta di Medicina e Chirurgia, Pavia, Lombardia, Italy.",
"authors": "Muslimani|Muhammad A|MA|;Di Palma-Grisi|James|J|http://orcid.org/0000-0001-6826-5572",
"chemical_list": "D003879:Dermatologic Agents; D000069549:Ustekinumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230415",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "immunological products and vaccines; infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D003879:Dermatologic Agents; D006801:Humans; D008297:Male; D011565:Psoriasis; D014122:Toxoplasma; D014123:Toxoplasmosis; D000069549:Ustekinumab",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31420435",
"pubdate": "2019-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30656642;28893407;16287762;12055206;26528819;22955326;26385522;29693053;25145755;8296196;25970800;28207934;10763053;26121196;30460322",
"title": "Severe acute toxoplasmosis infection following ustekinumab treatment in a patient with psoriasis vulgaris.",
"title_normalized": "severe acute toxoplasmosis infection following ustekinumab treatment in a patient with psoriasis vulgaris"
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"companynumb": "IT-JNJFOC-20190900495",
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"activesubstancename": "USTEKINUMAB"
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"abstract": "Disseminated mycobacterium avium complex (MAC) causing protein-losing enteropathy (PLE) due to intestinal lymphangiectasia (IL) in a non-HIV immunocompromised state is extremely rare. We present a case of 56-year-old male who was evaluated for worsening dyspnea and found to have right-sided chylous pleural effusion as well as worsening abdominal and retroperitoneal lymphadenopathy. He had a history of psoriasis for which hewas on etanercept and alefacept which were stopped two years prior to the presentation. The evaluation revealed a MAC infection in his lymph nodes--a low CD4 count but negative for HIV. He was started on MAC therapy. He subsequently developed noninfectious diarrhea, Hypoalbuminemia, recurrentpleural effusions, ascites, and Pneumocystis jiroveci pneumonia (PJP). Despite appropriate antibiotics and management--including total parental nutrition (TPN) with a medium-chain triglyceride enriched low fat diet--the patient's clinical condition deteriorated rapidly resulting in death.",
"affiliations": null,
"authors": "Konjeti|Venkata Rajesh|VR|;Paluri|Sravanthi|S|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D012709:Serum Albumin; D004977:Ethambutol; D017291:Clarithromycin; D012293:Rifampin",
"country": "United States",
"delete": false,
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"issn_linking": "0010-6178",
"issue": "78(6)",
"journal": "Connecticut medicine",
"keywords": null,
"medline_ta": "Conn Med",
"mesh_terms": "D000904:Antibiotics, Antitubercular; D001706:Biopsy; D018791:CD4 Lymphocyte Count; D002915:Chylous Ascites; D017291:Clarithromycin; D004977:Ethambutol; D017809:Fatal Outcome; D006801:Humans; D008201:Lymphangiectasis, Intestinal; D008297:Male; D008875:Middle Aged; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D010996:Pleural Effusion; D011504:Protein-Losing Enteropathies; D012293:Rifampin; D012709:Serum Albumin; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0372745",
"other_id": null,
"pages": "335-7",
"pmc": null,
"pmid": "25672059",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated mycobacterium avium complex as protein-losing enteropathy in a non-HIV patient.",
"title_normalized": "disseminated mycobacterium avium complex as protein losing enteropathy in a non hiv patient"
} | [
{
"companynumb": "US-AMGEN-USASP2012072263",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstancename": "ALEFACEPT"
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"abstract": "Patients with immune-mediated diseases treated with CD20 inhibitors may have worse COVID-19 outcomes due to impaired humoral immunity, but differences versus the general population are unknown.\nWe identified patients with immune-mediated diseases who received CD20 inhibitors within one year prior to the index date of PCR-confirmed COVID-19 between January 31, 2020, and January 31, 2021. Comparators with COVID-19 were matched up to 5:1 by age, sex, and PCR date. Hazard ratios (HRs) and 95% confidence intervals (CIs) for hospitalization, mechanical ventilation, and death in CD20 inhibitor users versus comparators were estimated using Cox regression.\nWe identified 114 cases with COVID-19 who had received CD20 inhibitors for immune-mediated diseases (mean age 55 years, 70% female) and 559 matched comparators with COVID-19 (mean age 54 years, 70% female). CD20 inhibitor-treated cases had higher mortality (aHR 2.16; 95% CI: 1.03 to 4.54) than matched comparators. Risks of hospitalization (aHR 0.88; 95% CI: 0.62 to 1.26) and mechanical ventilation (aHR 0.82; 95% CI: 0.36 to 1.87) were similar. Similar trends were seen in analyses according to type of indication (e.g., rheumatic or neurologic disease) and duration of CD20 inhibitor use (<1 or ≥1 year), and after excluding patients with interstitial lung disease, cancer, and those on glucocorticoids prior to COVID-19 diagnosis.\nPatients who received CD20 inhibitors for immune-mediated diseases prior to COVID-19 had higher mortality following COVID-19 than matched comparators, highlighting the urgent need to mitigate excess risks in CD20 inhibitor users during the ongoing pandemic.\nWhat is already known about this subject?: Patients with immune-mediated diseases treated with CD20 inhibitors may have worse COVID-19 outcomes than those treated with other immunomodulatory medications, but differences compared to the general population are unknown.What does this study add?: CD20 inhibitor-treated cases had over two-fold higher risk of mortality than matched general population comparators, although risks of hospitalization and mechanical ventilation were similar.How might this impact on clinical practice or future developments?: There is an urgent need for risk mitigation strategies, such as SARS-CoV-2 monoclonal antibodies or booster vaccinations, for patients with immune-mediated diseases treated with CD20 inhibitors during the ongoing COVID-19 pandemic.",
"affiliations": null,
"authors": "Patel|Naomi J|NJ|;D'Silva|Kristin M|KM|;Hsu|Tiffany Y-T|TY|;DiIorio|Michael|M|;Fu|Xiaoqing|X|;Cook|Claire|C|;Prisco|Lauren|L|;Martin|Lily|L|;Vanni|Kathleen M M|KMM|;Zaccardelli|Alessandra|A|;Zhang|Yuqing|Y|;Sparks|Jeffrey A|JA|;Wallace|Zachary S|ZS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1101/2021.08.05.21261643",
"fulltext": "\n==== Front\nmedRxiv\nMEDRXIV\nmedRxiv\nCold Spring Harbor Laboratory\n\n34401883\n10.1101/2021.08.05.21261643\npreprint\n1\nArticle\nCOVID-19 Outcomes Among Users of CD20 Inhibitors for Immune-Mediated Diseases: A Comparative Cohort Study\nPatel Naomi J. MD *‡\nD’Silva Kristin M. MD, MPH *‡§\nHsu Tiffany Y-T. MD, PhD ∥\nDiIorio Michael MD ∥\nFu Xiaoqing MS ‡§\nCook Claire MPH ‡§\nPrisco Lauren BA ∥\nMartin Lily BS ∥\nVanni Kathleen M.M. BA ∥\nZaccardelli Alessandra MS ∥\nZhang Yuqing ScD ‡§\nSparks Jeffrey A. MD, MMSc †∥\nWallace Zachary S. MD, MSc †‡§\n‡ Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA\n§ Clinical Epidemiology Program, Mongan Institute, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA\n∥ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, MA, USA\nAll at Harvard Medical School, Boston, MA.\n\nContributorship statement: NJP, KMD, TYH, MDI, JAS, and ZSW designed the study, were responsible for the acquisition, analysis, and interpretation of data, and drafted and revised the article. CC, LP, LM, KMMV and AZ were involved in data acquisition and revision of the manuscript. XF was involved in data analysis and interpretation and revision of the manuscript. YZ was involved in data interpretation and revision of the manuscript. All authors approved the final version of the article.\n\n* These authors contributed equally to this work (co-first authors).\n\n† These authors contributed equally to this work (co-last authors).\n\nCorresponding author: Zachary S. Wallace, MD, MSc, Clinical Epidemiology Program, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, 100 Cambridge Street, 16th Floor, Boston, MA 02114, 617-724-2507, zswallace@mgh.harvard.edu, @zach_wallace_md\n09 8 2021\n2021.08.05.21261643https://creativecommons.org/licenses/by-nd/4.0/ This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.\nnihpp-2021.08.05.21261643.pdf\nObjective:\n\nPatients with immune-mediated diseases treated with CD20 inhibitors may have worse COVID-19 outcomes due to impaired humoral immunity, but differences versus the general population are unknown.\n\nMethods:\n\nWe identified patients with immune-mediated diseases who received CD20 inhibitors within one year prior to the index date of PCR-confirmed COVID-19 between January 31, 2020, and January 31, 2021. Comparators with COVID-19 were matched up to 5:1 by age, sex, and PCR date. Hazard ratios (HRs) and 95% confidence intervals (CIs) for hospitalization, mechanical ventilation, and death in CD20 inhibitor users versus comparators were estimated using Cox regression.\n\nResults:\n\nWe identified 114 cases with COVID-19 who had received CD20 inhibitors for immune-mediated diseases (mean age 55 years, 70% female) and 559 matched comparators with COVID-19 (mean age 54 years, 70% female). CD20 inhibitor-treated cases had higher mortality (aHR 2.16; 95% CI: 1.03 to 4.54) than matched comparators. Risks of hospitalization (aHR 0.88; 95% CI: 0.62 to 1.26) and mechanical ventilation (aHR 0.82; 95% CI: 0.36 to 1.87) were similar. Similar trends were seen in analyses according to type of indication (e.g., rheumatic or neurologic disease) and duration of CD20 inhibitor use (<1 or ≥1 year), and after excluding patients with interstitial lung disease, cancer, and those on glucocorticoids prior to COVID-19 diagnosis.\n\nConclusions:\n\nPatients who received CD20 inhibitors for immune-mediated diseases prior to COVID-19 had higher mortality following COVID-19 than matched comparators, highlighting the urgent need to mitigate excess risks in CD20 inhibitor users during the ongoing pandemic.\n\nimmune-mediated diseases\nCOVID-19\ncoronavirus\nrituximab\nCD20 inhibitors\n==== Body\nIntroduction\n\nRisk of severe coronavirus disease 2019 (COVID-19) outcomes may vary among patients with immune-mediated diseases as a result of disease activity, use of immunosuppressive medications, and comorbid conditions (1–6). Anti-CD20 monoclonal antibodies such as rituximab and ocrelizumab are used to treat immune-mediated autoimmune diseases including rheumatoid arthritis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and multiple sclerosis, among other conditions. CD20 inhibitors cause elimination of circulating pre-B and B-cells, which results in an impaired immune response to COVID-19 (7, 8).\n\nResults from multiple disease-specific voluntary registries have shown that, compared to patients with immune-mediated diseases on other immunosuppressive or immunomodulatory medications, patients receiving CD20 inhibitors have increased odds of severe COVID-19 outcomes and death (5, 9–11). The risk of severe disease may be particularly high in patients who receive these therapies shortly before contracting COVID-19 (10). These registry data likely impact clinical practice but have limitations, including reporting bias and missing data regarding details of CD20 inhibitor use (e.g., duration of exposure). Additionally, while comparisons of CD20 inhibitor users to patients on other immunosuppressive treatments can address confounding by indication, it is unclear how the treatments used as the reference group in these studies impact the risk of poor COVID-19 outcomes compared to the general population. Therefore, interpretations of estimates generated from prior studies are limited, and the risk of severe COVID-19 outcomes among patients with immune-mediated diseases treated with CD20 inhibitors compared to the general population is poorly understood.\n\nDelays in CD20 inhibitor treatment to minimize COVID-19 risk put patients at risk for disease flare, irreversible organ damage, and disease-related death in some cases. Thus, additional data regarding COVID-19 risks among patients with immune-mediated diseases treated with CD20 inhibitors are needed to inform management decisions during the ongoing pandemic. Here, we evaluate the risk of severe COVID-19 outcomes in patients with immune-mediated diseases treated with CD20 inhibitors versus general population comparators.\n\nMethods\n\nStudy population\n\nMass General Brigham (MGB) is a large, multi-center healthcare system with 14 hospitals, including two tertiary care hospitals (Massachusetts General Hospital and Brigham and Women’s Hospital), and multiple primary and specialty outpatient centers in the greater Boston, Massachusetts, area. Using the MGB centralized data warehouse Research Patient Data Registry (RPDR)(12), we identified patients seen at MGB who were ≥18 years of age and had a positive electronic health record (EHR) flag for SARS-CoV-2 (determined by positive molecular testing at MGB or externally, as documented by infection control) between January 31, 2020, and January 31, 2021, and had received a CD20 inhibitor (rituximab, ocrelizumab, ofatumumab, or obinutuzumab) within one year prior to the date of the first positive COVID-19 test (index date). We manually reviewed the EHR to confirm COVID-19 diagnosis and receipt of a CD20 inhibitor prior to COVID-19 diagnosis. Because the RPDR screen only identified patients who received CD20 inhibitors within MGB, we also included patients from our physician-reported cohort of patients with rheumatic disease and confirmed COVID-19 infection, which we have collected from MGB rheumatologists since March 2020 (Figure 1). Some of the included cases have been included in prior studies but the observations made in this analysis in comparison to the general population are novel and have not been previously reported (1, 2, 4, 5). Given that our study was focused on patients with immune-mediated diseases, we excluded patients who received CD20 inhibitors for indications related to malignancy or organ transplantation. This study was approved by the MGB Institutional Review Board (2020P000833). Patients were not involved in the design, conduct, or reporting of this study.\n\nComparator Identification\n\nEach person with an immune-mediated disease treated with a CD20 inhibitor was matched to up to 5 comparators who had not received CD20 inhibitors from the same COVID-19-positive MGB population, based on age (± 5 years), sex, and the index date (± 5 days). We matched by date of COVID-19 diagnosis because testing criteria and treatment strategies changed over time.\n\nCovariates\n\nFor the CD20 inhibitor users, clinical variables of interest were extracted from the EHR by manual EHR review, including the indication for the CD20 inhibitor and dates of initial and most recent CD20 inhibitor administration. Other covariates of interest including immune-mediated disease diagnosis and duration, concomitant immunomodulatory medications (including specific dose of any glucocorticoid when available), and disease activity level (based on global assessment by the treating provider as documented in the EHR) were also obtained from EHR review.\n\nFor CD20 inhibitor users and comparators, additional variables were extracted from the COVID-19 Data Mart (13), an EHR-based data enclave established by MGB that includes all patients diagnosed with COVID-19. Covariates extracted from the COVID-19 Data Mart included demographics (age, sex, and self-identified race/ethnicity), smoking status, and medical comorbidities. Baseline characteristics including demographics, comorbidities, smoking history, and body mass index (BMI) were assessed in the one year prior to the index date, and the Charlson Comorbidity Index (CCI) (14) was calculated using all available data prior to the index date.\n\nOutcome Assessment\n\nMortality, the primary outcome, was ascertained from the Data Mart but also confirmed by manual EHR review and online searches of obituaries for all cases and comparators to capture deaths that may have occurred outside of the system (15). Secondary outcomes extracted from the Data Mart included hospitalization and mechanical ventilation.\n\nSubgroup and Sensitivity Analyses\n\nWe performed several subgroup analyses in which we limited cases to those with rheumatic disease or neurologic indications (separate analyses), recent CD20 exposure (within 3 months of index date), short-term duration of CD20 inhibitor exposure (<1 year), and long-term duration of CD20 inhibitor exposure (≥1 year). In sensitivity analyses, we excluded patients with interstitial lung disease or cancer (separate analyses) since these are indications for CD20 inhibitor use in some rheumatic diseases and may be independently associated with COVID-19 severity. We also performed a sensitivity analysis in which we excluded patients who also used glucocorticoids at the time of COVID-19 infection since this may be independently associated with COVID-19 severity. In these subgroup and sensitivity analyses, included cases were compared to their general population comparators.\n\nStatistical Analysis\n\nCategorical variables are presented as number (percentage), and continuous variables are presented as mean ± standard deviation or median ± interquartile range, as appropriate. Continuous variables were compared using a two-sample t-test for continuous normally distributed variables or Wilcoxon test for continuous non-normally distributed variables. Categorical variables were compared using Chi-square tests.\n\nThe index date was the date of COVID-19 diagnosis by molecular testing. Person-days of follow-up were determined for each subject from the index date to the first of the following: occurrence of the outcome of interest, date of the last encounter at MGB, or end of the study period (3/2/2021, to allow at least 30 days of follow-up per person). We calculated incidence rates per 1000 days by dividing the number of events by the number of person-days. Multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for hospitalization, mechanical ventilation, and death in separate models, comparing CD20 inhibitor users to non-users. The first multivariable model adjusted for age. The second multivariable model adjusted for age and race. The third multivariable model (the fully-adjusted model) adjusted for age, race, BMI, and CCI (dichotomized as < 2 or ≥2). Because of a limited number of observed outcomes in some subgroup and sensitivity analyses, only unadjusted or partially adjusted models are reported in some instances (i.e., when <7 outcomes per covariate were present, adjusted models were not performed). For analyses of risk of hospitalization and mechanical ventilation, death was treated as a competing risk using a cause-specific model yielding subdistribution HRs (16). The level of significance was set as a two-tailed p<0.05, and statistical analyses were completed using SAS statistical software (version 9.4; SAS Institute, Inc.).\n\nResults\n\nWe identified 114 patients with COVID-19 who had an immune-mediated disease treated with a CD20 inhibitor within 12 months preceding COVID-19 diagnosis for a non-oncologic and non-transplant indication and 559 matched comparators. The mean age was 55 years in the CD20 inhibitor group and 54 years in the comparator group, and 70% were female in each group (Table 1). The distribution of race/ethnicity was similar between groups. The Charlson Comorbidity Index was higher in the CD20 inhibitor group (median of 1 vs. 0, p=0.001).\n\nAmong the immune-mediated disease patients who received a CD20 inhibitor, 90 (79%) received rituximab and 26 (23%) received ocrelizumab; two patients had received rituximab initially but were later switched to ocrelizumab (Table 2). The most common indication for CD20 inhibitor use was rheumatic disease (54 [47%]), followed by neurologic conditions (43 [38%]) (Table 2). The duration of CD20 inhibitor use was <1 year in 33 (29%) patients, 1–3 years in 51 (45%), and >3 years in 30 (26%). Forty-eight patients (42%) had received their most recent CD20 inhibitor infusion within three months of COVID-19 diagnosis.\n\nPatients with immune-mediated disease treated with CD20 inhibitors had a higher risk of death (12 [11%] vs. 21 [4%]; adjusted HR 2.16; 95% CI: 1.03 to 4.54) than matched comparators. The risks of hospitalization (35 [31%] vs. 123 [22%]; adjusted HR 0.88; 95% CI: 0.62 to 1.26) and mechanical ventilation (6 [5%] vs. 26 [5%]; adjusted HR 0.82; 95% CI: 0.36 to 1.87) were similar in both groups (Table 3). Of note, in both groups, more patients died than were mechanically ventilated (Supplemental Table 1). Among CD20 inhibitor users, 6 (5%##) had a code status that indicated “Do Not Intubate” and ultimately died compared with 10 (2##%) in the comparator group. These differences suggest that the risk of needing mechanical ventilation among CD20 inhibitor users is likely an underestimate. No deaths were noted to be directly related to the immune-mediated disease. Among immune-mediated disease patients on CD20 inhibitors who developed COVID-19, 9 patients (8%) had COVID-19 antibodies tested after COVID-19 diagnosis (median 70 days, IQR 35 to 87 days) for clinical indications. Of these 9 patients, 2 had positive COVID-19 antibodies, and 7 patients had negative COVID-19 antibodies.\n\nIn subgroup analyses, we found that there was a similar trend among patients with rheumatic disease (Table 4) as the indication for CD20 inhibitor use. We found numerically higher risk of death among patients with neurologic disease as the indication for CD20 inhibitor use, though analysis was limited by low number of events (Table 5). Similar trends were also observed among short- and long-term CD20 inhibitor users, those with recent (within 3 months) exposure to a CD20 inhibitor, and after excluding patients with interstitial lung disease, cancer, and those receiving glucocorticoids prior to COVID-19 diagnosis (Supplemental Tables 2–6). Our ability to detect significant differences and perform multivariable adjustment in these subgroup analyses was limited by the number of observed events.\n\nDiscussion\n\nIn this multicenter cohort study, we found an increased risk of death following COVID-19 infection among patients with immune-mediated disease treated with CD20 inhibitors compared to general population comparators. This association was observed among more recent CD20 inhibitor initiators as well as among patients who had been on long-standing CD20 inhibitor treatment. The results remained consistent in analyses adjusting for comorbidity burden and across sensitivity and subgroup analyses meant to further address potential confounders. These findings raise concern regarding the impact of CD20 inhibitor exposure on COVID-19 risk and the need to investigate strategies to mitigate this potential risk, especially given the poor response to vaccines observed among CD20 inhibitor users (17, 18).\n\nCD20 inhibitors have been a particular concern during the COVID-19 pandemic because the humoral immune response plays an important role in the response to SARS-CoV-2 infection (8, 19, 20). During the early phase of infection, high antibody titers are associated with higher levels of neutralizing antibodies to the receptor binding domain of the spike protein, and antibody titers are significantly higher in patients with shorter duration of SARS-CoV-2 RNA positivity (21, 22). To this end, there have been several reports of patients receiving CD20 inhibitors with subsequent prolonged courses of COVID-19 (22–26). Post-mortem studies of lymph nodes from patients with fatal COVID-19 showed the absence of germinal centers and a reduction in germinal center B and T cells, suggesting that a dysregulated adaptive immune response occurs in fatal COVID-19 (27). Lastly, patients treated with CD20 inhibitors had a 36-fold reduction in humoral responses compared to immunocompetent patients at 1–2 weeks after the second dose of SARS-CoV-2 mRNA vaccines (17, 18, 28). Further research is needed to determine if prophylactic and therapeutic strategies such as convalescent plasma or SARS-CoV-2 monoclonal antibody therapy may be beneficial in the prevention and treatment of COVID-19 in patients with B cell depletion (29, 30).\n\nIn light of the critical importance of antibody formation for a robust immune response to COVID-19, we had hypothesized that long-term CD20 inhibitor use would be associated with a greater risk of death compared to the general population because of more sustained B cell depletion. Instead, we found a similar risk among short-term (<1 year) and long-term (≥1 year) CD20 inhibitor users. It is possible that long-term CD20 inhibitor users are a generally healthier cohort who have previously tolerated CD20 inhibition well without infections or other complications, thus resulting in similar risk of severe COVID-19 compared to short-term CD20 inhibitor users. However, our observations may suggest that continuous B cell depletion versus more recent B cell depletion initiation may not have a differential impact on the critical immediate immunologic response that is blunted by CD20 inhibitors and needed to control infection (31, 32). We cannot rule out the possibility that small sample sizes may have limited the ability to detect a difference when comparing outcomes among short-term and long-term CD20 inhibitor users. Similar to Avouac et al., we also found a significantly higher risk of death among those who had received their most recent CD20 inhibitor close to the time of COVID-19 infection (10).\n\nDespite the increased risk of death, we did not find any statistical difference in risk of hospitalization or mechanical ventilation between those who received CD20 inhibitors and matched comparators. This discrepancy between increased risk of death but not mechanical ventilation may be explained by the use of “Do Not Intubate” orders. These orders may have led to an underestimate of the effect of CD20 inhibitor use on mechanical ventilation risk if the proportion needing (but not receiving) mechanical ventilation was actually greater among the CD20 inhibitor users, as our findings suggest. We further conducted subgroup analyses to better understand specific factors driving the increased risk of death with CD20 inhibitor exposure and found that the risk was attenuated in multivariable models but similar trends persisted despite low event rates. Indeed, our findings persisted when we excluded patients with interstitial lung disease or malignancy, two populations commonly prescribed rituximab for immune-mediated conditions who might be at particularly high risk for poor COVID-19 outcomes because of other medical comorbidities.\n\nOur study has multiple strengths. First, we systematically identified patients who received CD20 inhibitors for a variety of immune-mediated conditions in a large healthcare system, increasing the generalizability of our observations to the diverse populations who use CD20 inhibitors. Second, details regarding CD20 inhibitor indication, length of exposure, and COVID-19 outcomes were available, in contrast to prior registry-based studies.\n\nDespite these strengths, our study has certain limitations. First, though our findings persisted after adjustment for covariates, there may be residual confounding by CD20 inhibitor indication, concomitant glucocorticoid use, or disease severity, as CD20 inhibitors are often used as initial induction therapy for severe immune-mediated diseases (e.g., ANCA-associated vasculitis) or as treatment for diseases that have been refractory to other therapies (e.g., rheumatoid arthritis). However, our findings remained robust in sensitivity analyses and subgroup analyses that addressed the potential impact of residual confounding. Regardless, one should cautiously interpret these results as applying to the population of patients with immune-mediated diseases treated with CD20 inhibitors in the context of the known effects of CD20 inhibitors on B cell responses and antibody production. Second, multivariable adjustment was limited in some subgroup and sensitivity analyses due to low event rates. However, the observed trends remained consistent with those observed in the primary analysis.\n\nIn conclusion, we found an increased risk of death in patients with immune-mediated diseases who had received CD20 inhibitors prior to COVID-19 diagnosis. CD20 inhibitors are the standard of care for induction and maintenance treatment of multiple immune-mediated diseases, some of which have few alternatives. Additional studies are needed to evaluate the potential use of anti-SARS-CoV-2 monoclonal antibodies, booster vaccinations, and other strategies to reduce the risk of poor COVID-19 outcomes in this population. Providers should interpret these results cautiously and weigh the risks and benefits of ongoing CD20 inhibitor use on an individual basis using shared decision-making.\n\nSupplementary Material\n\nSupplement 1\n\nFunding/Support:\n\nNJP is supported by the National Institutes of Health Ruth L. Kirschstein Institutional National Research Service Award [T32-AR-007258]. TYH is supported by the National Institutes of Health Ruth L. Kirschstein Institutional National Research Service Award [T32-AR-007530]. JAS is funded by NIH/NIAMS (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253, and P30 AR072577), the Rheumatology Research Foundation R Bridge Award, the Brigham Research Institute, and the R. Bruce and Joan M. Mickey Research Scholar Fund. ZSW is funded by NIH/NIAMS [K23AR073334 and R03AR078938].\n\nFigure 1. Identification of CD20 inhibitor users with COVID-19.\n\nCOVID-19, Coronavirus Disease 2019; RPDR, Research Patient Data Repository; PCR, Polymerase Chain Reaction, EHR, Electronic Health Record\n\nTable 1. Clinical characteristics of immune-mediated cases with CD20 inhibitor use prior to COVID-19 and age, sex, and COVID-19 diagnosis date-matched comparators.\n\nCharacteristic\tCD20 Inhibitor-Treated Immune-Mediated Cases (n=114)\tMatched Comparators (n=559)\tp-value\t\nAge, years, mean ± SD\t55 ± 15\t54 ± 15\t0.44\t\nFemale, n (%)\t80 (70)\t391 (70)\t0.96\t\nRace, n (%)\t\t\t\t\n White\t69 (61)\t316 (57)\t0.43\t\n Black or African American\t16 (14)\t70 (13)\t\t\n Asian\t4 (4)\t12 (2)\t\t\n Other\t25 (22)\t161 (29)\t\t\nHispanic or Latinx ethnicity, n (%)\t6 (5)\t46 (8)\t0.28\t\nBody mass index, kg/m2, mean ± SD\t28.7 ± 6.2\t29.7 ± 6.7\t0.16\t\nSmoking status, n (%)\t\t\t\t\n Never\t66 (58)\t271 (48)\t0.06\t\n Former\t29 (25)\t126 (23)\t\t\n Current\t3 (3)\t18 (3)\t\t\n Unknown\t16 (14)\t144 (26)\t\t\nCharlson Comorbidity Index, median (IQR)\t1 (0, 2)\t0 (0, 1)\t0.001\t\nComorbidities, n (%)\t\t\t\t\n Hypertension\t45 (39)\t120 (21)\t<0.0001\t\n Diabetes\t13 (11)\t56 (10)\t0.66\t\n Coronary artery disease\t8 (7)\t21 (4)\t0.12\t\n Heart failure\t8 (7)\t11 (2)\t0.003\t\n Asthma\t10 (9)\t32 (6)\t0.22\t\n Chronic obstructive pulmonary disease\t6 (5)\t6 (1)\t0.002\t\n Obstructive sleep apnea\t2 (2)\t25 (4)\t0.18\t\n Chronic kidney disease\t12 (11)\t26 (5)\t0.01\t\n Interstitial lung disease\t25 (22)\t55 (10)\t< 0.001\t\n Malignancy\t11 (10)\t6 (1)\t< 0.001\t\nCOVID-19, Coronavirus Disease 2019; SD, standard deviation; IQR, interquartile range.\n\nTable 2. Immune-mediated disease characteristics of cases with CD20 inhibitor use prior to COVID-19.\n\nCharacteristic\tCD20 Inhibitor-Treated Immune-Mediated Cases (n=114)\t\nIndication for CD20 inhibitor, n (%)\t\t\n Rheumatic condition only\t54 (47)\t\n Inflammatory arthritis*\t19 (17)\t\n Vasculitis\t17 (15)\t\n Systemic lupus erythematosus\t7 (6)\t\n Inflammatory myositis\t6 (5)\t\n Other rheumatic condition†\t3 (3)\t\n Multiple primary rheumatic diagnoses‡\t2 (2)\t\n Neurologic condition\t43 (38)\t\n Multiple sclerosis\t33 (29)\t\n Neuromyelitis optica\t4 (4)\t\n Other neurologic condition§\t6 (5)\t\n Ocular inflammation\t3 (3)\t\n Hematologic condition only\t5 (4)\t\n Thrombotic thrombocytopenic purpura\t3 (3)\t\n Autoimmune hemolytic anemia\t2 (2)\t\n Autoimmune hepatitis\t3 (3)\t\n Both rheumatic and hematologic conditions∥\t2 (2)\t\n Other miscellaneous conditions¶\t4 (4)\t\nImmune-mediated disease duration, years, median (IQR)\t6 (3, 15)\t\nImmune-mediated disease status\t\t\n Remission\t26 (23)\t\n Low activity\t58 (51)\t\n Moderate/high activity\t30 (26)\t\nType of CD20 inhibitor, n (%)**\t\t\n Rituximab or biosimilar\t90 (79)\t\n Ocrelizumab\t26 (23)\t\nDuration of CD20 inhibitor use, n (%)\t\t\n <1 year\t33 (29)\t\n 1–3 years\t51 (45)\t\n >3 years\t30 (26)\t\nMost recent CD20 inhibitor dose prior to COVID-19 onset, n (%)\t\t\n <3 months\t48 (42)\t\n 3–6 months\t44 (39)\t\n 6–12 months\t22 (19)\t\nConcomitant immunomodulatory medications at COVID-19 onset, n (%)\t\t\n Mycophenolate mofetil\t8 (7)\t\n Methotrexate\t6 (5)\t\n Hydroxychloroquine\t5 (4)\t\n Leflunomide\t3 (3)\t\n Other immunomodulatory medication††\t6 (5)\t\nOral glucocorticoid\t35 (31)\t\n Prednisone-equivalent daily dose mg, median (IQR)\t7.5 (5.0, 15.0)\t\n* Includes rheumatoid arthritis, other inflammatory arthritis, and juvenile idiopathic arthritis.\n\n† Includes Sjögren’s syndrome and IgG4-related disease.\n\n‡ Includes one patient with both rheumatoid arthritis and vasculitis and one patient with both inflammatory myopathy and inflammatory arthritis\n\n§ Includes myasthenia gravis, autoimmune encephalitis, acute disseminated encephalomyelitis, cavernous sinus mass, and small fiber polyneuropathy.\n\n∥ Includes a patient with rheumatoid arthritis and immune thrombocytopenic purpura (ITP), and a patient with vasculitis and antiphospholipid syndrome\n\n¶ Includes pemphigus vulgaris, 2 membranous nephropathy, and autoimmune interstitial lung disease.\n\n** No individuals were on obinutuzumab or ofatumumab. Two individuals were initially on rituximab and then transitioned to ocrelizumab.\n\n†† Includes azathioprine (n=1), cyclophosphamide (n=2), sulfasalazine (n=1), and tacrolimus (n=2).\n\nTable 3. COVID-19 outcomes in immune-mediated cases treated with CD20 inhibitors versus matched comparators.\n\nOutcomes\tCD20 Inhibitor-Treated Immune-Mediated Cases (n=114)\tMatched Comparators (n=559)\t\nHospitalization, n (%)\t35 (31)\t123 (22)\t\n Total follow-up time (person-days)\t11658\t62942\t\n Incidence rate/1000 days (95% CI)\t3.0 (2.0 to 4.0)\t2.0 (1.6 to 2.3)\t\n Unadjusted HR (95% CI)\t1.32 (0.96 to 1.80)\tRef\t\n Adjusted model 1 HR (95% CI)*\t1.24 (0.90 to 1.70)\tRef\t\n Adjusted model 2 HR (95% CI)\t1.16 (0.85 to 1.60)\tRef\t\n Adjusted model 3 HR (95% CI)\t0.88 (0.62 to 1.26)\tRef\t\nMechanical ventilation, n (%)\t6 (5)\t26 (5)\t\n Total follow-up time (person-days)\t14755\t78729\t\n Incidence rate/1000 days (95% CI)\t0.4 (0.1 to 0.7)\t0.3 (0.2 to 0.5)\t\n Unadjusted HR (95% CI)\t1.10 (0.48 to 2.52)\tRef\t\n Adjusted model 1 HR (95% CI)\t1.18 (0.50 to 2.79)\tRef\t\n Adjusted model 2 HR (95% CI)\t1.49 (0.63 to 3.49)\tRef\t\n Adjusted model 3 HR (95% CI)\t0.82 (0.36 to 1.87)\tRef\t\nDeath, n (%)\t12 (11)\t21 (4)\t\n Total follow-up time (person-days)\t15818\t84172\t\n Incidence rate/1000 days (95% CI)\t0.8 (0.3 to 1.2)\t0.2 (0.1 to 0.4)\t\n Unadjusted HR (95% CI)\t2.86 (1.51 to 5.41)\tRef\t\n Adjusted model 1 HR (95% CI)\t2.86 (1.52 to 5.37)\tRef\t\n Adjusted model 2 HR (95% CI)\t2.42 (1.18 to 4.93)\tRef\t\n Adjusted model 3 HR (95% CI)-\t2.16 (1.03 to 4.54)\tRef\t\nHR, hazard ratio; CI, confidence interval; BMI, body mass index; CCI, Charlson comorbidity index, Ref, reference.\n\n* Model 1 adjusted for age. Model 2 adjusted for age and race. Model 3 adjusted for age, race, BMI, and CCI (dichotomized as <2 or ≥2).\n\nTable 4. Risk of death following COVID-19 in patients treated with CD20 inhibitors for rheumatic disease indications versus comparators.\n\n\tCD20 Inhibitor-Treated Rheumatic Disease Cases (n=56)*\tMatched Comparators (n=276)\t\nDeaths, n (%)\t7 (13)\t15 (5)\t\nTotal follow-up time (person-days)\t7917\t42560\t\nIncidence rate/1000 days (95% CI)\t0.9 (0.2 to 1.5)\t0.4 (0.2 to 0.5)\t\nUnadjusted HR (95% CI)\t2.52 (1.07 to 5.90)\tRef\t\nAdjusted model 1 HR (95% CI)†\t2.42 (1.02 to 5.74)\tRef\t\nAdjusted model 2 HR (95% CI)\t2.02 (0.71 to 5.80)\tRef\t\nAdjusted model 3 HR (95% CI)‡\tNR\tRef\t\nHR, hazard ratio; CI, confidence interval; BMI, body mass index; CCI, Charlson comorbidity index; Ref, reference; NR, not reported\n\n* Rheumatic disease indication includes 54 patients with rheumatic disease indication only and 2 patients with combined rheumatic and hematologic indications.\n\n† Model 1 adjusted for age. Model 2 adjusted for age and race. Model 3 adjusted for age, race, BMI, and CCI (dichotomized as <2 or ≥2).\n\n‡ Model 3 not reported due to insufficient number of outcomes (<7 outcomes per adjusted covariate).\n\nTable 5. Risk of death following COVID-19 in patients treated with CD20 inhibitors for neurologic disease indications versus comparators.\n\n\tCD20 Inhibitor-Treated Neurologic Disease Cases (n=43)\tMatched Comparators (n=211)\t\nDeaths, n (%)\t2 (5)\t4 (2)\t\nTotal follow-up time (person-days)\t6551\t34051\t\nIncidence rate/1000 days (95% CI)\t0.3 (0.0 to 0.7)\t0.1 (0.0 to 0.2)\t\nUnadjusted HR (95% CI)\t2.41 (0.66 to 8.77)\tRef\t\nAdjusted model 1 HR (95% CI)*\tNR\tRef\t\nAdjusted model 2 HR (95% CI)\tNR\tRef\t\nAdjusted model 3 HR (95% CI)\tNR\tRef\t\nHR, hazard ratio; CI, confidence interval; BMI, body mass index; CCI, Charlson comorbidity index; Ref, reference; NR, not reported\n\n* Model 1 adjusted for age. Model 2 adjusted for age and race. Model 3 adjusted for age, race, BMI, and CCI (dichotomized as <2 or ≥2). Adjusted models not reported due to insufficient number of outcomes (<7 outcomes per adjusted covariate).\n\nKey Messages\n\nWhat is already known about this subject?\n\nPatients with immune-mediated diseases treated with CD20 inhibitors may have worse COVID-19 outcomes than those treated with other immunomodulatory medications, but differences compared to the general population are unknown.\n\nWhat does this study add?\n\nCD20 inhibitor-treated cases had over two-fold higher risk of mortality than matched general population comparators, although risks of hospitalization and mechanical ventilation were similar.\n\nHow might this impact on clinical practice or future developments?\n\nThere is an urgent need for risk mitigation strategies, such as SARS-CoV-2 monoclonal antibodies or booster vaccinations, for patients with immune-mediated diseases treated with CD20 inhibitors during the ongoing COVID-19 pandemic.\n\nCompeting interests: JAS reports research support from Bristol-Myers Squibb and consultancy fees from Bristol-Myers Squibb, Gilead, and Pfizer. ZSW reports research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio and MedPace. All other authors report no competing interests.\n==== Refs\nReferences\n\n1. D’Silva KM , Serling-Boyd N , Wallwork R , Clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US ‘hot spot’. Ann Rheum Dis. 2020;79 (9 ):1156–62. Epub 2020/05/28. doi: 10.1136/annrheumdis-2020-217888.32457048\n2. Serling-Boyd N , D’Silva KM , Hsu TY , Coronavirus disease 2019 outcomes among patients with rheumatic diseases 6 months into the pandemic. Ann Rheum Dis. 2020. Epub 2020/12/02. doi: 10.1136/annrheumdis-2020-219279.\n3. D’Silva KM , Jorge A , Cohen A , COVID-19 Outcomes in Patients with Systemic Autoimmune Rheumatic Diseases (SARDs) Compared to the General Population: A US Multi-Center Comparative Cohort Study. 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Khoury DS , Cromer D , Reynaldi A , Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nature Medicine. 2021;Advance online publication. doi: 10.1038/s41591-021-01377-8.\n\n",
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"title": "COVID-19 Outcomes Among Users of CD20 Inhibitors for Immune-Mediated Diseases: A Comparative Cohort Study.",
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"abstract": "Amiodarone is an iodine-based, potent antiarrhythmic drug bearing a structural resemblance to thyroxine (T4). It is known to produce thyroid abnormalities ranging from abnormal thyroid function testing to overt hypothyroidism or hyperthyroidism. These adverse effects may occur in patients with or without preexisting thyroid disease. Amiodarone-induced thyrotoxicosis (AIT) is a clinically recognized condition commonly due to iodine-induced excessive synthesis of thyroid, also known as type 1 AIT. In rare instances, AIT is caused by amiodarone-induced inflammation of thyroid tissue, resulting in release of preformed thyroid hormones and a hyperthyroid state, known as type 2 AIT. Distinguishing between the two states is important, as both conditions have different treatment implications; however, a mixed presentation is not uncommon, posing diagnostic and treatment challenges. We describe a case of a patient with amiodarone-induced type 2 hyperthyroidism and review the current literature on the best practices for diagnostic and treatment approaches.",
"affiliations": "Department of Internal Medicine, Marshfield Clinic, 1000 N. Oak Avenue, Marshfield, WI 54449, USA.;Department of Internal Medicine, Marshfield Clinic, 1000 N. Oak Avenue, Marshfield, WI 54449, USA.;Department of Endocrinology, Marshfield Clinic, Marshfield, WI 54449, USA.",
"authors": "Barvalia|Umang|U|;Amlani|Barkha|B|;Pathak|Ram|R|",
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"doi": "10.1155/2014/231651",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/231651Case ReportAmiodarone-Induced Thyrotoxic Thyroiditis: A Diagnostic and Therapeutic Challenge Barvalia Umang \n1\n\n*\nAmlani Barkha \n1\nPathak Ram \n2\n1Department of Internal Medicine, Marshfield Clinic, 1000 N. Oak Avenue, Marshfield, WI 54449, USA2Department of Endocrinology, Marshfield Clinic, Marshfield, WI 54449, USA*Umang Barvalia: barvalia.umang@gmail.comAcademic Editor: Grigorios Korosoglou\n\n2014 12 11 2014 2014 23165116 9 2014 23 10 2014 Copyright © 2014 Umang Barvalia et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Amiodarone is an iodine-based, potent antiarrhythmic drug bearing a structural resemblance to thyroxine (T4). It is known to produce thyroid abnormalities ranging from abnormal thyroid function testing to overt hypothyroidism or hyperthyroidism. These adverse effects may occur in patients with or without preexisting thyroid disease. Amiodarone-induced thyrotoxicosis (AIT) is a clinically recognized condition commonly due to iodine-induced excessive synthesis of thyroid, also known as type 1 AIT. In rare instances, AIT is caused by amiodarone-induced inflammation of thyroid tissue, resulting in release of preformed thyroid hormones and a hyperthyroid state, known as type 2 AIT. Distinguishing between the two states is important, as both conditions have different treatment implications; however, a mixed presentation is not uncommon, posing diagnostic and treatment challenges. We describe a case of a patient with amiodarone-induced type 2 hyperthyroidism and review the current literature on the best practices for diagnostic and treatment approaches.\n==== Body\n1. Introduction\nAmiodarone is a potent antiarrhythmic drug used in the treatment of various ventricular and supraventricular arrhythmias. It carries a structural resemblance to thyroxine (T4) and can produce a wide spectrum of thyroid gland dysfunctions. Amiodarone-induced thyrotoxicosis (AIT) is commonly due to iodine-induced excessive synthesis of thyroid, also known as type 1 AIT (AIT1). However, in rare instances, AIT is due to amiodarone-induced inflammation of the thyroid tissue resulting in release of preformed thyroid hormones or a hyperthyroid state, known as type 2 AIT (AIT2). Due to incomplete understanding of the pathogenesis, unreliable response to therapy, and lack of a systemic approach, AIT2 continues to challenge the clinical acumen of internists and endocrinologists. Besides thyroid function testing, ultrasonography, radioiodine uptake and scan, interleukin-6 (IL-6) level determination, and color flow Doppler sonography (CFDS) aid in diagnosis and assessing the response of AIT2 to therapy. Use of 99mTc-sestamibi (MIBI) scanning is emerging as a beneficial adjunct to diagnosis. The current literature still supports steroids as the mainstay for treatment of AIT2. Iopanoic acid and perchlorate are reasonable therapeutic options but have not been shown to provide benefit when used with steroids. Close monitoring is essential, as the onset of AIT2 has been found to be a predictor of adverse cardiovascular outcomes [1].\n\n2. Case Presentation\nA 63-year-old man had been on amiodarone therapy 200 mg/day for approximately 2 years for recurrent angina pain secondary to paroxysmal atrial fibrillation despite control of ventricular rate. He was referred to the endocrinology department for concerns of hyperthyroidism diagnosed during routine follow-up of thyroid function monitoring related to his exposure to amiodarone. He reported a 19-pound weight loss in the past year, some of it intentional, and worsening of a hand tremor that he had for years. He denied any other symptoms of hyperthyroidism.\n\nThe past medical history was significant for nonocclusive coronary artery disease, hypertension, morbid obesity, and peripheral vascular disease with claudication. His family history included a sister with thyroid-related symptomology, but he was not able to provide further details. The patient was alert, in no acute distress, with a body weight of 263 pounds. Examination of the thyroid gland did not reveal palpable nodules on either lobe. The gland moved freely during swallowing and was somewhat diffusely enlarged. No lymphadenopathy or tenderness was noted on palpation. Vital signs were normal with a blood pressure of 110/60 mm Hg. The remainder of the examination was unremarkable.\n\nThyroid function tests revealed a thyroid stimulating hormone (TSH) level of 0.01 mIU/mL (range 0.35–4.5 mIU/mL), free T4 of 2.7 ng/dL (range 0.6–1.2 ng/dL), and free T3 levels of 3.7 pg/mL (range 2.1–4.1 pg/mL). Thyroid ultrasound did not show hypervascularity (Figure 1). An ultrasound done 2 years previously had revealed a multinodular gland with a dominant right-sided 1.3 × 0.8 cm nodule that was found to be benign on fine needle aspiration biopsy. There was another 1.1 × 0.6 cm nodule on the left side that was not biopsied. The right-sided dominant nodule remained stable, and the left-side nodule had slightly increased to 1.2 cm in size. Radioiodine uptake and scan had 0.6% (range 4–20%) and 0.2% (range 5–30%) uptake at 4 hours and 24 hours, respectively, consistent with amiodarone-induced thyrotoxicosis in the clinical context (Figure 2). Screening for thyroglobulin antibody was normal at <20 IU/mL. The thyroglobulin level was 22.6 ng/mL, and IL-6 level was elevated at 8.63 pg/mL (range 0.31–5 pg/mL).\n\nAlthough none of the findings were diagnostic, they favored a diagnosis of AIT2, more so than the more common AIT1. The patient was treated with low-dose steroids (20 mg prednisone daily) for a month with deescalation of dosing following improvement in thyroid function tests. He reported improvement in the bilateral hand tremor, back to his baseline, and was euthyroid with TSH of 3.09 mIU/mL, free T4 of 1.0 ng/dL, and free T3 of 2.5 pg/mL during subsequent follow-up 3 months later. The patient remained euthyroid clinically and biochemically without recurrence of AIT, while continuing amiodarone therapy for 3 years following treatment of the AIT2.\n\n3. Discussion\nAmiodarone is used in treating various atrial and ventricular arrhythmias and is favored in patients with left ventricular dysfunction [2]. Due to the structural similarity with thyroid hormones and the iodine content in the medication, it is known to cause significant changes in thyroid function testing, often with a clinically significant impact [3].\n\n3.1. Mechanisms of Amiodarone-Related Thyroid Dysfunction\nAmiodarone inhibits type 1 5′-deiodinase activity in the liver/peripheral tissues, which may persist for weeks following withdrawal of the drug [4]. Further, the drug inhibits type 2 5′-deiodinase activity in the pituitary, which reduces conversion of T4 to T3 and increased TSH levels [5]. Whereas amiodarone has no effect on the metabolism (distribution and removal) of plasma T3 pool [6], the drug does inhibit thyroid hormone entry into circulation [7]. Table 1 summarizes the effects of amiodarone on thyroid function tests in euthyroid patients.\n\nDue to its intrinsic properties, amiodarone is associated more with hypothyroidism than thyrotoxicosis in iodine replete countries like the United Kingdom and the United States [8]. Pathogenesis of amiodarone-induced hyperthyroidism is still incompletely understood, which makes the diagnosis and treatment challenging. Two main types of AIT, with different mechanisms, have been described. AIT1 is due to iodine-induced excess synthesis and release of thyroid hormones, usually from abnormal thyroid glands. AIT2 is a form of destructive thyroiditis that leads to leakage of preformed hormones into the circulation. Though iodine excess may be an important pathogenic factor in both subtypes, some forms of AIT may be purely due to subacute thyroiditis and release of preformed hormones.\n\n3.2. Diagnoses of AIT2\nAIT usually has a sudden onset, presenting with a new or worsening arrhythmia, or it can be asymptomatic, especially in younger individuals [9, 10]. Because type 1 hyperthyroidism often occurs in patients with preexisting thyroid disease, the onset is within the first few months, whereas median time for occurrence of AIT2 is about 30 months following initiation of amiodarone therapy [11]. In either case, the initial evaluation should include the usual work-up for thyroid function including TSH, T3, T4, and antithyroid antibodies. Thyroid ultrasound with or without CFDS and radioiodine uptake (RAIU) and scan are useful in distinguishing the two AIT subtypes.\n\nIn AIT2, RAIU would be lower (<1%) compared to AIT1, where it is either normal or increased (>10%) [12]. In the United States, where most patients are iodine replete, RAIU can be low in both types of AIT, so CFDS is helpful in directing therapy [13, 14]. CFDS gives real time information on the blood flow inside the thyroid gland and its morphology. Due to follicular destruction, lymphocyte infiltration consequential to inflammatory responses seen in AIT2, the color flow on ultrasound would show increased vascularity and blood flow velocity [15]. These findings are indicative of a hyperfunctioning gland and are also seen in untreated Grave's disease. CFDS can serve to facilitate decision making due to its relative ease of use, ability to obtain faster results, and the noninvasive nature of the study, especially in patients with life-threatening tachyarrhythmias.\n\nMIBI scanning has been used for detection of hyperfunctioning parathyroid adenomas and some malignant or benign thyroid tumors. There has been recent interest in its use in distinguishing between the two types of AIT. A small study of 20 patients found that it was superior to CFDS in differentiating between AIT1 and AIT2 [16].\n\nInterleukin-6 (IL-6), a cytokine associated with inflammation, was proposed as a biomarker to distinguish between amiodarone-induced thyroiditis and iodine-induced hyperthyroidism. Marked elevations of IL-6 levels correlated closely with subacute thyroiditis in patients without preexisting thyroid disease. Normal to mild elevations of IL-6 were also found in patients with AIT1 [17]. Table 2 presents a comparative summary between the two types of amiodarone-induced hyperthyroidism.\n\n3.3. Treatment\nThe best available treatment option for AIT2 is oral glucocorticoids. They act by reducing the inflammation in the thyroid gland, the primary pathologic mechanism in AIT2, and also reduce the peripheral conversion of T4 to T3 [18]. Baseline free T4 concentrations and thyroid gland volume can predict delayed responders to glucocorticoids. In individuals at high risk, this may help identify individuals in whom surgery and/or iopanoic acid should be considered early in the course of the disease [19].\n\nIopanoic acid, an oral cholecystographic agent (OCA), acts by inhibiting type 1 5′-deiodinase activity, the enzyme responsible for peripheral conversion of T4 to T3. A 70% reduction of serum T3 levels was observed after 48 h of iopanoic acid administration in spontaneous hyperthyroid patients, with little effect on serum T4 concentration. However, iopanoic acid does not affect the destructive thyroiditis processes associated with AIT2 [20]. Iopanoic acid is a reasonable alternative to steroids to control hyperthyroidism in the short term, but it would take longer than the use of steroids in achieving the euthyroid state, as shown in a small, prospective, randomized control trial [21].\n\nDue to coexistence of both forms of AIT, there is often a variable response to glucocorticoid therapy in AIT2. Thionamides are sometimes needed in addition to glucocorticoids to achieve euthyroid status in these patients. IL-6 levels can aid in choosing therapy, but it may take days to weeks for the levels to be reported. Therefore, in severely ill patients, until the diagnosis is certain, it is prudent to treat both AIT1 and AIT2 with antithyroid drugs and glucocorticoids with or without perchlorate. Thyroidologists may employ a stepwise approach, where initial therapy would constitute using thionamides for 4 weeks and introduce steroids if there is insufficient or no response to thionamide therapy [22].\n\nGuitierrez-Repiso et al. [23] observed that, in an adult population with adequate and stable nutrition, the iodine excretion in a random urine sample represented 70–80% of the daily iodine intake. This fact was also utilized by several investigators for either diagnosis or treatment of drug-induced thyrotoxicosis [24–26]. Erdoğan and colleagues suggested treating AIT with prednisone, potassium perchlorate, and titrating methimazole using urinary iodine excretion [27].\n\nThe majority of thyroidologists in North America and Europe did not recommend measuring urinary iodine for management of AIT. Urinary iodine excretion would not be an ideal marker of individual iodine nutrition because of the intraindividual variability considering changes in dietary iodine intake and thyroid function [23]. In cases of recurrent, refractory, or mixed forms of AIT where euthyroid status is not achieved with steroids alone, monitoring monthly levels and continuing steroids or adding methimazole until urine iodine concentration normalizes (<200 μg/day) might be reasonable.\n\nAmiodarone and its derivative desethylamiodarone have a long half-life of 40 and 57 days, respectively, due to the lipophilic nature of the drug and subsequent concentration in various tissues including adipose tissue [28]. Hence, withdrawal of the drug should not have immediate beneficial effects. It remains unclear whether amiodarone should be continued after diagnosis. There have been instances of amiodarone-induced coronary vasospasm and ischemic ventricular fibrillation related to hyperthyroid states [29]. Bogazzi et al. showed that the drug delays restoration of euthyroid status, and there are higher chances of recurrence when amiodarone is continued [20]. Euthyroid states were still achieved with continuation of amiodarone [30]. Consequently, decisions must be made on a case-by-case basis, and the drug should be withdrawn only if it is not too risky for the patient.\n\nMeasurement of iodine uptake and/or urine iodine excretion can be done to make sure that the iodine load has resolved. In surveys, after restoration of euthyroidism and withdrawal of amiodarone, thyroid ablation was selected less frequently by North American thyroidologists in AIT1, while an expectant strategy was shared by both North Americans and Europeans in AIT2 [31–33]. If amiodarone therapy needs to be reinitiated, prophylactic RAI therapy or thyroidectomy was recommended in AIT1; “wait and watch” strategy was still adopted for majority of the patients with AIT2, unless there was a relapse [31–33].\n\nSubtotal or total thyroidectomy may be needed in cases of AIT that progresses despite aggressive medical therapy, especially in critically ill patients in whom discontinuing amiodarone can be life threatening. In patients with AIT and left ventricular systolic dysfunction, left ventricular ejection fraction improved when they underwent total thyroidectomy following failure to achieve euthyroid state with optimal medical treatment [34]. Several case reports have been published on treatment with lithium, plasmapheresis, and/or methimazole in refractory cases [35–37]. Perchlorate was hypothesized to ameliorate the cytotoxic side effects of amiodarone on thyrocytes and thereby help in restoration of euthyroid status when a mixed type of AIT was suspected. A multicenter randomized control in Netherlands showed that perchlorate, when used alone or in combination with prednisone, did not improve outcomes [30]. AIT patients generally have low RAIU values, and radioiodine ablation might not be feasible; however, an open study showed that it might be an option even in those patients [38]. Using recombinant TSH to allow radioiodine as a treatment modality has been proposed; however, subsequent elevation of thyroid hormone levels could potentially worsen underlying cardiac problems in these patients [39].\n\nIt is important to follow up patient's status with thyroid function testing, even after restoration to euthyroid state, as they may develop temporary or permanent hypothyroidism and may subsequently benefit from hormone replacement therapy [40].\n\n4. Conclusion\nAmiodarone-induced hyperthyroidism still remains a diagnostic challenge due to its incompletely understood pathogenesis, unreliable response to therapy, and lack of systemic approach. Steroids are the mainstay for treatment of AIT2. IL-6 levels and CFDS may be helpful in aiding with diagnosis and assessing response to therapy. Surgery should be considered on a case-by-case basis in patients with uncontrolled hyperthyroidism with conservative measures or in whom watchful medical management could have deleterious effects. In case of progressive deterioration, where restoration of euthyroid status is essential, a short course of iopanoic acid followed by surgical removal of the gland should be considered. Lithium, plasmapheresis, and radioactive treatment have been attempted, but there is currently limited evidence to recommend their use.\n\nDisclosure\nA poster of this case report was presented at the annual meeting of the American Thyroid Association.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Thyroid ultrasound with color Doppler flow study showing normal to minimally reduced vascularity of the glandular tissue. (a) Long axis view of the right thyroid lobe. (b) Long axis view of the left thyroid lobe. (c) Transverse axis view of both lobes of thyroid gland including the isthmus.\n\nFigure 2 Radioiodine uptake and scan using 143 μCi of I-123 showing 0.6% uptake at 4 hours (no activity within the thyroid gland).\n\nTable 1 Effects of amiodarone on thyroid function tests in euthyroid patients.\n\nTest\tDuration of treatment\t\nSubacute (<3 months)\tChronic (>3 months)\t\nT4\tModest increase\tRemains increased by up to 40% above baseline; may be in high reference range or moderately raised\t\nT3\tDecreased, usually to low reference range\tRemains in low reference range or slightly low\t\nTSH\tTransient increase (up to 20 mU/L)\tNormal, but there may be periods of high or low values\t\nrT3\tIncreased \tIncreased\t\nUsed with permission from Heart (Newman et al. 1998 [3]).\n\nTable 2 \n*Clinical and pathologic features distinguishing type 1 and type 2 amiodarone-induced hyperthyroidism†.\n\n \tType 1\tType 2\t\nUnderlying thyroid disease\tYes\tNo\t\nThyroid ultrasound\tDiffuse or nodular goiter\tNormal (hypoechoic) gland (small goiter) \t\nCFDS\tIncreased vascularity\tNormal to reduced vascularity\t\nThyroid RAIU\tLow/normal/increased\tLow/absent\t\nMIBI\tThyroid retention\tAbsent uptake\t\nPathogenesis\tIodine-induced hyperthyroidism\tDestructive thyroiditis\t\nSpontaneous remission\tNo\tPossible\t\nPreferred treatment\tThionamides (plus perchlorate)\tGlucocorticoids\t\nPosttherapy hypothyroidism\tUnlikely\tPossible\t\n\n*Modified from Table 1, Bogazzi et al. [12].\n\n\n†Mixed forms of AIT have not been fully understood and are believed to be a combination of iodine-induced hyperthyroidism and destructive thyroiditis from the drug itself. \n\nCFDS: color flow Doppler sonography; RAIU: radioiodine uptake; MIBI: 99mTc-sestamibi.\n==== Refs\n1 Yiu K.-H. Jim M.-H. Siu C.-W. Lee C.-H. Yuen M. Mok M. Shea Y.-F. Fan K. Tse H.-F. Chow W.-H. Amiodarone-induced thyrotoxicosis is a predictor of adverse cardiovascular outcome Journal of Clinical Endocrinology and Metabolism 2009 94 1 109 114 10.1210/jc.2008-1907 2-s2.0-58149396249 18940876 \n2 Julian D. G. Camm A. J. Frangin G. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT The Lancet 1997 349 9053 667 674 10.1016/S0140-6736(96)09145-3 2-s2.0-0031038213 \n3 Newman C. M. Price A. Davies D. W. Gray T. A. Weetman A. P. Amiodarone and the thyroid: a practical guide to the management of thyroid dysfunction induced by amiodarone therapy Heart 1998 79 2 121 127 10.1136/hrt.79.2.121 2-s2.0-0031941858 9538302 \n4 Aanderud S. Sundsfjord J. Aarbakke J. Amiodarone inhibits the conversion of thyroxine to triiodothyronine in isolated rat hepatocytes Endocrinology 1984 115 4 1605 1608 10.1210/endo-115-4-1605 2-s2.0-0021123286 6479103 \n5 Safran M. Fang S.-L. Bambini G. Pinchera A. Martino E. Braverman L. E. Effects of amiodarone and desethylamiodarone on pituitary deiodinase activity and thyrotropin secretion in the rat American Journal of the Medical Sciences 1986 292 3 136 141 10.1097/00000441-198609000-00003 2-s2.0-0022921782 3752159 \n6 Zaninovich A. Bosco S. Fernandez-Pol A. Amiodarone does not affect the distribution and fractional turnover of triiodothyronine from the plasma pool, but only its generation from thyroxine in extrathyroidal tissues The Journal of Clinical Endocrinology & Metabolism 1990 70 6 1721 1724 2-s2.0-0025364664 10.1210/jcem-70-6-1721 2347903 \n7 Krenning E. P. Docter R. Bernard B. Visser T. Hennemann G. Decreased transport of thyroxine (T4), 3,3′-5-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (rT3) into rat hepatocytes in primary culture due to a decrease of cellular ATP content and various drugs FEBS Letters 1982 140 2 229 233 10.1016/0014-5793(82)80900-9 2-s2.0-0020319067 7084465 \n8 Martino E. Aghini-Lombardi F. Mariotti S. Bartalena L. Braverman L. Pinchera A. Amiodarone: a common source of iodine-induced thyrotoxicosis Hormone Research 1987 26 1–4 158 171 10.1159/000180696 2-s2.0-0023277198 2885251 \n9 Basaria S. Cooper D. S. Amiodarone and the thyroid The American Journal of Medicine 2005 118 7 706 714 10.1016/j.amjmed.2004.11.028 2-s2.0-21244452633 15989900 \n10 Cohen-Lehman J. Dahl P. Danzi S. Klein I. Effects of amiodarone therapy on thyroid function Nature Reviews Endocrinology 2010 6 1 34 41 10.1038/nrendo.2009.225 2-s2.0-73949103448 \n11 Tomisti L. Rossi G. Bartalena L. Martino E. Bogazzi F. The onset time of amiodarone -induced thyrotoxicosis (AIT) depends on AIT type European Journal of Endocrinology 2014 171 3 363 368 363368 24935933 \n12 Bogazzi F. Bartalena L. Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis Journal of Clinical Endocrinology and Metabolism 2010 95 6 2529 2535 10.1210/jc.2010-0180 2-s2.0-77954484535 20525904 \n13 Bogazzi F. Martino E. Dell'Unto E. Thyroid color flow doppler sonography and radioiodine uptake in 55 consecutive patients with amiodarone-induced thyrotoxicosis Journal of Endocrinological Investigation 2003 26 7 635 640 10.1007/BF03347021 2-s2.0-12444337557 14594114 \n14 Bogazzi F. Bartalena L. Brogioni S. Mazzeo S. Vitti P. Burelli A. Bartolozzi C. Martino E. Color flow doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis Thyroid 1997 7 4 541 545 2-s2.0-0030848606 10.1089/thy.1997.7.541 9292940 \n15 Loy M. Perra E. Melis A. Cianchetti M. E. Piga M. Serra A. Pinna G. Mariotti S. Color-flow doppler sonography in the differential diagnosis and management of amiodarone-induced thyrotoxicosis Acta Radiologica 2007 48 6 628 634 2-s2.0-34547326065 10.1080/02841850701342138 17611870 \n16 Piga M. Cocco M. C. Serra A. Boi F. Loy M. Mariotti S. The usefulness of 99mTc-sestaMIBI thyroid scan in the differential diagnosis and management of amiodarone-induced thyrotoxicosis European Journal of Endocrinology 2008 159 4 423 429 10.1530/EJE-08-0348 2-s2.0-54049117169 18603573 \n17 Bartalena L. Brogioni S. Grasso L. Rago T. Vitti P. Pinchera A. Martino E. Interleukin-6: a marker of thyroid-destructive processes? Journal of Clinical Endocrinology and Metabolism 1994 79 5 1424 1427 10.1210/jc.79.5.1424 2-s2.0-0028153117 7962338 \n18 Bartalena L. Brogioni S. Grasso L. Bogazzi F. Burelli A. Martino E. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study Journal of Clinical Endocrinology and Metabolism 1996 81 8 2930 2933 10.1210/jc.81.8.2930 2-s2.0-0029787591 8768854 \n19 Bogazzi F. Bartalena L. Tomisti L. Rossi G. Tanda M. L. Dell'Unto E. Aghini-Lombardi F. Martino E. Glucocorticoid response in amiodarone-induced thyrotoxicosis resulting from destructive thyroiditis is predicted by thyroid volume and serum free thyroid hormone concentrations Journal of Clinical Endocrinology and Metabolism 2007 92 2 556 562 10.1210/jc.2006-2059 2-s2.0-33846985971 17148557 \n20 Bogazzi F. Bartalena L. Tomisti L. Rossi G. Brogioni S. Martino E. Continuation of amiodarone delays restoration of euthyroidism in patients with type 2 amiodarone-induced thyrotoxicosis treated with prednisone: a pilot study The Journal of Clinical Endocrinology & Metabolism 2011 96 11 3374 3380 10.1210/jc.2011-1678 2-s2.0-80655147352 21865355 \n21 Bogazzi F. Bartalena L. Cosci C. Brogioni S. Dell'Unto E. Grasso L. Aghini-Lombardi F. Rossi G. Pinchera A. Braverman L. E. Martino E. Treatment of type II amiodarone-induced thyrotoxicosis by either iopanoic acid or glucocorticoids: a prospective, randomized study Journal of Clinical Endocrinology and Metabolism 2003 88 5 1999 2002 2-s2.0-0038185192 10.1210/jc.2002-021874 12727944 \n22 Bogazzi F. Tomisti L. Rossi G. Dell'Unto E. Pepe P. Bartalena L. Martino E. Glucocorticoids are preferable to thionamides as first-line treatment for amiodarone-induced thyrotoxicosis due to destructive thyroiditis: a matched retrospective cohort study Journal of Clinical Endocrinology and Metabolism 2009 94 10 3757 3762 10.1210/jc.2009-0940 2-s2.0-70349929506 19622616 \n23 Guitierrez-Repiso C. Colomo N. Rojo-Martinez G. Evolution of urinary iodine excretion over eleven years in an adult population Clinical Nutrition 2014 10.1016/j.clnu.2014.08.003 \n24 Rao R. H. McCready V. R. Spathis G. S. 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Management of amiodarone-induced thyrotoxicosis in Latin America: an electronic survey Clinical Endocrinology 2006 65 4 433 438 10.1111/j.1365-2265.2006.02590.x 2-s2.0-33748807457 16984234 \n33 Tanda M. L. Piantanida E. Lai A. Liparulo L. Sassi L. Bogazzi F. Wiersinga W. M. Braverman L. E. Martino E. Bartalena L. Diagnosis and management of amiodarone-induced thyrotoxicosis: similarities and differences between North American and European thyroidologists Clinical Endocrinology 2008 69 5 812 818 10.1111/j.1365-2265.2008.03268.x 2-s2.0-54049140080 18410546 \n34 Tomisti L. Materazzi G. Bartalena L. Rossi G. Marchello A. Moretti M. De Napoli L. Mariotti R. Miccoli P. Martino E. Bogazzi F. Total thyroidectomy in patients with amiodarone-induced thyrotoxicosis and severe left ventricular systolic dysfunction Journal of Clinical Endocrinology and Metabolism 2012 97 10 3515 3521 10.1210/jc.2012-1797 2-s2.0-84867272318 22865896 \n35 Dickstein G. Shechner C. Adawi F. Kaplan J. Baron E. Ish-Shalom S. Lithium treatment in amiodarone-induced thyrotoxicosis The American Journal of Medicine 1997 102 5 454 458 10.1016/S0002-9343(97)00047-8 2-s2.0-0030983619 9217642 \n36 Erbil Y. Tihan D. Azezli A. Salmaslioǧlu A. Özlük Y. Büyükören A. Özarmaǧan S. Severe hyperthyroidism requiring therapeutic plasmapheresis in a patient with hydatidiform mole Gynecological Endocrinology 2006 22 7 402 404 10.1080/09513590600842372 2-s2.0-33746806277 16864152 \n37 Aghini-Lombardi F. Mariotti S. Fosella P. V. Grasso L. Pinchera A. Braverman L. E. Martino E. Treatment of amiodarone iodine-induced thyrotoxicosis with plasmapheresis and methimazole Journal of Endocrinological Investigation 1993 16 10 823 826 10.1007/BF03348934 2-s2.0-0027761960 8144857 \n38 Czarnywojtek A. Czepczynski R. Ruchala M. Radioiodine therapy in patients with amiodarone-induced thyrotoxicosis (AIT) Neuroendocrinology Letters 2009 30 2 209 214 2-s2.0-70349308401 19675515 \n39 Bogazzi F. Tomisti L. Ceccarelli C. Martino E. Recombinant human TSH as an adjuvant to radioiodine for the treatment of type 1 amiodarone-induced thyrotoxicosis: a cautionary note Clinical Endocrinology 2010 72 1 133 134 10.1111/j.1365-2265.2009.03600.x 2-s2.0-72249107079 19508595 \n40 Roti E. Minelli R. Gardini E. Bianconi L. Braverman L. E. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone: a possible consequence of a destructive process in the thyroid Archives of Internal Medicine 1993 153 7 886 892 10.1001/archinte.153.7.886 2-s2.0-0027523247 8466380\n\n",
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"references": "21865355;9377836;19508595;11294826;19935743;12727944;22130792;14552168;3944239;24935933;8768854;15473883;25155806;8466380;19675515;16864152;2885251;2347903;7084465;9217642;18940876;3752159;9292940;12699596;7962338;20525904;6479103;17148557;15989900;17611870;8144857;9078197;18603573;9538302;18410546;14594114;16984234;19622616;22865896;24783040",
"title": "Amiodarone-induced thyrotoxic thyroiditis: a diagnostic and therapeutic challenge.",
"title_normalized": "amiodarone induced thyrotoxic thyroiditis a diagnostic and therapeutic challenge"
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"abstract": "A 64-year old male presented to the hospital with a 1-week history of stools with bright red blood. Subsequent colonoscopy with a biopsy revealed a low-lying, moderately differentiated, rectal adenocarcinoma. A pelvic magnetic resonance imaging done afterwards showed a possible T3N1 rectal cancer with intact muscularis mucosa and a singular presacral lymph node enlargement. Furthermore, a suspicious peripheral prostatic enlargement and a possible left iliac crest sclerotic bone lesion were incidentally identified. 18F-FDG (fluorodeoxyglucose) PET (positron emission tomography) scan confirmed a primary FDG avid rectal tumor and a presacral lymph node; however, there was no prostate or iliac crest uptake. A serum prostate-specific antigen performed in the hospital returned with a value of 37 ng/mL, which prompted a prostate biopsy, eventually returning as positive for adenocarcinoma. Consequently, a 68Ga-PSMA PET scan to rule out possible metastatic prostate disease revealed increased PSMA expression in the prostate only. After consultation with the radiologist and nuclear medicine physician who concluded the iliac crest lesion is likely not cancerous, the final diagnosis of T3N1 rectal cancer with simultaneous high-grade prostate adenocarcinoma was declared. This case highlights the low sensitivity of 18F-FDG PET scans for prostate cancer, the need for routine serum prostate-specific antigen screening, and the progression of 68Ga-PSMA PET as a diagnostic tool for prostate cancer.",
"affiliations": "Central Michigan University, Saginaw, MI, USA.;Central Michigan University, Saginaw, MI, USA.;Central Michigan University, Saginaw, MI, USA.;Central Michigan University, Saginaw, MI, USA.;Geisinger Commonwealth School of Medicine, Scranton, PA, USA.;Geisinger Commonwealth School of Medicine, Scranton, PA, USA.;Westchester Medical Center, Valhalla, NY, USA.",
"authors": "Kichloo|Asim|A|0000-0003-4788-8572;Amir|Rawan|R|;Aljadah|Michael|M|;Wani|Farah|F|;Solanki|Shantanu|S|;Singh|Jagmeet|J|;Chugh|Savneek Singh|SS|",
"chemical_list": "D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D009842:Oligopeptides; D019275:Radiopharmaceuticals; C000718244:gallium 68 PSMA-11; D019788:Fluorodeoxyglucose F18; D004492:Edetic Acid; D017430:Prostate-Specific Antigen",
"country": "United States",
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"doi": "10.1177/2324709620941313",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620941313\n10.1177_2324709620941313\nCase Report\nFDG-PET Versus PSMA-PET: A Patient With Prostate Cancer\nhttps://orcid.org/0000-0003-4788-8572Kichloo Asim MD1 Amir Rawan MD1 Aljadah Michael MD1 Wani Farah MD1 Solanki Shantanu MD, MPH2 Singh Jagmeet MD2 Chugh Savneek Singh MD3 1 Central Michigan University, Saginaw, MI, USA\n2 Geisinger Commonwealth School of Medicine, Scranton, PA, USA\n3 Westchester Medical Center, Valhalla, NY, USA\nAsim Kichloo, MD, Department of Internal Medicine, Central Michigan University, 1000 Houghton Avenue, Saginaw, MI 48602, USA. Email: kichlooasim@gmail.com\n10 7 2020 \nJan-Dec 2020 \n8 232470962094131316 5 2020 13 6 2020 14 6 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).A 64-year old male presented to the hospital with a 1-week history of stools with bright red blood. Subsequent colonoscopy with a biopsy revealed a low-lying, moderately differentiated, rectal adenocarcinoma. A pelvic magnetic resonance imaging done afterwards showed a possible T3N1 rectal cancer with intact muscularis mucosa and a singular presacral lymph node enlargement. Furthermore, a suspicious peripheral prostatic enlargement and a possible left iliac crest sclerotic bone lesion were incidentally identified. 18F-FDG (fluorodeoxyglucose) PET (positron emission tomography) scan confirmed a primary FDG avid rectal tumor and a presacral lymph node; however, there was no prostate or iliac crest uptake. A serum prostate-specific antigen performed in the hospital returned with a value of 37 ng/mL, which prompted a prostate biopsy, eventually returning as positive for adenocarcinoma. Consequently, a 68Ga-PSMA PET scan to rule out possible metastatic prostate disease revealed increased PSMA expression in the prostate only. After consultation with the radiologist and nuclear medicine physician who concluded the iliac crest lesion is likely not cancerous, the final diagnosis of T3N1 rectal cancer with simultaneous high-grade prostate adenocarcinoma was declared. This case highlights the low sensitivity of 18F-FDG PET scans for prostate cancer, the need for routine serum prostate-specific antigen screening, and the progression of 68Ga-PSMA PET as a diagnostic tool for prostate cancer.\n\nprostate canceroncologyradiologycover-dateJanuary-December 2020typesetterts1\n==== Body\nBackground\nFluorodeoxyglucose-positron emission tomography (FDG-PET) is a powerful imaging modality used to diagnose various cancers and anatomically localize potential sites of metastasis. Over the last 10 years, it has become part of the standard of care in diagnosing patients with cancer. FDG-PET has an impressively high sensitivity, as high as 97% in lung cancer and 93% in breast cancer recurrence detection. However, the sensitivity of FDG-PET in detecting prostate cancer has been under scrutiny, with the efficacy of its role in diagnosing prostate cancer questioned.1,2 More recently, PSMA (prostate-specific membrane antigen)-PET has been recognized for its role in diagnosing prostate cancer, with a higher sensitivity when there is increased production of PSMA.3,4 However, further assessment of PSMA-PET needs to be done in order to establish clear guidelines for PSMA-PET use.\n\nCase Presentation\nA 64-year-old male with a past medical history of benign prostatic hyperplasia and recently diagnosed paroxysmal atrial fibrillation presented to the hospital with a complaint of stools with bright red blood for the past 1 week. He was recently started on 5 mg of apixaban twice daily. He was hemodynamically stable with normal electrolytes and blood counts at presentation. The patient had no family history of any colorectal or genitourinary cancer. Colonoscopy with biopsy done shortly after admission demonstrated low-lying, moderately differentiated, adenocarcinoma of the rectum. A subsequent magnetic resonance imaging (MRI) of the pelvis showed T3N1 rectal cancer, with intact muscularis mucosa, and an enlarged presacral lymph node. A suspicious peripheral prostatic enlargement with a left iliac crest sclerotic bone lesion was incidentally found.\n\nGiven the incidental finding of prostatic enlargement and possible sclerotic bone lesion of the left iliac crest appearing quite suspicious, an FDG-PET scan was done and confirmed the primary rectal tumor with a presacral lymph node, but did not reveal any increased uptake in the prostate or iliac crest (Figure 1). Prostate specific antigen (PSA) blood test was subsequently done that was elevated at 37 ng/mL. Due to high suspicion of a new concurrent primary prostate cancer, a biopsy was taken that revealed prostatic adenocarcinoma. PSMA-PET was then performed to identify any potential metastases from this primary site. PSMA-PET revealed increased uptake in the prostate, which was not previously detected by FDG-PET (Figure 2). There was no uptake in the iliac crest (Figure 3). After careful evaluation by the radiologist and nuclear medicine physician, it was determined that given the appearance of the lesion on MRI as calcification with well-defined margins and central necroses and the lack of uptake by PSMA-PET, which is highly sensitive for prostate metastases, the lesion likely represented an intraosseous iliac lipoma instead of a metastasis (Figure 4). On disclosure of the radiologist’s diagnosis to the patient, along with an explanation that the differential diagnosis included an intraosseous lipoma as well as sclerotic prostate metastases that would likely present with irregular necrotic margins, the patient ultimately decided not to pursue biopsy understanding this was the most definitive way to rule out metastasis. As a result, primary rectal adenocarcinoma with metastasis to a single presacral lymph node, in addition to concurrent primary prostate adenocarcinoma, was the final diagnosis.\n\nFigure 1. FDG-PET showing increased uptake at site of rectal tumor (top arrow) and presacral lymph node (bottom arrow). While FDG-PET did not pick up any activity in the prostate, it cannot be ruled out that a possible reason for lack of uptake was due to washout from a more intense signal from the rectal lesion as shown in the top arrow.\n\nFigure 2. PSMA-PET showing increased uptake in the prostate (red arrow).\n\nFigure 3. PSMA-PET showing a lesion in the iliac crest (red arrow), but without uptake (yellow).\n\nFigure 4. Sagittal MRI showing a left iliac bone lesion, which was classified as an intraosseous lipoma by the radiologist due to defined margin and central necrosis.\n\nThe patient was started on treatment for 2 primary perineal cancers, rectum as well as prostate. He received localized radiation therapy for rectal cancer and is scheduled for a repeat MRI of the pelvis for restaging of his rectal cancer postradiation. For his prostate adenocarcinoma, the decision was made to initiate antiandrogenic medication. If the patient qualifies and if an abdominoperineal resection is completed for the rectal cancer, he plans to undergo full-dose radiation therapy for prostate cancer in concurrence with his antiandrogen treatment.\n\nDiscussion\nProstate cancer is the second most common cancer in men worldwide.5 However, synchronous diagnosis of rectal and prostate cancer is extremely rare.6 In a Swedish retrospective study of almost 30 000 patients, only 29 patients had synchronous diagnoses between 1995 and 2011.6 Furthermore, of the 29 patients, 20 of the patients’ prostate cancer was diagnosed incidentally when diagnosing and staging for rectal cancer, as in the case we present in this article.6 Diagnostic modalities of prostate cancer range from simple digital rectal examinations up to ultrasound-guided and CT-guided biopsies. PET scans have recently gained recognition as a promising modality for staging cancer. FDG-PET is the most common form of PET scan used to stage cancers, detect recurrences, and monitor response to therapies. FDG-PET works by detecting increased glucose metabolism in highly active cancerous cells and has a high sensitivity of 97% in lung cancer and 93% in breast cancer, as examples.5 However, the sensitivity of FDG-PET in detecting prostate cancer is questionable and reports of its efficacy have been quite conflicting. One study of 24 patients with prostate cancer undergoing FDG-PET reported increased uptake in only 1 patient (sensitivity nearing 4.0%).1 Other studies have reported that FDG-PET has a higher sensitivity of nearly 80%, but only in advanced prostate cancers with high PSA levels or Gleason scores of higher than 7.2\n\nAttempting to find an ideal imaging method to identify prostate cancer proves to be challenging due to the complex nature of the disease itself. Prostate cancers demonstrate a wide variety of differentiation with varying degrees of aggressiveness; therefore, the preferred imaging modality should be able to distinguish aggressive markers from the remainder. Additionally, imaging should be sensitive to metastases to both bone and nodal sites as they represent the most common metastases sites.7\n\nPSMA is one marker that is elevated in more aggressive types of prostate cancer. PSMA is a transmembrane receptor composed of an internal and external domain, yet its role in the development and progression of prostate cancer has yet to be identified. However, overexpression of this receptor has made it a target for novel imaging modalities. PSMA-PET scans are a form of PET imaging that detects prostate cancer with increased PSMA production. To date, there are no studies comparing FDG-PET and PSMA-PET, yet there are limited studies comparing PSMA-PET to other PET imaging, mainly 18F-choline(FCH)-PET, which showed that PSMA-PET detected more lesions in comparison to the latter with 78 lesions detected in 32 patients versus 56 lesions detected in 26 patients.3 Other studies also noted that PSMA-PET detected lesions at lower PSA levels compared with FCH-PET with a 50% detection rate at a PSA level as low as 0.5 ng/mL.4 Last, the recent results of the ProPSMA randomized clinical trial showed that PSMA-PET/CT has superior accuracy with fewer uncertain results than standard CT and bone scan for staging prostate cancer.8 These positive reports have shed light on PSMA-PET for its potential role in staging prostate cancer.\n\nPreviously, there were no clear guidelines for the use of PSMA-PET. In 2017, the Society of Nuclear Medicine and Molecular Imaging and the European Association of Nuclear Medicine collaborated to provide procedure guidelines for prostate cancer imaging using PSMA-PET, based on multicenter experience. Recommendations focused on the use of PSMA in localizing prostate cancer recurrence and for primary staging. With regard to recurrence, it is recommended to use PSMA-PET in particular when PSA levels are low (0.2-10 ng/mL) to localize sites of recurrence, which can subsequently guide salvage therapy. As for primary staging, PSMA-PET has been found to be superior to other forms of imaging including CT and MRI in detecting bone metastasis and lymph node involvement with high-risk disease (ie, PSA >20, Gleason score >7, clinical staging T2C-3a). However, the benefit of this increased sensitivity to patients’ survival remains unclear.9\n\nNewer potential applications for PSMA-PET include monitoring response of prostatic metastasis to systemic treatment, attempting targeted biopsy in patients with high suspicion of prostate cancer, and previous negative results, in addition to staging pre- and post-PSMA–targeted therapy. However, these potential applications require more extensive studies to assess PSMA-PET performance in comparison to other currently used modalities.\n\nAuthor Contributions: All authors have contributed equally to the study.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information.\n\nORCID iD: Asim Kichloo \nhttps://orcid.org/0000-0003-4788-8572\n==== Refs\nReferences\n1 \nLiu I Zafar MB Lai YH Segall FM Terris MK \nFluorodeoxyglucose positron emission tomography studies in diagnosis and staging of clinically organ-confined prostate cancer\n. Urology . 2001 ;57 :108 -111\n.11164153 \n2 \nTateishi U Morita S Taguri M , et al\nA meta-analysis of 18F-fluoride positron emission tomography for assessment of metastatic bone tumor\n. Ann Nuclear Med . 2010 ;24 :523 -531\n.\n3 \nAfshar-Oromieh A Zechmann CM Malcher A , et al\nComparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer\n. Eur J Nucl Med Mol Imaging . 2014 ;41 :11 -20\n.24072344 \n4 \nMorigi JJ Stricker PD van Leeuwen PJ , et al\nProspective comparison of 18F-fluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy\n. J Nucl Med . 2015 ;56 :1185 -1190\n.26112024 \n5 \nKostakoglu L Agress H JrGoldsmith SJ \nClinical role of FDG PET in evaluation of cancer patients\n. Radiographics . 2003 ;23 :315 -340\n.12640150 \n6 \nSturludóttir M Martling A Carlsson S Blomqvist L \nSynchronous rectal and prostate cancer—the impact of MRI on incidence and imaging findings\n. Eur J Radiol . 2015 ;84 :563 -567\n.25638578 \n7 \nLindenberg L Choyke P Dahut W \nProstate cancer imaging with novel PET tracers\n. Curr Urol Rep . 2016 ;17 :18 .26874530 \n8 \nHofman MS Lawrentschuk N Francis RJ , et al\nProstate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study\n. Lancet . 2020 ;395 :1208 -1216\n.32209449 \n9 \nFendler WP Eiber M Beheshti M , et al\n68Ga-PSMA PET/CT: joint EANM and SNMMI procedure guideline for prostate cancer imaging: version 1.0\n. Eur J Nucl Med Mol Imaging . 2017 ;44 :1014 -1024\n.28283702\n\n",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "oncology; prostate cancer; radiology",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D004492:Edetic Acid; D019788:Fluorodeoxyglucose F18; D005709:Gallium Isotopes; D005710:Gallium Radioisotopes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D049268:Positron-Emission Tomography; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D019275:Radiopharmaceuticals",
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"title": "FDG-PET Versus PSMA-PET: A Patient With Prostate Cancer.",
"title_normalized": "fdg pet versus psma pet a patient with prostate cancer"
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"abstract": "OBJECTIVE\nTo describe the institutional experience of plerixafor plus filgrastim as the initial peripheral blood stem cell (PBSC) mobilization (first-line strategy) and as rescue therapy after failure with filgrastim plus cyclophosphamide (second-line strategy).\n\n\nMETHODS\nRetrospective medical record review.\n\n\nMETHODS\nAcademic medical center.\n\n\nMETHODS\nThirty-three patients (median age 62 yrs) who received plerixafor between January 2008 and December 2009.\n\n\nRESULTS\nWe collected data on total CD34(+) cell yield and number of apheresis sessions in both first-line and second-line plerixafor recipients. Mobilization with plerixafor plus filgrastim resulted in a median yield of 8.95 × 10(6) and 2.45 × 10(6) CD34(+) cells/kg in patients with multiple myeloma or non-Hodgkin's lymphoma, respectively. As rescue mobilization, plerixafor plus filgrastim successfully mobilized CD34(+) cells in 16 (84%) of 19 patients. When comparing first-line plerixafor plus filgrastim therapy with second-line therapy, we found an increase in CD34(+) yield and 1 less apheresis day in patients with multiple myeloma, but no difference in patients with non-Hodgkin's lymphoma.\n\n\nCONCLUSIONS\nA regimen of plerixafor plus filgrastim successfully mobilized CD34(+) cells in a median of 1 apheresis day for patients with multiple myeloma and 2 apheresis days for patients with non-Hodgkin's lymphoma, including patients who failed initial filgrastim plus cyclophosphamide mobilization. Plerixafor plus filgrastim could be a viable first-line option in patients with multiple myeloma, as it improved CD34(+) cell yield and decreased number of apheresis days compared with second-line plerixafor plus filgrastim therapy, whereas it was comparable to second-line therapy in patients with non-Hodgkin's lymphoma.",
"affiliations": "Department of Pharmacy, University of California San Diego Medical Center, San Diego, CA 92103-8765, USA. kloricacid@gmail.com",
"authors": "Lor|Kevin W|KW|;Helmons|Pieter J|PJ|;Belew|Helen|H|;Lane|James R|JR|;Ball|Edward D|ED|",
"chemical_list": "D018952:Antigens, CD34; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D000069585:Filgrastim; C088327:plerixafor",
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"journal": "Pharmacotherapy",
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"mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D001596:Benzylamines; D001781:Blood Component Removal; D000080027:Cyclams; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006571:Heterocyclic Compounds; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D011994:Recombinant Proteins; D012189:Retrospective Studies; D016879:Salvage Therapy; D014182:Transplantation, Autologous",
"nlm_unique_id": "8111305",
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"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Plerixafor as first- and second-line strategies for autologous stem cell mobilization in patients with non-Hodgkin's lymphoma or multiple myeloma.",
"title_normalized": "plerixafor as first and second line strategies for autologous stem cell mobilization in patients with non hodgkin s lymphoma or multiple myeloma"
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"abstract": "Lactic acidosis is a clinical entity that demands rapid assessment and treatment to prevent significant morbidity and mortality. With increased lactate use across many clinical scenarios, lactate values themselves cannot be interpreted apart from their appropriate clinical picture. The significance of Type B lactic acidosis is likely understated in the emergency department (ED). Given the mortality that sepsis confers, a serum lactate is an important screening study. That said, it is with extreme caution that we should interpret and react to the resultant elevated value. We report a patient with a significant lactic acidosis. Though he had a high lactate value, he did not require aggressive resuscitation. A different classification scheme for lactic acidosis that focuses on the bifurcation of the \"dangerous\" and \"not dangerous\" causes of lactic acidosis may be of benefit. In addition, this case is demonstrative of the potential overuse of lactates in the ED.",
"affiliations": "University of Texas Southwestern, Department of Emergency Medicine, Dallas, Texas.;University of Texas Southwestern, Department of Emergency Medicine, Dallas, Texas.",
"authors": "Hockstein|Maxwell|M|;Diercks|Deborah|D|",
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"fulltext": "\n==== Front\nClin Pract Cases Emerg MedClin Pract Cases Emerg MedClinical Practice and Cases in Emergency Medicine2474-252XUniversity of California Irvine, Department of Emergency Medicine publishing Western Journal of Emergency Medicine 10.5811/cpcem.2018.1.36024cpcem-02-128Case ReportSignificant Lactic Acidosis from Albuterol Hockstein Maxwell MDDiercks Deborah MDUniversity of Texas Southwestern, Department of Emergency Medicine, Dallas, TexasAddress for Correspondence: Maxwell Hockstein, MD, University of Texas Southwestern, Department of Emergency Medicine, 5323 Harry Hines Blvd., Dallas, TX. Email: max.hockstein@gmail.com.5 2018 14 3 2018 2 2 128 131 19 8 2017 22 12 2017 10 1 2018 © 2018 Hockstein.2018This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Lactic acidosis is a clinical entity that demands rapid assessment and treatment to prevent significant morbidity and mortality. With increased lactate use across many clinical scenarios, lactate values themselves cannot be interpreted apart from their appropriate clinical picture. The significance of Type B lactic acidosis is likely understated in the emergency department (ED). Given the mortality that sepsis confers, a serum lactate is an important screening study. That said, it is with extreme caution that we should interpret and react to the resultant elevated value. We report a patient with a significant lactic acidosis. Though he had a high lactate value, he did not require aggressive resuscitation. A different classification scheme for lactic acidosis that focuses on the bifurcation of the “dangerous” and “not dangerous” causes of lactic acidosis may be of benefit. In addition, this case is demonstrative of the potential overuse of lactates in the ED.\n==== Body\nINTRODUCTION\nGiven that increased lactate values (either capillary or true vascular sampling with values greater than 2mmol/L) are unequivocally associated with higher likelihoods of in-hospital mortality across many clinical scenarios (including both medical and traumatic disease), emergency physicians globally are being faced with attributing a lactate value to either a potentially devastating or not-devastating etiology. While different schematics have been presented to classify lactic acidosis, the “Type A” and “Type B” classification scheme is likely insufficient as it does not answer the question “sick or not sick?”\n\nCASE REPORT\nWe report the case of a 50-year-old male who presented to the emergency department (ED) complaining of dyspnea. The patient had a known history of asthma and felt that his symptoms were typical of his exacerbations. He noted a cough with yellow sputum but denied fevers or any pain. He also reported a history of tension headaches and hyperlipidemia; his medical history was negative for diabetes, seizures, or strokes. He had no prior surgeries. He reported taking amitriptyline 10mg as needed for headaches and was also on atorvastatin 40mg daily. He had no allergies to medications. He denied any and all alcohol intake and he was not clinically intoxicated.\n\nThe triage vital signs were as follow: blood pressure 139/105 mmHg, temperature 35.7ºC (96.3ºF), heart rate 104 beats per minute, oxygen saturation 94% on room air, and respiratory rate 20 breaths per minute. A chest radiograph did not reveal any acute abnormalities. The patient received a single dose of 15mg of albuterol, 1500mcg of ipratropium, and 60mg of prednisone shortly after his ED arrival. He remained somewhat dyspneic after this initial treatment and was given an additional 10mg of albuterol two hours later. Given that the patient required one additional treatment, the decision was made to transfer him to the observation unit for further monitoring.\n\nAs part of the admission process to the observation unit, a basic metabolic panel was ordered, which showed a sodium of 139 mmol/L, potassium of 3.2 mmol/L, chloride of 100 mmol/L, bicarbonate of 18 mmol/L, and an anion gap of 24 mmol/L. The creatinine was 0.91 mg/dL. The aspartate aminotransferase was 16 units/liter and the alanine transaminase was 22 units/liter. The white blood cell count was 7.19 x 109/L. The admitting team then ordered a lactate to address the anion gap, which resulted at 9.6 mmol/L with a corresponding pH from the venous blood gas of 7.31 and a partial pressure of carbon dioxide of 34 mmHg. The lactate was repeated one hour later and resulted at 10.3 mmol/L. A standard urine drug screen, examining for amphetamines, benzodiazapines, cannabinoids, cocaine metabolites, opiates, and phencyclidine, was negative. The patient’s symptoms had improved and he remained otherwise asymptomatic.\n\nThe conundrum we faced was to determine not only whether this was a Type A or Type B lactic acidosis but also its precipitant. Given the lack of toxic appearance, hypotension, and altered mental status it was strongly felt that Type A lactic acidosis was not the culprit. The patient was admitted to our medicine service and observed. Additional albuterol treatments were withheld and the serum lactate value cleared to 1.1 mmol/L approximately 24 hours later. The patient was discharged from the hospital without incident.\n\nDISCUSSION\nSince Huckabee’s landmark paper in 1961, which identified a group of patients with fatal lactic acidosis, lactate has been used as a test to screen for acute metabolic mismatch.1 Lactate is produced when pyruvate is not converted to acetyl coenzyme A (CoA) during glycolysis in the setting of normal (aerobic) cellular respiration. Contrary to popular belief, when lactate is formed from pyruvate the product exists as an anion, not with the attached proton.2 Therefore, it is not lactate itself that causes acidosis; rather, it is a surrogate marker for an increase in the number of protons accumulating in the failing hydrolysis of adenosine triphospate. Type A lactic acidosis is defined by the presence of shock (hypoperfusion of any tissue). Type B lactic acidosis is a term that describes any lactic acidosis not due to hypoperfusion. Therefore, the causes for Type B lactic acidosis are more varied than those for Type A lactic acidosis.\n\nType A Lactic Acidosis\nClinical scenarios such as cardiac arrest, sepsis, and mesenteric ischemia are associated with severe lactic acidosis and with poor outcomes. Given the profound mortality of septic shock, checking serum lactates has been encouraged since the publication of “Surviving Sepsis”3 in 2012 and has been used as a screening tool for serious illness in many additional settings. In general, patients with Type A lactic acidosis require restoration of perfusion, with fluid resuscitation and/or vasopressors. In addition to these clinical pictures, seizures may cause a Type A lactic acidosis; however, our patient did not seize.4 He displayed no concerns for a Type A lactic acidosis, and we were directed to consider an additional precipitant.\n\nType B Lactic Acidosis\nClinical entities such as drugs (therapeutic or otherwise), inborn errors of metabolism, malabsorption syndrome (responsible for elevated levels of D-Lactate, as opposed to L-Lactate) are responsible for Type B lactic acidosis. Germaine to the patient in question, the treatment team was initially perplexed as to what caused this lactate value. Causes of Type B lactic acidosis may be bifurcated as a disorder of either increased production of lactate or a decreased clearance of lactate.5 Increased production of lactate occurs when the rate of glycolysis increases: catecholamines, diminished pyruvate dehydrogenase activity (congenital or thiamine deficiency), malignancy, and oxidative insufficiencies (cyanide toxicity). Decreased lactate clearance occurs in hepatic enzyme inhibition, mitochondrial defects, and renal disease.\n\nCPC-EM Capsule\nWhat do we already know about this clinical entity?\n\nLactic acidosis has many etiologies but can be divided into Type A from hypoperfusion (e.g., sepsis) and Type B from other causes (e.g., medications such as albuterol).\n\nWhat makes this presentation of disease reportable?\n\nThis lactic acid value is significantly higher than previously reported values attributed solely to albuterol in an otherwise-healthy patient.\n\nWhat is the major learning point?\n\nThough potentially indicative of serious disease, increased lactate values can also indicate a metabolic derangement not necessarily requiring resuscitation.\n\nHow might this improve emergency medicine practice?\n\nThis case demonstrates that lactic acid values should be interpreted (and treated) in the appropriate clinical context.\n\nIncreased Lactate Production\nCatecholaminergic stimulation of the beta-2 receptor upregulates cyclic adenosine monophosphate, which in turn activates protein kinase A (PKA). PKA activation enhances glycogenolysis and yields glucose, a substrate for glycolysis. The acceleration of this process with exogenous catecholamines results in hyperlactatemia.6 In addition, a urine toxicology screen was checked to address sympathomimetics as they may cause an increased lactate. However, no drugs of abuse were detected. Our patient had received albuterol; however, this degree of lactate elevation from albuterol has only seldom been referenced in the literature, especially in such a well-appearing patient. Mean elevations of serum lactate after one hour of albuterol (10mg) administration in healthy volunteers have been reported to be 0.77.7 In known asthmatics, the mean lactate level after at least 10mg of albuterol treatment has been reported in two studies to escalate 2.94 mmol/L from normal baselines.8,9 Lactate levels in asthmatics are of particular concern because hyperlactatemia may inhibit the bronchodilatory response and that the accompanying acidosis may worsen respiratory effort.8\n\nThiamine is a cofactor in the pyruvate dehydrogenase (PDH) complex and therefore a deficiency of thiamine would decrease the activity of PDH. Decreased PDH activity would increase lactate concentrations by not catalyzing the conversion from pyruvate to acetyl-CoA. In addition to patients who chronically drink ethanol or who have beri beri, those receiving parenteral nutrition also are at risk for thiamine deficiency.10\n\nThe mechanisms for malignancy-driven Type B lactic acidosis are varied. The most common explanation lies in the fact that cancer cells possess high glycolytic activity, an observation termed “the Warburg effect,” initially described in 1924.11 This increased rate of glycolysis, as described earlier, increases serum lactate values.\n\nD-lactate, the isomer of L-lactate, is produced mainly in patients with short-gut syndrome where colonic bacteria are exposed to larger quantities of luminal carbohydrates.4 D-Lactate may also be observed with propylene glycol ingestion; it has the potential to cross the blood-brain barrier and cause neurologic sequelae such as encephalopathy (slurred speech, ataxia, hallucinations, somnolence), which can last from hours to days.12\n\nOne of the most well-known side effects of 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitors (statins) is myopathy. Infrequently, statins have been associated with increased serum lactate values of similar cardinalities. Lactic acidosis attributable to a statin is an uncommon event; rather, it is often associated with concomitant metabolic derangements.13,14 The proposed mechanism by which statins may contribute to lactic acidosis is a depletion of ubiquinone (also known as CoQ10 (an important cofactor for the electron transport chain). However, concrete evidence of a mechanism is lacking.\n\nDecreased Lactate Clearance\nThe liver is responsible for the majority (70–75%) of lactate clearance5,10 with the remainder eliminated by the kidneys. In patients with hepatic disease or hepatic injury (e.g., ischemic hepatitis) lactate may be elevated. However, a primary insult, which would elevate the lactate in the first place, must be considered. In septic patients without septic shock, the oxygen delivery to tissues is generally increased; therefore, increased lactate levels in this subset of patients are likely due to decreased clearance rather than increased production.5\n\nCONCLUSION\nThe significance of Type B lactic acidosis is likely understated in the ED. Given the mortality that sepsis confers, a serum lactate is an important screening study. That said, it is with extreme caution that we should interpret and react to the resultant value. This patient, though he had a high lactate value, likely did not require aggressive resuscitation. A more rigorous classification scheme for lactic acidosis might be of clinical benefit. Emergency physicians should be aware that lactate values may be dramatically elevated for several reasons, only one of them being albuterol.\n\nDocumented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.\n\nSection Editor: Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_cpcem\n\nConflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n1 Huckabee WE Abnormal resting blood lactate Am J Med 1961 30 840 8 13716482 \n2 Mizock BA Controversies in lactic acidosis JAMA 1987 258 4 497 501 3599345 \n3 Rivers E Nguyen B Havstad S Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock N Engl J Med 2001 345 1368 77 11794169 \n4 Anderson LW Mackenhauer J Roberts JC Etiology and therapeutic approach to elevated lactate Mayo Clin Proc 2013 88 10 1127 40 24079682 \n5 Barrie Phypers Pierce JM Lactate physiology in health and disease Contin Education in Anaesthesthesia, Critical Care, & Pain 2006 128 132 \n6 Barth E Albusizies G Baumgart K Glucose metabolism and catecholamines Crit Care Med 2007 35 9 Suppl S508 18 17713401 \n7 Zitek T Cleveland N Rahbar A Effect of nebulized albuterol on serum lactate and potassium in healthy subjects Acad Emerg Med 2016 23 6 718 21 26857949 \n8 Rodrigo GJ Rodrigo C Elevated plasma lactate level associated with high dose inhaled albuterol therapy in acute severe asthma Emerg Med J 2005 22 6 404 8 15911945 \n9 Lewis LM Ferguson I House SL Albuterol administration is commonly associated with increases in serum lactate in patients with asthma treated for acute exacerbation of asthma Chest 2014 145 1 53 9 23949578 \n10 Kraut JA Madias NE Lactic Acidosis N Eng J Med 2014 371 24 2309 19 \n11 Vander Heiden MG Cantley LC Thompson CB Understanding the Warburg effect: The metabolic requirements Science 2009 324 5930 1029 33 19460998 \n12 Uribarri J Oh MS Carroll HJ D-lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms Medicine (Baltimore) 1998 77 2 73 82 9556700 \n13 Goli AK Goli SA Byrd RP Jr Simvastatin-induced lactic acidosis: A rare adverse reaction? Clin Pharmacol Ther 2002 72 4 461 4 12386648 \n14 Neale R Reynolds TM Saweirs W Statin precipitated lactic acidosis? J Clin Pathol 2004 57 9 989 90 15333664\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2474-252X",
"issue": "2(2)",
"journal": "Clinical practice and cases in emergency medicine",
"keywords": null,
"medline_ta": "Clin Pract Cases Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "101718968",
"other_id": null,
"pages": "128-131",
"pmc": null,
"pmid": "29849230",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": "12386648;15911945;13716482;3599345;17713401;24079682;9556700;23949578;11794169;26857949;19460998;15333664;25494270",
"title": "Significant Lactic Acidosis from Albuterol.",
"title_normalized": "significant lactic acidosis from albuterol"
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{
"abstract": "As most active chemotherapy agents against Wilms tumor are incorporated into upfront therapy, particularly for those patients with high risk for recurrence, novel regimens are needed to treat children with relapsed Wilms tumor. We describe four consecutive patients with multiply relapsed Wilms tumor who were treated with a combination of vincristine, irinotecan, temozolomide, and bevacizumab. Two had a complete response, and two had a partial response to treatment. Hematological toxicity and diarrhea were the main side effects. This regimen has activity in patients with multiply relapsed Wilms tumor without excessive toxicity, and should be evaluated further in this setting.",
"affiliations": "Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California.",
"authors": "Venkatramani|Rajkumar|R|;Malogolowkin|Marcio H|MH|;Mascarenhas|Leo|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D014750:Vincristine; D000077146:Irinotecan; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide",
"country": "United States",
"delete": false,
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"issn_linking": "1545-5009",
"issue": "61(4)",
"journal": "Pediatric blood & cancer",
"keywords": "Wilms tumor; bevacizumab; chemotherapy; irinotecan; relapse; temozolomide; vincristine",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002166:Camptothecin; D002648:Child; D003606:Dacarbazine; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007680:Kidney Neoplasms; D008297:Male; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D000077204:Temozolomide; D014750:Vincristine; D009396:Wilms Tumor",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "756-9",
"pmc": null,
"pmid": "24115645",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of multiply relapsed wilms tumor with vincristine, irinotecan, temozolomide and bevacizumab.",
"title_normalized": "treatment of multiply relapsed wilms tumor with vincristine irinotecan temozolomide and bevacizumab"
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"companynumb": "US-FRESENIUS KABI-FK201504120",
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"activesubstancename": "BEVACIZUMAB"
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"abstract": "Please verify term, \"alternative\". Chronic immune-mediated demyelinating polyneuropathy (CIDP) is a treatable immune-related demyelinating polyneuropathy. Approximately 20% of cases do not respond to first-line therapies; most of these cases are due to alternative diagnoses, although some of them are due to severe CIDP. Unfortunately, a lack of universally accepted diagnostic criteria complicates the course of diagnosis and treatment. This article discusses videos of cases referred to a tertiary medical center for \"refractory CIDP\" and pitfalls in the diagnosis and management of this condition.",
"affiliations": "Nerve and Muscle Center of Texas, 6624 Fannin Street Suite 1670, Houston, TX 77030, USA; Baylor College of Medicine, Houston, TX, USA. Electronic address: ather@aol.com.;Nerve and Muscle Center of Texas, 6624 Fannin Street Suite 1670, Houston, TX 77030, USA.",
"authors": "Shaibani|Aziz|A|;Al Sultani|Husam|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ncl.2020.03.006",
"fulltext": null,
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"issn_linking": "0733-8619",
"issue": "38(3)",
"journal": "Neurologic clinics",
"keywords": "CIDP; Conduction block; Demyelinating; MAG antibodies; NF-155; Neuropathy; POEMS; Refractory",
"medline_ta": "Neurol Clin",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating",
"nlm_unique_id": "8219232",
"other_id": null,
"pages": "591-605",
"pmc": null,
"pmid": "32703471",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Refractory Chronic Immune-mediated Demyelinating Polyneuropathy.",
"title_normalized": "refractory chronic immune mediated demyelinating polyneuropathy"
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"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
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"abstract": "Tics are the hallmark of Tourette syndrome (TS). However, TS patients may have a particular vulnerability to develop other movement disorders (MDs), such as dystonia, chorea, stereotypy, and other hyperkinetic disorders that may be wrongly attributed to tics.\n\n\n\nWe studied a cohort of 201 patients with motor and phonic tics associated with TS to determine if they have additional, co-existent, MDs.\n\n\n\nThere were 67 (33.3%) patients with comorbid non-tic MDs. Phenomenology-wise, piano-playing movements resembling chorea or myoclonus, were the most common non-tic movement, observed in 11% of cases, followed by stereotypies (8.0%), tremor, dystonia and parkinsonism, 5.0% each. Drug-induced was the most common etiology (6.0%), followed by functional movement disorders (5.0%) and tardive phenomena (5.0%). No clear etiology was identified in most patients. Piano-playing movements, were associated with a younger age at onset (P = 0.004) and younger age at presentation (P < 0.001). Patients with drug-induced movements and tardive phenomena had a lower frequency of craniofacial tics. FMDs, and idiopathic MDS showed no specific associations with TS. Tic severity was not a predictor of any co-existent MD.\n\n\n\nAbout a third of patients with TS present with comorbid MDs which should be differentiated and distinguished from tics as their etiopathogenesis and treatment may be different.",
"affiliations": "Department of Sciences and Engineering, University of Guanajuato, Lomas del Bosque #103, Lomas del Campestre, C.P. 37150, León, GTO, Mexico. baizabaljf@hotmail.com.;Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, USA.",
"authors": "Baizabal-Carvallo|José Fidel|JF|0000-0002-8614-5563;Jankovic|Joseph|J|",
"chemical_list": null,
"country": "Austria",
"delete": false,
"doi": "10.1007/s00702-021-02386-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9564",
"issue": "128(8)",
"journal": "Journal of neural transmission (Vienna, Austria : 1996)",
"keywords": "Chorea minima; Piano-playing movements, tics, functional movement disorders; Psychogenic; Tardive",
"medline_ta": "J Neural Transm (Vienna)",
"mesh_terms": "D002819:Chorea; D006801:Humans; D009069:Movement Disorders; D013981:Tic Disorders; D020323:Tics; D005879:Tourette Syndrome",
"nlm_unique_id": "9702341",
"other_id": null,
"pages": "1177-1183",
"pmc": null,
"pmid": "34302221",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "26209715",
"title": "Beyond tics: movement disorders in patients with Tourette syndrome.",
"title_normalized": "beyond tics movement disorders in patients with tourette syndrome"
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"activesubstancename": "RISPERIDONE"
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... |
{
"abstract": "BACKGROUND\nCoronary artery ectasia is characterized by an abnormal dilatation of the coronary arteries. Coronary artery ectasia is observed in 3-8% of patients undergoing coronary angiography and sometimes leads to acute coronary syndrome regardless of the presence or absence of coronary stenosis or atrial fibrillation.\n\n\nMETHODS\nA 61-year-old Indonesian man presented with typical angina that began 1 week before admission and had worsened 3 hours prior to admission. Accompanying symptoms included dyspnea, nausea, and sweating. He was hemodynamically stable and had a history of tobacco smoking and dyslipidemia. An electrocardiogram showed ST-segment depression and T inversion. Laboratory results showed an international normalized ratio of 1.28. Dual antiplatelet therapy was administered along with fondaparinux, and symptoms were alleviated. Coronary angiography showed an ectatic and turbulent mid-distal right coronary artery and slow flow at the first presentation. There was a patent stent in the proximal-mid left anterior descending coronary artery. This patient had previously presented with recurrent acute coronary syndrome and received two coronary stents for the stenotic vessels.\n\n\nCONCLUSIONS\nHe had right coronary artery ectasia and experienced recurrent acute coronary syndrome. He received dual antiplatelet therapy along with warfarin after stenting of his left anterior descending coronary artery. However, he presented with unstable angina pectoris 7 months before the latest admission and at the latest admission despite a patent stent and no other significant obstructive lesion. The unstable angina pectoris might have been caused by slow flow, microvascular angina caused by small thrombi and/or vasospasm, or epicardial thrombosis at the ectatic coronary artery that dissolved after anticoagulation therapy prior to coronary angiography. Anticoagulant therapy may have a greater benefit than antiplatelet therapy in this patient due to the turbulence and stasis of blood in the ectatic vessel, although coexisting coronary conditions mandated antiplatelet therapy. His international normalized ratio was suboptimal and needed to be improved.\n\n\nCONCLUSIONS\nCoronary ectasia may play a role in recurrent acute coronary syndrome, and administration of an anticoagulant to prevent acute coronary syndrome in this patient was in accordance with the varying hemodynamic property of coronary artery ectasia.",
"affiliations": "Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Banten, Indonesia.;Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Banten, Indonesia. Raymond_pranata@hotmail.com.;Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Banten, Indonesia.",
"authors": "Damay|Vito|V|;Pranata|Raymond|R|http://orcid.org/0000-0003-3998-6551;Wiharja|Wendy|W|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-1979-x",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 197910.1186/s13256-019-1979-xCase ReportRecurrent acute coronary syndrome in a patient with right coronary artery ectasia: a case report Damay Vito vito.damay@uph.edu 12http://orcid.org/0000-0003-3998-6551Pranata Raymond +6282112918892Raymond_pranata@hotmail.com 12Wiharja Wendy wiharja.wendy@gmail.com 121 0000 0001 0232 6459grid.443962.eFaculty of Medicine, Universitas Pelita Harapan, Tangerang, Banten Indonesia 2 Department of Cardiology and Vascular Medicine, Siloam Hospitals Lippo Village, Tangerang, Banten Indonesia 9 3 2019 9 3 2019 2019 13 7813 8 2018 14 1 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\nCoronary artery ectasia is characterized by an abnormal dilatation of the coronary arteries. Coronary artery ectasia is observed in 3–8% of patients undergoing coronary angiography and sometimes leads to acute coronary syndrome regardless of the presence or absence of coronary stenosis or atrial fibrillation.\n\nCase presentation\nA 61-year-old Indonesian man presented with typical angina that began 1 week before admission and had worsened 3 hours prior to admission. Accompanying symptoms included dyspnea, nausea, and sweating. He was hemodynamically stable and had a history of tobacco smoking and dyslipidemia. An electrocardiogram showed ST-segment depression and T inversion. Laboratory results showed an international normalized ratio of 1.28. Dual antiplatelet therapy was administered along with fondaparinux, and symptoms were alleviated. Coronary angiography showed an ectatic and turbulent mid-distal right coronary artery and slow flow at the first presentation. There was a patent stent in the proximal-mid left anterior descending coronary artery. This patient had previously presented with recurrent acute coronary syndrome and received two coronary stents for the stenotic vessels.\n\nDiscussion\nHe had right coronary artery ectasia and experienced recurrent acute coronary syndrome. He received dual antiplatelet therapy along with warfarin after stenting of his left anterior descending coronary artery. However, he presented with unstable angina pectoris 7 months before the latest admission and at the latest admission despite a patent stent and no other significant obstructive lesion. The unstable angina pectoris might have been caused by slow flow, microvascular angina caused by small thrombi and/or vasospasm, or epicardial thrombosis at the ectatic coronary artery that dissolved after anticoagulation therapy prior to coronary angiography. Anticoagulant therapy may have a greater benefit than antiplatelet therapy in this patient due to the turbulence and stasis of blood in the ectatic vessel, although coexisting coronary conditions mandated antiplatelet therapy. His international normalized ratio was suboptimal and needed to be improved.\n\nConclusion\nCoronary ectasia may play a role in recurrent acute coronary syndrome, and administration of an anticoagulant to prevent acute coronary syndrome in this patient was in accordance with the varying hemodynamic property of coronary artery ectasia.\n\nKeywords\nCoronary artery ectasiaAcute coronary syndromeMicrovascularAnticoagulantRecurrenceissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nCoronary artery ectasia (CAE) is characterized by an abnormal dilatation of a coronary arterial segment of at least 1.5 times that of an adjacent normal coronary artery. CAE is observed in 3–8% of patients undergoing coronary angiography (CAG) and sometimes leads to acute coronary syndrome (ACS) regardless of the presence or absence of coronary stenosis or atrial fibrillation (AF) [1–3]. Approximately 20–30% of cases of CAE are thought to be congenital in origin (many of which coexist with coronary artery stenosis), 50% are attributable to atherosclerosis, and 10–20% are associated with inflammatory or connective tissue disease [1]. The slow flow phenomenon may lead to ischemia and thrombosis [4, 5]. These factors may then lead to ACS with varying pathophysiology that potentially requires a different approach.\n\nThe role of anticoagulants is still controversial in ACS with CAE. In this case report, we present a patient with recurrent ACS despite dual antiplatelet therapy (DAPT) and stenting of coronary arteries with significant stenosis in the presence of CAE. After intensified warfarin therapy, the patient was event-free at a 6-month follow-up, which indicated that anticoagulation is effective in such patients. To the best of our knowledge, at the time of this writing, our study was the first to report a fourth recurrence of ACS in a patient with right CAE.\n\nCase presentation\nA 61-year-old Indonesian man complained of typical chest pain that began 1 week before admission and had worsened 3 hours prior to admission. Accompanying symptoms were dyspnea, nausea, and sweating. On examination, his blood pressure was 110/80 mmHg, heart rate was 54 beats/minute, respiratory rate was 22 times/minute, and temperature was 37 °C. Cardiorespiratory examination results were within normal limits. A neurological examination was unremarkable. He had a history of dyslipidemia and hypertension, but there was no history of diabetes. His father had hypertension, but his family history was otherwise unremarkable. He quit smoking tobacco 17 months prior to admission. He did not drink alcohol. Current medications were captopril, bisoprolol, aspirin, clopidogrel, warfarin, isosorbide dinitrate (ISDN), and atorvastatin. He was not compliant with the warfarin regimen, particularly at a few weeks after hospital discharge and at 7 and 13 months before the present admission. Electrocardiography showed sinus rhythm of 54 beats/minute, left ventricular hypertrophy, horizontal ST-segment depression, and T wave inversion at leads I, aVL, and V4–6. A biphasic T wave was observed at lead V2–3 (Fig. 1). Laboratory results showed a suboptimal international normalized ratio (INR) of 1.28. The level of triglycerides was 273 mg/dL; low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels were within normal limits. The complete blood count and urea, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase–myocardial band (CK-MB), and high-sensitivity troponin (hs-troponin) T levels were within normal limits. He was given a loading dose of aspirin and clopidogrel along with fondaparinux, and his symptoms were alleviated.Fig. 1 Electrocardiography at current admission. Sinus rhythm of 54 beats/minute, left ventricular hypertrophy, horizontal ST-segment depression, and T wave inversion at leads I, aVL, and V4–6, and a biphasic T wave at lead V2–3\n\n\n\nCAG showed an ectatic and turbulent mid-distal right coronary artery (RCA) and slow flow. There was a patent stent in the mid-left anterior descending coronary artery (LAD) and first diagonal branch (D1) (Fig. 2).Fig. 2 Angiography at current admission. Coronary angiography at the current presentation revealed two stents (a) and right coronary artery ectasia (b) without any significant obstruction\n\n\n\nHe had previously presented with chest pain on exertion (stable angina) at 17 months before the present admission. CAG showed an ectatic RCA, 30% irregular diffuse proximal-distal flow, turbulent distal flow, and 70% stenosis at the proximal D1 vessel and 50–60% stenosis at the mid-LAD past the D1 vessel (Table 1) (Fig. 3). He requested medical treatment rather than percutaneous coronary intervention (PCI); he was given bisoprolol, aspirin, ISDN, and atorvastatin and was then scheduled for a repeat angiogram 6 months later. However, he presented with unstable angina pectoris (UAP) 14 months before the latest presentation, ahead of the scheduled CAG. CAG showed a similar lesion at the RCA and 70% stenosis at the proximal LAD, 90% at the proximal D1 vessel. The D1 vessel was stented. He was given DAPT. He presented again with UAP 1 month later, and CAG showed a similar lesion at the RCA, 70–80% stenosis at the mid-LAD, and a patent D1 stent. PCI was performed, and the LAD was stented. His coagulation panel was within normal limits. He was given an anticoagulant due to angina caused by coronary ectasia. He presented again with UAP 7 months before the present admission, and CAG showed ectatic, turbulent mid-distal flow and slow flow in the dominant vessel, Thrombolysis In Myocardial Infarction (TIMI) flow II–III distal to the nonstenotic RCA, and a patent stent at the mid-LAD and D1 vessels. His INR was suboptimal (1.4). He was suspected of having recurrent ACS due to microvascular occlusion caused by slow flow and an ectatic vessel; warfarin therapy was intensified, and he was educated regarding the importance of reaching the INR target. At the time of the writing of this article, he had been event-free for 6 months, and his INR was 2.3. He remained compliant with the drug regimen.Table 1 Summary of the patient’s chronology\n\nPresentation\tFeatures\tCoronary Angiography\tAntiplatelets/Anticoagulation\t\nCurrent\tUAP\tEctatic, turbulent mid-distal + slow flow without stenosis at RCA and patent stent at mid LAD and D1. INR was suboptimal (1.28)\tDAPT + Warfarin\t\n7 Months\tUAP\tEctatic, turbulent mid-distal + slow flow without stenosis at RCA and patent stent at mid LAD and D1. INR was suboptimal (1.4)\tDAPT + Warfarin\t\n13 Months\tUAP\tEctatic, turbulent mid-distal + slow flow without stenosis at RCA, a 70–80% stenosis at mid LAD, and a patent D1 stent. LAD stented\tDAPT + Warfarin\t\n14 Months\tUAP\tEctatic, turbulent mid-distal + slow flow without stenosis at RCA, a 70% stenosis at proximal LAD, 90% at D1 prox. D1 was stented\tDAPT\t\n17 Months\tSAP\tEctatic, turbulent mid-distal + slow flow without stenosis at RCA and 70% stenosis at D1 prox & 50–60% mid LAD after D1\tAspirin\t\nDAPT Dual Antiplatelet Therapy, INR International Normalized Ratio, LAD Left Anterior Descending, LCx Left Circumflex Artery, RCA Right Coronary Artery, SAP Stable Angina Pectoris, UAP Unstable Angina Pectoris.\n\nFig. 3 Angiography 17 months prior to present admission. Coronary angiography revealed 70% stenosis at the proximal D1 vessel and 50–60% stenosis mid-left anterior descending coronary artery past the D1 vessel (a) and ectatic, turbulent mid-distal flow and slow flow at the nonstenotic right coronary artery (b)\n\n\n\nDiscussion\nThis patient had right CAE with stents in significant coronary lesions. He experienced recurrent ACS while on DAPT and suboptimal warfarin therapy despite patent stents and the absence of an obstructive coronary lesion. To the best of our knowledge, at the time of this writing, the present case was the first to report a fourth recurrence of ACS in a patient with right CAE despite the absence of obstructive lesions upon angiography. After intensified warfarin therapy, which resulted in an INR of 2.3, our patient was event-free for 6 months, highlighting the importance of anticoagulant therapy in a patient with recurrent ACS and CAE without obstructive lesions.\n\nInitially, the angina was thought to be solely caused by obstructive coronary artery disease due to the presence of significant stenosis in the coronary vessel. After stenting the vessel, our patient presented again with ACS, and the second stent was deployed. He received DAPT along with warfarin after the second stenting. However, he presented with UAP at 7 months before latest admission and at the latest admission despite a patent stent and no other significant obstructive lesion. This observation led to the suspicion that both the CAE and coronary stenosis played a role in the recurrent acute pain. ACS in patients with CAE has varying pathophysiology and may be divided into pathology that is detectable by CAG, such as visible thrombosis of the epicardial coronary artery, or not detectable by CAG, such as slow flow, vasospasm, and thrombosis in the microvasculature. In our patient, there was an absence of a flow-limiting lesion, indicating that the ACS may be due to the latter type of CAE, especially the coronary slow flow (CSF) phenomenon [6]. Delayed distal vessel opacification in the absence of significant epicardial coronary artery disease is characteristic of CSF. CSF may cause myocardial ischemia and injury, especially during stress, which is thought to be related to coronary endothelial dysfunction [7, 8]. CSF might also be caused by microvascular angina due to small thrombi that are not visible or microvascular spasms during CAG. CSF might also be caused by a thrombus in the ectatic vessel that dissolves prior to CAG due to anticoagulant treatment and a loading dose of DAPT, as the symptoms were alleviated after drug administration.\n\nThe goal of therapy is to prevent further myocardial ischemia and minimize the risk of thrombosis due to an inflammatory state and slow flow. Thrombosis at the ectatic coronary artery is more likely to be a high burden and result in poor reflow after intervention, with poor outcomes [9]. Treatment with warfarin itself has not been prospectively studied, and the recommendation is not clear. In patients with isolated CAE, anticoagulant therapy alone may be appropriate due to turbulence and stasis of blood in the ectatic vessel [6]. A search of existing literature that reported cases of patients with recurrent ACS in CAE showed that there were two isolated cases of CAE in which the patient took DAPT without an anticoagulant and experienced recurrence [10–18]. To the best of our knowledge, there has not been a report of recurrent ACS after anticoagulation that has met the target of treatment, and there has not been a report of recurrent ACS after treatment with DAPT in a nonisolated case. Our patient did not have any significant lesion at the current presentation, and the pain may be due to “isolated CAE”; hence, anticoagulation might be helpful in our case. Interestingly, after being given warfarin, our patient was event-free for 6 and 7 months, whereas previously, the recurrence occurred at a shorter timeframe, coinciding with him becoming noncompliant a few weeks after warfarin was given (Table 1). However, he also had coexisting coronary artery disease and a stent in the coronary artery requiring DAPT. Because the benefit outweighed the risk of bleeding in this patient, triple therapy with aspirin, clopidogrel, and warfarin was continued. The INR in this patient was suboptimal and needed to be improved. Nitrates may exacerbate stress-induced myocardial ischemia by causing epicardial vasodilation in isolated CAE. Nitrates were to be used conservatively in this patient because the obstructive lesion had been addressed, and it was possible that the angina was solely due to CAE, which may be exacerbated by the administration of nitrates. Calcium channel blockers and beta-blockers should thus be the mainstay anti-ischemic vasodilator therapy in our patient [6].\n\nConclusion\nCAE may cause recurrent ACS with an obstructive or nonobstructive lesion on CAG. Administration of an anticoagulant should be considered to prevent ACS in these patients without ignoring the need for antiplatelet therapy in the presence of atheroma. Nitrates should be avoided in cases of pure CAE and used sparingly in those with coexisting coronary artery disease. Beta-blockers and calcium channel blockers are preferred over nitrates as anti-ischemic vasodilator agents.\n\nPatient’s perspective\nThe patient admitted that it is difficult to comply with the drug regimen because he has to take several pills a day. He also feared that taking too many pills would lead to renal damage. After reemphasizing the importance of anticoagulant therapy, the patient understood and planned to enlist the help of family members to remind him to take his medication and help him keep a diary.\n\nAcknowledgements\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nSupporting data and materials for this manuscript are available.\n\nAuthors’ contributions\nVD admitted and treated the patient. VD and RP drafted the manuscript. RP and WW performed extensive research on the topic. VD and RP made critical revisions to the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNo ethics committee approval was required at our institution for a case report involving a single patient.\n\nConsent for publication\nWritten informed consent was obtained from the patient for the publication of this manuscript and the accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hartnell GG Parnell BM Pridie RB Coronary artery ectasia, its prevalence, and clinical significance in 4993 patients Br Heart J 1985 54 392 395 10.1136/hrt.54.4.392 4052280 \n2. Mavrogeni S Coronary artery ectasia: from diagnosis to treatment Hell J Cardiol 2010 51 158 163 \n3. Papadakis MC Manginas A Cotileas P Documentation of slow coronary flow by the TIMI frame count in patients with coronary ectasia Am J Cardiol 2001 88 1030 1032 10.1016/S0002-9149(01)01984-1 11704003 \n4. Markis JE Joffe CD Cohn PF Feen DJ Herman MV Gorlin R Clinical significance of coronary arterial ectasia Am J Cardiol 1976 37 217 222 10.1016/0002-9149(76)90315-5 1108631 \n5. Sayın T Döven O Berkalp B Akyürek O Güleç S Oral D Exercise-induced myocardial ischemia in patients with coronary artery ectasia without obstructive coronary artery disease Int J Cardiol 2001 78 143 149 10.1016/S0167-5273(01)00365-5 11334658 \n6. Boles U Coronary artery ectasia as a culprit for acute myocardial infarction: review of pathophysiology and management Anadolu Kardiyol Derg 2013 13 695 701 24084147 \n7. Tatlı E Yıldırım T Aktoz M Does coronary slow flow phenomenon lead to myocardial ischemia? Int J Cardiol 2009 131 e101 e102 10.1016/j.ijcard.2007.07.069 17931724 \n8. Çelik T İyisoy A Kurşaklıoğlu H Yüksel C Turhan H Işık E ST elevation during treadmill exercise test in a young patient with slow coronary flow: a case report and review of literature Int J Cardiol 2006 112 e1 e4 10.1016/j.ijcard.2006.01.053 16766061 \n9. Yip HK Chen MC Wu CJ Hang CL Hsieh KY Fang CY Clinical features and outcome of coronary artery aneurysm in patients with acute myocardial infarction undergoing a primary percutaneous coronary intervention Cardiology 2002 98 132 140 10.1159/000066322 12417812 \n10. Tomioka T Takeuchi S Ito Y Shioiri H Koyama J Inoue K Recurrent Acute Myocardial Infarction in a Patient with Severe Coronary Artery Ectasia: Implication of Antithrombotic Therapy Am J Case Rep 2016 17 12 939 943 10.12659/AJCR.900474 27941711 \n11. Okada T Endo A Ito S Nakamura T Sugamori T Takahashi N Acute Coronary Syndrome in a Puerperal Patient with Coronary Artery Ectasia due to a Coronary Artery Fistula Intern Med 2016 55 18 2635 2638 10.2169/internalmedicine.55.6597 27629959 \n12. Furugen M Takagawa Y Staged interventional management of a massive thrombus related to coronary artery ectasia in acute coronary syndrome Cardiovasc Interv Ther 2012 27 1 57 61 10.1007/s12928-011-0083-y 24122644 \n13. Tuncer C Sokmen G Sokmen A Suner A Diffuse coronary ectasia and intracoronary thrombus involving left circumflex coronary artery and presenting as acute coronary syndrome: report of two cases Int J Cardiol 2008 128 1 e25 e27 10.1016/j.ijcard.2007.04.158 17804097 \n14. Lima B Varma SK Lowe JE Nonsurgical management of left main coronary artery aneurysms: report of 2 cases and review of the literature Tex Heart Inst J 2006 33 3 376 379 17041701 \n15. Perlman PE Ridgeway NA Thrombosis and anticoagulation therapy in coronary ectasia Clin Cardiol 1989 12 9 541 542 10.1002/clc.4960120912 2791375 \n16. Boles U Rakhit R Shiu MF Patel K Henein M Coronary artery ectasia as a culprit for acute myocardial infarction: review of pathophysiology and management Anadolu Kardiyol Derg 2013 13 7 695 701 24084147 \n17. Mrdovic I Jozic T Asanin M Perunicic J Ostojic M Myocardial Reinfarction in a Patient with Coronary Ectasia Cardiology 2004 102 32 34 10.1159/000077000 15004454 \n18. Latt H Aung S Kyaw K Seher R Coronary artery ectasia presenting with acute inferior wall myocardial infarction in a young adult J Community Hosp Intern Med Perspect 2017 7 4 262 264 10.1080/20009666.2017.1369376 29046758\n\n",
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"journal": "Journal of medical case reports",
"keywords": "Acute coronary syndrome; Anticoagulant; Coronary artery ectasia; Microvascular; Recurrence",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000925:Anticoagulants; D017023:Coronary Angiography; D003324:Coronary Artery Disease; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D010353:Patient Education as Topic; D010975:Platelet Aggregation Inhibitors; D016896:Treatment Outcome; D014859:Warfarin",
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"title": "Recurrent acute coronary syndrome in a patient with right coronary artery ectasia: a case report.",
"title_normalized": "recurrent acute coronary syndrome in a patient with right coronary artery ectasia a case report"
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"abstract": "We describe 2 children with cobalamin G disease, a disorder of vitamin B12 metabolism with normal serum B12 levels. They presented with megaloblastic anemia progressing rapidly to severe thrombotic microangiopathy. In infants presenting with acute thrombotic microangiopathy, cobalamin disorders should be considered early as diagnosis and targeted treatment can be lifesaving.",
"affiliations": "Baylor College of Medicine, Department of Pediatrics, Section of Hematology/Oncology, Texas Children's Hospital, Houston, TX. Electronic address: dxmullik@texaschildrens.org.;Baylor College of Medicine, Department of Molecular and Human Genetics, Texas Children's Hospital, Houston, TX.;Department of Human Genetics, Emory University, Atlanta, GA.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.;Baylor College of Medicine, Department of Pediatrics, Section of Nephrology, Texas Children's Hospital, Houston, TX.;Baylor College of Medicine, Department of Molecular and Human Genetics, Texas Children's Hospital, Houston, TX.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.;Department of Human Genetics, Emory University, Atlanta, GA.;Department of Human Genetics, Emory University, Atlanta, GA.;Baylor College of Medicine, Department of Molecular and Human Genetics, Texas Children's Hospital, Houston, TX.;Baylor College of Medicine, Department of Pediatrics, Section of Hematology/Oncology, Texas Children's Hospital, Houston, TX.;Baylor College of Medicine, Department of Molecular and Human Genetics, Texas Children's Hospital, Houston, TX.;Baylor College of Medicine, Department of Pediatrics, Section of Hematology/Oncology, Texas Children's Hospital, Houston, TX.",
"authors": "Mullikin|Dolores|D|;Pillai|Nishitha|N|;Sanchez|Rossana|R|;O'Donnell-Luria|Anne H|AH|;Kritzer|Amy|A|;Tal|Leyat|L|;Almannai|Mohammed|M|;Berry|Gerard T|GT|;Gambello|Michael J|MJ|;Li|Hong|H|;Graham|Brett|B|;Srivaths|Lakshmi|L|;Sutton|Vernon Reid|VR|;Grimes|Amanda|A|",
"chemical_list": "D006879:Hydroxocobalamin",
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"issn_linking": "0022-3476",
"issue": "202()",
"journal": "The Journal of pediatrics",
"keywords": "Cobalamin G disease; Coblamain C disease; hyperhomocysteinemia; megaloblastic anemia; methionine synthase; thrombotic microangiopathy",
"medline_ta": "J Pediatr",
"mesh_terms": "D000749:Anemia, Megaloblastic; D001774:Blood Chemical Analysis; D001803:Blood Transfusion; D002675:Child, Preschool; D018450:Disease Progression; D042241:Early Diagnosis; D005183:Failure to Thrive; D006403:Hematologic Tests; D006801:Humans; D006879:Hydroxocobalamin; D007223:Infant; D007273:Injections, Intramuscular; D008297:Male; D011379:Prognosis; D018570:Risk Assessment; D012720:Severity of Illness Index; D057049:Thrombotic Microangiopathies; D016896:Treatment Outcome; D014806:Vitamin B 12 Deficiency",
"nlm_unique_id": "0375410",
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"pages": "315-319.e2",
"pmc": null,
"pmid": "30057141",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Megaloblastic Anemia Progressing to Severe Thrombotic Microangiopathy in Patients with Disordered Vitamin B12 Metabolism: Case Reports and Literature Review.",
"title_normalized": "megaloblastic anemia progressing to severe thrombotic microangiopathy in patients with disordered vitamin b12 metabolism case reports and literature review"
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"abstract": "BACKGROUND\nPulmonary alveolar proteinosis (PAP) is characterized by the accumulation of surfactant proteins within the alveolar spaces. Autoimmune PAP (APAP) caused by elevated levels of GM-CSF autoantibodies (GM-Ab) is very rarely associated with systemic autoimmune disease. Here we report a case of APAP manifested during immunosuppressive treatment for polymyositis with interstitial lung disease.\n\n\nMETHODS\nA 52-year-old woman treated at our hospital because of polymyositis with interstitial pneumonia had maintained remission by immunosuppressive treatment for 15 years. She had progressive dyspnea subsequently over several months with her chest CT showing ground-glass opacities (GGO) in bilateral geographic distribution. Her bronchoalveolar lavage fluid with cloudy appearance revealed medium-sized foamy macrophages and PAS-positive amorphous eosinophilic materials by cytological examination. We diagnosed her as APAP due to an increased serum GM-CSF autoantibody level. Attenuating immunosuppression failed to lead GGO improvement, but whole lung lavage (WLL) was effective in her condition.\n\n\nCONCLUSIONS\nPAP should be considered as one of the differential diseases when the newly interstitial shadow was observed during immunosuppressive treatment. WLL should be regarded as the treatment option for APAP concurred in connective tissue disease (CTD).",
"affiliations": "Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan. smallerss@hotmail.com.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553, Japan.;Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minami-Uonuma, Japan.",
"authors": "Sato|S|S|http://orcid.org/0000-0003-2285-9038;Akasaka|K|K|;Ohta|H|H|;Tsukahara|Y|Y|;Kida|G|G|;Tsumiyama|E|E|;Kusano|K|K|;Oba|T|T|;Nishizawa|T|T|;Kawabe|R|R|;Yamakawa|H|H|;Amano|M|M|;Matsushima|H|H|;Takada|T|T|",
"chemical_list": "D001323:Autoantibodies; D007166:Immunosuppressive Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
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"fulltext": "\n==== Front\nBMC Pulm Med\nBMC Pulm Med\nBMC Pulmonary Medicine\n1471-2466 BioMed Central London \n\n1110\n10.1186/s12890-020-1110-5\nCase Report\nAutoimmune pulmonary alveolar proteinosis developed during immunosuppressive treatment in polymyositis with interstitial lung disease: a case report\nhttp://orcid.org/0000-0003-2285-9038Sato S. smallerss@hotmail.com 1 Akasaka K. 1 Ohta H. 1 Tsukahara Y. 1 Kida G. 1 Tsumiyama E. 1 Kusano K. 1 Oba T. 1 Nishizawa T. 1 Kawabe R. 1 Yamakawa H. 1 Amano M. 1 Matsushima H. 1 Takada T. 2 1 0000 0000 8733 7415grid.416704.0Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5, Shintoshin, Chuo-ku, Saitama, 330-8553 Japan \n2 0000 0004 0639 8670grid.412181.fUonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minami-Uonuma, Japan \n6 4 2020 \n6 4 2020 \n2020 \n20 8419 1 2020 10 3 2020 © The Author(s). 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nPulmonary alveolar proteinosis (PAP) is characterized by the accumulation of surfactant proteins within the alveolar spaces. Autoimmune PAP (APAP) caused by elevated levels of GM-CSF autoantibodies (GM-Ab) is very rarely associated with systemic autoimmune disease. Here we report a case of APAP manifested during immunosuppressive treatment for polymyositis with interstitial lung disease.\n\nCase presentation\nA 52-year-old woman treated at our hospital because of polymyositis with interstitial pneumonia had maintained remission by immunosuppressive treatment for 15 years. She had progressive dyspnea subsequently over several months with her chest CT showing ground-glass opacities (GGO) in bilateral geographic distribution. Her bronchoalveolar lavage fluid with cloudy appearance revealed medium-sized foamy macrophages and PAS-positive amorphous eosinophilic materials by cytological examination. We diagnosed her as APAP due to an increased serum GM-CSF autoantibody level. Attenuating immunosuppression failed to lead GGO improvement, but whole lung lavage (WLL) was effective in her condition.\n\nConclusions\nPAP should be considered as one of the differential diseases when the newly interstitial shadow was observed during immunosuppressive treatment. WLL should be regarded as the treatment option for APAP concurred in connective tissue disease (CTD).\n\nKeywords\nPulmonary alveolar proteinosisPolymyositisGM-CSFImmunosuppressive treatmentJapan Society for the Promotion of ScienceJP16K09530issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPulmonary alveolar proteinosis (PAP) is a rare syndrome resulting from the accumulation of lipoproteinaceous materials in the alveoli and terminal airways due to impairment of surfactant clearance by alveolar macrophage [1]. PAP can be classified into several types based on the pathogenesis [2]. Primary PAP is characterized by the disruption of granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling pathway: autoimmune (caused by elevated levels of GM-CSF autoantibodies) or hereditary (due to mutations in encoding GM-CSF receptor subunits). Secondary PAP results from various underlying diseases. Congenital PAP is caused by mutations in genes involved in surfactant production. Interestingly, autoimmune PAP (APAP) is very rarely associated with systemic autoimmune disease. Only a few cases can be found in registry studies and case reports [3–9].. Furthermore, APAP complicated with dermatomyositis/polymyositis was reported only in one case of aminoacyl-tRNA synthetases (ARS) related dermatomyositis [7]. Here we report a case of APAP manifested during long-term immunosuppressive treatment for polymyositis with interstitial lung disease.\n\nCase presentation\nA 52-year-old Japanese woman visited our hospital in 2004 with complaints of dyspnea, dry cough, and myalgia. She had signs of myalgia and muscle weakness of the upper limbs, increased serum creatine kinase (1315 IU/L), and fibrillation potential and short duration neuromuscular unit (NMU) in electromyogram. We diagnosed her as polymyositis based on the diagnostic criteria of the Ministry of Health, Labour and Welfare’s Autoimmune Disease Research Group of Japan. No skin symptoms were observed. Chest CT findings revealed reticular shadows and ground-glass opacities (GGOs) in bilateral lower lobes peripherally from around the bronchovascular bundle. The bronchoalveolar lavage fluid (BALF) with transparent appearance contained 2.4 × 105 cells/mL, 44.6% macrophages, 52.2% lymphocytes, 1.8% neutrophils, and 1.4% eosinophils. Lymphocytes increment was observed but no findings suggesting PAP on cytology. Microbiological tests for bacteria, fungi, or acid-fast bacilli in BALF were also negative. The titer of GM-Ab was not measured.\n\nShe was diagnosed as polymyositis with interstitial pneumonia. Corticosteroid therapy (prednisolone;40 mg/day) immediately improved both myalgia and dyspnea. Serum creatine kinase and KL-6 levels also decreased to normal ranges. As for CT findings, the reticular opacities and GGOs diminished. We gradually tapered prednisolone doses and her medical condition had been well-controlled by immunosuppressive treatment over 15 years since the diagnosis (Figs. 1, 2A).\nFig. 1 Clinical course. The patient had no recurrence for fifteen years with immunosuppressive treatment after diagnosis with polymyositis and myositis-associated interstitial pneumonia. In 2019 she was admitted to our hospital complaining progressive dyspnea with increased KL-6.\n\n\nFig. 2 Chest CT findings. A Four months before admission, her chest CT showed a subpleural and basal predominant reticular pattern with peripheral traction bronchiectasis. B On admission, extensive GGOs with geographic distribution appeared bilaterally. C Immediately before WLL, GGOs worsened further in both lung fields four months after the diagnosis. D After WLL, GGOs improved significantly with no change in the underlying interstitial pneumonia.\n\n\n\nIn early 2019, she visited our hospital because of progressive dyspnea and slight productive cough for 4 months under treatment with prednisolone 7.5 mg/day (Fig. 1). Chest auscultation revealed fine crackles on inspiration in the bibasilar area. The physical examination revealed no skin lesions such as sclerosis, Gottron’s sign, heliotrope rash, mechanic’s hands, or Raynaud’s phenomenon, and no myalgia, muscle atrophy, or arthralgia. Chest CT showed subpleural reticular opacities predominantly in the lower lobes accompanying contraction and extensive GGOs in geographic distribution (Fig. 2B).\n\nLaboratory examinations revealed significantly high serum levels of KL-6 (6843 U/mL) and SP-D (362 ng/mL). The serum creatine kinase (72 IU/L), aldolase (5.3 IU/L), and C-reactive protein levels (0.27 mg/dL) were within the normal range. The serum anti-ARS antibody level was positive at 115 index, whereas anti-melanoma differentiation-associated gene 5 (MDA-5) antibody level was negative. RNA immunoprecipitation assay indicated the positivity of anti-SS-A/Ro52 and anti-EJ, one of the anti-ARS antibodies. An arterial blood gas analysis showed decreased partial pressure of oxygen (PaO2) (74.5 Torr) with elevated alveolar-arterial oxygen gradient (A-aDO2) (22.3 Torr). The respiratory function tests showed severely impaired forced vital capacity (FVC) of 0.6 L (28.5%, %predicted) and forced expiratory volume in 1 s (FEV1) of 0.69 L (35.2%, % predicted) with 100.0% of FEV1/FVC ratio. The diffusing capacity of carbon monoxide (DLCO) could not evaluate due to low FVC.\n\nThe BALF with cloudy appearance contained 3.7 × 105 cells/mL consisting of 85.2% macrophages, 9.6% lymphocytes, 3.6% neutrophils, and 1.4% eosinophils. Microbiological tests, including\nPneumocystis jirovecii\npolymerase chain reaction (PCR) in BALF, were negative. A cytological examination of BALF revealed medium-sized foamy macrophages with acellular periodic acid-Schiff (PAS) positive bodies. Transbronchial lung biopsy specimens showed myxoid-appearing organization in alveolar space and alveolar duct, but no amorphous PAS-positive materials. Because these pathological findings strongly suggested PAP, we measured serum GM-CSF autoantibody (GM-Ab) levels and found positive at 80.1 μg/mL (cut off value < 1.0 μg/mL) [10, 11]. Based on these results, we diagnosed her as APAP in myositis with interstitial pneumonia with severity 2 according to the disease severity score (DSS) [3].\n\nAccording to the previous report [7] prednisolone dose was decreased from 7.5 mg/day to 5.0 mg/day. However, in a gradual progression of her chest imaging findings (Fig. 2C), we performed whole lung lavage (WLL) 4 months after the diagnosis of APAP. The washed-out recovery fluid revealed milky appearance typical of PAP with sediment. It contained foamy macrophages with a background of eosinophilic proteinaceous granular materials (Fig. 3). After the treatment, the GGOs in both lung fields were remarkably improved on CT (Fig. 2D). We found no obvious recurrence of myositis, interstitial pneumonia, or PAP for the following several months.\nFig. 3 Washed-out recovery fluid of WLL. A Gross findings showed a milky appearance with sediment. B Microscopic results revealed foamy macrophages backed by eosinophilic proteinaceous granular materials\n\n\n\nDiscussion and conclusions\nWe experienced a case of APAP complicated with polymyositis accompanying interstitial lung disease. As the interstitial lung abnormality confirmed at first visit day, we considered it to be the myositis-related interstitial pneumonia. The disorder revealed no cloudy appearance of BALF with no pathological findings suggesting PAP, and resolved with immunosuppressive treatment including corticosteroid. We previously reported that corticosteroid therapy might exacerbate APAP [12]. Thus, although the GM-Ab titer was not measured, it is unlikely that the patient had a mild form of APAP when diagnosed as polymyositis with interstitial pneumonia. The patient developed APAP during the immunosuppressive treatment for polymyositis for 15 years. Attenuation of the immunosuppression did not affect newly appeared GGO, but whole lung lavage (WLL) remarkably improved her CT findings and respiratory condition.\n\nThere are very few cases of PAP complicated with connective tissue disease (CTD). Seymour reported only 7 out of 410 PAP cases (1.7%) diagnosed within the period from 1958 to 2002 [1]. According to a report from the Japanese registry, CTD was only found in 3 out of 223 cases of APAP (1.3%, 1999–2006) [3]. We confirmed six cases with CTD complicated with APAP from 1998 to 2019 by searching in the PubMed website (Table 1) [5–9]. All cases were treated by immunosuppressive agents.\nTable 1 Previously reported cases with autoimmune PAP complicated with CTDs\n\nCase\tAuthor\tAge\tSex\tDuration\tTime to\tCTD\tCTD\tGM-Ab\tRegular\tPAP\t\nonset\tprecedence\t(μg/mL)\tTreatment\tTreatment\t\n1 [5]\tNagasawa\t26\tF\tmonth to year\t2 M\tYes\tSLE\t10.6\tPSL + IVCY\treduce PSL + discontinue IVCY\t\n2 [6]\tYamasue\t64\tF\t1.1Y\tYes\tSSc\t10.8\tPSL + IVCY\treduce PSL + discontinue TAC\t\n3 [7]\tImura\t58\tF\t3.5Y\tYes\tDM\t1.8\tPSL + CyA\treduce PSL\t\n4 [8]\tIto\t65\tF\tyear to decade\t5Y\tYes\tRA\t26.1\tMTX + SASP\tWLL + inhalation GM-CSF\t\n5\tOur case\t52\tF\t15Y\tYes\tPM\t80.1\tPSL\treduce PSL + WLL\t\n6 [9]\tSakamoto\t65\tM\t20Y\tYes\tUC\t62.8\tSASP\tWLL\t\n7 [8]\tIto\t68\tF\t26Y\tYes\tRA\t42.3\tSASP\tWLL + inhalation GM-CSF\t\nCTD connective tissue disease, CyA cyclosporine A, DM dermatomyositis, GM-Ab granulocyte-macrophage colony-stimulating factor autoantibody, GM-CSF granulocyte-macrophage colony-stimulating factor, IVCY intravenous cyclophosphamide, MTX methotrexate, RA rheumatoid arthritis, SASP salazosulfapyridin, SLE systemic lupus erythematosus, SSc systemic sclerosis, TAC tacrolimus, UC ulcerative colitis, WLL whole lung lavage\n\n\n\nSeveral case reports showed improved CT findings with only corticosteroid reduction [5–7]. We hypothesize that immunosuppressive treatment with corticosteroid might cause alveolar macrophage dysfunction and increase the accumulation of phospholipids in the alveolar air space. Then it is plausible that the use of immunosuppressive agents could promote the development of potential PAP [12–15] and that corticosteroid reduction caused improvement of CT findings.\n\nGM-CSF regulates the clearance of surfactant by alveolar macrophages. GM-Ab, antibodies to GM-CSF neutralize the effect of GM-CSF on alveolar macrophages, resulting in the maturation arrest of those cells and the development of PAP. GM-Ab in APAP only consisted of the IgG isotype [11]. Immunosuppressive drugs with corticosteroids usually decrease the serum level of IgG. Some patients, however, develop APAP under treatment, which implies that IgG of GM-Ab may be produced independently in immunosuppressive therapy.\n\nThe 6 cases listed on the Table 1 can be divided into two groups. The first group (Case 1–3) developed APAP in 2 months to 3.5 years during an intensive immunosuppressive treatment and improved by tapering the therapy without WLL. Whereas the other group with our case (Case 4–7) developed APAP in 5 to 26 years during mild immunosuppressive treatment and required WLL. This long-term group showed more elevated GM-Ab levels than the short-term group. GM-Ab was likely produced by continuous GM-CSF stimulation in the long-term remedy for CTD. These results suggest that immunoinflammatory pathology for the development of APAP might be different between these groups.\n\nPhysicians rarely consider PAP as a diagnosis when they found unanticipated interstitial opacity during the treatment course of CTDs. Most probable differential diagnoses are as follows: opportunistic infection including Pneumocystis jirovecii or CMV pneumonia, a progression of CTD-related interstitial pneumonia, and drug-induced lung injury. None of these differential disorders was likely in this case because of no positive microbiological tests of BALF, no exacerbation of CTD, and no newly administered drugs. Kitamura recently reported, however, that APAP occurs more frequently than previous reports [16], which suggests that PAP cases might be overlooked among CTD cases treated with immunosuppressive agents.\n\nRecently, a high incidence of juvenile idiopathic arthritis-associated lung disease is reported [17]. Eighteen patients with the disease showed a pulmonary histopathology pattern of endogenous lipoid pneumonia and PAP without GM-Ab. The heritability of APAP has not been proven and is considered to be unrelated to HLA [18]. PAP may be more likely to occur in CTD with or without the GM-Ab. One reason is that we suspect that immunosuppressive drugs could manifest APAP by macrophage dysfunction or opportunistic infection. We may need to be more cautious with CTDs that potentially coexists with PAP [18].\n\nIn the present case, we performed WLL with no significant complications. However, it was also a great concern about postoperative pneumonia, respiratory failure, and acute exacerbation of interstitial pneumonia. In the cases of refractory PAP, rituximab and plasmapheresis were also reported as treatment options [19, 20]. Recently, Tazawa et al. reported that inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension in a randomized, controlled trial [21]. The efficacy and safety of recombinant human GM-CSF for the PAP with pulmonary fibrosis should be studied.\n\nIn conclusion, we experienced a case of APAP associated with polymyositis and myositis-related interstitial pneumonia. This rare concurrence might not a coincidence because of previous reports. Among CTD cases treated with immunosuppressive agents, PAP should be considered as one of the differential diagnosis when unexpected interstitial opacities were observed. WLL is useful as a standard treatment for those cases.\n\nAbbreviations\nAPAPAutoimmune pulmonary alveolar proteinosis\n\nARSAminoacyl-tRNA synthetase;\n\nBALFBronchoalveolar lavage fluid\n\nCKCreatine kinase\n\nCTDConnective tissue disease\n\nCyACyclosporine A\n\nGGOGround-glass opacity\n\nGM-AbGM-CSF autoantibody\n\nGM-CSFGranulocyte-macrophage colony-stimulating factor\n\nKL-6Krebs von den lungen-6\n\nPAPPulmonary alveolar proteinosis\n\nWLLWhole lung lavage\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nWe would like to thank Koh Nakata, Niigata University, for grateful discussions. Also, Yuko Itoh, Niigata University, for measuring serum GM-Ab levels. We appreciate Jiro Kamiyama, Toshiya Tomioka, and other members who joined the medical team for the treatment.\n\nAuthors’ contributions\nSS and AK were involved in the acquisition of the data; SS, AK, OH, TY, KG, TE, KK, OT, NT, KR, YH, AM, MH and TT were involved in the analysis and interpretation of the clinical data; and SS and AK were involved in the drafting of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThis work was supported by a grant of Grants-in-Aid for Scientific Research, Grant Number JP16K09530 (AK), from Japan Society for the Promotion of Science (JSPS) to measure GM-CSF autoantibody.\n\nAvailability of data and materials\nAll the data regarding the findings are available within the manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten, informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Seymour JF Presneill JJ Pulmonary alveolar proteinosis: progress in the first 44 years Am J Respir Crit Care Med 2002 166 215 235 10.1164/rccm.2109105 12119235 \n2. Trapnell BC Nakata K Bonella F Campo I Griese M Hamilton J Pulmonary alveolar proteinosis Nat Rev Dis Primers 2019 5 16 10.1038/s41572-019-0066-3 30846703 \n3. Ishii H Tazawa R Kaneko C Saraya T Inoue Y Hamano E Clinical features of secondary pulmonary alveolar proteinosis: premortem cases in Japan Eur Respir J 2011 37 465 468 10.1183/09031936.00092910 21282812 \n4. Inoue Y Trapnell BC Tazawa R Arai T Takada T Hizawa N Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan Am J Respir Crit Care Med 2008 177 752 762 10.1164/rccm.200708-1271OC 18202348 \n5. Nagasawa J Kurasawa K Maezawa R Owada T Hanaoka R Fukuda T Systemic lupus erythematosus complicating autoimmune pulmonary alveolar proteinosis that was worsened by immunosuppressive therapy Lupus. 2013 22 1060 1063 10.1177/0961203313498798 23886640 \n6. Yamasue M Nureki SI Usagawa Y Ono T Matsumoto H Kan T Elevated serum anti-GM-CSF antibodies before the onset of autoimmune pulmonary alveolar Proteinosis in a patient with Sarcoidosis and systemic sclerosis Tohoku J Exp Med 2017 243 77 83 10.1620/tjem.243.77 28966213 \n7. Imura Y Yukawa N Handa T Nakashima R Murakami K Yoshifuji H Two cases of autoimmune and secondary pulmonary alveolar proteinosis during imunosuppressive therapy in dermatomyositis with interstitial lung disease Mod Rheumatol 2018 28 724 729 10.3109/14397595.2016.1153443 26872621 \n8. Ito S Wakahara K Kojima T Takahashi N Nishiwaki K Yamaguchi E Two cases of autoimmune pulmonary alveolar proteinosis with rheumatoid arthritis Allergol Int 2017 66 507 509 10.1016/j.alit.2017.02.002 28242199 \n9. Sakamoto N Nakashima S Ishimoto H Kakugawa T Hara A Yura H Pulmonary alveolar Proteinosis with ulcerative colitis Intern Med 2018 57 2705 2708 10.2169/internalmedicine.0555-17 29709938 \n10. Uchida K Nakata K Carey B Chalk C Suzuki T Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis J Immunol Methods 2014 402 57 70 10.1016/j.jim.2013.11.011 24275678 \n11. Kitamura T Uchida K Tanaka N Tsuchiya T Watanabe J Yamada Y Serological diagnosis of idiopathic pulmonary alveolar proteinosis Am J Respir Crit Care Med 2000 162 658 662 10.1164/ajrccm.162.2.9910032 10934102 \n12. Akasaka K Tanaka T Kitamura N Ohkouchi S Tazawa R Takeda T Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study BMC Pulm Med 2015 15 88 10.1186/s12890-015-0085-0 26264717 \n13. Wilson DO Rogers RM Prolonged spontaneous remission in a patient with untreated pulmonary alveolar proteinosis Am J Med 1987 82 1014 1016 10.1016/0002-9343(87)90166-5 3578336 \n14. Rinehart JJ Sagone AL Balcerzak SP Ackerman GA LoBuglio AF Effects of corticosteroid therapy on human monocyte function N Engl J Med 1975 292 236 241 10.1056/NEJM197501302920504 1089191 \n15. Linden M Brattsand R Effects of a corticosteroid, budesonide, on alveolar macrophage and blood monocyte secretion of cytokines: differential sensitivity of GM-CSF, IL-1 beta, and IL-6 Pulm Pharmacol 1994 7 43 47 10.1006/pulp.1994.1004 8003851 \n16. Kitamura N, Ohkouchi S, Tazawa R, Ishii H, Takada T, Sakagami T, et al. Incidence of autoimmune pulmonary alveolar proteinosis estimated using Poisson distribution. ERJ Open Res. 2019. 10.1183/23120541.\n17. Schulert GS Yasin S Carey B Chalk C Do T Systemic juvenile idiopathic arthritis-associated lung disease: characterization and risk factors Arthritis Rheumatol 2019 71 1943 1954 10.1002/art.41073 31379071 \n18. Anderson K Carey B Martin A Roark C Chalk C Pulmonary alveolar proteinosis: an autoimmune disease lacking an HLA association PLoS One 2019 14 e0213179 10.1371/journal.pone.0213179 30845238 \n19. Kavuru MS Malur A Marshall I Barna BP Meziane M Huizar I An open-label trial of rituximab therapy in pulmonary alveolar proteinosis Eur Respir J 2011 38 1361 1367 10.1183/09031936.00197710 21478218 \n20. Garber B Albores J Wang T Neville TH A plasmapheresis protocol for refractory pulmonary alveolar proteinosis Lung. 2015 193 209 211 10.1007/s00408-014-9678-2 25557091 \n21. Tazawa R Ueda T Abe M Tasumi K Eda R Kondoh S Inhaled GM-CSF for Pulmonary Alveolar Proteinosis N Engl J Med 2019 381 923 932 10.1056/NEJMoa1816216 31483963\n\n",
"fulltext_license": "CC BY",
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"journal": "BMC pulmonary medicine",
"keywords": "GM-CSF; Immunosuppressive treatment; Polymyositis; Pulmonary alveolar proteinosis",
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"mesh_terms": "D001323:Autoantibodies; D001327:Autoimmune Diseases; D001992:Bronchoalveolar Lavage Fluid; D004417:Dyspnea; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D007166:Immunosuppressive Agents; D008168:Lung; D017563:Lung Diseases, Interstitial; D008875:Middle Aged; D017285:Polymyositis; D011649:Pulmonary Alveolar Proteinosis; D014057:Tomography, X-Ray Computed",
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"title": "Autoimmune pulmonary alveolar proteinosis developed during immunosuppressive treatment in polymyositis with interstitial lung disease: a case report.",
"title_normalized": "autoimmune pulmonary alveolar proteinosis developed during immunosuppressive treatment in polymyositis with interstitial lung disease a case report"
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"abstract": "OBJECTIVE\nTo evaluate the efficacy of a low-dose oral contraceptive pill (OCP) for patients with dysmenorrhea associated with endometriosis.\n\n\nMETHODS\nA double-blind, randomized, placebo-controlled trial.\n\n\nMETHODS\nClinical trial sites in Japan.\n\n\nMETHODS\nOne hundred patients with dysmenorrhea associated with endometriosis. Most enrolled patients had radiologic evidence of endometriosis rather than surgical diagnosis.\n\n\nMETHODS\nPatients were randomly assigned to receive either monophasic OCP (ethinylestradiol plus norethisterone) or placebo. Participants used their usual pain medications as needed during the trial.\n\n\nMETHODS\nAfter four cyclic treatments, we used a zero- to three-point verbal rating scale and a visual analogue scale to measure the severity of disability because of dysmenorrhea in daily life, and the patients' use of analgesics.\n\n\nRESULTS\nTotal dysmenorrhea scores assessed by the verbal rating scale were significantly decreased at the end of treatment in both groups. From the first cycle through the end of treatment, dysmenorrhea in the OCP group was significantly milder than in the placebo group. Nonmenstrual pelvic pain was present at baseline in 24.5% (12 of 49) of the OCP group and 34.0% (16 of 47) of the placebo group. The volume of endometrioma (larger than 3 cm in diameter) was significantly decreased in the OCP group, but not in the placebo group. No serious adverse events related to using OCPs occurred.\n\n\nCONCLUSIONS\nThe present study clearly demonstrated for the first time that OCPs could be used to effectively and safely treat pain associated with endometriosis.",
"affiliations": "Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan. tasuku@grape.med.tottori-u.ac.jp",
"authors": "Harada|Tasuku|T|;Momoeda|Mikio|M|;Taketani|Yuji|Y|;Hoshiai|Hiroshi|H|;Terakawa|Naoki|N|",
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"mesh_terms": "D000328:Adult; D000700:Analgesics; D003276:Contraceptives, Oral; D003277:Contraceptives, Oral, Combined; D003280:Contraceptives, Oral, Synthetic; D004311:Double-Blind Method; D004412:Dysmenorrhea; D004715:Endometriosis; D004997:Ethinyl Estradiol; D005260:Female; D006801:Humans; D007564:Japan; D009640:Norethindrone; D010147:Pain Measurement; D017699:Pelvic Pain; D011788:Quality of Life; D013997:Time Factors; D016896:Treatment Outcome",
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"references": null,
"title": "Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial.",
"title_normalized": "low dose oral contraceptive pill for dysmenorrhea associated with endometriosis a placebo controlled double blind randomized trial"
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"abstract": "We here present the first case of a metronidazole resistant nimD positive Bacteroides stercoris. The isolate originated from a polymicrobial intra-abdominal abscess in a 70-year-old woman. The nimD gene was detected by use of whole-genome shotgun sequencing and the subsequent use of the ResFinder 2.1 web service.",
"affiliations": "Department of Clinical Microbiology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: erikotte@rm.dk.;Department of Clinical Microbiology, Aalborg University Hospital, Aalborg, Denmark.;The Microbial Genomics and Antimicrobial Resistance Group, National Food Institute, Technical University of Denmark, Lyngby, Denmark; Antimicrobial Resistance Reference Laboratory and Surveillance Unit, Statens Serum Institut, Copenhagen, Denmark.;Department of Clinical Microbiology, Aalborg University Hospital, Aalborg, Denmark.",
"authors": "Otte|Erik|E|;Nielsen|Hans Linde|HL|;Hasman|Henrik|H|;Fuglsang-Damgaard|David|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D008795:Metronidazole",
"country": "England",
"delete": false,
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"keywords": "Abscess; Anaerobic infection; Bacteroides stercoris; Metronidazole resistance; Nitroimidazole resistance (nim) genes; nimD-positive",
"medline_ta": "Anaerobe",
"mesh_terms": "D018784:Abdominal Abscess; D000368:Aged; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001439:Bacteroides; D001442:Bacteroides Infections; D004269:DNA, Bacterial; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D008795:Metronidazole; D008826:Microbial Sensitivity Tests; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "9505216",
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"title": "First report of metronidazole resistant, nimD-positive, Bacteroides stercoris isolated from an abdominal abscess in a 70-year-old woman.",
"title_normalized": "first report of metronidazole resistant nimd positive bacteroides stercoris isolated from an abdominal abscess in a 70 year old woman"
} | [
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"companynumb": "DK-BAUSCH-BL-2017-000839",
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"activesubstancename": "CIPROFLOXACIN"
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... |
{
"abstract": "OBJECTIVE\nThe study aimed to evaluate the comparative risk of oral ulcerations among antipsychotic medications.\n\n\nMETHODS\nWe analyzed the National Health Insurance Research Database of Taiwan and included patients newly initiated with a single antipsychotic agent including haloperidol, sulpiride, olanzapine, quetiapine, risperidone, or amisulpride during 2002 to 2010. The outcome of interest was oral ulceration, defined by the presence diagnoses of stomatitis and mucositis, aphthous-like ulceration and oral burns, or dispensing of stomatological corticosteroids included triamcinolone, dexamethasone, hydrocortisone, and prednisolone. We conducted Cox proportional hazards regression to compare the risks of oral ulceration among antipsychotics.\n\n\nRESULTS\nThe rate of oral ulcerations was highest in the amisulpride group (217.7 per 1000 person-year), followed by quetiapine (193.9 per 1000 person-year), olanzapine (161.9 per 1000 person-year), sulpiride (147.1 per 1000 person-year), risperidone (115.6 per 1000 person-year), haloperidol (107.5 per 1000 person-year) and aripiprazole (49.8 per 1000 person-year). Compared with haloperidol users, the adjusted hazard ratio (AHR) was 1.40 (95% CI, 1.12-1.73) in olanzapine, 1.48 (95% CI, 1.30-1.69) in quetiapine, 1.27 (95% CI, 1.19-1.44) in sulpiride, 1.68 (95% CI, 0.97-2.59) in amisulpride, 1.02 (95% CI, 0.83-1.45) in risperidone, and 0.41 (95% CI, 0.24-0.72) in aripiprazole users by Cox regression model.\n\n\nCONCLUSIONS\nOlanzapine, quetiapine, and sulpiride posed a higher risk, while aripiprazole posed a lower risk of oral ulcerations compared with haloperidol in subjects with newly initiated antipsychotic therapy. Risperidone and amisulpride tended to have higher risk of oral ulcerations, but this was not statistically significant.",
"affiliations": "Duke Clinical Research Institute, Durham, NC, USA.;School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan.;Geriatric Medicine Unit, Massachusetts General Hospital, Boston, MA, USA.;Department of Pharmacy Administration, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.;Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan.;School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan.;Duke Clinical Research Institute, Durham, NC, USA.",
"authors": "Lai|Edward Chia-Cheng|EC|;Hsieh|Cheng-Yang|CY|;Wong|Monera B|MB|;Lin|Swu-Jane|SJ|;Yang|Yang-Kuang|YK|;Kao Yang|Yea-Huei|YH|;Setoguchi|Soko|S|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D013469:Sulpiride; D000077582:Amisulpride; D000077152:Olanzapine",
"country": "England",
"delete": false,
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"issue": "25(2)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "antipsychotics; aripiprazole; olanzapine; oral health; pharmacoepidemiology; quetiapine; schizophrenia; sulpiride",
"medline_ta": "Pharmacoepidemiol Drug Saf",
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"pages": "123-32",
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"pubdate": "2016-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Comparative risk of oral ulcerations among antipsychotics users - population-based retrospective cohort study.",
"title_normalized": "comparative risk of oral ulcerations among antipsychotics users population based retrospective cohort study"
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"abstract": "Pediatric gliosarcoma (GS) is a rare variant of glioblastoma multiforme. The authors describe the case of an unusual pontine location of GS in a 9-year-old boy who was initially diagnosed with low-grade astrocytoma (LGA) that was successfully controlled for 4 years. Subsequently, his brain tumor transformed into a GS. Prior treatment of his LGA included subtotal tumor resection 3 times, standard radiation therapy, and Gamma Knife procedure twice. His LGA was also treated with a standard chemotherapy regimen of carboplatin and vincristine, and his GS with subtotal resection, high-dose cyclophosphamide, and thiotepa with stem cell rescue and temozolomide. Unfortunately, he developed disseminated disease with multiple lesions and leptomeningeal involvement including a tumor occupying 80% of the pons. Upon presentation at our clinic, he had rapidly progressing disease. He received treatment with antineoplastons (ANP) A10 and AS2-1 for 6 years and 10 months under special exception to our phase II protocol BT-22. During his treatment with ANP his tumor stabilized, then decreased, and, ultimately, did not show any metabolic activity. The patient's response was evaluated by magnetic resonance imaging and positron emission tomography scans. His pathology diagnosis was confirmed by external neuropathologists, and his response to the treatment was determined by central radiology review. He experienced the following treatment-related, reversible toxicities with ANP: fatigue, xerostomia and urinary frequency (grade 1), diarrhea, incontinence and urine color change (grade 2), and grade 4 hypernatremia. His condition continued to improve after treatment with ANP and, currently, he complains only of residual neurological deficit from his previous surgery. He achieved a complete response, and his overall and progression-free survival is in excess of 13 years. This report indicates that it is possible to obtain long-term survival of a child with a highly aggressive recurrent GS with diffuse pontine involvement with a currently available investigational treatment.",
"affiliations": "Burzynski Clinic, Houston, TX.",
"authors": "Burzynski|Stanislaw R|SR|;Janicki|Tomasz J|TJ|;Burzynski|Gregory S|GS|;Marszalek|Ania|A|",
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"country": "United States",
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"doi": "10.1097/MPH.0000000000000020",
"fulltext": "\n==== Front\nJ Pediatr Hematol OncolJ. Pediatr. Hematol. OncolMPHJournal of Pediatric Hematology/Oncology1077-41141536-3678Lippincott Williams & Wilkins 10.1097/MPH.000000000000002000023Online Articles: Clinical and Laboratory ObservationsLong-term Survival (>13 Years) in a Child With Recurrent Diffuse Pontine Gliosarcoma: A Case Report Burzynski Stanislaw R. MD, PhDJanicki Tomasz J. MDBurzynski Gregory S. MDMarszalek Ania MDBurzynski Clinic, Houston, TXReprints: Gregory S. Burzynski, MD, Burzynski Clinic, 9432 Katy Freeway, Houston, TX 77055 (e-mail: gsb@burzynskiclinic.com).10 2014 24 9 2014 36 7 e433 e439 27 2 2013 20 8 2013 Copyright © 2013 by Lippincott Williams & Wilkins2014This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, 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. http://creativecommons.org/licenses/by-nc-nd/3.0.Pediatric gliosarcoma (GS) is a rare variant of glioblastoma multiforme. The authors describe the case of an unusual pontine location of GS in a 9-year-old boy who was initially diagnosed with low-grade astrocytoma (LGA) that was successfully controlled for 4 years. Subsequently, his brain tumor transformed into a GS. Prior treatment of his LGA included subtotal tumor resection 3 times, standard radiation therapy, and Gamma Knife procedure twice. His LGA was also treated with a standard chemotherapy regimen of carboplatin and vincristine, and his GS with subtotal resection, high-dose cyclophosphamide, and thiotepa with stem cell rescue and temozolomide. Unfortunately, he developed disseminated disease with multiple lesions and leptomeningeal involvement including a tumor occupying 80% of the pons. Upon presentation at our clinic, he had rapidly progressing disease. He received treatment with antineoplastons (ANP) A10 and AS2-1 for 6 years and 10 months under special exception to our phase II protocol BT-22. During his treatment with ANP his tumor stabilized, then decreased, and, ultimately, did not show any metabolic activity. The patient’s response was evaluated by magnetic resonance imaging and positron emission tomography scans. His pathology diagnosis was confirmed by external neuropathologists, and his response to the treatment was determined by central radiology review. He experienced the following treatment-related, reversible toxicities with ANP: fatigue, xerostomia and urinary frequency (grade 1), diarrhea, incontinence and urine color change (grade 2), and grade 4 hypernatremia. His condition continued to improve after treatment with ANP and, currently, he complains only of residual neurological deficit from his previous surgery. He achieved a complete response, and his overall and progression-free survival is in excess of 13 years. This report indicates that it is possible to obtain long-term survival of a child with a highly aggressive recurrent GS with diffuse pontine involvement with a currently available investigational treatment.\n\nKey Words:\nantineoplastons A10AS2-1gliosarcomaphase 2 trialdiffuse intrinsic pontine gliomabrainstem gliomaOPEN-ACCESSTRUESTATUSONLINE-ONLY\n==== Body\nGliosarcoma (GS) is classified as a variant of glioblastoma multiforme (GBM), which consists of both glial and mesenchymal components.1 Up to 40% of both tumor types demonstrate TP53 mutations and CDKN2A and PTEN deletions, but in a GS, contrary to GBM, the abnormalities of EGFR are not frequent. In this respect GS resembles a mesenchymal variety of GBM.1,2 It is estimated that the incidence of GS among pediatric GBM is ∼2%.3 It is a very rare tumor, and, to the best of our knowledge, only 24 cases have been described in English-language professional journals, and none with pontine location.3–5 The literature describes the treatment of newly diagnosed cases of GS, which has resulted in a very poor median overall survival (OS) of <9 months.3 Despite an extensive search in literature, we could not find any case report on pediatric GS that recurred after surgery, radiation, and chemotherapy. Here, we discussed a case of GS with long-term OS and progression-free survival (PFS) after treatment with antineoplastons (ANP), which are synthetic analogs of naturally occurring amino acid derivatives that have an inhibitory effect on neoplastic growth.6,7 ANP A10 injection is a formulation comprising a 4:1 ratio of phenylacetylglutaminate sodium (PG) and phenylacetylisoglutaminate sodium (isoPG). ANP AS2-1 injection is a formulation of 4:1 ratio of phenylacetate sodium (PN) and PG. ANP A10 capsules contain 500 mg of 3-phenylacetylamino-2,6-piperidinedione, which is metabolized in the body to 4:1 ratio of PG, and isoPG and AS2-1 capsules contain 500 mg of 4:1 ratio of PN and PG.6\n\nCASE REPORT\nA 9-year-old white boy presented to our clinic in December 1999 with a 5-year history of brain tumor. He was in good health until the end of 1994 when he experienced repeated episodes of vomiting, which required multiple admissions to the local hospital. In March 1995 he suffered a series of grand mal seizures and was subsequently found to have a large right temporal brain tumor. He underwent craniotomy with 80% tumor resection; tumor biopsy resulted in a diagnosis of low-grade astrocytoma (LGA). He did well until 2½ years later when his symptoms and tumor recurred. He underwent a second craniotomy with the same pathologic diagnosis. From September 1997 he was treated for 14 months with a combination chemotherapy regimen of carboplatin and vincristine, which resulted in disease stabilization for 3 months. In February 1999 he developed massive progression, and his tumor tripled in size. He underwent a third craniotomy with 70% resection of the right hemispheric tumor, and partial temporal lobectomy. On this occasion, the initial pathologic diagnosis was high-grade glioma. The tissue was subsequently submitted to a consulting neuropathologist. The final diagnosis was GS. A month later, he underwent the Gamma Knife (GK) procedure, and on March 17, 1999 started radiation therapy (RT) of 5500 cGy to the tumor bed, which was completed on May 5, 1999. In early June 1999 his disease progressed, and 2 new lesions developed in the pons and midbrain for which he received treatment with high-dose cyclophosphamide and thiotepa, followed by stem cell rescue. He achieved reduction of the recurrent tumor, but unfortunately, a month later magnetic resonance imaging (MRI) indicated significant progression. On September 5, 1999, he was started on temozolomide (TMZ), but his disease progressed and he developed disseminated disease including diffuse intrinsic pontine tumor. On November 10, 1999, he underwent a second GK procedure to the brainstem area, which was not successful because of widespread metastatic disease with 8 major areas of involvement. A summary of treatment before admission to the Burzynski Clinic (BC) is provided in Table 1. The patient suffered typical adverse effects from his prior chemotherapy and RT. He developed severe neutropenia and thrombocytopenia and anemia. He had occasional temperature spikes, which may have been indicative of possible septicemia. He was frequently treated with antibiotics and was on pentamidine prophylaxis against Pneumocystis pneumonia. He was very tired, somnolent, and complained of generalized weakness. The child was evaluated at our clinic on December 2, 1999, his pathology diagnosis of initial LGA and GS having been established by external pathologists. At presentation he had a 2-month history of cranial nerve deficits including decreased vision, loss of left peripheral vision, drooling from the left side of the mouth and difficulty swallowing, ataxia, slurred speech, aphasia, left-sided weakness, tiredness, somnolence, fatigue, headaches, easy bruising, nocturnal urinary incontinence, mood swings, and difficulty with coordination. In the 2 weeks before presentation he had developed nausea without vomiting and experienced occasional epileptic seizures.\n\nTABLE 1 Summary of Prior Treatment\n\nHis physical examination confirmed his recent clinical history and was significant for visual deficit in the left eye with the left pupil smaller than the right, both with minimal reaction to light and accommodation. Extraocular movements were grossly intact. There was horizontal nystagmus with lateral gaze. The patient had facial nerve paresis with drooping of the left side of the face together with significant weakness and diminished sensory of the left side of the body. He also had significant adiadochokinesis and difficulty with finger-to-nose and heel-to-shin test on the right side, and was unable to perform those tests on the left. Babinski was upgoing, bilaterally. The Oppenheim sign was negative. The patient had significant ataxia. Deep tendon reflexes were normal on the left side, but diminished on the right. His Karnofsky Performance Status (KPS) was 40.\n\nMATERIALS AND METHODS\nOn December 3, 1999, the patient was admitted for treatment with A10 and AS2-1 intravenous infusions, on the basis of the FDA’s special exception to protocol BT-22. The exception was required as the patient had a KPS of <60 and brainstem involvement. Treatment with TMZ had been discontinued >4 weeks before the first administration of ANP with the most recent GK procedure carried out 3 weeks prior, and limited to the brainstem area. Protocol BT-22 was designed for children with primary malignant brain tumors who developed progressive disease within 8 weeks or less after completion of RT (including GK).\n\nThe study is listed by the National Cancer Institute and reviewed by the independent institutional review board, and all of the study subjects read, understood, and signed a written informed consent before enrollment. This study was conducted in accordance with the US code of federal regulations, Title 21, Parts 11, 50, 56, and 312; the Declaration of Helsinki (1964) including all amendments and revisions; the Good Clinical Practices: Consolidated Guideline (E6): International Conference on Harmonization; and the FDA’s Guidance for the Industry. The study was sponsored by the Burzynski Research Institute and conducted by the BC in Houston, TX. The patient did not pay for the investigational agents.\n\nHistopathologic Examination\nThe initial pathologic examination was performed in the Department of Pathology at leading children’s hospitals in the United States. The first pathologic diagnosis was established on March 9, 1995, and was consistent with astrocytoma; but meningioma and schwannoma were also considered. The tissue was sent to a consulting pathologist, who, on March 31, 1995, confirmed that the histologic features were consistent with astrocytoma. The immunohistochemical staining analyses, performed at an outside laboratory, revealed negative glial fibrillary acidic protein and S-100, but were positive for vimentin in some cells, probably reflecting neoplastic astrocytes.\n\nA second consultation was obtained from a chief pathologist at a leading medical university in the United States, who, on August 10, 1995, determined diagnosis of pilocytic astrocytoma on the basis of the slides from the first hospital, which did not include immunohistochemical stains.\n\nThe histopathologic evaluation of the tumor tissue, obtained on February 10, 1999, revealed features of high-grade glioma. The tissue was sent for evaluation by a neuropathologist at a different medical university, who determined, on February 26, 1999, the final diagnosis of GS, on the basis of identification of mesenchymal and glial components. The tumor had the typical features of frequent mitoses and a high proliferative index. It was highly positive for vimentin and glial fibrillary acidic protein. Reticulin stain was positive, which supported the diagnosis of GS.5 At the request of the parents, the slides were evaluated by a third consulting pathologist who did not perform immunostaining, and was not aware of prior immunohistochemical studies, and established the diagnosis of anaplastic astrocytoma. The neurooncologist in charge of the treatment of this patient, at a major children’s hospital in the United States, accepted the diagnosis of GS. The summary of prior pathologic diagnoses is provided in Table 2.\n\nTABLE 2 Summary of Prior Pathologic Diagnoses\n\nTreatment\nANP A10 and AS2-1 were delivered by a dual-channel infusion pump and a single-lumen subclavian indwelling catheter (Broviac or Groshung) every 4 hours. On the first day of administration of ANP the starting dosages were A10 0.62 g/kg/d and AS2-1 0.17 g/kg/d. The initial flow rate of the pump was 50 mL/h. Beginning on the second day, the dosages were escalated and maintained at A10 10 to 13 g/kg/d and AS2-1 0.3 to 0.4 g/kg/d. The flow rate of the pump was increased to 75 mL/h on the second day, and to 150 mL/h on the third day, and subsequently maintained at this rate.\n\nFrom June 19, 2000, the dosages of A10 were decreased to between 3 and 8 g/kg/d and AS2-1 to between 0.3 and 0.4 g/kg/d. From November 20, 2000, there was further decrease in the dosages of A10 to 2 to 4 g/kg/d and AS2-1 to 0.2 to 0.4 g/kg/d. The treatment with intravenous infusions was discontinued on January 18, 2001. On January 22, 2001, the patient began treatment with ANP A10 and AS2-1 0.5 g capsules. His initial dosage was 0.07 g/kg/d for both formulations and was gradually increased to 0.2 to 0.4 g/kg/d. On October 1, 2001, the dosage of A10 was decreased to 0.1 g/kg/d and AS2-1 to 0.35 to 0.4 g/kg/d. The treatment was discontinued on October 12, 2006 (Table 3).\n\nTABLE 3 Treatment and Response Data\n\nThe rationale for using 2 formulations of ANP was based on prior clinical trials.6 The escalation of the dosage of ANP was required on the basis of the results of prior studies to determine whether the patient was able to tolerate large-volume infusions of intravenous fluids associated with higher dosage of ANP.6 As a safety precaution, it was recommended that the escalation of the dosages continue to the phase II and phase III trial programs. The initial 3 weeks of therapy were administered by the BC staff on an outpatient basis in Houston, TX. The treatment did not require hospitalization. The patient and his parents were trained by the clinic staff to self administer ANP during this time. Starting on week 4, ANP was administered at home, with 24-hour support available by means of phone and e-mail. Treatment and monitoring of the patient’s conditions, through self-administration therapy, continued under the supervision of the patient’s local physician.\n\nBefore the start of treatment, a gadolinium-enhanced MRI measured all contrast-enhancing lesions. The products of the 2 greatest perpendicular diameters of all lesions were calculated and totaled, providing a baseline evaluation. As was common practice in this and other clinical trials carried out at this time the tumor measurements were based on contrast-enhanced lesions, but the overall tumor size was also measured including T2 and FLAIR images.8,9 Positron emission tomography (PET) scans were performed to differentiate between tumor progression, pseudoprogression, and treatment necrosis.10 The baseline provided the reference for determining response outcomes to the treatment. Blood and urine tests, complete blood count (with differential), platelet count, reticulocyte count, and standard serum chemistry, anticonvulsant serum levels, prothrombin time, and partial thromboplastin time were evaluated before start to establish the normal baseline. The initial pretreatment measurements included KPS, vital signs, clinical disease status, demographics, medical history and current medications, physical examination with neurological emphasis, and chest x-ray. Toxicity is evaluated according to the Common Terminology of Criteria for Adverse Events (CTCAE v3.0). During the patient’s transition to home-based therapy administration, clinic staff made daily telephone contact for the first 2 months to ensure protocol compliance, to resolve any issues with therapy administration, and to continue assessing toxicity. Weekly contact was made starting from the third month, on the basis of which continuation of patient treatment with ANP was determined on a weekly basis depending on the trial protocol, patient health status, and the response to treatment.\n\nMedications that were considered necessary for the patient’s welfare and that did not interfere with the evaluation of treatment were given at the discretion of the investigator.\n\nDuring his lengthy course of treatment, the patient continued to take dexamethasone, which he had been prescribed before coming to the clinic. His initial dose of dexamethasone was 16 mg orally daily, which was increased to 24 mg daily in the second week of treatment. The gradual tapering of the dosage of dexamethasone back to 16 mg daily began a month later. There was further gradual reduction in dose resulting in 6 mg daily 6 weeks later, and 4 mg daily for the next 6 weeks. Over the remainder of the year this gradual reduction in dose continued with 0.5 mg daily being administered in May 2011. Dexamethasone was finally discontinued on June 22, 2001. Summary of treatment with ANP and dexamethasone is provided in Table 3.\n\nFor seizure control the patient was taking phenytoin, divalproex sodium, lamotrigine, and levetiracetam. The immunosuppression that developed after prior treatments and that resulted in occasional infections required various antibiotics during this time: ciprofloxacin, cephalexin, amoxicillin, clindamycin ophthalmic solution, dapsone, and acyclovir. He was also taking ranitidine, baclofen, acetaminophen, loperamide, polyethylene glycol, levothyroxine, calcium and potassium supplements, sodium bicarbonate, folic acid, and vitamin D.\n\nRESULTS\nThe patient’s progress was evaluated by MRI and PET. His baseline MRI on December 3, 1999 revealed multiple contrast-enhancing nodules located in the pons, cerebellum, both hemispheres, and leptomeninges. A pontine lesion occupied 82% of pons on T2-weighted axial image and enhancing portion measured 1.0×1.6 cm. The right quadrigeminal lesion measured 2.2×5.2 cm and the largest cerebellar nodule 1.0×2.0 cm. Baseline PET scan on November 5, 1999 revealed a hypermetabolic area encasing the right cerebellar hemisphere. The disease progression at baseline was confirmed by independent external radiologists not associated with BC. The impact of RT and chemotherapy was seriously considered in relation to disease progression and possible pseudoprogression. The initial GK procedure to the residual tumor was performed 9 months before baseline, and RT to the tumor bed was completed 7 months before commencing the treatment. In the intervening period, there was clear evidence of massive disease progression as shown by 4 MRIs and 1 PET scan. At least 8 major areas of tumor involvement developed, including the pons and leptomeninges, and almost all of them were outside of the RT fields. Additional GK procedure was delivered to the brainstem area approximately 1 month before commencing the treatment, but since then there had been further progression both in the pons and in the other areas.\n\nHigh-dose chemotherapy and stem cell rescue resulted in initial decrease of the primary tumor size, but it was followed by massive progression shortly thereafter, as indicated by the MRI of August 19, 1999. TMZ failed to produce a response, which was documented by 2 consecutive MRIs, and TMZ was then discontinued by the treating neurooncologist. The patient presented with widely disseminated disease, and most of the lesions were outside the field of his prior RT, and occurred after chemotherapy.\n\nMRIs were repeated periodically approximately every 8 weeks during the first 2 years of treatment, quarterly during the third to fifth years, and then annually. The multiple lesions visible on MRI were difficult to measure because of their irregular shape and infiltrative nature. PET scans were also performed to follow-up metabolic activity of the lesions. The scans were routinely evaluated by external radiologists, but on 3 occasions they were admitted for central radiology review (CRR). A partial response (PR) was determined by the CRR on June 19, 2000, and a complete response (CR) was confirmed on September 26, 2000 on the basis of an MRI scan performed on August 22, 2000 and a PET scan on August 25, 2000. It was the opinion of the CRR that the areas of enhancement in the primary tumor bed and in the prepontine area were not metabolically active, and were attributed to prior treatment (RT and GK). By MRI criteria there had been a decrease of contrast-enhancing lesions by >53% after 1 year and 4 months of treatment, and >70% by June 26, 2006. A PET scan carried out in April 2000 and repeated scans in August 2000, January 2001, and July 2006 did not show any hypermetabolic lesions, indicating a CR (Fig. 1). The BT-22 protocol permits determination of CR even though the patient has continued with a reduced physiological replacement dosage of corticosteroids, which is consistent with current standards of evaluation and response.9 Taking this under consideration and the opinion of the CRR, a CR was determined on August 25, 2000 (the date of the negative PET scan) despite the fact that dexamethasone was discontinued on July 22, 2001.\n\nFIGURE 1 A, Baseline magnetic resonance imaging (MRI). B, Follow-up MRI indicating partial response. Axial T-1 contrast-enhanced images. A complete response was confirmed by positron emission tomography scans. Arrows indicate contrast enhanced nodules.\n\nDuring the course of ANP treatment the patient demonstrated a marked improvement in his condition. When evaluated on October 6, 2000, although he continued to have visual deficit in the left eye there was no nystagmus. There was persistent involvement of the eighth and fifth cranial nerves, but the rest of the cranial nerves were grossly intact. The patient continued to have left hemiparesis with significant adiadochokinesis and difficulty with finger-to-nose and heel-to-shin test on the right. He remained unable to perform those tests on the left. Deep tendon reflexes were hyperactive on the left and decreased on the right 2/5. Babinski sign was positive on the left and negative on the right. His KPS at this time was 50. He had continuous improvement in the following years. By January 2008 his KPS had increased to 80. At the time of this report (May 2013), the patient is in good health. He became a scout earlier this year, and he is currently taking 1 college course. His OS and PFS survival is >13 years.\n\nThe patient had the following adverse events: grade 1 fatigue, xerostomia and urinary urgency, grade 2 diarrhea, incontinence and urine color change, and grade 4 hypernatremia. The toxicities were easily reversible, and there was no chronic toxicity.\n\nThe preexisting toxicities gradually improved and did not reoccur during the treatment. Toxicities possibly related to treatment were xerostomia, urinary urgency, and incontinence, with the last 2 possibly related to the intravenous administration of ANP A10, which has increased osmolality. They were controlled by oral hydration and occasional reduction of the flow rate of the pump. The fatigue occurred after the parents misprogrammed the pump, which delivered a higher dose of ANP AS2-1 (not exceeding the daily maximum), and this resolved spontaneously the next day. On 2 occasions the color of the urine became light green, but such change did not last longer than a day and was asymptomatic. The patient had several episodes of grade 2 diarrhea when he was taking ANP A10 and AS2-1 capsules, which were controlled by changes to the diet and medications that did not require prescriptions. Grade 4 hypernatremia required hospitalization for 2 days and administration of intravenous fluids, but it resolved without complications.\n\nDISCUSSION\nIn this report we describe an interesting and very rare case of pediatric recurrent GS involving the pons. The patient was initially diagnosed with LGA, which was successfully controlled for 4 years. Subsequently, his brain tumor transformed into a highly malignant GS, which took a very aggressive course. The patient received multiple treatments as previously described.\n\nIt is important to note that the patient’s pathology diagnosis of GS was subject to review by 3 different independent pathologists. For various reasons described in the text, the treating neurooncologist accepted, as the final diagnosis, the opinion of the first consulting neuropathologist (Table 2) as these included IHC studies. The diagnosis of GS and the extremely aggressive course of the disease was established by an experienced neuropathologist and confirmed by IHC.\n\nDuring his treatment with ANP, the patient’s tumor stabilized then decreased and ultimately did not show any metabolic activity. Notably, the patient’s response was evaluated by periodic MRI and PET scans, which were evaluated by an outside radiologist with responses confirmed by the CRR. It was postulated that the patient has remained in CR since August 25, 2000.\n\nRegarding the adverse drug events reported and their management, before admission to BC, the patient suffered immunosuppression and recurrent infections. For this reason he had been treated with numerous antibiotics and supplements before admission to BC. For a long time he was taking dexamethasone to reduce peritumoral edema and antacids to counteract side effects of corticosteroid adverse events. The adverse events observed before ANP treatment gradually improved during ANP administration, and were no longer present even though the patient continued ANP therapy. For this reason, it was felt that they were not related to ANP. His neurological deficit was also preexistent. During the course of ANP treatment a number of grade 1 and grade 2, reversible toxicities have been reported, which resolved without sequelae. He had only a single incident of grade 4, reversible toxicity from ANP consistent with hypernatremia, and did not exhibit any chronic toxicity. His condition gradually improved and currently he complains only of residual neurological deficit from his operations. Although it might be postulated that the GK procedures contributed to his response, we would argue that this is very unlikely, as he had developed multiple tumors and his tumors, which were not treated by GK, were already radio-resistant.\n\nNewly diagnosed pediatric GS typically occurs in cerebral hemispheres and is treated with total surgical resection, standard RT, followed by chemotherapy.3,4 Survival after total surgical resection without RT and chemotherapy is usually <6 months, but OS after RT and chemotherapy can extend to slightly over 2 years,3,4 making this case study’s report of OS and PFS of >13 years of significant clinical interest. The benefit of TMZ has not yet been established.11 There are no reports of successful treatment modalities for pediatric recurrent and disseminated GS.\n\nTo our knowledge, pontine location of pediatric GS has not been previously described in the English-language medical literature. Such location combines the aggressiveness of GS with the grim prognosis of recurrent diffuse intrinsic pontine glioma. There are no effective treatments available for this condition, and median PFS is typically between 2 and 6 months.12–17 It is hoped that the planned genomic study will provide data that will link genetic abnormalities to the remarkable response in this case. The complete report on the BT-22 study and the report on the series of GS patients treated with ANP in phase II trials is currently in preparation. The details of the preclinical and clinical studies and the mechanism of action of ANPs are available in the literature.6,18–20\n\nThe patient reported in this case study is currently able to live a normal life and is studying in college. His OS and PFS are in excess of 13 years. This report suggests, therefore, that it is possible to obtain long-term OS and PFS in a child suffering from highly aggressive recurrent GS. The results of phase II studies of ANP in primary malignant brain tumors and GS patients treated in all of our phase II trials, which are in preparation, will provide more data on the significance of this response.\n\nACKNOWLEDGMENTS\nThe authors thank the additional physicians involved in the care of the patient: Robert A. Weaver, MD and Eva Kubove, MD, and employees of the clinic involved in the preparation of the manuscript: Mohammad Khan, MD, Darlene Hodge, Carolyn Powers, and Adam Golunski. Editorial assistance was provided by Malcolm Kendrick, MD.\n\nThe clinical trial was sponsored by the Burzynski Research Institute Inc.\n\nS.R.B. is chairman of the Board of Directors and President of BRI Inc. G.S.B. is a member of the Board of Directors of BRI Inc.T.J.J. is the Vice President of Clinical Trials at BRI Inc. All authors are employed by Burzynski Clinic.\n==== Refs\nREFERENCES\n1 Reis RM Konu-Lebleblicioglu D Lopes JM . Genetic profile of gliosarcomas . Am J Pathol. \n2000 ;156 :425 –432 10666371 \n2 Sturm D Witt H Hovestadt V . Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma . Cancer Cell. \n2012 ;22 :425 –437 23079654 \n3 Karremann M Rausche U Fleischhack G . Clinical and epidemiological characteristics of pediatric gliosarcomas . J Neurooncol. \n2010 ;97 :257 –265 19806321 \n4 Salvati M Lenzi J Brogna C . Childhood’s gliosarcomas: pathological and therapeutical considerations on three cases and critical review of the literature . Childs Nerv Syst. \n2006 ;22 :1301 –1306 16541294 \n5 Neelima R Abraham M Kapilamoorthy TR . Pediatric gliosarcoma of thalamus . Neurol India. \n2012 ;60 :674 –676 23287350 \n6 Burzynski SR . The present state of antineoplaston research (1) . Integr Cancer Ther. \n2004 ;3 :47 –58 15035876 \n7 Burzynski SR . Treatment for astrocytic tumors . Pediatr Drugs. \n2006 ;8 :167 –178 \n8 Wen PY Macdonald DR Reardon DA . Updated response assessment criteria for high-grade gliomas: response assessment in Neuro-oncology Working Group . J Clin Oncol. \n2010 ;28 :1963 –1972 20231676 \n9 Weller M Cloughesy T Perry JR . Standards of care for treatment of recurrent glioblastoma—are we there yet ? Neuro-oncol. \n2013 ;15 :4 –27 23136223 \n10 Verma N Cowperthwaite MC Burnett MG . Differentiating tumor recurrence from treatment necrosis: a review of neuro-oncologic imaging strategies . Neuro-oncol. \n2013 ;15 :515 –534 23325863 \n11 Han SJ Yang I Tihan T . Primary gliosarcoma: key clinical and pathologic distinctions from glioblastoma with implications as a unique oncologic entity . J Neurooncol. \n2010 ;96 :313 –320 19618114 \n12 Lashford LS Thiesse P Jouvet A . Temozolomide in malignant gliomas of childhood: a United Kingdom Children’s Cancer Study Group and French Society for Pediatric Oncology Intergroup study . J Clin Oncol. \n2002 ;20 :4684 –4691 12488414 \n13 Dreyer ZE Kadota RP Stewart CF . Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237 . Neuro-oncol. \n2003 ;5 :261 –267 14565163 \n14 Warren K Jakacki R Widemann B . Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children’s Oncology Group . Cancer Chemother Pharmacol. \n2006 ;58 :343 –347 16408203 \n15 Fouladi M Nicholson HS Zhou T . A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children’s Oncology Group study . Cancer. \n2007 ;110 :2535 –2541 17932894 \n16 Gururangan S Chi SN Young Poussaint T . Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study . J Clin Oncol. \n2010 ;28 :3069 –3075 20479404 \n17 Minturn JE Janss AJ Fisher PG . A phase II study of metronomic oral topotecan for recurrent childhood brain tumors . Pediatr Blood Cancer. \n2011 ;56 :39 –44 21108437 \n18 Burzynski SR Yang AV . Targeted therapy for brain tumors . Brain Cancer: Therapy and Surgical Interventions (Horizons in Cancer Research). \n2006 .New York : Nova Science Publishers Inc. ;77 –111 \n19 Burzynski SR Janicki TJ Weaver RA . Targeted therapy with antineoplastons A10 and AS2-1 of high-grade, recurrent, and progressive brainstem glioma . Integr Cancer Ther. \n2006 ;5 :40 –47 16484713 \n20 Burzynski SR . Recent clinical trials in diffuse intrinsic brainstem glioma . Cancer Ther. \n2007 ;5 :379 –390\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1077-4114",
"issue": "36(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D020295:Brain Stem Neoplasms; D002648:Child; D005909:Glioblastoma; D018316:Gliosarcoma; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D016634:Radiosurgery; D012074:Remission Induction",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e433-9",
"pmc": null,
"pmid": "24136026",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16541294;21108437;19618114;23079654;16484713;19806321;16408203;20479404;12488414;10666371;17932894;15035876;16774296;23287350;14565163;20231676;23325863;23136223",
"title": "Long-term survival (>13 years) in a child with recurrent diffuse pontine gliosarcoma: a case report.",
"title_normalized": "long term survival 13 years in a child with recurrent diffuse pontine gliosarcoma a case report"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-106896",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "TEMOZOLOMIDE"
},
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{
"abstract": "Inhalation injury (IHI) causes significant morbidity and mortality in burn victims due to both local and systemic effects. Nebulized heparin promotes improvement in lung function and decreased mortality in IHI by reducing the inflammatory response and fibrin cast formation. The study objective was to determine if nebulized heparin 10,000 units improves lung function and decreases mechanical ventilation duration, mortality, and hospitalization length in IHI with minimal systemic adverse events. This retrospective, case-control study evaluated efficacy and safety of nebulized heparin administered to mechanically ventilated adults admitted within 48 hr of confirmed IHI. Nebulized heparin 10,000 units was administered Q4H for 7 days, or until extubation if sooner, alternating with albuterol and a mucolytic. Patients were matched on a case-by-case basis based on percent TBSA burn and age to patients from a historical group with IHI before heparin protocol implementation. The primary outcome was duration of mechanical ventilation. Secondary outcomes included lung injury score, ventilator-free days during the first 28 days, 28-day mortality, hospitalization length, ventilator-associated pneumonia incidence, bronchoscopy incidence, and bleeding events. Data were collected in 72 patients, 36 of which received nebulized heparin and 36 historical controls. Two patients from the heparin group and three patients from the control group died/were discharged while on the ventilator. Data were analyzed separately with 1) all subjects included and 2) with subjects who died/were discharged on the ventilator excluded. In the latter comparison, patients receiving nebulized heparin demonstrated a statistically significant decrease in median (interquartile range) duration of initial mechanical ventilation compared with controls [7.0 (4.0, 13.5) vs. 14.5 (5.3, 22.3) days; P = .044]. Patients in the heparin group had a significantly increased number of median (interquartile range) ventilator-free days in the first 28 days [21.0 (14.5-24.0) vs 13.5 (4.3-22.8) days; P = .031]. There were no differences in hospitalization length, lung injury score during the first 7 days post injury, 28-day mortality, ventilator-associated pneumonia rate, or bleeding events. Nebulized heparin 10,000 units in conjunction with a beta-agonist and mucolytic produced a significant decrease in duration of mechanical ventilation and increase in ventilator-free days in adult patients with IHI. Nebulized heparin was safe and did not result in an increase in bleeding events. To our knowledge, this is the first case-control study with matched cohorts based on age and %TBSA which are significant factors contributing to morbidity and mortality in IHI.",
"affiliations": "From the *Department of Pharmacy, Eskenazi Health, Indianapolis, Indiana; †Clinical Pharmacy Specialist - Trauma and Surgical Critical Care, ‡Clinical Pharmacy Specialist - Adult Critical Care, §Purdue University, College of Pharmacy, ‖Richard M. Fairbanks Burn Center, Division Chief of Plastic Surgery - IU School of Medicine, and ¶Pharmacy Manager - Clinical Services, Clinical Pharmacy Specialist - Burn/Critical Care, Residency Program Director - PGY2 Critical Care, Eskenazi Health, Indianapolis, Indiana.",
"authors": "McIntire|Allyson M|AM|;Harris|Serena A|SA|;Whitten|Jessica A|JA|;Fritschle-Hilliard|Andrew C|AC|;Foster|David R|DR|;Sood|Rajiv|R|;Walroth|Todd A|TA|",
"chemical_list": "D000925:Anticoagulants; D001993:Bronchodilator Agents; D005100:Expectorants; D006493:Heparin; D000420:Albuterol",
"country": "England",
"delete": false,
"doi": "10.1097/BCR.0000000000000439",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1559-047X",
"issue": "38(1)",
"journal": "Journal of burn care & research : official publication of the American Burn Association",
"keywords": null,
"medline_ta": "J Burn Care Res",
"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000420:Albuterol; D000925:Anticoagulants; D001993:Bronchodilator Agents; D002059:Burns, Inhalation; D005100:Expectorants; D005260:Female; D006493:Heparin; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D012121:Respiration, Artificial; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101262774",
"other_id": null,
"pages": "45-52",
"pmc": null,
"pmid": "27532613",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcomes Following the Use of Nebulized Heparin for Inhalation Injury (HIHI Study).",
"title_normalized": "outcomes following the use of nebulized heparin for inhalation injury hihi study"
} | [
{
"companynumb": "US-MYLANLABS-2018M1018547",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
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... |
{
"abstract": "Refractory hypertension (RfHTN), a phenotype of antihypertensive treatment failure, is defined as uncontrolled automated office blood pressure (AOBP) ≥130/80 mm Hg and awake ambulatory blood pressure (ABP) ≥130/80 mm Hg on ≥5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist. Previous studies suggest that RfHTN is attributable to heightened sympathetic tone. The current study tested whether reserpine, a potent sympatholytic agent, lowers blood pressure (BP) in patients with RfHTN.\n\n\n\nTwenty-one out of 45 consecutive patients with suspected RfHTN were determined to be fully adherent with their antihypertensive regimen. Seven patients agreed to participate in the current clinical trial with reserpine and 6 patients completed the study. Other sympatholytic medications, such as clonidine or guanfacine, were tapered and discontinued before starting reserpine. Reserpine 0.1 mg daily was administered in an open-label fashion for 4 weeks. All patients were evaluated by AOBP and 24-hour ABP at baseline and after 4 weeks of treatment.\n\n\n\nReserpine lowered mean systolic and diastolic AOBP by 29.3 ± 22.2 and 22.0 ± 15.8 mm Hg, respectively. Mean 24-hour systolic and diastolic ABPs were reduced by 21.8 ± 13.4 and 15.3 ± 9.6 mm Hg, mean awake systolic and diastolic ABPs by 23.8 ± 11.8 and 17.8 ± 9.2 mm Hg, and mean asleep systolic and diastolic ABPs by 21.5 ± 11.4 and 13.7 ± 6.4 mm Hg, respectively.\n\n\n\nReserpine, a potent sympatholytic agent, lowers BP in patients whose BP remained uncontrolled on maximal antihypertensive therapy, lending support to the hypothesis that excess sympathetic output contributes importantly to the development of RfHTN.",
"affiliations": "Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Division of Cardiology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.;Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.;Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.",
"authors": "Siddiqui|Mohammed|M|;Bhatt|Hemal|H|;Judd|Eric K|EK|;Oparil|Suzanne|S|;Calhoun|David A|DA|",
"chemical_list": "D000959:Antihypertensive Agents; D012110:Reserpine",
"country": "United States",
"delete": false,
"doi": "10.1093/ajh/hpaa042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0895-7061",
"issue": "33(8)",
"journal": "American journal of hypertension",
"keywords": "blood pressure; hypertension; refractory hypertension; reserpine; sympathetic activity",
"medline_ta": "Am J Hypertens",
"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D001795:Blood Pressure Determination; D018660:Blood Pressure Monitoring, Ambulatory; D002853:Chromatography, Liquid; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006973:Hypertension; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D000075082:Proof of Concept Study; D012110:Reserpine; D053719:Tandem Mass Spectrometry; D017211:Treatment Failure",
"nlm_unique_id": "8803676",
"other_id": null,
"pages": "741-747",
"pmc": null,
"pmid": "32179903",
"pubdate": "2020-08-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15021078;30354828;26414968;23890931;16410740;23337469;24029863;29866740;15985180;28696223;11518840;15699287;22235818;8069403;24324035;12468575;31813346;8834700;16364821;19171788;29146535;17296647;31209397;30827125;21444835;24220593;24571101;6616774;25987662",
"title": "Reserpine Substantially Lowers Blood Pressure in Patients With Refractory Hypertension: A Proof-of-Concept Study.",
"title_normalized": "reserpine substantially lowers blood pressure in patients with refractory hypertension a proof of concept study"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-017506",
"fulfillexpeditecriteria": "1",
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"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CLONIDINE HYDROCHLORIDE"
}... |
{
"abstract": "To study preoperative HBV-DNA negative HBV-related hepatocellular carcinoma (HCC) which was reactivated after surgery and could influence liver function and HCC recurrence.\n\n\n\nPatients were divided into two groups according to preoperative antiviral therapy status. The control group comprised of 102 preoperative HBV-DNA-negative patients who had not undergone antiviral therapy before surgery. In the treatment group, all HBV-DNA-negative patients (n=63) received entecavir 3-5 days before surgery and for 12 months after surgery. Patients were followed-up regularly, during the preoperative period, and at 1, 3, 6, 12, 18, 24, 30 and 36 months postoperatively. The data for the two groups were analyzed including the level of HBV-DNA and HBV-DNA activation; liver function; 1-, 2- and 3-year survival rate; cumulative survival time; and tumor recurrence.\n\n\n\nLiver function in the treatment group was better than that of the control group12 months after surgery. Compared to the control group, total bilirubin in the treatment group was significantly better at 6 and 12 months after surgery (p<0.05 and p<0.001, respectively). Serum albumin, alanine aminotransferase and prothrombin time in the treatment group was significantly better than that of controls 12 months after surgery (p<0.001). In the treatment group, two cases (3.17%) had HBV-DNA activation while there were 13 cases (12.75%) with HBV-DNA activation in the control group (p<0.05). There were 51 cases with tumor recurrence in the control group, that was statistically significantly higher than recurrent cases in the treatment group (p<0.05). Postoperative 1-, 2- and 3-year cumulative overall survival rates were 94.12%, 81.37% and 52.94%, respectively, for the control group and 93.65%, 77.78% and 71.43%, respectively, for the treatment group (p=0.006). There was no statistically significant difference in disease-free survival between the two groups (p=0.231).\n\n\n\nAntiviral treatment of HBV-related HCC with negative HBV-DNA is beneficial to liver function, coagulation function, disease control, prevention of tumor recurrence, improvement of patient quality of life, reduces the death rate and prolongs survival duration.",
"affiliations": "Department of Hepatobiliary Surgery, Affiliated Yantai Yuhuangding Hospital, Qingdao University Medical College, Yantai, P.R. China Liu634@263.net.;Department of Hepatobiliary Surgery, Affiliated Yantai Yuhuangding Hospital, Qingdao University Medical College, Yantai, P.R. China.;Department of Hepatobiliary Surgery, Affiliated Yantai Yuhuangding Hospital, Qingdao University Medical College, Yantai, P.R. China.;Department of Hepatobiliary Surgery, Affiliated Yantai Yuhuangding Hospital, Qingdao University Medical College, Yantai, P.R. China.;Department of Hepatobiliary Surgery, Affiliated Yantai Yuhuangding Hospital, Qingdao University Medical College, Yantai, P.R. China.;Department of Hepatobiliary Surgery, Affiliated Yantai Yuhuangding Hospital, Qingdao University Medical College, Yantai, P.R. China.",
"authors": "Liu|Xiao-Fang|XF|;Zhang|Tong|T|;Tang|Kun|K|;Sui|Lu-Lu|LL|;Xu|Gang|G|;Liu|Qiang|Q|",
"chemical_list": "D000998:Antiviral Agents; D014408:Biomarkers, Tumor; D004279:DNA, Viral",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11875",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "37(8)",
"journal": "Anticancer research",
"keywords": "Antiviral treatment; HBV-DNA; hepatocellular carcinoma (HCC)",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D014408:Biomarkers, Tumor; D001777:Blood Coagulation; D006528:Carcinoma, Hepatocellular; D004279:DNA, Viral; D005260:Female; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D008111:Liver Function Tests; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011300:Preoperative Care; D012008:Recurrence; D016019:Survival Analysis; D016896:Treatment Outcome; D047368:Tumor Burden; D014775:Virus Activation",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4701-4706",
"pmc": null,
"pmid": "28739774",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Study of Preoperative Antiviral Treatment of Patients with HCC Negative for HBV-DNA.",
"title_normalized": "study of preoperative antiviral treatment of patients with hcc negative for hbv dna"
} | [
{
"companynumb": "CN-CIPLA LTD.-2018CN03362",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENTECAVIR"
},
"drugadditional": "3",
... |
{
"abstract": "There are a variety of cardiac complications of anorexia nervosa including arrythmias, valvopathies, and myopathies. Spontaneous coronary artery dissection (SCAD) has not been widely reported among this patient population. This case report describes a middle-aged female with severe anorexia nervosa, who presented after being found unconscious, and was later diagnosed with SCAD. A literature review revealed one previous case of SCAD in a patient with anorexia nervosa and prompted a discussion of a series of possible predisposing factors for SCAD in this patient population. Patients with anorexia nervosa may be at increased risk for SCAD due to their complex nutritional and endocrine imbalances. This case highlights a possible underdiagnosed cardiac complication of anorexia nervosa.",
"affiliations": "Department of Medicine, Massachusetts General Hospital, Massachusetts, USA.;Harvard Medical School, Massachusetts, USA.;Department of Medicine, Massachusetts General Hospital, Massachusetts, USA.;Department of Medicine, Massachusetts General Hospital, Massachusetts, USA.",
"authors": "O'Neil|Jessica|J|https://orcid.org/0000-0002-2459-2309;Mazumder|Soumyaa|S|;Sanborn|Danita Yoerger|DY|;Wu|Samantha|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/5526022",
"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404\n2090-6412\nHindawi\n\n10.1155/2021/5526022\nCase Report\nA Case of Spontaneous Coronary Artery Dissection in a Patient with Severe Anorexia Nervosa\nhttps://orcid.org/0000-0002-2459-2309\nO'Neil Jessica joneil@mgh.harvard.edu\n1\nMazumder Soumyaa 2\nSanborn Danita Yoerger 1 3\nWu Samantha 1 4\n1Department of Medicine, Massachusetts General Hospital, Massachusetts, USA\n2Harvard Medical School, Massachusetts, USA\n3Department of Cardiology, Massachusetts General Hospital, Massachusetts, USA\n4Hospital Medicine Unit Massachusetts General Hospital, Massachusetts, USA\nAcademic Editor: Tong Liu\n\n2021\n23 6 2021\n2021 552602214 2 2021\n6 6 2021\n10 6 2021\nCopyright © 2021 Jessica O'Neil et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nThere are a variety of cardiac complications of anorexia nervosa including arrythmias, valvopathies, and myopathies. Spontaneous coronary artery dissection (SCAD) has not been widely reported among this patient population. This case report describes a middle-aged female with severe anorexia nervosa, who presented after being found unconscious, and was later diagnosed with SCAD. A literature review revealed one previous case of SCAD in a patient with anorexia nervosa and prompted a discussion of a series of possible predisposing factors for SCAD in this patient population. Patients with anorexia nervosa may be at increased risk for SCAD due to their complex nutritional and endocrine imbalances. This case highlights a possible underdiagnosed cardiac complication of anorexia nervosa.\n==== Body\n1. Introduction\n\nSCAD is a significant cause of acute coronary syndrome (ACS) in young and middle-aged women, accounting for nearly a quarter of ACS in women under the age of 50 [1]. Although advances in intracoronary imaging have helped increase the recognition of SCAD, it continues to be underdiagnosed [2]. SCAD has primarily been associated with predisposing arteriopathies (e.g., fibromuscular dysplasia and connective tissue disorders), high-stress conditions (e.g., intense exercise and significant emotional stress), and hormonal triggers (e.g., pregnancy). There has been little reported about the connection between SCAD and AN. AN is an illness marked by several nutritional and endocrine imbalances. It is associated with a number of cardiovascular complications including arrhythmias, heart failure, valvular disease, and sudden cardiac death [3]. This case raises the question of whether SCAD is an underappreciated diagnosis amongst patients with AN and may contribute to the high rate of cardiac morbidities in this population.\n\n2. Case Presentation\n\nA 55-year-old woman with a severe anorexia nervosa (AN) was found unresponsive for an unknown period of time with hypoglycemia (POCT glucose 14 mg/dL) and hypothermia (90.2°F). Her mentation and temperature normalized with intravenous dextrose and rewarming. She did not recall the events leading up to her presentation. She denied suicidal ideation or intentional ingestion. She reported previous mild dyspnea on exertion but denied chest pain. A few weeks prior to her presentation her father passed away leading to significant emotional stress. She was diagnosed with AN at age 18 which was primarily restrictive subtype; however, she did report prior episodes of purging. Her medical history also included hypothyroidism, for which she was on 125 mcg levothyroxine daily, hyponatremia, and iron deficiency anemia. On examination, she weighed 35 kg with a body mass index (BMI) of 12. Cardiac exam revealed regular rate and rhythm, normal S1 and S2, no murmurs, and no jugular venous distension. There was pitting edema to her ankles bilaterally. She was also noted to have gingival swelling and a petechial rash over her lower extremities, raising clinical concern for scurvy.\n\nLaboratory values revealed hypomagnesemia (1.5 mmol/L), hypocalcemia (6.5 mgl/dL), and hypoalbuminemia (2.7 g/dL). Serum creatinine was 0.84 mg/dL. Thyroid-stimulating hormone (TSH) was within normal limits (1.27 uIU/mL) and triiodothyronine (T3) was at the lower bound of the normal range (76 ng/dL) though free thyroxine (FT4) was elevated to 3.3 ng/dL. This was attributed to a supratherapeutic dose of levothyroxine. Vitamin C (0.3 mg/dL) and 25–OH vitamin D (21.9 ng/mL) levels were low. Investigation also demonstrated an elevation in high sensitivity troponin elevated to 129 ng/L peaking to 364 ng/dL. ECG revealed Q-waves and ST elevation in leads V1-V3 c/w a septal infarct, new compared to an ECG from 4 months prior. Transthoracic echocardiogram (TTE) revealed an ejection fraction of 52% with akinesis of the septum at the midventricular level and hypokinesis of the apical septum. There was moderate mitral regurgitation. These abnormalities were new compared to a TTE from 2 years prior. A computed tomography coronary angiogram showed no atherosclerosis but demonstrated a linear hypodensity within the proximal segment of the first septal perforator artery and abrupt tapering of the vessel 5 mm from the origin consistent with SCAD. Cardiology was consulted and recommended conservative therapy with initiation of aspirin, metoprolol, and cardiac rehabilitation.\n\n3. Discussion\n\nSCAD is caused by the formation of an intramural hematoma (IMH) within the coronary artery wall that compresses the true lumen leading to ischemia. There are two leading theories describing of how the IMH arises: (1) it develops from damage to the vascular endothelium (possibly from an intimal tear), allowing blood to pool in a false lumen, or (2) the IMH forms following a spontaneous rupture of the vasa vasorum within the arterial wall [4]. There has been one previously reported case of SCAD in a patient with AN [5]. Sedham et al. postulated that hormonal imbalances in anorexia may contribute to poor smooth muscle development, leading to increased risk for arterial dissection. Vascular endothelial dysfunction is hypothesized to play a role in SCAD. A number of endocrine functions frequently altered in severe anorexia, support vascular endothelial health. Derangements in the hypothalamic-pituitary-thyroid axis often manifest in severe anorexia nervosa with low triiodothyronine (T3). T3 enhances endothelial and smooth muscle function and low T3 levels have a demonstrated association with cardiovascular disease [6]. However, thyroid function tests in this patient were confounded by a supratherapeutic levothyroxine dose. Significant changes in catecholamine metabolism have been observed in patients with AN when weight is 20% below ideal body weight [7]. Catecholamine surges have been previously implicated in the pathophysiology of SCAD. In fact, Chow et al. proposed that surges in catecholamines lead to vascular myointimal dysplasia and this may underlie the association observed between emotional stress and SCAD [8]. Additionally, estradiol levels are also often blunted in AN, and estradiol is protective of the vascular endothelium in several animal models [9].\n\nA number of micronutrients often deficient in AN are important for vascular endothelial health. Zinc and selenium deficiencies are common in patients with severe anorexia [10] and have both been implicated as a mediator of inflammation in endothelial function [6, 11]. Vitamin C also has a well-established role in the development and maintenance of endothelial cells and the vascular basement membrane [12]. Recent studies have shown that patients with AN generally have increased inflammatory cytokines [13, 14]. This state of increased inflammation could lead to endothelial dysfunction, weakening the vascular intimal layer and predisposing to the development of SCAD. Finally, patients with AN may be at risk to mechanical injury to the vasculature. Prolonged retching, a behavior observed in patients with purging subtypes of eating disorders, has been identified as a precipitating factor in SCAD cases [15].\n\nFigure 1 summarizes the proposed endocrine, nutritional, and physical stressors present in patients with severe anorexia that may predispose this population to SCAD. Considering our patient, it is possible that her preceding emotional and physical stress triggered her development of SCAD though she may have been predisposed to this injury due to her state of chronic severe malnutrition, endocrine dysregulation, and history of purging leading to a compromised vascular endothelium. This case adds to the one previously reported case of SCAD in AN. Further studies will be needed to understand whether patients with AN may be at increased risk for SCAD and may contribute to the high cardiac comorbidities in this population. Better understanding the relationship between AN and SCAD could inform treatment strategies aimed at the prevention of this potentially life-threatening cardiovascular complication.\n\nData Availability\n\nThe underlying data supporting the content of the case report can be found in the Mass General Brigham Research Data Repository. Authors can make data available on request through the Mass General Brigham Institutional Review Board.\n\nConflicts of Interest\n\nThe authors have no conflicts of interest to declare.\n\nFigure 1 Hypothesized stressors predisposing to SCAD in patients with severe anorexia nervosa.\n==== Refs\n1 Saw J. Aymong E. Mancini G. B. Sedlak T. Starovoytov A. Ricci D. Nonatherosclerotic coronary artery disease in young women The Canadian Journal of Cardiology 2014 30 7 814 819 10.1016/j.cjca.2014.01.011 2-s2.0-84903189735 24726091\n2 Yip A. Saw J. Spontaneous coronary artery dissection-a review Cardiovascular Diagnosis and Therapy 2015 5 1 37 48 10.3978/j.issn.2223-3652.2015.01.08 25774346\n3 Jáuregui-Garrido B. Jáuregui-Lobera I. Sudden death in eating disorders Vascular Health and Risk Management 2012 8 91 98 10.2147/VHRM.S28652 2-s2.0-84864022330 22393299\n4 Hayes S. N. Kim E. S. H. Saw J. Spontaneous coronary artery dissection: current state of the science: a scientific statement from the American Heart Association Circulation 2018 137 19 e523 e557 10.1161/CIR.0000000000000564 2-s2.0-85043516435 29472380\n5 Sedhom D. Hiltner E. Patel C. Prister J. Spontaneous coronary artery dissection in an anorexic patient: a rare and challenging case American Journal of Respiratory and Critical Care Medicine 2018 197 p. A3449\n6 Napoli R. Guardasole V. Angelini V. Acute effects of triiodothyronine on endothelial function in human subjects The Journal of Clinical Endocrinology and Metabolism 2007 92 1 250 254 10.1210/jc.2006-1552 2-s2.0-33846036529 17047021\n7 Gross H. A. Lake C. R. Ebert M. H. Ziegler M. G. Kopin I. J. Catecholamine metabolism in primary anorexia nervosa The Journal of Clinical Endocrinology and Metabolism 1979 49 6 805 809 10.1210/jcem-49-6-805 2-s2.0-0018598938 511970\n8 Chow L. T. C. Chow M. B. C. Y. Coronary artery myointimal dysplasia in patients with pheochromocytoma—possible causal relationship: pathophysiology and clinical implication with reference to Takotsubo cardiomyopathy and spontaneous coronary dissection Cardiovascular Pathology 2018 37 45 53 10.1016/j.carpath.2018.10.001 2-s2.0-85054918690 30342321\n9 Tolbert T. Oparil S. Cardiovascular effects of estrogen American Journal of Hypertension 2001 14 11 S186 S193 10.1016/S0895-7061(01)02087-8\n10 Hanachi M. Dicembre M. Rives-Lange C. Micronutrients deficiencies in 374 severely malnourished anorexia nervosa inpatients Nutrients 2019 11 4 p. 792 10.3390/nu11040792 2-s2.0-85064542300 30959831\n11 Little P. J. Bhattacharya R. Moreyra A. E. Korichneva I. L. Zinc and cardiovascular disease Nutrition 2010 26 11-12 1050 1057 10.1016/j.nut.2010.03.007 2-s2.0-77957778826 20950764\n12 Ashor A. W. Siervo M. Lara J. Oggioni C. Afshar S. Mathers J. C. Effect of vitamin C and vitamin E supplementation on endothelial function: a systematic review and meta-analysis of randomised controlled trials The British Journal of Nutrition 2015 113 8 1182 1194 10.1017/S0007114515000227 2-s2.0-84929464133 25919436\n13 Solmi M. Veronese N. Favaro A. Inflammatory cytokines and anorexia nervosa: a meta-analysis of cross-sectional and longitudinal studies Psychoneuroendocrinology 2015 51 237 252 10.1016/j.psyneuen.2014.09.031 2-s2.0-84920603322 25462897\n14 Dalton B. Campbell I. C. Chung R. Breen G. Schmidt U. Himmerich H. Inflammatory markers in anorexia nervosa: an exploratory study Nutrients 2018 10 11 p. 1573 10.3390/nu10111573 2-s2.0-85055611214 30355978\n15 Velusamy M. Fisherkeller M. Keenan M. E. Kiernan F. J. Fram D. B. Spontaneous coronary artery dissection in a young woman precipitated by retching The Journal of Invasive Cardiology 2002 14 4 198 201 11923575\n\n",
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"title": "A Case of Spontaneous Coronary Artery Dissection in a Patient with Severe Anorexia Nervosa.",
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"abstract": "Allergic angina and allergic myocardial infarction (Kounis syndrome) occurring during the course of a drug-induced allergic reaction in the absence of angiographically stenosed coronary arteries, is rare in clinical practice. This paper reports the case of a 70-year-old woman with no significant risk factors for coronary artery disease who developed coronary artery spasm after intravenous injection of cefuroxime. A subsequent coronary angiogram revealed normal coronary arteries (type I variant of the syndrome). The allergic reaction following cefuroxime administration seems to have triggered the development of coronary artery spasm. Susceptible individuals expressing an amplified mast cell degranulation effect may be more vulnerable to coronary artery spasm. The clinical implications of this syndrome are also discussed.",
"affiliations": "Department of Cardiology, University of Patras, Medical School, Patras, Greece.",
"authors": "Mazarakis|Andreas|A|;Koutsojannis|Constantinos M|CM|;Kounis|Nicholas G|NG|;Alexopoulos|Dimitrios|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002444:Cefuroxime",
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"mesh_terms": "D000368:Aged; D000787:Angina Pectoris; D000900:Anti-Bacterial Agents; D002444:Cefuroxime; D017023:Coronary Angiography; D003329:Coronary Vasospasm; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D013577:Syndrome",
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"title": "Cefuroxime-induced coronary artery spasm manifesting as Kounis syndrome.",
"title_normalized": "cefuroxime induced coronary artery spasm manifesting as kounis syndrome"
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"abstract": "The evolving pandemic of Coronavirus Disease 2019 has posed a substantial health risk worldwide. However, there is a paucity of data regarding the clinical course and the therapeutic management of patients with chronic kidney disease and COVID-19 infection. To date, most evidence has come from renal transplantation, with about 45 patients reported thus far, and the current data from the ERA-EDTA (ERACODA) registry for transplanted patients and patients on Renal Replacement Therapy (RRT); as for those with glomerular diseases, data are lacking. Herein, we report the case of a 62-year-old patient with severe membranoproliferative glomerulonephritis who had been receiving a high burden of immunosuppression until four months before the COVID-19 infection. He developed severe disease with acute respiratory failure requiring mechanical ventilation. After treatment with hydroxychloroquine and azithromycin, despite his low chances, he gradually recovered and survived. To the best of our knowledge, this is one of the few reported patients with glomerulonephritis who had COVID-19 Besides our single case with glomerulonephritis early during the disease outbreak, the very low prevalence of COVID-19 infection in the country's transplant recipients (0.038%) and dialysis patients (0.24%) reflects the impact of the rapid implementation of social distancing rules as well as of preventive measures for disease control in the hospitals and dialysis units in our country.",
"affiliations": "Clinic of Nephrology and Renal Transplantation, Medical School, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece.;Clinic of Nephrology and Renal Transplantation, Medical School, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece.;Clinic of Nephrology and Renal Transplantation, Medical School, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece.;Infectious Diseases Clinic A, Sotiria Chest Diseases Hospital, 11527 Athens, Greece.;Infectious Diseases Clinic A, Sotiria Chest Diseases Hospital, 11527 Athens, Greece.;Independent Researcher, 12 Protopappa Avenue, 16345 Athens, Greece.;Clinic of Nephrology and Renal Transplantation, Medical School, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece.",
"authors": "Marinaki|Smaragdi|S|;Tsiakas|Stathis|S|;Skalioti|Chrysanthi|C|;Lourida|Panayiota|P|;Argyraki|Aikaterini|A|0000-0002-9095-7724;Grigorakos|Konstantinos|K|;Boletis|Ioannis|I|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007155:Immunologic Factors; D000069283:Rituximab; D006886:Hydroxychloroquine; D002443:Ceftriaxone; D017963:Azithromycin; D003520:Cyclophosphamide; D003404:Creatinine; D008775:Methylprednisolone",
"country": "Switzerland",
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"doi": "10.3390/medicina56070355",
"fulltext": "\n==== Front\nMedicina (Kaunas)\nmedicina\nMedicina\n1010-660X 1648-9144 MDPI \n\n10.3390/medicina56070355\nmedicina-56-00355\nCase Report\nA Patient with Cryoglobulinemic Membranoproliferative GN (MPGN) Who Survived COVID-19 Disease: Case Presentation and Current Data of COVID-19 Infection in Dialysis and Transplanted Patients in Greece\nMarinaki Smaragdi 1 Tsiakas Stathis 1 Skalioti Chrysanthi 1* Lourida Panayiota 2 https://orcid.org/0000-0002-9095-7724Argyraki Aikaterini 2 Grigorakos Konstantinos 3 Boletis Ioannis 1 1 Clinic of Nephrology and Renal Transplantation, Medical School, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; smaragdimarinaki@yahoo.com (S.M.); stathis.tsiakas@gmail.com (S.T.); laikneph@laiko.gr (I.B.)\n2 Infectious Diseases Clinic A, Sotiria Chest Diseases Hospital, 11527 Athens, Greece; giotalourida@gmail.com (P.L.); katrin.argyraki@gmail.com (A.A.)\n3 Independent Researcher, 12 Protopappa Avenue, 16345 Athens, Greece; gk_pediatr@yahoo.gr\n* Correspondence: c_skalioti@yahoo.com\n17 7 2020 \n7 2020 \n56 7 35505 6 2020 14 7 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).The evolving pandemic of Coronavirus Disease 2019 has posed a substantial health risk worldwide. However, there is a paucity of data regarding the clinical course and the therapeutic management of patients with chronic kidney disease and COVID-19 infection. To date, most evidence has come from renal transplantation, with about 45 patients reported thus far, and the current data from the ERA-EDTA (ERACODA) registry for transplanted patients and patients on Renal Replacement Therapy (RRT); as for those with glomerular diseases, data are lacking. Herein, we report the case of a 62-year-old patient with severe membranoproliferative glomerulonephritis who had been receiving a high burden of immunosuppression until four months before the COVID-19 infection. He developed severe disease with acute respiratory failure requiring mechanical ventilation. After treatment with hydroxychloroquine and azithromycin, despite his low chances, he gradually recovered and survived. To the best of our knowledge, this is one of the few reported patients with glomerulonephritis who had COVID-19 Besides our single case with glomerulonephritis early during the disease outbreak, the very low prevalence of COVID-19 infection in the country’s transplant recipients (0.038%) and dialysis patients (0.24%) reflects the impact of the rapid implementation of social distancing rules as well as of preventive measures for disease control in the hospitals and dialysis units in our country.\n\nCOVID-19pneumoniaglomerulonephritisimmunosuppressiontransplantationRenal Replacement Therapy (RRT)\n==== Body\n1. Introduction\nWe are currently in the midst of the third epidemic of coronaviruses in the last 20 years. The new virus SARS-CoV-2 belongs to the β-coronavirus cluster, which also comprises the viruses that cause Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), emerging in 2003 and2012, respectively [1].\n\nThe new virus causes SARS-CoV-2-related disease 2019 (COVID-19). It started in December 2019 in the city of Wuhan in central China and spread rapidly across the world, reaching proportions of a “global pandemic” by 15 March 2020 [2].\n\nAlong with other European countries, Greece has been affected, with the first confirmed case being identified on 26 February 2020. \n\nIn our Clinic for Nephrology and Renal Transplantation of Laiko Hospital of Athens, a tertiary hospital with an extensive kidney transplantation program, a total of 1450 transplanted patients are monitored every year. As the clinic further includes a Reference Center for Glomerular Diseases, an additional 520 patients with glomerular diseases are also under follow-up. Furthermore, we have a Hemodialysis Unit with 55 patients on Renal Replacement Therapy (RRT). It is noteworthy that, since the disease outbreak in our country and for the entire period of the past three months, our department had no kidney transplant recipients or RRT patientswith COVID-19 infection and only this single patient with glomerular disease with COVID-19 infection. \n\n2. Case Report\nA 62-year-old male patient with a history of Chronic Lymphocytic Leukemia (CLL) (RAI stage 0) was initially evaluated in our department in July 2019 for nephrotic syndrome (Upr:12.7g/day) and impaired kidney function (Cr:1.98mg/dL). His kidney biopsy revealed features of cryoglobulinemic glomerulonephritis. Treatment with rituximab (four weekly doses of 375 mg/m2), cyclophosphamide (threemonthly iv doses of 500 mg/m2) and corticosteroids (prednisolone 0.75 mg/kg for threeweeks, followed by a slow taper) was initiated. The last infusion of cyclophosphamide was administered in October 2019. At his last follow-up in February 2020, sixmonths after therapy initiation, the patient had a creatinine level of 1.59 mg/dL with proteinuria 4.93 g/day while he was still receiving 6 mg of methylprednisolone per day. \n\nOn 16 March, he presented to the emergency department with high fever and dry cough. He reported no contact with a coronavirus-infected patient or travel history. His symptoms started fivedays before presentation and rapidly deteriorated on the day of admission. On physical examination, he was tachypnoeic with SatO2: 93%. The throat swab sample for SARS-CoV-2 (RT-PCR) was positive, and the patient was transferred to a referral hospital for COVID-19. His blood tests revealed a white blood cell count of 5800 × 109/L (neutrophils 58%, lymphocytes 36%), a C-reactive protein level of 65 mg/L (nr < 5) and slightly elevated d-dimers. A hepatic panel, LDH value and procalcitonin level were normal. A chest CTscan showed diffuse bilateral infiltrates (Figure 1). Besides respiratory support with oxygen therapy, treatment with hydroxychloroquine (200 mg bid) and ceftriaxone was initiated. The patient’s clinical status deteriorated rapidly, and, twodays later, he was transferred to the intensive care unit (ICU), where he was put on mechanical ventilation due to respiratory failure. Azithromycin (500 mg od for seven days) was added in the ICU. Remdesivir was not administered because of renal impairment (peak creatinine level of 2.8 mg/dL, corresponding to an eGFR of 23 mL/min/1.73 m2 by the CKD-EPI equation). The patient remained hemodynamically stable without vasopressors and maintained a satisfactory urine output despite a transient renal function deterioration. His respiratory function gradually improved, and he was discharged from the ICU after seven days and transferred to the rehabilitation unit. Meanwhile, a second CT scan on the 16th day of hospitalization showed a significant improvement of the lung lesions. After 25 days of hospitalization, he was discharged, and he remains in good clinical condition. His creatinine level has returned to 1.4 mg/dL.\n\n3. Discussion\nVery few patients on immunosuppressive treatment due to primary or secondary glomerular disease with confirmed SARS-CoV-2 infection have been reported thusfar [3]. Our patient with membranoproliferative glomerulonephritis (MPGN) survived after the development of severe pneumonia and acute respiratory failure requiring mechanical ventilation. Very little is known about COVID-19 infection in patients with glomerular diseases. These patients have been advised to respect social distancing rules since the early stages of the COVID-19 outbreak in all European countries. Most of the existing evidence comes from kidney transplantation.\n\nDespite their increased vulnerability, the prevalence of COVID-19 virus infection has remained low in kidney transplant recipients, with reported rates varying from 1.6% to 3% among European countries [4,5] and the lowest reported rate being 0.33% [6]. This is due to the even stricter implementation of hygiene and social isolation measures relative to those in the general population and the compliance by the patients themselves. At the same time, according to the European Centre for Disease Prevention and Control, the prevalence of COVID-19 infection in the general population in the countries of the Eurozone is 0.29% [7].\n\n3.1. Symptoms at Presentation\nOur patient had the typical initial presentation of COVID-19 as in the general population, with fever and dry cough as the primary symptoms.\n\nMost transplanted patients have also reported the typically described “flu-like” symptoms with fever, dry cough and malaise; only a minority have presented with diarrhea and abdominal pain [8].\n\n3.2. Risk Factors\nOur patient had several risk factors for severe COVID-19 disease: he was a middle-aged male with severe MPGN nephritis since 2019 with Chronic Kidney Disease (CKD) stage III (eGFR 46 mL/min, CKD-EPI) nephrotic-range (4.9 g/24 h) proteinuria and concomitant, albeit quiescent, CLL. He had received immunosuppression with the mAb Rituximab, a total of 3 g of cyclophosphamide and high-dose steroids 4.5 months before the COVID-19 infection.\n\n3.3. Disease Course and Treatment of Immunocompromised Individuals\nAccording to the European Centre for Disease Prevention and Control (ECDC), the majority of infected individuals (>80%) will run an indolent course with mild disease, another 15% will have a more severe form, and a minority, about 5%, will develop life-threatening disease [6]. A three-stage classification system that describes the three grades of increasing severity of COVID-19 disease was recently proposed by Siddiqi et al. [9]. According to this classification, our patient had severe illness (Stage IIb pneumonia with hypoxia), and, fortunately, he did not progress to Stage III, despite his comorbidities and immunocompromised status. Many questions about the behavior of COVID infection in immunocompromised individuals are still unanswered. Little is known about the exact disease course, while most evidence again comes from transplanted patients.\n\nImmunosuppression undoubtedly places the patient into a high-risk group for acquiring as well as transmitting the virus [10]. Most agree that, as in our patient, the initial presentation does not differ from that in the general population [11].\n\nKidney transplant recipients who are infected with the COVID-19 virus have, as expected, a more severe disease and worse prognosis with higher rates of hospitalization and a need for mechanical ventilation support, as well as higher case fatality rates [5,6].\n\nAs for treatment, preventive measures are the same as those for the general population, with increased vigilance [12]. Most drugs used in other patients with COVID-19 virus infection may be used, with dose adjustments according to reduced renal function and consideration of their interactions with immunosuppressants.\n\nRegarding the handling of immunosuppression, the general principles applicable to all severe, opportunistic or viral infections also apply for COVID-19 infection: most important is a reduction in the overall burden of immunosuppression. The first step is to discontinue immunosuppressive drugs that not only promote viral replication but also cause leukopenia, such as antimetabolites (mycophenolic acid and less often azathioprine), while, in more severe cases, calcineurin inhibitors (CNIs) can also be drastically reduced and/or discontinued. In any case, the decision is individualized by taking into account both the severity of the infection and the life threat against the consequence of potential graft loss.\n\nThe most recent review of COVID-19 infection in kidney transplant recipients includes 12 studies reporting on a total of 40 patients [13]. There was a broad variation in the time from renal transplantation, ranging from 1 month to 22 years, in baseline immunosuppression and in disease course and severity. Of the 40 reported patients, 18% developed life-threatening disease and eightdied (case fatality rate of 20%).\n\nIt must be emphasized, however, that most of the reported recipients were transplanted long before infection and were on low-dose maintenance immunosuppression, which was drastically reduced or discontinued during COVID-19 disease. This is a striking difference from patients with glomerular diseases, who might have received, as ours did, a high immunosuppressive load a short time before the infection. Our patient had received 3 g of cyclophosphamide and a cumulative methylprednisolone dose of 5 g a few months before the COVID infection. He also had received Rituximab six months before, and we assume that B-cells must have still been depleted [14]. Perhaps the patient’s previous good performance status, immediate diagnosis and prompt treatment initiation contributed to his favorable outcome.\n\nThe current opinion-based advice from the ERA-EDTA Immunonephrology Working Group for CKD patients with glomerulonephritis or vasculitis is to continue with immunosuppressive treatment in asymptomatic COVID-19 and reduce it cautiously, balancing the risk of relapse, in symptomatic patients. New-onset or relapsing vasculitis should be treated with immunosuppressive drugs, but, for new-onset glomerulonephritis, supportive care may be recommended as first-line treatment, and immunosuppression should be withheld and the anti-CD20 mAb Rituximab as maintenance therapy should be postponed if possible [15].\n\n3.4. Epidemiology and Impact of Preventive Measures\nIn Greece, the first COVID-19 case was confirmed on 26 February 2020.\n\nOn 10 March with officially 8 cases/1 million population and 0 deaths, the Greek Government decided to close all educational structures and, on 13 March, to suspend the operation of leisure shops, museums, shopping malls, sports facilities and restaurants. On 16 March, all commercial stores were closed except for food and household businesses. On 23 March, significant restrictions were imposed on the movement of citizens [16].\n\nThe total number of confirmed cases in the country as of 24 May is 2878 (55% men), the current number of intubated patients is 19 (68% men) and the death toll is 171 (71% men), with 100 patients having been discharged from the ICU (Figure 2) [17]. The average age of infected individuals is 48 years (range 0–102 years), while the average age of those who died is 76 years (range 35–102 years). In total, 153,963 clinical samples were tested, of which 4612 (3.0%) were positive for coronavirus (including more than one sample per person tested) [17].\n\nThe extensive and rapidly implemented measures taken by the Greek state are already reflected in the country’s epidemiological data.\n\nIn relation to its population, Greece has 16 deaths per million population (1 M), which ranks the country in 70th place internationally (44.5/1 M, 215 countries), 39th in Europe (169.6/1 M, 50 countries) and 15th in the Eurozone (198/1 M, 19 countries) (Figure 3). The Case Fatality Rate (CFR: ratio between confirmed deaths and confirmed cases) in Greece is 5.9%, which is below the global average (6.2%) [18,19,20]. \n\nFrom the beginning of the COVID-19 outbreak in Greece, preventive measures were rapidly implemented in our hospital: personnel training and application of infection control measures (hand hygiene, facial mask and gloves);\n\napredefined pathway in the Emergency Department for suspected cases, namelyscreening with NAT and isolation in a separate ward until the first COVID-19 PCR, after whichpatients with positive tests are transferred to one of the four referral hospitals of Athens, andpatients with negative tests are transferred to the normal ward under isolation until the second negative test; and\n\nlimitation of elective surgical procedures, including cessation of living donor transplantations.\n\nGuidelines were provided by the Hellenic Transplant Organisation on 15 March and the Hellenic Society of Nephrology on 17 March to all transplant centers and to all hospitals and dialysis units, respectively.\n\nPatients undergoing maintenance dialysis were briefly evaluated for symptoms consistent with COVID-19 and had their body temperature measured before entering the Dialysis Unit. Handwashing and facemask use were mandatory upon entrance to the facility. Patients were separated by a distance of at least 1.5 m from each other and were required to keep their facemasks on during the entire dialysis session. No food or fluid intake was allowed while in the treatment area. \n\n\n\nPatients were advised to stay home between dialysis sessions. In case of fever or respiratory symptoms, they were instructed to notify the Dialysis Unit before arriving to the facility. A divided area was organized for evaluating and testing these patients. Suspected cases were dialyzed in an isolation room in the dialysis ward. Confirmed cases were referred to a COVID-19 designated Dialysis Unit.\n\nIt is remarkable that, in the period from the beginning of the pandemic to date, from a total of 2567 patients with kidney transplantation all over the country, there has been only a single case of COVID-19 infection (prevalence of 0.038%) among the kidney transplant recipients who were tested.The patient had mild disease, was hospitalized and survived without developing life-threatening disease.\n\nThis clearly demonstrates the effectiveness of the social isolation measures and strict recommendations given by the nephrology units as well as the importance and efficacy of tele-medicine, which was successfully applied to monitor the population of kidney transplant recipients and patients with glomerular diseases during the “lock-down” period of the pandemic, while, since mid-May, a program of “controlled restart” of the regular outpatient clinics has been implemented.\n\nFinally, a comparison between dialysis and transplantation during the COVID-19 era in our country comes out in favor of transplantation: to date, 28 confirmed cases of COVID-19 from a total population of 11,590 hemodialysis patients have been recorded in Greece (prevalence of 0.24%), and there have been sixdeaths (case fatality rate of 21%) (Table 1); data are lacking for patients with CKD Stages 1–4 [21]. This is in accordance with other countries where reported case fatality rates in hemodialysis patients are in the range of 20–30% [6].\n\n4. Conclusions\nOur sole COVID-19-infected patient with severe underlying glomerulonephritis survived, despite his very low chances. This is encouraging since nothing is more important than one saved life. Nevertheless, it is important to realize that, besides optimizing care for the single individual, preventive measures are essential for the control of the disease outbreak in the general population, which is eventually also reflected in very low infection rates in the vulnerable, immunocompromised patient populations of solid organ transplant recipients and glomerular disease patients on immunosuppressive treatment [5].\n\nAcknowledgments\nWe thank the patient for providing permission to share his information.\n\nAuthor Contributions\nConceptualization, S.M. and I.B.; methodology, S.M.; software, K.G.; validation, S.M., K.G. and I.B.; formal analysis, S.M. and S.T.; resources, S.T., C.S., P.L., and A.A.; data curation, S.M. and K.G.; writing—original draft preparation, S.M. and K.G.; writing, review, and editing, S.M., C.S., K.G., and I.B.; and supervision, S.M. and I.B. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 Multifocal ground glass density lesions were observed on a CT scan in the lower lobes bilaterally.\n\nFigure 2 Total number of confirmed COVID-19 cases during the outbreak in Eurozone countries.\n\nFigure 3 Registered deaths of COVID-19 per million population in Eurozone countries.\n\nmedicina-56-00355-t001_Table 1Table 1 Epidemiology of COVID-19 in Greece, as of 24 May 2020.\n\n\n\tTotal Population\tConfirmed Cases\tPrevalence\tConfirmed Deaths\tMortality\tCase Fatality Rate\t\nHemodialysispatients\t11,590\t28\t0.24%\t6\t0.23%\t21%\t\nTransplantrecipients\t2567\t1\t0.038%\t0\t0%\t0%\t\nGeneral population\t10,724,000\t2878 ¹\t0.026% ¹\t171\t0.0015%\t5.9%\t\n¹ The number of confirmed cases is lower than the number of actual cases because of testing limitations.\n==== Refs\nReferences\n1. Xu J. Zhao S. Teng T. Abdalla A.E. Zhu W. Xie L. Wang Y. Guo X. Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV Viruses 2020 12 244 10.3390/v12020244 32098422 \n2. Sun P. Lu X. Xu C. Sun W. Pan B. Understanding of COVID-19 based on current evidence J. Med. Virol. 2020 92 548 551 10.1002/jmv.25722 32096567 \n3. Bomback A.S. Canetta P.A. Ahn W. Ahmad S.B. Radhakrishnan J. Appel G.B. How COVID-19 Has Changed the Management of Glomerular Diseases Clin. J. Am. Soc. Nephrol. 2020 15 876 879 10.2215/CJN.04530420 32332048 \n4. Alberici F. Delbarba E. Manenti C. Econimo L. Valerio F. Pola A. Maffei C. Possenti S. Piva S. Latronico N. Management of Patients on Dialysis and With Kidney Transplantation During the SARS-CoV-2 (COVID-19) Pandemic in Brescia, Italy Kidney Int. Rep. 2020 5 580 585 10.1016/j.ekir.2020.04.001 32292866 \n5. Banerjee D. Popoola J. Shah S. Ster I.C. Quan V. Phanish M. COVID-19 infection in kidney transplant recipients Kidney Int. 2020 97 1076 1082 10.1016/j.kint.2020.03.018 32354637 \n6. ERACODA—The ERA-EDTA COVID-19 Database for Patients on Kidney Replacement Therapy Available online: https://www.era-edta.org/en/covid-19-news-and-information/ (accessed on 6 May 2020) \n7. European Centre for Disease Prevention and Control “COVID-19 Situation Update for the EU/EEA” Available online: https://www.ecdc.europa.eu/en/cases-2019-ncov-eueea (accessed on 24 May 2020) \n8. Guillen E. Pineiro G.J. Revuelta I. Rodriguez D. Bodro M. Moreno A. Campistol J.M. Diekmann F. Ventura-Aguiar P. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Arab. Archaeol. Epigr. 2020 20 1875 1878 10.1111/ajt.15874 32198834 \n9. Siddiqi H.K. Mehra M.R. COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal J. Hear. Lung Transplant. 2020 39 405 407 10.1016/j.healun.2020.03.012 32362390 \n10. Zhu L. Gong N. Liu B. Lu X. Chen D. Chen S. Shu H. Ma K. Xu X. Guo Z. Coronavirus Disease 2019 Pneumonia in Immunosuppressed Renal Transplant Recipients: A Summary of 10 Confirmed Cases in Wuhan, China Eur. Urol. 2020 77 748 754 10.1016/j.eururo.2020.03.039 32317180 \n11. Nacif L.S. Zanini L.Y. Waisberg D.R. Pinheiro R.S. Galvão F. Andraus W. D’Albuquerque L.C. COVID-19 in solid organ transplantation patients: A systematic review Clinics 2020 75 e1983 10.6061/clinics/2020/e1983 32520225 \n12. Jüni P. Rothenbühler M. Bobos P. Thorpe K.E. Da Costa B.R. Fisman D.N. Slutsky A.S. Gesink D. Impact of climate and public health interventions on the COVID-19 pandemic: A prospective cohort study Can. Med Assoc. J. 2020 192 E566 E573 10.1503/cmaj.200920 32385067 \n13. Johnson K.M. Belfer J.J. Peterson G.R. Boelkins M.R. Dumkow L.E. Managing COVID-19 in Renal Transplant Recipients: A Review of Recent Literature and Case Supporting Corticosteroid-sparing Immunosuppression Pharmacother. J. Hum. Pharmacol. Drug Ther. 2020 40 517 524 10.1002/phar.2410 \n14. Thiel J. Rizzi M. Engesser M. Dufner A.-K. Troilo A. Lorenzetti R. Voll R.E. Venhoff N. B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients Arthritis Res. 2017 19 101 10.1186/s13075-017-1306-0 \n15. COVID-19 News and Information for the ERA-EDTA Community and Kidney Patients Available online: https://www.era-edta.org/en/covid-19-news-and-information/#toggle-id-8 (accessed on 5 May 2020) \n16. National Public Health Organization (NPHO) “Current State of Covid-19 Outbreak in Greece and Timeline of Key Containment Events” Available online: https://eody.gov.gr/en/current-state-of-covid-19-outbreak-in-greece-and-timeline-of-key-containment-events/ (accessed on 4 March 2020) \n17. National Public Health Organization (NPHO) Available online: https://eody.gov.gr/0410_briefing_covid19/ (accessed on 24 May 2020) \n18. Reported Cases and Deaths by Country, Territory, or Conveyance Available online: https://www.worldometers.info/coronavirus/#countries (accessed on 24 May 2020) \n19. Johns Hopkins Coronavirus Resource Center Available online: https://coronavirus.jhu.edu/data/mortality (accessed on 24 May 2020) \n20. University of Oxford Available online: https://ourworldindata.org/coronavirus#confirmed-cases-vs-deaths (accessed on 24 May 2020) \n21. Greek Ministry of Health The National Registry of Patients with End Stage Renal Disease, Coordination and Control Service of the Programme of End Stage Renal Disease Athens, Greece 2020\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1010-660X",
"issue": "56(7)",
"journal": "Medicina (Kaunas, Lithuania)",
"keywords": "COVID-19; Renal Replacement Therapy (RRT); glomerulonephritis; immunosuppression; pneumonia; transplantation",
"medline_ta": "Medicina (Kaunas)",
"mesh_terms": "D000900:Anti-Bacterial Agents; D017963:Azithromycin; D000073640:Betacoronavirus; D000086382:COVID-19; D002443:Ceftriaxone; D018352:Coronavirus Infections; D003404:Creatinine; D003449:Cryoglobulinemia; D003520:Cyclophosphamide; D004791:Enzyme Inhibitors; D015432:Glomerulonephritis, Membranoproliferative; D005938:Glucocorticoids; D006115:Greece; D006801:Humans; D006886:Hydroxychloroquine; D016867:Immunocompromised Host; D007155:Immunologic Factors; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008168:Lung; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D006435:Renal Dialysis; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9425208",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32708858",
"pubdate": "2020-07-17",
"publication_types": "D002363:Case Reports",
"references": "32520225;32292866;32339304;32354637;28521808;32385067;32332048;32098422;32096567;32362390;32198834;32317180",
"title": "A Patient with Cryoglobulinemic Membranoproliferative GN (MPGN) Who Survived COVID-19 Disease: Case Presentation and Current Data of COVID-19 Infection in Dialysis and Transplanted Patients in Greece.",
"title_normalized": "a patient with cryoglobulinemic membranoproliferative gn mpgn who survived covid 19 disease case presentation and current data of covid 19 infection in dialysis and transplanted patients in greece"
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"abstract": "Rasmussen encephalitis (RE) is a disorder characterized by drug-resistant seizures and progressive unihemispheric atrophy, hemiparesis, and varying degrees of cognitive decline. The pathophysiology of RE remains elusive, with hypotheses suggesting underlying autoimmune- and T cell-mediated processes. In this case report, we describe a single patient's clinical course from the first day of presentation until definitive treatment for atypical Rasmussen encephalitis at a tertiary care pediatric center. The patient exhibited several atypical features of Rasmussen encephalitis, including a posterior predominance of initial seizure onset with the development of severe choreoathetosis and ipsilateral cerebellar atrophy. He subsequently developed coexistent autoimmune disorders in the form of psoriasis and uveitis, and underwent multiple forms of immunotherapy with limited benefit. This patient shows an association of RE with other autoimmune conditions supporting an autoimmune mechanism of disease while exhibiting several atypical features of RE. Rarely, occipital lobe seizures have been documented as the presenting semiology of this syndrome. This case highlights the need to be mindful of atypical features that may delay hemispherectomy, which remains the definitive treatment. It also suggests that children may be predisposed to the development of autoimmune disorders in later stages of the disease.",
"affiliations": "Division of Epilepsy and Neurophysiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.;Division of Immunology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.;Division of Epilepsy and Neurophysiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.;Department of Radiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.;Department of Ophthalmology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.;Department of Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.;Department of Neurosurgery, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.;Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA.;Division of Epilepsy and Neurophysiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.;Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.",
"authors": "Sansevere|Arnold J|AJ|;Henderson|Lauren A|LA|;Stredny|Coral M|CM|;Prabhu|Sanjay P|SP|;Shah|Ankoor|A|;Sundel|Robert|R|;Madsen|Joseph|J|;Dufreney|Chantal|C|;Poduri|Annapurna|A|;Gorman|Mark P|MP|",
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"doi": "10.1016/j.ebr.2020.100360",
"fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864 Elsevier \n\nS2589-9864(20)30008-3\n10.1016/j.ebr.2020.100360\n100360\nArticle\nPosterior-onset Rasmussen's encephalitis with ipsilateral cerebellar atrophy and uveitis resistant to rituximab\nSansevere Arnold J. arnold.sansevere@childrens.harvard.eduab⁎ Henderson Lauren A. lauren.henderson@childrens.harvard.educ Stredny Coral M. coral.stredny@childrens.harvard.eduab Prabhu Sanjay P. sanjay.prabhu@childrens.harvard.edud Shah Ankoor ankoor.shah@childrens.harvard.edue Sundel Robert robert.sundel@childrens.harvard.eduf Madsen Joseph joseph.madsen@childrens.harvard.edug Dufreney Chantal chantal.dufreny@hms.harvard.eduh Poduri Annapurna annapurna.poduri@childrens.harvard.eduab Gorman Mark P. mark.gorman@childrens.harvard.edub a Division of Epilepsy and Neurophysiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA\nb Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA\nc Division of Immunology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA\nd Department of Radiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA\ne Department of Ophthalmology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA\nf Department of Pathology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA\ng Department of Neurosurgery, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA\nh Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA\n⁎ Corresponding author at: Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, 300 Longwood Ave, Fegan 9, Boston, MA 02115, USA. arnold.sansevere@childrens.harvard.edu\n21 3 2020 \n2020 \n21 3 2020 \n14 10036016 10 2019 18 2 2020 28 2 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Rasmussen encephalitis (RE) is a disorder characterized by drug-resistant seizures and progressive unihemispheric atrophy, hemiparesis, and varying degrees of cognitive decline. The pathophysiology of RE remains elusive, with hypotheses suggesting underlying autoimmune- and T cell-mediated processes. In this case report, we describe a single patient's clinical course from the first day of presentation until definitive treatment for atypical Rasmussen encephalitis at a tertiary care pediatric center. The patient exhibited several atypical features of Rasmussen encephalitis, including a posterior predominance of initial seizure onset with the development of severe choreoathetosis and ipsilateral cerebellar atrophy. He subsequently developed coexistent autoimmune disorders in the form of psoriasis and uveitis, and underwent multiple forms of immunotherapy with limited benefit.\n\nThis patient shows an association of RE with other autoimmune conditions supporting an autoimmune mechanism of disease while exhibiting several atypical features of RE. Rarely, occipital lobe seizures have been documented as the presenting semiology of this syndrome. This case highlights the need to be mindful of atypical features that may delay hemispherectomy, which remains the definitive treatment. It also suggests that children may be predisposed to the development of autoimmune disorders in later stages of the disease.\n\nHighlights\n• Occipital seizure localization and semiology should not dissuade the diagnosis of Rasmussen's encephalitis\n\n• Movement disorders, can accompany Rasmussen's encephalitis\n\n• Ipsilateral cerebellar atrophy has been described in Rasmussen's encephalitis\n\n• Children with Rasmussen's encephalitis may be predisposed to autoimmune disorders in the later stages of the disease\n\n\n\nKeywords\nRasmussen encephalitisatypical Rasmussen encephalitisBien criteriaDrug resistant epilepsy\n==== Body\n1 Introduction\nRasmussen encephalitis (RE) is classically characterized by progressive, frontally predominant, unilateral hemispheric atrophy with corresponding focal neurological deficits and drug-resistant focal motor seizures [1,2]. Movement disorders and non-motor seizures as manifestations of RE have been reported, but only rarely [3,4]. Cerebellar atrophy contralateral to the affected cerebral hemisphere may occur, and ipsilateral cerebellar atrophy rarely has been reported [5].\n\nBased on the pathological findings of a T-cell predominant encephalitis, various forms of immunotherapy have been used but with limited success, often leading to hemispherectomy for seizure control [[6], [7], [8], [9], [10]]. In addition to the pathological findings, the co-existence of autoimmune disorders is rare and has strengthened the autoimmune hypothesis [4,[11], [12], [13]].\n\nHere, we present a patient with RE to highlight several noteworthy atypical features. These features include posterior predominance of the early seizure onset, slow progression to hemispheric atrophy, ipsilateral cerebellar atrophy, severe choreoathetosis, failure of immunotherapy (including rituximab) to control seizures, and the subsequent development of psoriasis and uveitis affecting the eye ipsilateral to the affected hemisphere.\n\n2 Case report\nFollowing normal birth and development, a 6-year-old boy had a focal to bilateral tonic-clonic seizure, which initially started with visual phenomena, leftward eye deviation, and preserved consciousness. Family history was significant for maternal inflammatory bowel disease, paternal psoriasis, and multiple sclerosis in the maternal great uncle. Physical exam showed left hemi-ataxia, which resolved by 48 h after the seizure. Electroencephalography (EEG) revealed right occipital and parietal slowing while a brain MRI and MRA were normal. Seizures recurred 15 months after the first seizure. His seizure semiology at that time consisted of visual phenomena of multicolored formed images (described by the patient as “beach balls”) lasting for 30 s to 1 min, at times longer, accompanied by nausea and followed by limpness and leftward eye deviation. Seizures were occurring at first weekly with waxing and waning periods of seizure control, but soon became daily after the first 6 months of treatment, at which point care was transferred to an epileptologist. Over the next 2 years, his seizures became drug-resistant to several anti-seizure medications (ASMs), including levetiracetam, oxcarbazepine, valproic acid, zonisamide, topiramate, and diazepam. Long-term EEG monitoring was performed 6 months after treatment started, initially showing 9 to 28 seizures per day. The semiology remained the same with stereotyped visual phenomena and remained focal. The seizures were mostly electroclinical with occasional exclusively electrographic seizures both with onset in the right posterior quadrant accompanied by right occipital slowing.\n\nThree years after the initial presentation, the patient had almost continuous visual phenomena. His parents noted increasing left-sided clumsiness and gait abnormalities. Physical exam was notable for left-hand tremor. Despite treatment with valproic acid and topiramate, an EEG showed nearly continuous partial seizures with a maximum in the right posterior quadrant (Fig. 1). Accordingly, fosphenytoin was given acutely and added to the medication regimen temporarily with modest effect.Fig. 1 Continuous right posterior quadrant seizures.\n\nThis is an A-P longitudinal bipolar montage. The top Fig. 1a shows semi-rhythmic right posterior quadrant slowing depicted by the blue arrow. Fig. 1b shows a buildup of activity with fast spikes having a maximum negativity at O2 depicted by the green arrow. Fig. 1c shows spread to the posterior temporal region and continued evolution depicted by the red arrow.\n\nFig. 1\n\nEEG monitoring at age 11 years showed increased seizure frequency to approximately 4 to 5 seizures per hour, with 25% having clinical correlate. The patient subsequently developed left-sided high amplitude choreoathetoid movements, suppressed only by sleep, without clearly associated epileptiform changes on EEG. Brain MRI was again repeated and showed subcortical and gyral T2 prolongation with gyral swelling in the right temporal, parasagittal, parietal, occipital lobes, and right pulvinar without caudate involvement (Fig. 2). There was also right cerebral and cerebellar volume loss (Fig. 3). His ASMs were changed to lacosamide and phenobarbital. Repeat prolonged EEG revealed electrographic seizures arising more anteriorly in the right parasagittal and superior frontal regions, in addition to the right posterior region. There were now multiple right hemispheric spikes in all quadrants. Extensive diagnostic testing was notable for a positive antinuclear anti-body (titer 1:160); however, inflammatory markers (erythrocyte sedimentation rate [ESR] and C reactive protein [CRP]), complement levels, and other tested autoantibodies that included anti-double stranded DNA, anti-Smith, and endomysial and anti-deamidated gliadin IgA and IgG antibodies were normal. Cerebrospinal fluid (CSF) analysis showed 5 WBC/mm3 with normal glucose, protein, and lactate levels. Infectious studies included normal culture and gram stain, in addition to PCR for HSV, EBV, CMV, and enterovirus. The CSF IgG index was elevated at 2.46 (normal 0.28–0.66), and 12 CSF-restricted oligoclonal bands were noted. B cells comprised 15% of the lymphocyte gate on CSF flow cytometry. Serum and CSF autoimmune epilepsy panel were negative. This included CSF anti-neuronal nuclear antibody type 1 (anti-Hu), anti-glutamic acid decarboxylase 65 and anti-N-methyl-d-aspartate receptor antibodies. Targeted mitochondrial mutation analysis for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) tRNA Leu gene and POLG-1 analysis were unrevealing.Fig. 2 Right occipital lobe cortical and subcortical T2/FLAIR hyperintensity and gyral swelling.\n\nThe top figure (Fig. 2a) is a T2 weighted axial image comparing the initial MRI (left) to subsequent images (right). The blue arrow depicts T2 prolongation in the right posterior temporal and occipital region. The bottom figure (Fig. 2b) is the axial FLAIR image with the red arrow pointing to the same area of abnormality.\n\nFig. 2Fig. 3 Right occipital lobe gyral swelling and T2 hyperintensity (blue curved arrow) and ipsilateral cerebellar volume loss (red straight arrow).\n\nThis is a coronal T2 weighted image comparing the initial MRI (left) to subsequent images (right). The blue curved arrow depicts right occipital lobe gyral swelling and T2 hyperintensity while the red arrow depicts ipsilateral cerebellar volume loss.\n\nFig. 3\n\nBased on the presence of drug-resistant epilepsy, progressive course, and progressive MRI findings, the patient's differential diagnoses included RE, small vessel CNS vasculitis, and a systemic inflammatory condition with CNS involvement. He was given intravenous immunoglobulin (IVIG) 2 g/kg over 2 days, followed 1 week later by 5 days of intravenous methylprednisolone 1 g daily. Starting two days after completion of the steroid course, 5 sessions of plasmapheresis were performed without improvement. To clarify the nature of the patient's condition, biopsy of the right occipital cortex and subcortical white matter and overlying dura was performed. The biopsy was consistent with meningoencephalitis with diffuse lymphoid and macrophage infiltrates, rare microglial nodules, and gliosis. There was a predominance of CD3 + T cells (CD8 > CD4) with admixed CD 20 + B cells. Immunostains for cytomegalovirus, Epstein Barr virus, herpes simplex virus, and varicella zoster virus were negative.\n\nThe patient was diagnosed with RE based on the constellation of clinical, electrographic, and radiographic components of Part A and B of the European consensus statement on RE [2,6,8]. This diagnosis was also supported by the pathological findings. Following the biopsy, the patient was treated with methylprednisolone 30 mg/kg/day for 5 days followed by a prednisone taper starting at 40 mg once per day. Based on a prior report and evidence of a CD20 + B cell population on the biopsy, rituximab 375 mg/m2 weekly for four weeks was given [8]. Despite these treatments, the patient's seizures and choreiform movements continued.\n\nFunctional hemispherectomy with deafferentation of the right hemisphere was performed three months after the final dose of rituximab. The pathologic specimen consisted of right frontal, lateral temporal, hippocampus, and corpus callosum, and showed meningoencephalitis with scattered microglial nodules, perivascular lymphocytes, and wide-spread gliosis with no major differences compared to the prior biopsy. Three months after hemispherectomy, there was no evidence of clinical seizures or hemichorea. At 6 months following hemispherectomy, all of the patient's ASMs were discontinued. EEG at that time showed numerous right-sided electrographic seizures with frequent sharp waves over the right hemisphere, without propagation to the left hemisphere or clinical correlate. Examination was significant for the expected left homonymous hemianopsia and left hemiparesis with ability to bear weight and walk independently.\n\nPrior to the procedure, a neuropsychological assessment was performed and demonstrated poor nonverbal skills, problems with visual perception and motor integration, difficulty with left-hand dexterity, and social challenges consistent with non-dominant hemisphere dysfunction. Additionally, neurobehavioral deficits were seen in executive function and impulse regulation, while he was found to struggle with anxiety. The assessment was repeated 18 months after surgery, showing continued struggles with executive function and working memory but improved impulse control. The patient showed some improvements across many language-based areas with stable neuropsychological function.\n\nOne year after hemispherectomy, the patient developed psoriasis involving the ears, popliteal fossa, gluteal clefts, and umbilicus. One year later, the patient was found to have a right-sided, non-reactive pupil with gray discoloration of the iris during a routine neurologic examination. Ophthalmologic evaluation showed evidence of chronic anterior uveitis with 2 + cells and flare in the anterior chamber, posterior synechiae, cataract, and decreased visual acuity in the right eye. Rheumatology was consulted and no other clinical manifestations of autoimmunity such as arthritis were noted. Laboratory studies were notable for an elevated ESR of 60 mm/h and CRP of 3.3 mg/dL. His anti-nuclear antibody (ANA) titer continued to be positive at 1:80 while antineutrophilic cytoplasmic antibody (ANCA), lysozyme, angiotensin converting enzyme (ACE level), and HLAB27 antigen testing were negative. Infectious evaluation, including assessment for toxoplasmosis, Toxocara, Bartonella, Lyme disease, and syphilis was unrevealing. Given the patient's multiple manifestations of autoimmunity, there was concern for an underlying immunodeficiency and a specific evaluation of immune function was conducted. The patient had normal T cell subsets, T cell proliferation to mitogens and antigens, and immunoglobulin levels; however, his switched and unswitched memory B cells were low, and his response to pneumococcal vaccines and tetanus was marginal. Despite this extensive workup, the patient was not thought to have a known rheumatologic or immunologic condition.\n\nThe uveitis initially responded to topical steroid drops applied every 2 h; however, the inflammation recurred when the frequency of the eye drops decreased. Ultimately, remission of the patient's uveitis was attained with oral prednisone 20 mg daily and mycophenolate mofetil 1000 mg twice daily.\n\nThe patient underwent cataract extraction and intraocular lens implantation at age 12 years. Two months after surgery, recurrent inflammation in the right eye was noted and mycophenolate 1000 mg twice daily and oral prednisone was continued. The inflammatory markers remained persistently elevated with a CRP of 4.32 mg/dL and ESR of 63 mm/h. He was subsequently admitted and received 1 g of IV methylprednisolone daily for a 3 day course. A brain MRI was stable. Infliximab was added to the treatment regimen and titrated up 15 mg/kg every 3 weeks with good response. He remains on prednisone 5 mg daily, mycophenolate 1500 mg twice daily, and prednisolone eye drops. The patient continues to be followed closely by multiple services including Epilepsy, Ophthalmology, and Rheumatology and continues to remain seizure-free.\n\n3 Discussion\nAlthough the patient presented here ultimately met established diagnostic criteria for RE as the clinical course evolved, he also manifested several unique and atypical features [2,6,8]. In this case report, we highlight three main features. First, posterior seizures and a long prodrome of focal epilepsy can be seen in RE. Second, movement disorders, although rare, can be part of RE. Finally, patients with RE are at risk for autoimmune disorders. We highlight these features to facilitate early diagnosis subsequently leading to early treatment of future cases in hopes of ameliorating neuropsychological sequelae of frequent seizures and failed antiseizure medication trials.\n\nIn this patient, the seizure semiology and electrographic and radiographic findings were all consistent with a process that initially predominated in the occipital lobe. Occipital seizures are noted in atypical adolescent- and adult-onset RE, but rarely in childhood-onset RE [14]. Radiographically, parieto-occipital atrophy may be seen in younger patients with more widespread hemispheric involvement, but frontal and insular regions remain predominantly affected [15]. Pathologic changes in RE are sparse in the occipital lobe compared to other regions [16]. Thus, while most cases of RE show a frontal predilection, occipital localization and semiology should not necessarily dissuade clinicians from the diagnosis of RE. Our patient developed cerebellar atrophy ipsilateral to the affected cerebral hemisphere. Most previously reported cases of cerebellar atrophy in RE describe its occurrence contralateral to the affected cerebral hemisphere, which is explained by crossed cerebral to cerebellar afferent inputs; however, rare cases of ipsilateral cerebellar atrophy have been described [5,17,18]. Finally, this patient had a long prodrome of focal epilepsy before his case declared itself as RE. Prolonged time from disease onset to meeting criteria for RE has been described, but is more typical in adolescents and adults than in young children [11]. We highlight the early features in particular because prior to developing seizures, he was not suspected to have the neurobehavioral profile or deficits documented through standardized testing. While an early diagnosis initially may not have led directly to hemispherectomy, it might have been performed sooner, increasing the chances of improved neurobehavioral outcomes.\n\nIn addition to the several atypical cranial manifestations of RE highlighted, this patient also developed several unique extracranial features. He developed a severe choreoathetoid movement disorder at the time when seizures had become drug-resistant and the seizure onset zone had spread from the occipital region to involve a larger region of the right hemisphere. Our case adds to the small existing literature documenting the occurrence of movement disorders in RE and further supports the involvement of the basal ganglia [3,4]. Finally, he developed uveitis ipsilateral to the cerebral hemisphere involved in addition to diffuse psoriasis. This comorbid autoimmunity has been rarely described [12].\n\nTaken together, the early, unusual features in our case made the diagnosis of RE challenging until more typical features evolved years later. Nonetheless, in the setting of drug-resistant epilepsy and unihemispheric MRI abnormalities suggestive of an inflammatory process, RE should be a leading consideration, being mindful of these previously reported albeit rare features.\n\nDespite a prior report and open-label trial that suggested potential benefit of rituximab in RE, our patient showed no appreciable improvement following its use [8,19]. While our case adds to the disappointing record for immunotherapy in RE, it is possible that rituximab might have been more effective if it had been used earlier in the disease course or more time was given following its use. Alternatively, although rituximab may have secondary effects on T cell function. Therapies directly targeting T cells or the innate immune system, which have been shown to be key effector mechanisms in RE, may be more effective. Seizure frequency was decreased with natalizumab in one case, and adalimunab in 5 out of 11 patients in an open-label pilot study [13,20]. However, as is more often the case, immunotherapy may slow the progression of cortical atrophy or motor weakness without significant effect on seizure burden, delaying definitive treatment with hemispherectomy despite ongoing, drug-resistant seizures. This was noted in the only randomized RE trial to date, comparing IVIG with tacrolimus to historical controls in which patients experienced delayed deterioration with either agent without appreciable seizure effect [21]. Overall, future multicenter immunotherapy trials in RE with novel, early targets are needed.\n\nFinally, in the setting of a family history of multiple autoimmune disorders, our patient subsequently developed psoriasis and uveitis affecting the eye ipsilateral to the affected hemisphere. Family history of autoimmune disorders has been described in RE [22]. Uveitis has been rarely described, with ipsilateral, contralateral, and bilateral involvement [11,12]. We have also recently shown an association between numerous systemic autoimmune conditions, including psoriasis, and epilepsy suggesting potential shared mechanisms [23].\n\nAutoimmune disorders with similar pathophysiologic processes are known to affect different organ systems within individual family members. This has been described in numerous conditions, specifically multiple sclerosis, a demyelinating condition with a presumed autoimmune mechanism leading to T cell mediated inflammation. These observations support the concept of a shared genetic diathesis to autoimmunity with additional “second hits” leading to specific disease expression. Unlike most other presumed autoimmune disorders, RE is strikingly unilateral in its effects on the cerebrum. The occurrence of cerebellar atrophy and uveitis ipsilateral to the affected cerebral hemisphere in our patient highlights the unilateral processes involved in RE. In some cases of RE such as ours, patients may inherit a genetic predisposition to autoimmunity with a “second hit” leading to the peculiar unilateral disease manifestations. This theory is supported further by our patient's development of uveitis well after the brain involvement. This is in comparison to other reported cases of uveitis associated with this disorder in pediatrics that occurred at the time of the progressive phase of RE [12]. Further research is needed to identify both the underlying genetic architecture of RE as well as potential “second hit” mechanisms (trauma, viral infection, somatic mutations) underlying this phenomenon. Awareness of atypical features of RE may lead to early immune-based therapy and seizure-alleviating surgery when appropriate.\n\nStudy funding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclarations of interest\nNone.\n\nData statement\nThe data that support the findings of this case report are available on request from the corresponding author, A.S. The data are not publicly available due to their containing information that could compromise the privacy of the patient in this case report.\n==== Refs\nReferences\n1 Rasmussen T. Olszewski J. Lloydsmith D. Focal seizures due to chronic localized encephalitis Neurology 8 1958 435 445 10.1212/wnl.8.6.435 13566382 \n2 Olson H.E. Lechpammer M. Prabhu S.P. Ciarlini P.D. Poduri A. Gooty V.D. Clinical application and evaluation of the Bien diagnostic criteria for Rasmussen encephalitis Epilepsia 54 2013 1753 1760 10.1111/epi.12334 23980696 \n3 Frucht S. Dystonia, athetosis, and epilepsia partialis continua in a patient with late-onset Rasmussen’s encephalitis Mov Disord 17 2002 609 612 10.1002/mds.10131 12112219 \n4 Kankirawatana P. Dure Lst Bebin E.M. Chorea as manifestation of epilepsia partialis continua in a child Pediatr Neurol 31 2004 126 129 10.1016/j.pediatrneurol.2004.01.005 15301833 \n5 Chiapparini L. Granata T. Farina L. Ciceri E. Erbetta A. Ragona F. Diagnostic imaging in 13 cases of Rasmussen’s encephalitis: can early MRI suggest the diagnosis? Neuroradiology 45 2003 171 183 10.1007/s00234-002-0923-7 12684722 \n6 Bien C.G. Granata T. Antozzi C. Cross J.H. Dulac O. Kurthen M. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement Brain 128 2005 454 471 10.1093/brain/awh415 15689357 \n7 Bien C.G. Schramm J. Treatment of Rasmussen encephalitis half a century after its initial description: promising prospects and a dilemma Epilepsy Res 86 2009 101 112 10.1016/j.eplepsyres.2009.06.001 19615863 \n8 Thilo B. Stingele R. Knudsen K. Boor R. Bien C.G. Deuschl G. A case of Rasmussen encephalitis treated with rituximab Nat Rev Neurol 5 2009 458 462 10.1038/nrneurol.2009.98 19657347 \n9 Schwab N. Bien C.G. Waschbisch A. Becker A. Vince G.H. Dornmair K. CD8 + T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery Brain 132 2009 1236 1246 10.1093/brain/awp003 19179379 \n10 Papetti L. Nicita F. Granata T. Guerrini R. Ursitti F. Properzi E. Early add-on immunoglobulin administration in Rasmussen encephalitis: the hypothesis of neuroimmunomodulation Med Hypotheses 77 2011 917 920 10.1016/j.mehy.2011.08.011 21885203 \n11 Kashihara K. Ohno M. Takahashi Y. Twenty-one-year course of adult-onset Rasmussen’s encephalitis and bilateral uveitis: case report J Neurol Sci 294 2010 127 130 10.1016/j.jns.2010.03.016 20447655 \n12 Harvey A.S. Andermann F. Hopkins I.J. Kirkham T.H. Berkovic S.F. Chronic encephalitis (Rasmussen’s syndrome) and ipsilateral uveitis Ann Neurol 32 1992 826 829 10.1002/ana.410320621 1471877 \n13 Bittner S. Simon O.J. Gobel K. Bien C.G. Meuth S.G. Wiendl H. Rasmussen encephalitis treated with natalizumab Neurology 81 2013 395 397 10.1212/WNL.0b013e31829c5ceb 23794679 \n14 Hart Y.M. Andermann F. Fish D.R. Dubeau F. Robitaille Y. Rasmussen T. Chronic encephalitis and epilepsy in adults and adolescents: a variant of Rasmussen’s syndrome? Neurology 48 1997 418 424 10.1212/wnl.48.2.418 9040732 \n15 Wagner J. Schoene-Bake J.C. Bien C.G. Urbach H. Elger C.E. Weber B. Automated 3D MRI volumetry reveals regional atrophy differences in Rasmussen encephalitis Epilepsia 53 2012 613 621 10.1111/j.1528-1167.2011.03396.x 22309137 \n16 Pardo C.A. Vining E.P. Guo L. Skolasky R.L. Carson B.S. Freeman J.M. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies Epilepsia 45 2004 516 526 10.1111/j.0013-9580.2004.33103.x 15101833 \n17 Quesada C.M. Urbach H. Elger C.E. Bien C.G. Rasmussen encephalitis with ipsilateral brain stem involvement in an adult patient J Neurol Neurosurg Psychiatry 78 2007 200 201 10.1136/jnnp.2006.097816 17229752 \n18 Moreira G.P. Arantes P. Ono C.R. Passarelli V. Castro L.H.M. S132: ipsilateral cerebellar atrophy and crossed ictal cerebellar diaschisis in a case of Rasmussen encephalitis Clin Neurophysiol 129 Suppl. 1 2018 e191 10.1016/j.clinph.2018.04.492 \n19 Laxer K.D. Wilfong A. Morris G.L. III Andermann F. 1.277: Pilot study of rituximab to treat chronic focal encephalitis Epilepsia 49 Suppl. 7 2008 121 10.1111/j.1528-1167.2008.01871_1.x \n20 Lagarde S. Villeneuve N. Trebuchon A. Kaphan E. Lepine A. McGonigal A. Anti-tumor necrosis factor alpha therapy (adalimumab) in Rasmussen’s encephalitis: an open pilot study Epilepsia 57 2016 956 966 10.1111/epi.13387 27106864 \n21 Bien C.G. Tiemeier H. Sassen R. Kuczaty S. Urbach H. von Lehe M. Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins Epilepsia 54 2013 543 550 10.1111/epi.12042 23216622 \n22 Amrom D. Kinay D. Hart Y. Berkovic S.F. Laxer K. Andermann F. Rasmussen encephalitis and comorbid autoimmune diseases: a window into disease mechanism? Neurology 83 2014 1049 1055 10.1212/WNL.0000000000000791 25142901 \n23 Ong M. Kohane I.S. Cai T. Gorman M.P. Mandl K.D. Population-level evidence for an autoimmune etiology of epilepsy JAMA Neurol 71 2014 569 574 10.1001/jamaneurol.2014.188 24687183\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2589-9864",
"issue": "14()",
"journal": "Epilepsy & behavior reports",
"keywords": "Bien criteria; Drug resistant epilepsy; Rasmussen encephalitis; atypical Rasmussen encephalitis",
"medline_ta": "Epilepsy Behav Rep",
"mesh_terms": null,
"nlm_unique_id": "101750909",
"other_id": null,
"pages": "100360",
"pmc": null,
"pmid": "32368732",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "21885203;19179379;24687183;27106864;1471877;12684722;23216622;12112219;15301833;17229752;13566382;9040732;23980696;20447655;15689357;23794679;19657347;19615863;22309137;25142901;15101833",
"title": "Posterior-onset Rasmussen's encephalitis with ipsilateral cerebellar atrophy and uveitis resistant to rituximab.",
"title_normalized": "posterior onset rasmussen s encephalitis with ipsilateral cerebellar atrophy and uveitis resistant to rituximab"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP006562",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional... |
{
"abstract": "A 71-year-old male with 50-year history of Crohn's disease was evaluated for acute onset of dizziness and slurred speech. Blood ethanol levels were elevated despite abstinence from alcohol for over 30 years. CT enterography demonstrated massive dilation of the small bowel with anastomotic stricture.\n\n\nCONCLUSIONS\nAuto-brewery syndrome may be considered in a patient with chronic obstruction or hypomotility presenting with elevated serum ethanol levels in the setting of high carbohydrate intake. Although treatment algorithms lack validation, judicious use of antibiotic therapy, carbohydrate control, and short courses of antifungal therapy have all been reported in the literature. Importantly, clinical consideration of 'auto-brewery' should be undertaken with substantial caution, given the lack of validated mechanisms linking endogenous ethanol production to peripheral blood ethanol.",
"affiliations": "Mayo Clinic Department of Radiology, Rochester, MN, USA welch.brian@mayo.edu.;Mayo Clinic Department of Gastroenterology and Hepatology, Rochester, MN, USA.;Mayo Clinic Department of Radiology, Rochester, MN, USA.;Mayo Clinic Department of Radiology, Rochester, MN, USA.",
"authors": "Welch|B T|BT|;Coelho Prabhu|N|N|;Walkoff|L|L|;Trenkner|S W|SW|",
"chemical_list": "D004040:Dietary Carbohydrates; D000431:Ethanol",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjw098",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "10(12)",
"journal": "Journal of Crohn's & colitis",
"keywords": null,
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000368:Aged; D003424:Crohn Disease; D004040:Dietary Carbohydrates; D000431:Ethanol; D006801:Humans; D007421:Intestine, Small; D008297:Male; D013577:Syndrome; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "1448-1450",
"pmc": null,
"pmid": "27161390",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Auto-brewery Syndrome in the Setting of Long-standing Crohn's Disease: A Case Report and Review of the Literature.",
"title_normalized": "auto brewery syndrome in the setting of long standing crohn s disease a case report and review of the literature"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0100936",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANATE POTASSIUM"
},
"... |
{
"abstract": "An 82-year-old woman who underwent total thyroidectomy and left cervical lymph node dissection 21 years ago admitted our hospital because of left cervical pain. Neck CT scan showed a 6 cm tumor on the left clavicle. Pathological diagnosis by needle biopsy revealed poorly differentiated to undifferentiated carcinoma, positive for TTF-1, and diagnosed as thyroid cancer lymph node metastasis anaplastic transformation. Administration of lenvatinib was started after radiation therapy. Since thrombocytopenia was observed, lenvatinib was gradually reduced from 14 mg and the dose was continued at 4 mg. The tumor shrinked and the effect of chemotherapy was partial response. She survived for 3 years while continuing lenvatinib. We reported long-term survival due to radiation therapy and lenvatinib of anaplastic transformation of thyroid cancer in lymph node metastasis due to radiation therapy and lenvatinib.",
"affiliations": "Dept. of Surgery, Kashiwara Municipal Hospital.",
"authors": "Masuda|Go|G|;Hori|Takeshi|T|;Tani|Naoki|N|;Sakimura|Chie|C|;Teramura|Kazuhiro|K|;Tendo|Masashige|M|;Nakata|Bunzo|B|;Ishikawa|Tetsuro|T|;Hirakawa|Kosei|K|",
"chemical_list": "D010671:Phenylurea Compounds; D011804:Quinolines; C531958:lenvatinib",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "48(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D010671:Phenylurea Compounds; D011804:Quinolines; D013964:Thyroid Neoplasms; D013965:Thyroidectomy",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "148-150",
"pmc": null,
"pmid": "33468750",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Long-Term Survival of Anaplastic Transformation of Thyroid Cancer in Lymph Node Metastasis Due to Radiation Therapy and Lenvatinib.",
"title_normalized": "a case of long term survival of anaplastic transformation of thyroid cancer in lymph node metastasis due to radiation therapy and lenvatinib"
} | [
{
"companynumb": "JP-EISAI MEDICAL RESEARCH-EC-2021-089463",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LENVATINIB"
},
"drugadditional... |
{
"abstract": "Anaphylaxis to propofol is rare; however, providers face a clinical quandary as medication warnings still exist regarding propofol administration to egg-, soy-, and peanut-allergic patients.\n\n\n\nThe primary aim evaluated the rate of allergic reactions during propofol-containing anesthesia in patients listed allergic to egg, soy, or peanut compared with nonallergic patients who received propofol. The secondary aim evaluated the relationship between food allergy history and allergy testing data.\n\n\n\nA retrospective chart review conducted between May 2012 and October 2018 identified pediatric patients listed allergic to egg, soy, and/or peanut, who received propofol. Allergy testing and results are presented. Evidence of allergic reaction to propofol during anesthesia was evaluated, and compared with a large nonallergic cohort who received propofol.\n\n\n\nOf the 232 392 anesthetics administered, 177 360 (76%) included propofol and 11308 (6%) involved a patient listed allergic to at least 1 index food. A large number of patients had no food allergy testing (n = 6153) or negative testing (n = 2198). Of the 3435 patients listed egg-allergic, 976 tested positive; 750 tested negative; and 1709 had no testing. Of the 2011 patients listed soy-allergic, 322 tested positive; 585 tested negative; and 1104 had no testing. Additionally, 5862 patients were listed peanut-allergic; 1659 tested positive; 863 tested negative and 3340 had no testing. One record of proven propofol anaphylaxis occurred; it was in a patient without a history of food allergies. There were 6 other cases of suspected allergy to propofol. One had a peanut and tree nut allergy and was lost to follow-up; one had no testing available, while 4 patients had positive propofol allergy testing and positive allergy tests to other medications. The rate of proven propofol anaphylaxis during anesthesia in the nonallergic cohort was 0.06/10 000, and the rate in egg- and soy-allergic patients was 0/5446. One patient with a listed peanut allergy had a possible reaction to propofol.\n\n\n\nIn the listed food-allergic cohort, the majority had no allergy testing or negative testing. We found no evidence of a relationship between food allergy history and perioperative propofol reaction. We suggest multiply allergic and atopic patients may have a similar likelihood of propofol reaction as with other medications.",
"affiliations": "Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.",
"authors": "Bagley|Lisa|L|0000-0002-5108-6364;Kordun|Anna|A|;Sinnott|Sean|S|;Lobo|Kimberly|K|0000-0003-4328-4894;Cravero|Joseph|J|0000-0003-0629-6511",
"chemical_list": "D015742:Propofol",
"country": "France",
"delete": false,
"doi": "10.1111/pan.14147",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "31(5)",
"journal": "Paediatric anaesthesia",
"keywords": "allergy; anaphylaxis; anesthesia; food allergy; pediatrics; propofol; reaction",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D002648:Child; D021181:Egg Hypersensitivity; D005512:Food Hypersensitivity; D006801:Humans; D021183:Peanut Hypersensitivity; D015742:Propofol; D012189:Retrospective Studies",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "570-577",
"pmc": null,
"pmid": "33529424",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Food allergy history and reaction to propofol administration in a large pediatric population.",
"title_normalized": "food allergy history and reaction to propofol administration in a large pediatric population"
} | [
{
"companynumb": "US-APOTEX-2021AP044928",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"d... |
{
"abstract": "A 65-year-old male with uncontrolled diabetes, received posterior subtenon triamcinolone (PST) injection in the right eye for diabetic macular edema. Two days following PST, he developed scleral abscess at the injection site. The Gram stain showed Gram positive cocci in clusters. He responded favorably with systemic control of diabetes, topical concentrated cefazolin, concentrated tobramycin, and intravenous antibiotics. Possibility of infective complications should be considered when using periocular steroids, especially in diabetics. Strict control of diabetes and aggressive systemic antibiotics favor rapid healing in such cases.",
"affiliations": "Unit I, Department of Retina and Uvea, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.;Unit I, Department of Retina and Uvea, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.;Unit I, Department of Retina and Uvea, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.;Unit I, Department of Retina and Uvea, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.;Unit I, Department of Retina and Uvea, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.;Unit I, Department of Retina and Uvea, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India.",
"authors": "Tripathy|Koushik|K|;Sharma|Yog Raj|YR|;Singh|Harsh Inder|HI|;Vohra|Rajpal|R|;Venkatesh|Pradeep|P|;Basheer|Shabeer|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.sjopt.2015.12.007",
"fulltext": "\n==== Front\nSaudi J OphthalmolSaudi J OphthalmolSaudi Journal of Ophthalmology1319-4534Elsevier S1319-4534(15)00131-910.1016/j.sjopt.2015.12.007Case ReportScleral abscess following posterior subtenon triamcinolone acetonide injection for diabetic macular edema Tripathy Koushik koushiktripathy@gmail.com⁎Sharma Yog Raj yograjsharma@yahoo.comSingh Harsh Inder dr.harshindersingh@gmail.comVohra Rajpal vohrarajpal@gmail.comVenkatesh Pradeep venkyprao@yahoo.comBasheer Shabeer drshabeer_vtk@yahoo.comUnit I, Department of Retina and Uvea, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India⁎ Corresponding author at: Room 488, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India. Tel.: +91 9013644243; fax: +91 1126588919.Room 488Dr. Rajendra Prasad Centre for Ophthalmic SciencesAll India Institute of Medical Sciences (AIIMS)New Delhi110029India koushiktripathy@gmail.com02 1 2016 Apr-Jun 2016 02 1 2016 30 2 130 132 7 2 2015 1 6 2015 21 12 2015 © 2015 The Authors2015This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 65-year-old male with uncontrolled diabetes, received posterior subtenon triamcinolone (PST) injection in the right eye for diabetic macular edema. Two days following PST, he developed scleral abscess at the injection site. The Gram stain showed Gram positive cocci in clusters. He responded favorably with systemic control of diabetes, topical concentrated cefazolin, concentrated tobramycin, and intravenous antibiotics. Possibility of infective complications should be considered when using periocular steroids, especially in diabetics. Strict control of diabetes and aggressive systemic antibiotics favor rapid healing in such cases.\n\nKeywords\nDMEDiabetic retinopathyInfective scleritisPeriocular infectionSubconjunctival abscess\n==== Body\nIntroduction\nDiabetic macular edema (DME) is the most common cause of visual impairment in patients with diabetes mellitus.1 Posterior subtenon triamcinolone acetonide (PST) has been used effectively in DME, as primary treatment option,2 as adjuvant to laser, and in refractory cases. It is devoid of most systemic side effects of steroids with good local delivery. We report a case of bacterial scleral abscess following PST injection for DME.\n\nCase report\nA 65-year-old diabetic male presented with redness and pain in right eye for 15 days. He had history of diabetes for 25 years and hypertension for 10 years. He received posterior subtenon triamcinolone acetonide (20 mg in 0.5 ml) injection for cystoid diabetic macular edema 17 days back. The injection was given by Nozik’s technique with aseptic precaution using a 26G needle in superotemporal quadrant of right eye after proper consent. Topical moxifloxacin 0.5% drops were prescribed after PST in the right eye. The patient did not undergo any contact procedures including applanation tonometry or contact lens aided posterior segment laser on the same day. Best corrected visual acuity (BCVA) at presentation was 6/18 OD and 6/12 OS. Ocular motility was normal. There was a localized scleral abscess measuring 7 mm ∗ 5 mm with mucopurulent discharge at the site of PST on presentation (Fig. 1). There was no relative afferent pupillary defect OD. Both eyes were pseudophakic. In either eye, there was nonproliferative diabetic retinopathy with clinically significant macular edema. The central macular thickness (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA) was 331 micron OD and 333 micron OS. There was no history of pain, redness, or discharge in the right eye before this episode. Clinically there was no evidence of previous scleritis, like scleral thinning. There was no punctal regurgitation in either eye on pressure over the lacrimal sac region. There was no history of topical or oral steroid use in the right eye. No history of systemic immunosuppression was present. There was no history of intravitreal injections or laser in the right eye. On presentation, hypertension was well controlled (Blood Pressure 130/76 mm of Hg) on oral medication and diabetes was poorly controlled (HbA1c – 11.7%, Fasting Blood sugar – 369 mg/dl and Post Prandial blood sugar – 435 mg/dl on oral hypoglycemic agents). There was history of diabetic nephropathy; however, on presentation the kidney function tests were normal. We optimized diabetes control in consultation with the endocrinologist who started insulin. After sending the discharge for Gram stain, KOH stain and bacterial and fungal culture, the patient was started empirically on topical concentrated cefazolin 5% 1 hourly, topical tobramycin 1.3% 1 hourly, intravenous vancomycin 1 g twice daily, and intravenous ceftriaxone 2 g twice daily. The slough at the site of abscess was cleaned with sterile moist swab sticks daily. Within 2 days of this empirical therapy clinical improvement was noted, so we continued the same medications. The Gram stain showed Gram positive cocci in clusters, and KOH stain was negative. Both bacterial and fungal cultures failed to show any growth. After intravenous antibiotic therapy for 7 days, the patient was started on oral co-amoxiclav 625 mg thrice daily for 14 days. With these medications, the infective scleritis had resolved after 14 days.\n\nDiscussion\nPST is an affordable and effective primary treatment option for DME especially with cystoid morphology.3 Scleral abscess following PST in diabetic macular edema is a rarity. First such occurrence in DME was reported by Oh et al.4 A 62-year-old woman who received PST injection and panretinal photocoagulation for DME with proliferative retinopathy, developed periocular abscess after one month. She developed atrophic bulbi despite long term systemic and topical itraconazole therapy. The causative agent was Pseudallescheria boydii. The second case, reported by Sukhija et al.,5 was a 54-year-old female with poorly controlled diabetes. She developed orbital abscess due to Gram positive cocci, 3 days after PST and focal laser for DME. She responded to oral linezolid and topical moxifloxacin, with healed scar formation at 3 weeks. This was the first ever reported case of bacterial scleral abscess after PST in DME. Orbital abscess due to Scedosporium apiospermum has been reported 3 months after PST given for DME.6 This case ultimately required pars plana vitrectomy for endophthalmitis with good visual recovery of 6/12. Orbital abscess following PST has been reported in cases of macular edema following branch retinal venous occlusion.7 Scleral abscess has also been reported after PST in uveitis with cystoid macular edema.8 Kusaka et al.,9 reported orbital infection due to Nocardia species 2 weeks after PST in a case of Behcet disease. He was on systemic and topical steroids and had uncontrolled diabetes. Subconjunctival mycetoma due to Exophiala jeanselmei was noted by Galor et al.,10 after 1 week of PST for age related macular degeneration. Steroids are known to promote bacterial and fungal infections especially in immunocompromised patients. Our case is the second reported case of presumed bacterial scleral abscess after PST injection in DME. In our case, most probably the causative organism was coagulase negative Staphylococcus (Staphylococcus epidermidis), which is a known commensal of the conjunctiva. The fungal orbital infections after PST present late and usually have grave prognosis unlike bacterial ones which present early and respond with proper antibiotic. The infections most likely occur due to commensals in conjunctiva in immunocompromised patients (eg. poorly controlled diabetes), and when PST is given in conjunction with laser. Systemic optimization with prompt initiation of aggressive therapy can yield good response in bacterial infections following PST. The risk of infection, bacterial or fungal following PST should be always kept in mind.\n\nConflict of interest\nThe authors declared that there is no conflict of interest.\n\nAcknowledgment\nWe are grateful to Trina Sengupta Tripathy for her immense help in preparing the manuscript.\n\nPeer review under responsibility of Saudi Ophthalmological Society, King Saud University.\n\nFigure 1 The scleral abscess was localized at the site of posterior subtenon triamcinolone.\n==== Refs\nReferences\n1 Tripathy K. Sharma Y.R. Karthikeya R. Chawla R. Gogia V. Singh S.K. Recent advances in management of diabetic macular edema Curr Diabetes Rev 11 2 2015 79 97 25801496 \n2 Choi Y.J. Oh I.K. Oh J.R. Huh K. Intravitreal versus posterior subtenon injection of triamcinolone acetonide for diabetic macular edema Korean J Ophthalmol KJO 20 4 2006 205 209 17302204 \n3 Cellini M. Pazzaglia A. Zamparini E. Leonetti P. Campos E.C. Intravitreal vs. subtenon triamcinolone acetonide for the treatment of diabetic cystoid macular edema BMC Ophthalmol 8 2008 5 18366650 \n4 Oh I.K. Baek S. Huh K. Oh J. Periocular abscess caused by Pseudallescheria boydii after a posterior subtenon injection of triamcinolone acetonide Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Für Klin Exp Ophthalmol 245 1 2007 164 166 \n5 Sukhija J. Dogra M.R. Ram J. Ichhpujani P. Gupta A. Acute orbital abscess complicating deep posterior subtenon triamcinolone injection Indian J Ophthalmol 56 3 2008 246 247 18417832 \n6 Ikewaki J. Imaizumi M. Nakamuro T. Motomura Y. Ohkusu K. Shinoda K. Peribulbar fungal abscess and endophthalmitis following posterior subtenon injection of triamcinolone acetonide Acta Ophthalmol (Copenh) 87 1 2009 102 104 \n7 Engelman C.J. Palmer J.D. Egbert P. Orbital abscess following subtenon triamcinolone injection Arch Ophthalmol 122 4 2004 654 655 15078688 \n8 Azarbod P. Mohammed Q. Akram I. Moorman C. Localised abscess following an injection of subtenon triamcinolone acetonide Eye Lond Engl 21 5 2007 672 674 \n9 Kusaka S. Ikuno Y. Ohguro N. Hori Y. Tano Y. Orbital infection following posterior subtenon triamcinolone injection Acta Ophthalmol Scand 85 6 2007 692 693 17590202 \n10 Galor A. Karp C.L. Forster R.K. Dubovy S.R. Gaunt M.L. Miller D. Subconjunctival mycetoma after sub-Tenon’s corticosteroid injection Cornea 28 8 2009 933 935 19654518\n\n",
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"title": "Scleral abscess following posterior subtenon triamcinolone acetonide injection for diabetic macular edema.",
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"affiliations": "Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.",
"authors": "Higashi|Y|Y|;Tada|K|K|;Shimokawa|M|M|;Kawai|K|K|;Kanekura|T|T|",
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"abstract": "In the aging society, many patients with movement disorders, pain syndromes, or psychiatric disorders who are candidates for deep brain stimulation (DBS) surgery suffer also from cardiovascular co-morbidities that require chronic antiplatelet or anticoagulation treatment. Because of a presumed increased risk of intracranial hemorrhage during or after surgery and limited knowledge about perioperative management, chronic antiplatelet or anticoagulation treatment often has been considered a relative contraindication for DBS. Here, we evaluate whether or not there is an increased risk for intracranial hemorrhage or thromboembolic complications in patients on chronic treatment (paused for surgery or bridged with subcutaneous heparin) as compared to those without.\n\n\n\nOut of a series of 465 patients undergoing functional stereotactic neurosurgery, 34 patients were identified who were on chronic treatment before and after receiving DBS. In patients with antiplatelet treatment, medication was stopped in the perioperative period. In patients with vitamin K antagonists or novel oral anticoagulants (NOACs), heparin was used for bridging. All patients had postoperative stereotactic CT scans, and were followed up for 1 year after surgery.\n\n\n\nIn patients on chronic antiplatelet or anticoagulation treatment, intracranial hemorrhage occurred in 2/34 (5.9%) DBS surgeries, whereas the rate of intracranial hemorrhage was 15/431 (3.5%) in those without, which was statistically not significant. Implantable pulse generator pocket hematomas were seen in 2/34 (5.9%) surgeries in patients on chronic treatment and in 4/426 (0.9%) without. There were only 2 instances of thromboembolic complications which both occurred in patients without chronic treatment. There were no hemorrhagic complications during follow-up for 1 year.\n\n\n\nDBS surgery in patients on chronic antiplatelet or anticoagulation treatment is feasible. Also, there was no increased risk of hemorrhage in the first year of follow-up after DBS surgery. Appropriate patient selection and standardized perioperative management are necessary to reduce the risk of intracranial hemorrhage and thromboembolic complications.",
"affiliations": "Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany. runge.joachim@mh-hannover.de.;Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.;Department of Neurosurgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.;Department of Neurosurgery, Division of Functional Neurosurgery and Stereotaxy, Friedrich-Alexander University, Erlangen-Nürnberg, Erlangen, Germany.;Department of Neurology, Hannover Medical School, Hannover, Germany.;Department of Neurosurgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.;Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.;Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.",
"authors": "Runge|Joachim|J|;Cassini Ascencao|Luisa|L|;Blahak|Christian|C|;Kinfe|Thomas M|TM|;Schrader|Christoph|C|;Wolf|Marc E|ME|;Saryyeva|Assel|A|;Krauss|Joachim K|JK|",
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"fulltext": "\n==== Front\nActa Neurochir (Wien)\nActa Neurochir (Wien)\nActa Neurochirurgica\n0001-6268\n0942-0940\nSpringer Vienna Vienna\n\n34342730\n4931\n10.1007/s00701-021-04931-y\nOriginal Article - Functional Neurosurgery - Other\nDeep brain stimulation in patients on chronic antiplatelet or anticoagulation treatment\nRunge Joachim runge.joachim@mh-hannover.de\n\n1\nCassini Ascencao Luisa 1\nBlahak Christian 23\nKinfe Thomas M. 4\nSchrader Christoph 5\nWolf Marc E. 26\nSaryyeva Assel 1\nKrauss Joachim K. 17\n1 grid.10423.34 0000 0000 9529 9877 Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany\n2 grid.7700.0 0000 0001 2190 4373 Department of Neurosurgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany\n3 grid.458391.2 0000 0004 0558 6346 Department of Neurology, Ortenau Klinikum Lahr-Ettenheim, Lahr, Germany\n4 grid.5330.5 0000 0001 2107 3311 Department of Neurosurgery, Division of Functional Neurosurgery and Stereotaxy, Friedrich-Alexander University, Erlangen-Nürnberg, Erlangen, Germany\n5 grid.10423.34 0000 0000 9529 9877 Department of Neurology, Hannover Medical School, Hannover, Germany\n6 grid.459701.e 0000 0004 0493 2358 Department of Neurology, Katharinenhospital Stuttgart, Stuttgart, Germany\n7 grid.412970.9 0000 0001 0126 6191 Center of Systems Neuroscience, Hannover, Germany\n3 8 2021\n3 8 2021\n2021\n163 10 28252831\n16 3 2021\n28 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nBackground\n\nIn the aging society, many patients with movement disorders, pain syndromes, or psychiatric disorders who are candidates for deep brain stimulation (DBS) surgery suffer also from cardiovascular co-morbidities that require chronic antiplatelet or anticoagulation treatment. Because of a presumed increased risk of intracranial hemorrhage during or after surgery and limited knowledge about perioperative management, chronic antiplatelet or anticoagulation treatment often has been considered a relative contraindication for DBS. Here, we evaluate whether or not there is an increased risk for intracranial hemorrhage or thromboembolic complications in patients on chronic treatment (paused for surgery or bridged with subcutaneous heparin) as compared to those without.\n\nMethods\n\nOut of a series of 465 patients undergoing functional stereotactic neurosurgery, 34 patients were identified who were on chronic treatment before and after receiving DBS. In patients with antiplatelet treatment, medication was stopped in the perioperative period. In patients with vitamin K antagonists or novel oral anticoagulants (NOACs), heparin was used for bridging. All patients had postoperative stereotactic CT scans, and were followed up for 1 year after surgery.\n\nResults\n\nIn patients on chronic antiplatelet or anticoagulation treatment, intracranial hemorrhage occurred in 2/34 (5.9%) DBS surgeries, whereas the rate of intracranial hemorrhage was 15/431 (3.5%) in those without, which was statistically not significant. Implantable pulse generator pocket hematomas were seen in 2/34 (5.9%) surgeries in patients on chronic treatment and in 4/426 (0.9%) without. There were only 2 instances of thromboembolic complications which both occurred in patients without chronic treatment. There were no hemorrhagic complications during follow-up for 1 year.\n\nConclusions\n\nDBS surgery in patients on chronic antiplatelet or anticoagulation treatment is feasible. Also, there was no increased risk of hemorrhage in the first year of follow-up after DBS surgery. Appropriate patient selection and standardized perioperative management are necessary to reduce the risk of intracranial hemorrhage and thromboembolic complications.\n\nKeywords\n\nAnticoagulation\nAntiplatelet\nDeep brain stimulation\nFunctional neurosurgery\nNOAC\nVitamin K antagonist\nMedizinische Hochschule Hannover (MHH) (3118)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© Springer-Verlag GmbH Austria, part of Springer Nature 2021\n==== Body\npmcIntroduction\n\nThe management of chronic antiplatelet or anticoagulation treatment is a common problem in patients considered for elective surgery. Perioperative discontinuation of antiplatelet or anticoagulation treatment may increase the risk of thromboembolic and cardiovascular events [3, 8, 13] while continued treatment increases the risk of hemorrhage [23]. Particularly, in cerebral surgery, the risk of intracranial hemorrhage is significantly increased, making antiplatelet or anticoagulation treatment a relative contraindication for neurosurgical procedures [34]. Also, the timing of discontinuation of medication, the perioperative bridging of anticoagulation, and its resumption after neurosurgery are a matter of ongoing debate [21, 34].\n\nDeep brain stimulation (DBS) with chronically implanted electrodes and implantable pulse generators (IPG) has become a common and widely accepted therapy for various movement disorders, chronic pain, and psychiatric disorders [14, 17, 19, 22]. Intracranial hemorrhage has been considered the most serious complication of DBS resulting in prolonged hospitalization, additional surgery, or permanent disability [20, 24, 29, 35]. While the frequency of asymptomatic hemorrhage ranges between 0.2 and 3.7%, symptomatic hemorrhage occurs in 0.0–1.6% of patients with an overall mortality of 0.0–0.7% [11, 38]. Therefore, there is an urgent clinical need to prevent hemorrhage and to develop strategies for its avoidance.\n\nPerioperative management is crucial for an elective procedure such as DBS. There is an increasing number of elderly patients with movement disorders or chronic pain syndromes who often suffer also from co-morbidities such as cardiovascular diseases which require lifelong antiplatelet or anticoagulation treatment [4].\n\nIn general, any form of chronic anticoagulation treatment has been considered a relative contraindication for DBS [4, 11]. The question, however, arises whether an established therapy such as DBS can be denied to these groups of patients. While many neurosurgeons worldwide perform DBS in patients with chronic antiplatelet or anticoagulation treatment, there is very limited published data addressing this problem [4, 25, 31, 33, 36]. Furthermore, there are different drugs for antiplatelet or anticoagulation treatment, each with distinctive mechanisms and duration of action.\n\nHere, we report our experience on the perioperative management of chronic antiplatelet or anticoagulation treatment in a series of 34 DBS patients and focus on the occurrence of hemorrhagic or thromboembolic complications with a follow-up for 1 year.\n\nMaterials and methods\n\nBetween 2005 and 2018, 465 patients underwent functional stereotactic surgeries (DBS or radiofrequency lesioning) at Hannover Medical School, performed or supervised by the senior neurosurgeon (JKK). Indications were Parkinson’s disease (PD), dystonia, tremor, chronic pain syndromes, and psychiatric disorders. Results on clinical outcome and neurophysiology have been published in detail elsewhere [7, 9, 27, 28, 32].\n\nInclusion criteria for the present study were (1) chronic antiplatelet or anticoagulation treatment prior to and continued after functional stereotactic surgery; (2) implantation of DBS electrodes and an implantable pulse generator (IPG) for chronic stimulation. Exclusion criteria were transient test stimulation only via the DBS electrodes or radiofrequency lesioning.\n\nFor the present study, a retrospective analysis of the prospectively collected data was performed. All hemorrhagic and thromboembolic complications (intracranial and IPG pocket hematoma) were recorded during the perioperative period and for follow-up for 1 year. The patients were divided into three subgroups based on therapy regimes: antiplatelet drugs, vitamin K antagonists, and novel oral anticoagulants (NOACs). The subgroups were compared to each other and with the larger collective of patients without chronic antiplatelet or anticoagulation medication.\n\nAll patients with antiplatelet or anticoagulation treatment were first seen as outpatients. Patients were instructed to consult their general physician to assess their individual risk of transient withdrawal of treatment. Thereafter, they were instructed routinely how to proceed with treatment prior to the planned day of admission based on the different therapy regimes. Preoperative standard examination included an extensive anesthesiological work-up. Antiplatelet medication, such as aspirin or clopidogrel, regardless if used for primary or secondary prophylaxis, was stopped 7–10 days preoperatively. No bridging with high or low molecular weight heparin was initiated in these cases. The patients with vitamin K antagonists were instructed to stop medication and start bridging with subcutaneous low molecular weight heparin as soon as the international normalization ratio (INR) was below 2 before being admitted for surgery [23]. Patients with NOACs discontinued medication 2–3 days before surgery (approximately 5 half-lives) and bridged also with subcutaneous low molecular weight heparin. All patients gave informed consent to the planned procedure.\n\nOn the day of admission, coagulation lab values were determined including the INR and partial thromboplastin time (PTT). It was considered safe to perform DBS surgery with an INR < 1.2 (Quick > 80%), a PTT < 36 s, and a platelet count > 100.000. When used for bridging, fractionated heparin was stopped > 12 h prior to surgery, and continued 24 h after surgery.\n\nThe operative technique has been described in detail elsewhere [1, 9, 30]. Preoperative MRI scans were obtained in all patients. A Riechert-Mundinger stereotactic frame with the Zamorano-Duchovny semi-arc was used in all surgeries. Target and trajectory planning was performed on different work stations (Medtronic® StealthStation 3, StealthStation 7, Brainlab®) based on stereotactic 1.25-mm axial CT scans.\n\nPatients were operated under local anesthesia via precoronal burr holes. Transventricular approaches were accepted. When the globus pallidus internus (GPi) or the subthalamic nucleus (STN) were targeted, microelectrode recording was performed as described previously [1, 30]. Intraoperative macrostimulation was achieved via the DBS electrodes to determine thresholds for effects and side effects. Standard quadripolar DBS electrodes were implanted via a guiding-cannula (Medtronic® 3387 or 3389; Boston Scientific® Vercise DBS Lead or Versice Cartesia Directional Lead) and used for chronic stimulation.\n\nStereotactic CTs were obtained immediately postoperatively in all patients to verify the electrode position and to detect any intracranial complications. The IPG was implanted under general anesthesia directly thereafter during the same operative session or within the following days.\n\nSubcutaneous weight-adapted fractionated heparin was commenced 24 h postoperatively in all patients of the three subgroups for prophylaxis of thrombosis and to continue bridging. Intravenous antibiotics were administered for 48 h. Programming of the IPG was started after monopolar review and impedance measurements on the day after implantation of the IPG. Stitches were removed between days 10 and 12 after surgery. Bridging therapy with heparin was continued for 2 weeks after surgery. Thereafter, permanent antiplatelet or anticoagulation treatment was resumed and adjusted by the patients´ general physicians.\n\nThe Ethical Commission of Hannover Medical School indicated that no formal approval was needed for the present study.\n\nFor statistical analysis, the chi-square test (Fischer’s exact test) was used. Statistical significance was determined as p < 0.05.\n\nResults\n\nOut of the total cohort of 465 patients, 34 patients (7.3%) were identified who were under chronic antiplatelet or anticoagulation treatment according to our inclusion and exclusion criteria. There were 24 men and 10 women, and mean age at surgery was 68.1 years (range ± 11.6). Out of these 34, 18 were on antiplatelet therapy, 13 had vitamin K antagonists, and 3 had NOACs. Demographical data, diagnoses, and DBS targets are shown in Table 1.Table 1 Demographic data, diagnoses, and DBS targets in 34 patients\n\n\tAntiplatelet drugs\tVitamin K antagonists\tNOACs\t\nTotal\t18\t13\t3\t\nGender\t\n Male\n\n Female\n\n\t12\n\n6\n\n\t10\n\n3\n\n\t2\n\n1\n\n\t\nAge (years)\t67.1 ± 10.3\t67.6 ± 13.6\t76 ± 2.8\t\nDiagnosis\t\n PD\n\n ET\n\n Dystonia\n\n Pain\n\n\t7\n\n5\n\n5\n\n1\n\n\t1\n\n10\n\n2\n\n\t1\n\n2\n\n\t\nDBS target\t\n STN\t4\t1\t\t\n Vim\n\n GPi\n\n\t5\n\n6\n\n\t10\n\n2\n\n\t3\t\n GPi + Vim\n\n CM-Pf + VPL\n\n\t2\n\n1\n\n\t\t\t\nCM-Pf, centromedian-parafascicular complex; DBS, deep brain stimulation; ET, essential tremor; GPi, globus pallidus internus; NOAC, novel oral anticoagulants; PD, Parkinson disease; STN, subthalamic nucleus; Vim, ventral intermediate nucleus; VPL, ventral posterior lateral nucleus\n\nThe group of patients with long-term antiplatelet therapy consisted of 18 patients (12 men, 6 women, mean age 67.1 ± 10.3 years). The indications for DBS were as follows: PD (7 patients)—4 bilateral STN, 1 bilateral Vim, 2 bilateral GPi; essential tremor (ET) (5 patients)—4 bilateral ventral intermediate (Vim) thalamic nucleus, 1 unilateral Vim + GPi; dystonia (5 patients)—4 bilateral GPi, 1 bilateral GPi + Vim; and chronic pain (1 patient)—unilateral centromedian-parafascicular complex (CM-Pf) and ventral posterior lateral (VPL) nucleus.\n\nThe group of patients with vitamin K antagonist therapy consisted of 13 patients (10 men, 3 women, mean age 67.6 ± 13.6). The indications for DBS were PD (1 patient)—bilateral STN; ET (10 patients)—10 bilateral Vim; dystonia (2 patients)—2 bilateral GPi. In the NOAC medication subgroup, there were 3 patients (2 men, 1 woman, mean age 76 ± 2.8 years). The indications for DBS were PD (1 patient)—bilateral Vim; and ET (2 patients)—2 bilateral Vim.\n\nThe most common indications for chronic antiplatelet or anticoagulation treatment were atrial fibrillation and coronary artery disease. Details are shown in Table 2. Three patients had multiple diagnoses which required combined treatment.Table 2 Chronic antiplatelet or anticoagulant treatment in 34 DBS patients\n\n\tAntiplatelet drugs\tVitamin K antagonists\tNOACs\t\nCardiac diseases\t\n Atrial fibrillation\n\n Coronary artery disease\n\n Mechanical valve\n\n\t4\n\n9\n\n-\n\n\t6\n\n-\n\n3\n\n\t3\n\n1\n\n-\n\n\t\nCerebrovascular disorders\t\n Previous stroke\n\n Carotid stenosis\n\n\t4\n\n2\n\n\t2\n\n1\n\n\t-\n\n-\n\n\t\nFactor V thrombophilia\t-\t2\t-\t\nTreatment had been established by the patients’ general physician, internists, or cardiologists. Three patients had multiple disorders and required combined treatment (n = 37)\n\nThere were no intraoperative adverse events or complications, except in one patient who suffered from mild intraoperative air embolism with coughing, but without dyspnea or hemodynamic instability.\n\nThe postoperative stereotactic CT scan detected primary asymptomatic hemorrhage in 2/34 patients (5.9%). A 74-year-old man with tremor-dominant PD and long-term treatment with apixaban because of atrial fibrillation had an intraventricular hemorrhage associated with a transventricular electrode in the postoperative CT. After four asymptomatic days, his condition worsened due to hydrocephalus, requiring an external ventricular drainage for 5 days. At 3-month follow-up, hydrocephalus was no longer present and the tremor was remarkably improved under chronic DBS. A 39-year-old woman with unilateral tremor and aspirin prophylaxis because of a previous stroke had a small, asymptomatic intracerebral bleeding along the electrode trajectory in the postoperative CT scan. There were no long-term consequences.\n\nThe number of intracranial hemorrhages on the postoperative CT scan in patients without chronic antiplatelet or anticoagulation treatment was 15/431 (3.5%) which was not significantly different from the study group (p = 0.36, see Table 3).Table 3 Intracranial hemorrhage, IPG pocket hematoma, and thromboembolic complications in patients without or on chronic antiplatelet or anticoagulation treatment\n\n\tChronic antiplatelet or anticoagulation treatment\n(n = 34)\tNo chronic antiplatelet or anticoagulation treatment\n(n = 431)\tStatistical significance\t\nIntracranial hemorrhage\t2 (5.9%)\t15 (3.5%)\t\t\nNo intracranial hemorrhage\t32 (94.1%)\t416 (96.5%)\tn.s. (p = .36)\t\nIPG pocket hematoma\t2 (5.9%)\t4 (1%)\t\t\nNo IPG pocket hematoma\t32 (94.1%)\t417 (99%)\tn.s. (p = .07)\t\nThromboembolic complication\t0 (0%)\t2 (0.5%)\t\t\nNo thromboembolic complication\t34 (100%)\t429 (99.5%)\tn.s. (p = 1)\t\n\nArterial hypertension was present in 16/34 (47.1%) of patients on chronic antiplatelet or anticoagulation treatment, and in 77/432 (17.9%) without. Intracranial hemorrhage occurred only in 2/93 patients with arterial hypertension (2.2%) and did not present as an independent risk factor in our series.\n\nIPG pocket hematomas occurred in 2/34 patients (5.9%) in the group of patients on chronic antiplatelet or anticoagulation treatment. These patients had chronic medication with vitamin K antagonists. In the group of patients without antiplatelet or anticoagulation treatment, there were 4/421 (1%) IPG pocket hematomas. Note that 10 patients were excluded from this analysis as they either had radiofrequency lesions or no IPG was implanted. When comparing the two groups, there was no statistical significance (p = 0.07, see Table 3).\n\nNo thromboembolic or thrombotic complications occurred in patients on antiplatelet or anticoagulation treatment during the 30-day postoperative period, while such complications were noticed, however, in 2/431 patients (0.5%) who were not on chronic treatment.\n\nDuring follow-up until 12 months after surgery, no additional thromboembolic or thrombotic or hemorrhagic complications occurred in the 34 patients on chronic antiplatelet or anticoagulation treatment. In particular, there were no instances of chronic subdural hematoma.\n\nDiscussion\n\nDBS surgery has become a widespread and accepted therapy worldwide with an estimate of more than 180,000 patients that have been operated [19]. Along with its application to new indications, in particular considering psychiatric disorders [19], there is also a continuous process of reevaluation of what should be considered a relative contraindication for DBS. While decades ago, for example, very young age or advanced age was considered red flags, there are now published studies on DBS for childhood dystonia in infants [37] or ET in geriatric patients [16]. Moreover, psychiatric disorders and dementia, formerly considered contraindications for DBS surgery, have now increasingly moved into focus [19]. Another example is the concomitant use of cardiac pacemakers and DBS neurostimulation systems. While initially it was thought that the risk of a concomitant use would be prohibitive, this practice has become accepted over the years given certain precautions being taken [10, 15].\n\nIn the present study, we show that DBS can be performed in patients on various forms of chronic antiplatelet or anticoagulation treatment with a reasonable risk/safety profile. We did not find an increased occurrence of hemorrhagic or thromboembolic/thrombotic complications after stopping treatment and providing perioperative bridging therapy, when indicated, in comparison to patients without chronic antiplatelet or anticoagulation treatment and between different types of drugs. The management of prophylactic treatment in the perioperative phase basically was in line with the proceedings used in other neurosurgical operations. There was also no increase of chronic hemorrhagic complications such as the development of subdural hematoma for up to 1-year follow-up.\n\nThe only patient who had a symptomatic hemorrhage in our present series was operated via a transventricular approach. There is disagreement whether such an approach might constitute per se an increased risk for hemorrhage or not [18, 26, 40].\n\nThe subject of our study has received only little attention thus far, despite the increasing age in the population and a more frequent use of antiplatelet or anticoagulant therapy [2]. In a previous study on 143 patients undergoing DBS surgery, no increased risk for intracranial hemorrhage was detected in 23 patients with previous use of anticoagulant medication [29]. The risk of IPG pocket hematoma and the occurrence of thromboembolic complications, however, were not evaluated and there was no differentiation between different forms of antiplatelet or anticoagulant therapies. Another study showed that postoperative prophylaxis with or without subcutaneous heparin for venous thromboembolism did not increase the risk for intracranial hemorrhage significantly [5]. More detailed analysis of the handling of chronic anticoagulation treatment in patients undergoing DBS or with existing DBS systems has been provided mainly in the form of case report or small case series [4, 25, 31, 33, 39]. We have reported previously on a patient who received bilateral pallidal DBS for severe chorea due to antiphospholipid antibody syndrome with a need for chronic phenprocoumon treatment. There were no complications of combined treatment at 2-year follow-up. In a series of 4 patients with DBS and chronic anticoagulation treatment, one IPG pocket hematoma occurred, but no intracranial hemorrhage [4].\n\nThe overall safety of DBS surgery in patients on chronic anticlotting therapy was also demonstrated in a recent study on a series of 226 patients of whom 90 patients were on chronic anticoagulation. There was no difference in adverse events between patients on anticlotting medication as compared to those without. Similarly like in our study, anticlotting treatment was paused before surgery, and a bridging protocol was installed when needed. Three hemorrhages occurred in the group who did not have chronic anticlotting treatment, and there was no instance of thromboembolic events within 90 days after surgery.\n\nIntracranial hemorrhage in patients with DBS and subsequent anticoagulation therapy was reported very rarely. In one patient, high-dose intravenous heparin was administered on the first postoperative day for acute myocardial infarction [25], and in two other patients, edoxaban was restarted already on day 5 and day 7 after surgery [20, 33]. One of these patients also had a recurrent hemorrhage later. Delayed hemorrhage occurring 9 weeks after DBS surgery was described in a patient taking low dose aspirin, but this patient suffered also from arterial hypertension [39].\n\nThe incidence of IPG pocket hematoma was remarkably low in our study, although it was higher in patients on chronic antiplatelet or anticoagulation treatment than in those without. In this context, it is also of interest to review the practice of cardiac pacemaker surgery. One study showed that continued anticoagulation therapy with warfarin in pacemaker or defibrillator surgery actually reduced the incidence of clinically significant IPG pocket hematoma as compared to bridging therapy with subcutaneous heparin [6]. Another large prospective study on perioperative bridging of anticoagulation treatment with vitamin K antagonists in patients with atrial fibrillation showed that complete pausing of anticoagulation was noninferior to perioperative bridging with low molecular weight heparin for the prevention of thromboembolic complications and that it decreased the risk of major bleeding without causing more thromboembolic complications [12].\n\nConclusion\n\nWe demonstrate the feasibility of implanting DBS systems in selected patients on chronic antiplatelet or anticoagulation treatment when taking certain precautions and we confirm its safety and efficiency over a follow-up period of 1 year.\n\nAbbreviations\n\nDBS Deep brain stimulation\n\nNOACs Novel oral anticoagulants\n\nIPG Implantable pulse generators\n\nPD Parkinson disease\n\nINR International normalization ratio\n\nPTT Partial thromboplastin time\n\nGPi Globus pallidus internus\n\nSTN Subthalamic nucleus\n\nET Essential tremor\n\nVim Ventral intermediate nucleus\n\nCM-Pf Centromedian-parafascicular complex\n\nVPL Ventral posterior lateral nucleus\n\nAcknowledgements\n\nWe would like to thank Hans E. Heissler for his expert support in statistics.\n\nAuthor contribution\n\nConception and design: Krauss, Saryyeva. Acquisition of data: Runge, Cassini Ascencao, Kinfe, Blahak, Wolf, Saryyeva, Krauss. Analysis and interpretation of data: Runge, Cassini Ascencao, Saryyeva, Krauss. Drafting the article: Runge, Cassini Ascencao, Krauss. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Statistical analysis: Runge, Cassini Ascencao.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nDeclarations\n\nEthical approval\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The Ethical Commission of Hannover Medical School indicated further that no formal approval was needed for the present study.\n\nInformed consent\n\nInformed consent was obtained from all individual participants included in the study.\n\nConflict of interest\n\nLuisa Cassini Ascencao: received travel grants from Medtronic; Joachim Runge: received travel grants from Medtronic; Christian Blahak: received travel grants from Ipsen; Thomas M. Kinfe: is a consultant to Medtronic and to Abbott; Christoph Schrader: none; Marc E. Wolf: none; Assel Saryyeva: received travel grants from Medtronic; Joachim K. Krauss: is a consultant to Medtronic and to Boston Scientific.\n\nThis article is part of the Topical Collection on Functional Neurosurgery—Other\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nComments\n\nStraightforward description of the preoperative/periroperative management of antiplatelet and anticoagulation treatments in patients receiving DBS surgery. Feasibility of the procedure in selective patients is documented with no significant increase of risk for both, intracranial hemorrhage and implantable pulse generator pocket hematomas.\n\nAna-Laura Cif.\n\nMontpellier, France\n\nJoachim Runge and Luisa Cassini Ascencao contributed equally to this work.\n==== Refs\nReferences\n\n1. 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Butchart EG Gohlke-Bärwolf C Antunes MJ Tornos P De Caterina R Cormier B Prendergast B Iung B Bjornstad H Leport C Hall RJC Vahanian A Recommendations for the management of patients after heart valve surgery Eur Heart J 2005 26 2463 3247 10.1093/eurheartj/ehi426 16103039\n9. Capelle HH Blahak C Schrader C Bäzner H Kinfe TM Herzog J Dengler R Krauss JK Chronic deep brain stimulation in patients with tardive dystonia without a history of major psychosis Mov Disord 2010 25 1477 1481 10.1002/mds.23123 20629157\n10. Capelle HH Simpson RK Kronenbuerger M Michaelsen J Tronnier V Krauss JK Long-term deep brain stimulation in elderly patients with cardiac pacemakers J Neurosurg 2005 102 53 59 10.3171/jns.2005.102.1.0053\n11. Deer TR Narouze S Provenzano DA Pope JE Falowski SM Russo MA Benzon H Slavin K Pilitsis JG Alo K Carlson JD McRoberts P Lad SP Arle J Levy RM Simpson B Mekhail N The Neurostimulation Appropriateness Consensus Committee (NACC): recommendations on bleeding and coagulation management in neurostimulation devices Neuromodulation 2017 20 51 62 10.1111/ner.12542 28042905\n12. Douketis JD Spyropoulos AC Kaatz S Becker RC Caprini JA Dunn AS Garcia DA Jacobson A Jaffer AK Kong DF Schulman S Turpie AGG Hasselblad V Ortel TL Perioperative bridging anticoagulation in patients with atrial fibrilation N Engl J Med 2015 373 823 833 10.1056/NEJMoa1501035 26095867\n13. El Ahmadieh TY Aoun SG Daou MR El Tecle NE Ràhme RJ Graham RB Adel JG Batjer HH Bendok BR New-generation oral anticoagulants for the prevention of stroke: implications for neurosurgery J Clin Neurosci 2013 20 1350 1356 10.1016/j.jocn.2013.05.009 23835467\n14. Fasano A Aquino CC Krauss JK Honey CR Bloem BR Axial disability and deep brain stimulation in patients with Parkinson’s disease Nat Rev Neurol 2015 11 98 110 10.1038/nrneurol.2014.252 25582445\n15. Heard T Coyne T Silburn P Deep brain stimulation in patients with concomitant cardiac pacemakers: a case series Oper Neurosurg (Hagerstown) 2019 17 549 553 10.1093/ons/opz018 30851040\n16. Klein J Büntjen L Jacobi G Galazky I Panther P Zaehle T Kaufmann J Heinze HJ Voges J Kupsch A Bilateral thalamic deep brain stimulation for essential tremor in elderly patients J Neural Transm (Vienna) 2017 124 1093 1096 10.1007/s00702-017-1741-8 28593500\n17. Krack P Volkmann J Tinkhauser G Deuschl G Deep brain stimulation in movement disorders: from experimental surgery to evidence-based therapy Mov Disord 2019 34 1795 1810 10.1002/mds.27860 31580535\n18. Kramer DR Halpern CH Danish SF Jaggi JL Baltuch GH The effect of intraventricular trajectory on brain shift in deep brain stimulation Stereotact Funct Neurosurg 2012 90 20 34 10.1159/000332056 22190056\n19. Lozano AM Lipsman N Bergman H Brown P Chabardes S Chang JW Matthews K McIntyre CC Schlaepfer TE Schulder M Temel Y Volkmann J Krauss JK Deep brain stimulation: current challenges and future directions Nat Rev Neurol 2019 15 148 160 10.1038/s41582-018-0128-2 30683913\n20. Martin AJ Starr PA Ostrem JL Larson PS Hemorrhage detection and incidence during magnetic resonance-guided deep brain stimulator implantations Stereotact Funct Neurosurg 2017 95 307 314 10.1159/000479287 28889128\n21. Mirzayan MJ Calvelli K Capelle HH Weigand J Krauss JK Subdural hematoma and oral anticoagulation: a therapeutic dilemma from the neurosurgical point of view J Neurol Surg A Cent Eur Neurosurg 2016 77 31 35 26291887\n22. Mitchell KT Ostrem JL Surgical treatment of Parkinson disease Neurol Clin 2020 38 293 307 10.1016/j.ncl.2020.01.001 32279711\n23. Nowak-Göttl U Langer F Limperger V Mesters R Trappe RU Bridging: perioperative management of chronic anticoagulation or antiplatelet therapy Dtsch Med Wochenschr 2014 139 1301 1306 10.1055/s-0034-1370110 24892468\n24. Patel DM Walker HC Brooks R Omar N Ditty B Guthrie BL Adverse events associated with deep brain stimulation for movement disorders: analysis of 510 consecutive cases Neurosurgery 2015 11 Suppl 2 190 199 25599204\n25. Polanski W Koy J Juratli T Wolz M Klingelhöfer L Fauser M Storch A Schackert G Sobottka SB Anticoagulation management of myocardial infarction after deep brain stimulation: a comparison of two cases Acta Neurochir (Wien) 2013 155 1661 1665 10.1007/s00701-013-1679-z 23563744\n26. 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Sansur CA Frysinger RC Pouratian N Fu KM Bittl M Oskouian RJ Laws ER Elias WJ Incidence of symptomatic hemorrhage after stereotactic electrode placement J Neurosurg 2007 107 998 1003 10.3171/JNS-07/11/0998 17977273\n30. Schepers IM Beck AK Bräuer S Schwabe K Abdallat M Sandmann P Dengler R Rieger JW Krauss JK Human centromedian-parafascicular complex (CM-Pf) signals sensory cues for goal-oriented behavior selection Neuroimage 2017 152 390 399 10.1016/j.neuroimage.2017.03.019 28288908\n31. Schrader C Aumüller M Lütjens G Saryyeva A Capelle HH Krauss JK Bilateral pallidal stimulation improves chorea in antiphospholipid antibody syndrome with oral anticoagulation Mov Disord Clin Pract 2015 2 194 196 10.1002/mdc3.12146 30713895\n32. Schrader C Capelle HH Kinfe TM Blahak C Bäzner H Lütjens DD Krauss JK GPi-DBS may induce a hypokinetic gait disorder with freezing of gait in patients with dystonia Neurology 2011 77 483 488 10.1212/WNL.0b013e318227b19e 21775741\n33. Sivakumar W Garber ST Schrock LE House PA Recurrent, delayed hemorrhage associated with edoxaban after deep brain stimulation lead placement Case Rep Neurol Med 2013 2013 691840 23365773\n34. Skardelly M Mönch L Order C Hockel K Tatagiba MS Ebner FH Survey of the management of perioperative bridging of anticoagulation and antiplatelet therapy in neurosurgery Acta Neurochir (Wien) 2018 160 2077 2085 10.1007/s00701-018-3679-5 30238395\n35. Terao T Takahashi H Yokochi F Taniguchi M Okiyama R Hamada I Hemorrhagic complication of stereotactic surgery in patients with movement disorders J Neurosurg 2003 98 1241 1246 10.3171/jns.2003.98.6.1241 12816271\n36. Topp G Ghulam-Jefani Z Chockalingam A Kumar V Byraju K Sukul V Pilitsis JG Safety of deep brain stimulation lead placement on patients requiring anticlotting therapie World Neurosurg 2021 145 e320 e325 10.1016/j.wneu.2020.10.047 33068799\n37. Tustin K Elze MC Lumsden DE Gimeno H Kaminska M Lin JP Gross motor function outcomes following deep brain stimulation for childhood-onset dystonia: a descriptive report Eur J Paediatr Neurol 2019 23 473 483 10.1016/j.ejpn.2019.02.005 30846371\n38. Voges J Hilker R Bötzel K Kiening KL Kloss M Kupsch A Schnitzler A Schneider GH Steude U Deuschl G Pinsker MO Thirty days complication rate following surgery performed for deep-brain-stimulation Mov Disord 2007 22 1486 1489 10.1002/mds.21481 17516483\n39. Zesiewicz TA Sullivan KL Hoffmann M Benes LM Smith DA Ward CL Hauser RA Delayed thalamic intracranial hemorrhage in an essential tremor patient following deep brain stimulation Eur Neurol 2008 59 187 189 10.1159/000114041 18230878\n40. Zrinzo L Foltynie T Limousin P Hariz MI Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic literature review J Neurosurg 2012 116 84 94 10.3171/2011.8.JNS101407 21905798\n\n",
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"journal": "Acta neurochirurgica",
"keywords": "Anticoagulation; Antiplatelet; Deep brain stimulation; Functional neurosurgery; NOAC; Vitamin K antagonist",
"medline_ta": "Acta Neurochir (Wien)",
"mesh_terms": "D000284:Administration, Oral; D000925:Anticoagulants; D046690:Deep Brain Stimulation; D006470:Hemorrhage; D006801:Humans; D010975:Platelet Aggregation Inhibitors",
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"title": "Deep brain stimulation in patients on chronic antiplatelet or anticoagulation treatment.",
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"abstract": "BACKGROUND\nClinically amyopathic dermatomyositis with anti-Melanoma Differentiation-Associated gene 5 (MDA5) antibody often presents with severe interstitial lung disease. Although serum ferritin level is known to reflect interstitial lung disease activity, there are few case reports describing this association.\n\n\nMETHODS\nA 58-year-old man was referred to our outpatient clinic with a 3-week history of cough and respiratory distress. He had erythema over the V area of the neck and a Gottron's sign. Chest computed tomography revealed diffuse ground-glass opacities and reticular shadows in both lungs. Test for anti-MDA5 antibody was positive. After admission, he received triple combination therapy (methylprednisolone pulse therapy, tacrolimus, and cyclophosphamide). However, his respiratory condition worsened as the serum ferritin level increased. Despite no apparent deterioration on chest radiography, he ultimately died due to respiratory failure.\n\n\nCONCLUSIONS\nIn this case, triple combination therapy was not effective for the patient's respiratory condition. The serum ferritin level was correlated with disease activity and was more useful than chest radiography for monitoring clinical status.",
"affiliations": "Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. kazuasai@med.osaka-cu.ac.jp.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.;Diagnostic Pathology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.;Diagnostic Pathology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.;Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.",
"authors": "Yamada|Kazuhiro|K|;Asai|Kazuhisa|K|;Okamoto|Atsuko|A|;Watanabe|Tetsuya|T|;Kanazawa|Hiroshi|H|;Ohata|Mai|M|;Ohsawa|Masahiko|M|;Hirata|Kazuto|K|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D005293:Ferritins; D016559:Tacrolimus; D008775:Methylprednisolone",
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"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 314610.1186/s13104-018-3146-7Research NoteCorrelation between disease activity and serum ferritin in clinically amyopathic dermatomyositis with rapidly-progressive interstitial lung disease: a case report Yamada Kazuhiro kazuhironishiyamato@gmail.com 1Asai Kazuhisa kazuasai@med.osaka-cu.ac.jp 1Okamoto Atsuko m1169499@med.osaka-cu.ac.jp 1Watanabe Tetsuya tetsuyaw5353@gmail.com 1Kanazawa Hiroshi kanazawa-h@med.osaka-cu.ac.jp 1Ohata Mai maimaiono@yahoo.co.jp 2Ohsawa Masahiko m-ohsawa@med.osaka-cu.ac.jp 2Hirata Kazuto kazutoh@msic.med.osaka-cu.ac.jp 11 0000 0001 1009 6411grid.261445.0Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan 2 0000 0001 1009 6411grid.261445.0Diagnostic Pathology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan 16 1 2018 16 1 2018 2018 11 3427 7 2017 9 1 2018 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nClinically amyopathic dermatomyositis with anti-Melanoma Differentiation-Associated gene 5 (MDA5) antibody often presents with severe interstitial lung disease. Although serum ferritin level is known to reflect interstitial lung disease activity, there are few case reports describing this association.\n\nCase presentation\nA 58-year-old man was referred to our outpatient clinic with a 3-week history of cough and respiratory distress. He had erythema over the V area of the neck and a Gottron’s sign. Chest computed tomography revealed diffuse ground-glass opacities and reticular shadows in both lungs. Test for anti-MDA5 antibody was positive. After admission, he received triple combination therapy (methylprednisolone pulse therapy, tacrolimus, and cyclophosphamide). However, his respiratory condition worsened as the serum ferritin level increased. Despite no apparent deterioration on chest radiography, he ultimately died due to respiratory failure.\n\nConclusions\nIn this case, triple combination therapy was not effective for the patient’s respiratory condition. The serum ferritin level was correlated with disease activity and was more useful than chest radiography for monitoring clinical status.\n\nKeywords\nClinically amyopathic dermatomyositisCADMRapidly progressive interstitial lung diseaseRP-ILDMelanoma Differentiation-Associated gene 5MDA5CorticosteroidsTacrolimusCyclophosphamideissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPatients with clinically amyopathic dermatomyositis (CADM) with anti-Melanoma Differentiation-Associated gene 5 (MDA5) antibody often develop treatment-resistant, and rapidly-progressive interstitial lung disease (RP-ILD) [1]. In CADM-ILD, 80% of fatal cases died due to refractory ILD within 90 days of initial presentation [2]. Early treatment of CADM with RP-ILD is essential to improve the prognosis [3, 4]. Triple combination therapy (corticosteroids, tacrolimus, and cyclophosphamide) is considered effective for CADM with RP-ILD. Although the serum ferritin level is known to predict prognosis in anti-MDA5 antibody-associated ILD with dermatomyositis and is also known to reflect disease activity, few case reports have described this association. We report a case in which the serum ferritin level was closely correlated with disease activity.\n\nCase presentation\nA 58-year-old man was referred to our outpatient clinic with a 3-week history of cough and respiratory distress. He was a current smoker (40 pack-years) but had no other medical history. His body temperature was 37.2 °C, blood pressure was 82/51 mmHg, pulse rate was 110 beats/min, respiratory rate was 20 breaths/min, and oxygen saturation was 84% in room air. He had erythema over the V area of the neck and a Gottron’s sign (Fig. 1a), but no signs of muscle weakness. Fine crackles were auscultated in the bilateral lung bases. The serum level of creatine kinase was not elevated (68.0 U/L). The serum aldolase, Krebs von den Lungen-6, lactate dehydrogenase, and ferritin levels were increased (11.0, 1.040, 658 U/L and 1.679 ng/mL, respectively). Anti-aminoacyl tRNA synthetase and other antibodies suggestive of autoimmune disorders were not detected (Table 1). Chest radiography showed bilateral reticular shadows, predominantly in the right lung (Fig. 1b). Chest computed tomography (CT) showed bilateral, asymmetric, ground-glass opacities and reticular shadows, predominantly in the lower lungs, suspicious for CADM with RP-ILD (Fig. 1c). Bronchoalveolar lavage was performed from right B5. The total cell count was 0.394 × 105/mL, and the percentages of neutrophils, eosinophils, and lymphocytes were 47.2, 1.8, and 21.6%, respectively. A transbronchial lung biopsy specimen from right B2b showed a diffuse alveolar damage pattern (Fig. 2a). Following bronchoscopy, methylprednisolone pulse therapy (1000 mg daily for 3 days) and tacrolimus were initiated, followed by cyclophosphamide pulse therapy (500 mg for 1 day). After starting treatment, test for anti-MDA5 antibody was confirmed to be positive. Therefore, the diagnosis was CADM with anti-MDA5 antibody. His respiratory condition gradually improved, and the serum ferritin, lactate dehydrogenase, and aldolase levels decreased. However, after 4 weeks, his respiratory condition gradually worsened in association with an increasing serum ferritin level, but there was no deterioration on chest radiography (Figs. 3, 4). Although courses of methylprednisolone and cyclophosphamide pulse therapy were repeated, his respiratory condition worsened, and he died on hospital day 43. An autopsy showed diffuse fibrosis in all three right lung lobes. Some lymphocytic infiltrate was present in the alveolar wall. Diffuse fibrosis was present and local organizing pneumonia was observed in the left lung (Fig. 2b).Fig. 1 a The clinical presentation on admission. Papules were observed near the interphalangeal articulations (Gottron’s sign). b Chest radiography showed bilateral reticular shadows, in the right lung. c Chest CT scan showed bilateral, asymmetric, ground-glass opacities and reticular shadows, predominantly in the lower lung\n\n\nTable 1 Laboratory data\n\nHematology\t\tSerology\t\n RBC\t467×104/μL\t CRP\t3.28 mg/dL\t\n Hb\t13.4 g/dL\t IgG\t1742 mg/dL\t\n Ht\t40.7%\t IgA\t443 mg/dL\t\n WBC\t9400/μL\t IgM\t68 mg/dL\t\n Neutro\t76%\t KL-6\t1040 U/mL\t\n Lymph\t14%\tImmunological test\t\n Mono\t4%\t RF\t< 5 U/mL\t\n Eosino\t5%\t Anti nuclear Ab\t40-fold\t\n Plt\t37.8 × 104/μL\t Anti CCP Ab\t< 0.6 U/mL\t\nBlood chemistry\t\t Anti Ds-DNA Ab\t2.9 U/mL\t\n TP\t7.0 g/dL\t Anti RNP Ab\tNegative\t\n Alb\t2.7 g/dL\t Anti SS-A Ab\t< 1.0 U/mL\t\n T-bil\t0.5 mg/dL\t Anti SS-B Ab\t< 1.0 U/mL\t\n AST\t72 U/L\t Anti Scl-70\t< 1.0 U/mL\t\n ALT\t27 U/L\t PR3-ANCA\t< 1.0 U/mL\t\n LDH\t658 U/L\t MPO-ANCA\t< 1.0 U/mL\t\n CK\t68 U/L\t Anti ARS Ab\t< 5.0 U/mL\t\n BUN\t21 mg/dL\tBlood gas (O2 3 L/min by nasal plugs)\t\n Cre\t0.65 mg/dL\t PH\t7.444\t\n\t PaCO2\t36 Torr\t\n PaO2\t72 Torr\t\n HCO3−\t24.3 mEq/L\t\n B.E.\t1.0 mEq/L\t\n SaO2\t94%\t\n\nFig. 2 a Transbronchial lung biopsy showed proliferative-phase diffuse alveolar damage with a glassy eosinophilic substance in the alveolar spaces and interstitial fibrosis associated with type 2 pneumocyte hyperplasia. b Autopsy lung section showed fibrotic-phase diffuse alveolar damage with diffuse fibrotic change and type 2 pneumocyte hyperplasia, with lymphocyte infiltration into alveolar septa\n\n\nFig. 3 The concentration of oxygen required changed in association with the serum ferritin level\n\n\nFig. 4 Chest radiography did not show apparent deterioration in association with the serum ferritin level\n\n\n\n\nDiscussion and conclusion\nReportedly increasing in the past decade, CADM-ILD is often refractory and rapidly progressive, and CADM-ILD with anti-MDA5 antibody has a poor prognosis. For early initiation of proper treatment, quick and accurate diagnosis is needed. This case showed a Gottron’s and V-neck signs; however, muscle weakness was not apparent. Chest CT showed bilateral, asymmetric, ground-glass opacities and reticular shadows, in the lower lungs, suspicious for CADM-ILD. Testing for anti-MDA5 antibody was positive. For initiation of proper treatment, accurate estimation of prognosis is needed. Gono et al. reported that elevated serum ferritin levels were related to the severity of ILD in patients with dermatomyositis. Interestingly, they found that the cumulative survival rate was lower in the subset with ferritin ≥ 1500 ng/mL than in the subset with ferritin < 1500 ng/mL [5]. Ferritin is the primary iron storage molecule; it is secreted by activated macrophages and plays a crucial role in sequestration of potentially harmful reactive iron molecules. High serum ferritin level may reflect aberrant activation of macrophages in patients with CADM-ILD. In this case, the serum ferritin level was 1679 ng/mL on the day of admission. A transbronchial lung biopsy specimen from right B2b showed proliferative phase diffuse alveolar damage (DAD). DAD is reportedly associated with a poorer prognosis than other histopathological patterns, such as unusual interstitial pneumonia [6].\n\nBased both on the serum ferritin level and pathological findings, we predicted a poor prognosis and immediately initiated intensive treatment with triple combination therapy (corticosteroid, tacrolimus, and cyclophosphamide). T cells play a vital role in development of ILD in polymyositis/dermatomyositis [7, 8]; therefore, use of calcineurin inhibitors of T-cell activity is considered important. Cyclosporine inhibits the activity of calcineurin by binding to cyclophilin, whereas tacrolimus exhibits inhibitory activity by binding to FK binding protein. The pharmacological effect of tacrolimus is 100 times stronger than that of cyclosporine, and its half-life is longer than that of cyclosporine [9]. The superiority of tacrolimus to cyclosporine in renal, liver, or bone marrow transplantation has been demonstrated in randomized controlled trials [10–13]. Kameda et al. reported that 5 of 10 dermatomyositis patients with RP-ILD responded to triple combination therapy [14]. These reports indicate that triple combination therapy is warranted in cases of CADM with RP-ILD. Therefore, we administered cyclophosphamide from the beginning of treatment. Unfortunately, triple combination therapy was not effective. The patient’s respiratory condition worsened without apparent deterioration on chest radiography. An adequate treatment-monitoring tool is needed to enable disease control.\n\nThe serum ferritin level is reportedly correlated with disease activity in anti-MDA5 antibody-associated ILD with dermatomyositis [5, 15] In this case, the treatment was initially effective; however, his respiratory condition worsened in association with an increasing serum ferritin level, and he died on hospital day 43. Lung specimens at autopsy showed fibrotic phase DAD. The serum ferritin level was closely correlated with disease activity (Fig. 3). There was no apparent deterioration of ILD on chest radiography (Fig. 4). This case indicated that a high serum ferritin level in anti-MDA5 antibody-associated ILD with dermatomyositis was very useful for monitoring disease activity. High serum ferritin level reflected disease activity in anti-MDA5 antibody-associated ILD with dermatomyositis. In this case, the serum ferritin level was more useful than chest radiography for monitoring of disease progression.\n\nAbbreviations\nCADMclinically amyopathic dermatomyositis\n\nMDA5Melanoma Differentiation-Associated gene 5\n\nRP-ILDrapidly progressive interstitial lung disease\n\nCTchest computed tomography\n\nDADdiffuse alveolar damage\n\nAuthors’ contributions\nKY edited the case presentation, performed the literature review and wrote the discussion. AO, TW, KA, HK and KH revised the manuscript. MO1 and MO2 carried out the pathological diagnosis. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank to Ms. Sachi Ibuki in Kyoto University for her technical support to detect autoantibodies.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nAll available information is included within the manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent to publish\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nFunding\nThe authors declare that no funding was received for the publication of this case report.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Mukae H Ishimoto H Sakamoto N Hara S Kakugawa T Nakayama S Ishimatsu Y Kawakami A Eguchi K Kohno S Clinical differences between interstitial lung disease associated with clinically amyopathic dermatomyositis and classic dermatomyositis Chest 2009 136 5 1341 1347 10.1378/chest.08-2740 19581351 \n2. Ikeda S Arita M Misaki K Mishima S Takaiwa T Nishiyama A Ito A Furuta K Yokoyama T Tokioka F Incidence and impact of interstitial lung disease and malignancy in patients with polymyositis, dermatomyositis, and clinically amyopathic dermatomyositis: a retrospective cohort study Springerplus 2015 4 240 10.1186/s40064-015-1013-8 26101728 \n3. Kotani T Makino S Takeuchi T Kagitani M Shoda T Hata A Tabushi Y Hanafusa T Early intervention with corticosteroids and cyclosporin A and 2-h post dose blood concentration monitoring improves the prognosis of acute/subacute interstitial pneumonia in dermatomyositis J Rheumatol 2008 35 2 254 259 18085732 \n4. Nagata K Tomii K Nanjo S Kubota M Tachikawa R Nishio M Four cases of interstitial pneumonia associated with amyopathic dermatomyositis characterized by the anti-CADM-140 antibody Nihon Kokyuki Gakkai Zasshi 2011 49 1 30 36 21384679 \n5. Gono T Kawaguchi Y Hara M Masuda I Katsumata Y Shinozaki M Ota Y Ozeki E Yamanaka H Increased ferritin predicts development and severity of acute interstitial lung disease as a complication of dermatomyositis Rheumatology (Oxford) 2010 49 7 1354 1360 10.1093/rheumatology/keq073 20385617 \n6. Tazelaar HD Viggiano RW Pickersgill J Colby TV Interstitial lung disease in polymyositis and dermatomyositis. Clinical features and prognosis as correlated with histologic findings Am Rev Respir Dis 1990 141 3 727 733 10.1164/ajrccm/141.3.727 2310101 \n7. Rosenschein U Radnay J Shoham D Shainberg A Klajman A Rozenszajn LA Human muscle-derived, tissue specific, myocytotoxic T cell lines in dermatomyositis Clin Exp Immunol 1987 67 2 309 318 3496994 \n8. Goebels N Michaelis D Engelhardt M Huber S Bender A Pongratz D Johnson MA Wekerle H Tschopp J Jenne D Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis J Clin Invest 1996 97 12 2905 2910 10.1172/JCI118749 8675705 \n9. Dumont FJ FK506, an immunosuppressant targeting calcineurin function Curr Med Chem 2000 7 7 731 748 10.2174/0929867003374723 10702636 \n10. Webster A Woodroffe RC Taylor RS Chapman JR Craig JC Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients Cochrane Database Syst Rev 2005 4 CD003961 \n11. Krämer BK Montagnino G Del Castillo D Margreiter R Sperschneider H Olbricht CJ Krüger B Ortuño J Köhler H Kunzendorf U Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results Nephrol Dial Transplant 2005 20 5 968 973 10.1093/ndt/gfh739 15741208 \n12. McAlister VC Haddad E Renouf E Malthaner RA Kjaer MS Gluud LL Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis Am J Transplant 2006 6 7 1578 1585 10.1111/j.1600-6143.2006.01360.x 16827858 \n13. Nash RA Antin JH Karanes C Fay JW Avalos BR Yeager AM Przepiorka D Davies S Petersen FB Bartels P Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors Blood 2000 96 6 2062 2068 10979948 \n14. Kameda H Nagasawa H Ogawa H Sekiguchi N Takei H Tokuhira M Amano K Takeuchi T Combination therapy with corticosteroids, cyclosporin A, and intravenous pulse cyclophosphamide for acute/subacute interstitial pneumonia in patients with dermatomyositis J Rheumatol 2005 32 9 1719 1726 16142867 \n15. Nakashima R Imura Y Kobayashi S Yukawa N Yoshifuji H Nojima T Kawabata D Ohmura K Usui T Fujii T The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody Rheumatology (Oxford) 2010 49 3 433 440 10.1093/rheumatology/kep375 20015976\n\n",
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"keywords": "CADM; Clinically amyopathic dermatomyositis; Corticosteroids; Cyclophosphamide; MDA5; Melanoma Differentiation-Associated gene 5; RP-ILD; Rapidly progressive interstitial lung disease; Tacrolimus",
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"mesh_terms": "D000893:Anti-Inflammatory Agents; D003520:Cyclophosphamide; D003882:Dermatomyositis; D018450:Disease Progression; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005293:Ferritins; D006801:Humans; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D012720:Severity of Illness Index; D016559:Tacrolimus",
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"title": "Correlation between disease activity and serum ferritin in clinically amyopathic dermatomyositis with rapidly-progressive interstitial lung disease: a case report.",
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"abstract": "OBJECTIVE\nThere is no standard second-line chemotherapy after progression on first-line therapy including gemcitabine and platinum combination in advanced gall bladder cancer patients. So this study was undertaken to assess the efficacy and safety of FOLFOX-4 regimen in this setting.\n\n\nMETHODS\nIn this observational study, patients with performance status ≤2, who progressed on first-line therapy, were enrolled from May 2010 to June 2014. FOLFOX-4 based treatment was administered until progression, unacceptable toxicity or up to 12 cycles.\n\n\nRESULTS\nA total of 66 patients were enrolled in this study. The median age of patients was 52.5 years (32-66 years),of which 24 (36.36%) were males and 42 (63.63%) were females. The median number of cycles could be given were 9.5 (2-12). Only 43.93% patients in this study completed full 12 cycles of chemotherapy. Sixteen patients (24.24%) in this study required the dose reduction at least in one cycle of chemotherapy due to toxicities. Disease control rate was seen in 39 (59.09%) patients, with complete response in none, partial response in 16 (24.24%), stable disease in 23 (34.84%) and progressive disease in 27 (40.90%) patients. The median progression free survival was 3.9 months; median overall survival was 7.6 months. The main Grade 3/4 side effects seen were hematological in 31.81% (n = 21) and gastrointestinal in 25.75% (n = 17) patients. Majority of patients (46%) had Grade 1/2 peripheral neuropathy.\n\n\nCONCLUSIONS\nFOLFOX-4 is an effective and well-tolerated regimen as a second-line treatment in advanced gall bladder cancer patients. Further studies are required, especially in the Indian subcontinent.",
"affiliations": "Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi doval.dc@rgcirc.org.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi.;Senior Resident, Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, New Delhi, India.",
"authors": "Dodagoudar|Chandragouda|C|;Doval|Dinesh Chandra|DC|;Mahanta|Anupam|A|;Goel|Varun|V|;Upadhyay|Amitabh|A|;Goyal|Pankaj|P|;Talwar|Vineet|V|;Singh|Sajjan|S|;John|Mithun Chacko|MC|;Tiwari|Srikant|S|;Patnaik|Nivedita|N|",
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"keywords": "FOLFOX-4; carcinoma gall bladder; gemcitabine; platinum; second line",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil; D005706:Gallbladder Neoplasms; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D017211:Treatment Failure; D016896:Treatment Outcome",
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"title": "FOLFOX-4 as second-line therapy after failure of gemcitabine and platinum combination in advanced gall bladder cancer patients.",
"title_normalized": "folfox 4 as second line therapy after failure of gemcitabine and platinum combination in advanced gall bladder cancer patients"
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"abstract": "A growing body of evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to be a powerful option to improve the cardiovascular (CV) prognosis in high CV-risk patients with type 2 diabetes. Despite a significant reduction in major adverse CV events with SGLT2 inhibitor treatment, however, an unexpected increased risk of amputation was observed in the CANVAS program and the subsequent pharmacovigilance analysis. Although the underlying mechanisms are currently unknown, because amputation has a large negative impact on patient clinical course, clinicians want to know the exact reason for the increased amputation in the canagliflozin treatment. We herein discuss a need to elucidate the actual reasons with more appropriate statistical consideration, taking into account individual clinical course potentially involved in the diabetes-related amputation. Decreases in the hardendpoints by canagliflozin might result in an alternate increase in the other diabetes-related complications, including amputation. In addition, if amputation occurred after stopping canagliflozin, the incidence might be caused by worsened glycemic control and a decrease in hematocrit, accompanied by a subsequent worsening of diabetic foot disease. More detailed approach considering individual clinical course potentially involved in the amputation, would help to further unravel the cause for suspected risk of amputation with canagliflozin.",
"affiliations": "Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.;Department of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan. node@cc.saga-u.ac.jp.",
"authors": "Tanaka|Atsushi|A|;Node|Koichi|K|0000-0002-2534-0939",
"chemical_list": "D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin",
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"fulltext": "\n==== Front\nCardiovasc DiabetolCardiovasc DiabetolCardiovascular Diabetology1475-2840BioMed Central London 61110.1186/s12933-017-0611-xCommentaryIncreased amputation risk with canagliflozin treatment: behind the large cardiovascular benefit? Tanaka Atsushi mikechann@gmail.com http://orcid.org/0000-0002-2534-0939Node Koichi +81-952-34-2364node@cc.saga-u.ac.jp 0000 0001 1172 4459grid.412339.eDepartment of Cardiovascular Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501 Japan 12 10 2017 12 10 2017 2017 16 12922 9 2017 4 10 2017 © The Author(s) 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.A growing body of evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to be a powerful option to improve the cardiovascular (CV) prognosis in high CV-risk patients with type 2 diabetes. Despite a significant reduction in major adverse CV events with SGLT2 inhibitor treatment, however, an unexpected increased risk of amputation was observed in the CANVAS program and the subsequent pharmacovigilance analysis. Although the underlying mechanisms are currently unknown, because amputation has a large negative impact on patient clinical course, clinicians want to know the exact reason for the increased amputation in the canagliflozin treatment. We herein discuss a need to elucidate the actual reasons with more appropriate statistical consideration, taking into account individual clinical course potentially involved in the diabetes-related amputation. Decreases in the hardendpoints by canagliflozin might result in an alternate increase in the other diabetes-related complications, including amputation. In addition, if amputation occurred after stopping canagliflozin, the incidence might be caused by worsened glycemic control and a decrease in hematocrit, accompanied by a subsequent worsening of diabetic foot disease. More detailed approach considering individual clinical course potentially involved in the amputation, would help to further unravel the cause for suspected risk of amputation with canagliflozin.\n\nissue-copyright-statement© The Author(s) 2017\n==== Body\nA great deal of clinical interest was generated by the EMPA-REG OUTCOME trial, which evaluated the cardiovascular (CV) safety of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes (T2D) and high CV risk [1]. Based on the potential multiple beneficial effects of SGLT2 inhibitors on the CV and renal systems [2], the results of subsequent studies with SGLT2 inhibitors have received much attention. As expected, the CANVAS program [3] revealed recently that canagliflozin also improved CV and renal outcomes in a population similar to the EMPA-REG OUTCOME trial. These studies highlighted a promising clinical application of SGLT2 inhibitors for high-quality CV and diabetes care, and suggested that these agents should play an important role in the improvement of clinical outcomes in patients with T2D.\n\nAccumulating evidence has demonstrated that canagliflozin treatment can achieve favorable long-term improvement in glycemic and metabolic parameters and is well tolerated as either mono-therapy or in combination with other anti-hyperglycemic agents, including insulin [4–8]. Furthermore, Januzzi et al. [9] recently reported that canagliflozin attenuated the serial escalation of serum levels of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I, relative to placebo, over a 104-week period in older patients with T2D. These multi-factorial benefits obtained from canagliflozin treatment may support, at least in part, the improvement of CV outcomes observed in the CANVAS program.\n\nConversely, due to their unique mode of action, SGLT2 inhibitors have several signature adverse effects, such as genital/urinary tract infection, and such adverse effects were observed in both CV safety trials. In contrast, in the CANVAS program an unexpected increase (approximately twofold) in the risk of lower-extremity amputation (minor: 71%, major: 29%) was observed in the canagliflozin-treated group [3]. Most recently, Fandini et al. [10] reported that canagliflozin was associated with a higher risk of amputation relative to empagliflozin and dapagliflozin in a pharmacovigilance analysis using the US Food and Drug Administration Adverse Event Reporting System. As the authors noted, the records may not be sufficient to explain a precise causal relationship between canagliflozin exposure and amputation [10]. Furthermore, the underlying mechanisms are currently unknown, and whether the amputation risk is specific to canagliflozin remains to be elucidated. However, because amputation has a large negative impact on patient clinical course, we clinicians want to know the exact reason for the increased incidence of amputation with canagliflozin treatment.\n\nAlthough the risk of lower-extremity amputation in patients with T2D has declined substantially during the past couple of decades [11, 12], globally, diabetic foot disease (DFD) is still a large clinical and socioeconomic concern [13, 14]. In patients with DFD, diabetes itself and CV pathophysiology are also likely to be of advanced clinical status. Hence, amputation risk is inherently increased in diabetes, and a history of DFD and amputation are risk factors for CV events, including re-amputation, and poorer prognosis [15, 16]. Results of a population-based cohort study showed that the risk of amputation was particularly high during the first 6 months following revascularization for critical limb ischemia [17]. Actually, a history of amputation and DFD were also strong and independent risk factors for amputation in the CANVAS program [3]. On the other hand, in a subgroup analysis of patients stratified by disease history, risk reduction in pre-defined major adverse CV events (MACE) in patients with a history of amputation was greater than in those without. Furthermore, according to the early separation of development of MACE between SGLT2 inhibitor treatment and placebo in the two trials, clinical benefits appear relatively early in the course of SGLT2 inhibitor intervention. Meanwhile, amputation in the CANVAS program occurred more often during the late phase of the study period. Therefore, it may be speculated that a favorable clinical course of reduction in MACE might influence the increased incidence of amputation, indicating a possibility that an alternate risk of amputation potentially increased in the canagliflozin-treated population who received the benefits in MACE. It may be plausible that a risk-shift to diabetes-related soft-complications, including amputation, has been raised by canagliflozin treatment. Thus, we should recognize that in the CV safety trials, the incidence of each event in the placebo group represents the natural history of the participants, while that in the specific treatment group shows the test agent-modified clinical course.\n\nAlthough it may not be appropriate to compare the results of separate studies, we are left to question why the risk of amputation was increased in the CANVAS program, but not in the EMPA-REG OUTCOME trial [18]. Focusing on the differences in the other clinical characteristics between the two trials may provide a clue as to factors potentially contributing to the increase in the frequency of amputation. The EMPA-REG OUTCOME trial population was receiving secondary prevention for CV disease, while the CANVAS program population contained patients receiving both primary and secondary prevention. However, the prevalence of peripheral artery disease at baseline was almost similar (approximately 20%) between the two studies, possibly having less impact. Most recently, a real-world retrospective cohort study in which patients with T2D and established CV disease were also included (approximately 20%) demonstrated that no increased signal of incidence of below-knee lower extremity amputation was observed in new users of canagliflozin compared to other SGLT2 inhibitors and anti-hyperglycemic agents [19]. This may indicate a possibility that the risk of amputation documented in the CANVAS program resulted, in part, from variance in other factors between the trials.\n\nWe next noticed that adverse events related to volume depletion occurred more often in the canagliflozin-treated group than in the placebo group, despite a similar incidence in the EMPA-REG OUTCOME trial, which might accordingly contribute to the circulatory failure in the distal peripheral arterial beds. However, diuresis and subsequent volume depletion would be more evident at the early phase of SGLT2 inhibitor treatment, inconsistent with the phase of increased incidence of amputation.\n\nWith regard to adherence to the study drugs, a total of 25% of the participants in the EMPA-REG OUTCOME trial and 29% in the CANVAS program discontinued their assigned treatment. In the EMPA-REG OUTCOME trial, the incidence of stroke showed a higher tendency in the analysis of the intent-to-treat population than in the on-treatment analysis. When administration of an SGLT2 inhibitor is stopped, several SGLT2 inhibitor-mediated favorable effects on metabolic and hemodynamic parameters might be eliminated (e.g., worsened glycemic control and decrease in hematocrit levels), followed by progression of distal peripheral arteriosclerosis prone to ischemia and foot ulcer, leading to possible increases in amputation. Although it is still not easy to determine or explain the specific reason for an increased frequency of amputation with canagliflozin treatment, more detailed statistical approaches considering the individual clinical course potentially involved in diabetes-related amputation should further help us to understand why and how its risk increased in the canagliflozin-treated population.\n\nFor clinicians, especially in the cardiovascular field, the emerging SGLT2 inhibitors should be a promising option to improve CV outcomes in the care of patients with T2D at high CV risk. If possible reason(s) for the increased risk of amputation with canagliflozin treatment are uncovered behind the large CV benefit, our understanding of SGLT2 inhibitors would be much better for providing effective and safe CV-diabetes care. The ultimate goal is to exploit the CV benefit of SGLT2 inhibitors, while avoiding adverse effects, for appropriate patients who need SGLT2 inhibitor-mediated CV benefits, because SGLT2 inhibitor treatment in the recent landmark studies markedly reduced the incidence of MACE paramount to the clinical outcomes.\n\nAbbreviations\nCVcardiovascular\n\nDFDdiabetic foot disease\n\nMACEmajor adverse CV events\n\nSGLT2sodium–glucose cotransporter 2\n\nT2Dtype 2 diabetes\n\nAuthors’ contributions\nAT wrote the draft of the article, which was critically supervised by KN. Both authors read and approved the final manuscript.\n\nAcknowledgements\nAuthors thank Ms. Aya Yamada for her excellent secretarial assistance.\n\nCompeting interests\nAT has no financial interests to disclose related to this manuscript. KN has received honoraria from Eli Lilly, Boehringer Ingelheim, Mitsubishi Tanabe, and Astellas; research funding from Astellas and Boehringer Ingelheim; and scholarships from Astellas, Mitsubishi Tanabe, and Boehringer Ingelheim.\n\nAvailability of data and materials\nNot applicable.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nFunding\nNone.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Zinman B Wanner C Lachin JM Fitchett D Bluhmki E Hantel S Mattheus M Devins T Johansen OE Woerle HJ Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes New Engl J Med 2015 373 22 2117 2128 10.1056/NEJMoa1504720 26378978 \n2. Heerspink HJ Perkins BA Fitchett DH Husain M Cherney DZ Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications Circulation 2016 134 10 752 772 10.1161/CIRCULATIONAHA.116.021887 27470878 \n3. Neal B Perkovic V Mahaffey KW de Zeeuw D Fulcher G Erondu N Shaw W Law G Desai M Matthews DR Canagliflozin and cardiovascular and renal events in type 2 diabetes New Engl J Med 2017 377 7 644 657 10.1056/NEJMoa1611925 28605608 \n4. Stenlof K Cefalu WT Kim KA Alba M Usiskin K Tong C Canovatchel W Meininger G Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise Diabetes Obes Metab 2013 15 4 372 382 10.1111/dom.12054 23279307 \n5. Forst T Guthrie R Goldenberg R Yee J Vijapurkar U Meininger G Stein P Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone Diabetes Obes Metab 2014 16 5 467 477 10.1111/dom.12273 24528605 \n6. Neal B Perkovic V de Zeeuw D Mahaffey KW Fulcher G Ways K Desai M Shaw W Capuano G Alba M Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes Diabetes Care 2015 38 3 403 411 10.2337/dc14-1237 25468945 \n7. Karagiannis T Bekiari E Tsapas A Canagliflozin in the treatment of type 2 diabetes: an evidence-based review of its place in therapy Core Evid 2017 12 1 10 10.2147/CE.S109654 28352212 \n8. Inagaki N Harashima S Maruyama N Kawaguchi Y Goda M Iijima H Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus Cardiovasc Diabetol 2016 15 89 10.1186/s12933-016-0407-4 27316668 \n9. Januzzi JL Jr Butler J Jarolim P Sattar N Vijapurkar U Desai M Davies MJ Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes J Am Coll Cardiol 2017 70 6 704 712 10.1016/j.jacc.2017.06.016 28619659 \n10. Fadini GP Avogaro A SGTL2 inhibitors and amputations in the US FDA adverse event reporting system Lancet Diabetes Endocrinol 2017 5 9 680 681 10.1016/S2213-8587(17)30257-7 28733172 \n11. Li Y Burrows NR Gregg EW Albright A Geiss LS Declining rates of hospitalization for nontraumatic lower-extremity amputation in the diabetic population aged 40 years or older: US, 1988–2008 Diabetes Care 2012 35 2 273 277 10.2337/dc11-1360 22275440 \n12. Baba M Davis WA Norman PE Davis TM Temporal changes in the prevalence and associates of diabetes-related lower extremity amputations in patients with type 2 diabetes: the fremantle diabetes study Cardiovasc Diabetol 2015 14 152 10.1186/s12933-015-0315-z 26684912 \n13. Rinkel WD Luiten J van Dongen J Kuppens B Van Neck JW Polinder S Castro Cabezas M Coert JH In-hospital costs of diabetic foot disease treated by a multidisciplinary foot team Diabetes Res Clin Pract 2017 132 68 78 10.1016/j.diabres.2017.07.029 28802698 \n14. Winell K Venermo M Ikonen T Sund R Indicators for comparing the incidence of diabetic amputations: a nationwide population-based register study Eur J Vasc Endovasc Surg 2013 46 5 569 574 10.1016/j.ejvs.2013.07.010 24007756 \n15. Johannesson A Larsson GU Ramstrand N Turkiewicz A Wirehn AB Atroshi I Incidence of lower-limb amputation in the diabetic and nondiabetic general population: a 10-year population-based cohort study of initial unilateral and contralateral amputations and reamputations Diabetes Care 2009 32 2 275 280 10.2337/dc08-1639 19001192 \n16. Mohammedi K Woodward M Hirakawa Y Zoungas S Colagiuri S Hamet P Harrap S Poulter N Matthews DR Marre M Presentations of major peripheral arterial disease and risk of major outcomes in patients with type 2 diabetes: results from the ADVANCE-ON study Cardiovasc Diabetol 2016 15 1 129 10.1186/s12933-016-0446-x 27590190 \n17. Baubeta Fridh E Andersson M Thuresson M Sigvant B Kragsterman B Johansson S Hasvold P Falkenberg M Nordanstig J Amputation rates, mortality, and pre-operative comorbidities in patients revascularised for intermittent claudication or critical limb ischaemia: a population based study European J Vasc Endovasc Surg 2017 54 4 480 486 10.1016/j.ejvs.2017.07.005 28797662 \n18. Kohler S Zeller C Iliev H Kaspers S Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I–III clinical trials Adv Ther 2017 34 7 1707 1726 10.1007/s12325-017-0573-0 28631216 \n19. Yuan Z DeFalco FJ Ryan PB Schuemie MJ Stang PE Berlin JA Desai M Rosenthal N Risk of lower extremity amputations in patients with type 2 diabetes mellitus treated with SGLT2 inhibitors in the United States: a retrospective cohort study Diabetes Obes Metab 2017 28898514\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1475-2840",
"issue": "16(1)",
"journal": "Cardiovascular diabetology",
"keywords": null,
"medline_ta": "Cardiovasc Diabetol",
"mesh_terms": "D000671:Amputation; D000068896:Canagliflozin; D002318:Cardiovascular Diseases; D003924:Diabetes Mellitus, Type 2; D006801:Humans; D007004:Hypoglycemic Agents; D012307:Risk Factors; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "101147637",
"other_id": null,
"pages": "129",
"pmc": null,
"pmid": "29025400",
"pubdate": "2017-10-12",
"publication_types": "D016422:Letter",
"references": "28619659;28631216;24528605;23279307;28898514;27590190;27316668;26684912;22275440;27470878;26378978;28733172;24007756;28605608;28797662;25468945;28802698;28352212;19001192",
"title": "Increased amputation risk with canagliflozin treatment: behind the large cardiovascular benefit?",
"title_normalized": "increased amputation risk with canagliflozin treatment behind the large cardiovascular benefit"
} | [
{
"companynumb": "JP-JNJFOC-20171101767",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CANAGLIFLOZIN"
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... |
{
"abstract": "A 19-year-old woman suspect of a suicidal drug intoxication was exhumed after a 10-month earth-grave, because the police was accused of manslaughter and neglected help by the relatives of the deceased. Toxicologic analysis revealed as the cause of death an acute chloroquine intoxication. An expert opinion had to deal with the question if the woman would have been saved if the police had appeared earlier. Therefore the duration of agonal period after suicidal chloroquine ingestion was important. An estimation of the time since death was possible on the one hand ex-post from the development of cadaveric changes and supravital reactions and on the other hand, based on premortal changes detectable on the body together with the findings of the authorities. Taking into account all evidence the woman was probably already dead at or prior to the arrival of the police (110 min after ingestion), at least this could not be excluded. Chloroquine has to be considered to be useful for fatal poisoning, which is also recommended in some publications on methods to commit suicide.",
"affiliations": "Institute of Legal Medicine, Rheinische Friedrich-Wilhelms-University, Stiftsplatz 12, 53111, Bonn, Germany. f.musshoff@uni-bonn.de",
"authors": "Musshoff|F|F|;Madea|B|B|",
"chemical_list": "D000962:Antimalarials; D002738:Chloroquine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/s0379-0738(01)00635-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "125(2-3)",
"journal": "Forensic science international",
"keywords": null,
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000962:Antimalarials; D002738:Chloroquine; D005260:Female; D005554:Forensic Medicine; D006801:Humans; D008297:Male; D011180:Postmortem Changes; D013405:Suicide; D013997:Time Factors",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "201-4",
"pmc": null,
"pmid": "11909664",
"pubdate": "2002-02-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Demonstration of a chloroquine fatality after 10-month earth-grave.",
"title_normalized": "demonstration of a chloroquine fatality after 10 month earth grave"
} | [
{
"companynumb": "US-IMPAX LABORATORIES, INC-2016-IPXL-02417",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CHLOROQUINE PHOSPHATE"
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{
"abstract": "OBJECTIVE\nTo report a case of drug-induced immune hemolytic anemia (DIIHA) that was suspected to have been caused by cefmetazole.\n\n\nMETHODS\nA 93-year-old woman with no previous history of liver complications underwent a contrast-enhanced computed tomography scan, which resulted in a diagnosis of acute cholecystitis. The patient experienced intravascular hemolysis and rapid progression of anemia after being exposed to 2 g/day of cefmetazole. After 48 hours of cefmetazole administration, the patient was transferred to the intensive care unit (ICU) of our facility. In view of the severe autoimmune hemolytic anemia, the patient was started on steroid immunosuppression. The patient's condition further deteriorated for 13 hours after treatment and showed increased lactic acidosis and decreased consciousness, thus, the patient was intubated and managed on a ventilator. Lactic acidosis was not easily controlled, and the patient required continuous renal replacement therapy within 15 hours of ICU admission. Blood pressure was unable to be maintained even with the use of catecholamine, and the patient subsequently died 28 hours after ICU admission. Blood taken immediately after death was used to perform a drug-dependent antibody test where DIIHA due to cefmetazole was diagnosed.\n\n\nCONCLUSIONS\nIf there is rapid progression of anemia following drug administration, the possibility of DIIHA needs to be considered. If DIIHA is suspected, identification and immediate discontinuation of the causal drug are essential, and a drug-dependent antibody test should be considered.
.",
"affiliations": null,
"authors": "Fukuda|Masafumi|M|;Nabeta|Masakazu|M|;Oya|Shuki|S|;Takasu|Osamu|O|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.5414/CP204095",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": null,
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "9423309",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34672255",
"pubdate": "2021-10-21",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe drug-induced immune hemolytic anemia due to cefmetazole: A case report
.",
"title_normalized": "severe drug induced immune hemolytic anemia due to cefmetazole a case report"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-04179",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
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{
"abstract": "BACKGROUND\nWhen patients suddenly become restless and are unable to sit or stand still, especially in general medical settings, anxiety is often the topmost differential on every clinician's mind. However, the possibility of the very subjectively distressing condition called 'akathisia' should always be considered.\n\n\nOBJECTIVE\nThe aim of this article is to discuss a clinical approach to the management of akathisia, drawing on the presentation of a patient who was admitted to a general medical ward.\n\n\nCONCLUSIONS\nAkathisia, a subjective and very distressing feeling of restlessness, has been found to be caused by a wide range of medications used in general medical settings, such as azithromycin, antiemetics and antipsychotics. Despite its high incidence and association with an increase in suicidal thoughts, it often goes unrecognised. This paper highlights the need for its early recognition, provides a diagnostic guide and an approach to its management.",
"affiliations": null,
"authors": "Tachere|Richardson Oghoteru|RO|;Modirrousta|Mandana|M|",
"chemical_list": "D000928:Antidepressive Agents; D000932:Antiemetics; D014150:Antipsychotic Agents; D002936:Cinnarizine; D008750:Methyldopa; D012110:Reserpine; D004110:Diltiazem; D002065:Buspirone",
"country": "Australia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8495",
"issue": "46(5)",
"journal": "Australian family physician",
"keywords": null,
"medline_ta": "Aust Fam Physician",
"mesh_terms": "D000328:Adult; D000928:Antidepressive Agents; D000932:Antiemetics; D014150:Antipsychotic Agents; D001007:Anxiety; D002065:Buspirone; D002936:Cinnarizine; D004110:Diltiazem; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008750:Methyldopa; D011595:Psychomotor Agitation; D012110:Reserpine; D059020:Suicidal Ideation",
"nlm_unique_id": "0326701",
"other_id": null,
"pages": "296-298",
"pmc": null,
"pmid": "28472575",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Beyond anxiety and agitation: A clinical approach to akathisia.",
"title_normalized": "beyond anxiety and agitation a clinical approach to akathisia"
} | [
{
"companynumb": "CA-BAUSCH-BL-2019-007879",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ERYTHROPOIETIN"
},
"drugadditional": null,
... |
{
"abstract": "Pediatric craniosynostosis repair with cranial vault reconstructive surgery can be associated with significant blood loss. Tranexamic acid (TXA), an antifibrinolytic agent, has been shown to decrease blood loss and transfusion volume in craniofacial surgery. Nonetheless data regarding the safety of TXA remains limited. The authors describe a case of ulnar artery thrombosis following ulnar arterial line placement in a patient who received TXA for cranial vault reconstructive surgery.",
"affiliations": "Department of Anesthesiology, Perioperative and Pain Medicine, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.;Department of Anesthesiology, Perioperative and Pain Medicine, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.",
"authors": "Chung|Eugene|E|;Karlberg|Helena I|HI|",
"chemical_list": "D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid",
"country": "United States",
"delete": false,
"doi": "10.1097/SCS.0000000000004905",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1049-2275",
"issue": "30(1)",
"journal": "The Journal of craniofacial surgery",
"keywords": null,
"medline_ta": "J Craniofac Surg",
"mesh_terms": "D000933:Antifibrinolytic Agents; D016063:Blood Loss, Surgical; D002675:Child, Preschool; D003398:Craniosynostoses; D005260:Female; D006801:Humans; D013927:Thrombosis; D014148:Tranexamic Acid; D017535:Ulnar Artery",
"nlm_unique_id": "9010410",
"other_id": null,
"pages": "186-187",
"pmc": null,
"pmid": "30444787",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ulnar Artery Thrombosis Following Tranexamic Acid Administration for Craniosynostosis Repair.",
"title_normalized": "ulnar artery thrombosis following tranexamic acid administration for craniosynostosis repair"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201903024",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRANEXAMIC ACID"
},
"drugadditional": "1"... |
{
"abstract": "Pulmonary vein stenosis is a rare but severe complication of catheter ablation for arterial fibrillation (AF). Symptoms include dyspnea, hemoptysis, recurrent pneumonia, and pulmonary hypertension. We herein discuss a 27-year-old male patient who presented with hemoptysis and dyspnea three months after catheter ablation for AF. Computed tomography demonstrated an occluded left inferior pulmonary vein (LIPV) and left lower lung edema secondary to severe stenosis of the LIPV. The patient underwent treatment, including drug-coated balloon (DCB) venoplasty. Treatment of pulmonary vein stenosis involving percutaneous interventions with balloon angioplasty and stenting carry a high risk of restenosis. DCB therapy may be used to prevent stenosis. <Learning objective: The use of a drug-coated balloon is feasible and may provide good long-term outcomes in acquired pulmonary vein stenosis after radiofrequency ablation.>.",
"affiliations": "Department of Cardiology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.;Department of Cardiology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.;Department of Cardiology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.",
"authors": "Ito|Kansuke|K|;Kato|Ken|K|;Tanaka|Hiroyuki|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2020.08.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "23(1)",
"journal": "Journal of cardiology cases",
"keywords": "Acquired pulmonary vein stenosis; Drug-coated balloon venoplasty; Radiofrequency ablation",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "3-5",
"pmc": null,
"pmid": "33437330",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": "12952852;26075706;10758058;25615282;27145055;21088005;19261037;22062795;27793993",
"title": "Experience using drug-coated balloon venoplasty for acquired pulmonary vein stenosis after radiofrequency ablation.",
"title_normalized": "experience using drug coated balloon venoplasty for acquired pulmonary vein stenosis after radiofrequency ablation"
} | [
{
"companynumb": "JP-DSJP-DSJ-2021-103041",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMethotrexate-associated lymphoproliferative disorder (MTX-LPD) can present as a benign lymphoid proliferation or a malignant lymphoma in patients taking MTX. Almost 50% of MTX-LPD cases show spontaneous remission after withdrawal of MTX treatment. Studies have suggested that the hyper-immune state of rheumatoid arthritis, the immunosuppressive state associated with MTX, and the carcinogenicity of the Epstein-Barr virus might contribute to MTX-LPD development. Although most cases of MTX-LPD occur at extranodal sites, few cases of MTX-LPD affecting the stomach and duodenum have been reported. To our knowledge, no other study has reported on the endoscopic observations of dramatic withdrawal and appearance of multiple digestive tract lesions in a short period of time. Herein, we report the clinical course and imaging findings of our case, which may be useful for understanding the pathological condition of MTX-LPD.\n\n\nMETHODS\nWe describe the case of a 70-year-old woman with MTX-LPD of the stomach and duodenum. Disease regression was temporarily achieved after cessation of MTX treatment; however, it subsequently recurred, and complete response was only achieved after six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R-CHOP) chemotherapy.\n\n\nCONCLUSIONS\nThe first-choice therapy for patients taking MTX who develop suspected MTX-LPD should be the withdrawal of MTX treatment. Even after remission is achieved, patients should be kept under careful observation, and if the disease recurs, chemotherapy should be commenced promptly.",
"affiliations": "Department of Gastroenterology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. toyonaga.pc@gmail.com.;Department of Gastroenterology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.;Department of Gastroenterology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.;Department of Gastroenterology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.",
"authors": "Toyonaga|Haruka|H|http://orcid.org/0000-0001-7300-3665;Fukushima|Masashi|M|;Shimeno|Naoto|N|;Inokuma|Tetsuro|T|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone; D008727:Methotrexate",
"country": "England",
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"doi": "10.1186/s12876-019-0982-4",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 98210.1186/s12876-019-0982-4Case ReportMethotrexate-associated lymphoproliferative disorder in the stomach and duodenum: a case report http://orcid.org/0000-0001-7300-3665Toyonaga Haruka +81-78-302-4321toyonaga.pc@gmail.com Fukushima Masashi +81-78-302-4321mfuku4585@hotmail.com Shimeno Naoto +81-78-302-4321shimeno@kcho.jp Inokuma Tetsuro +81-78-302-4321inokuma@kcho.jp Department of Gastroenterology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan 25 4 2019 25 4 2019 2019 19 6218 7 2018 10 4 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\nMethotrexate-associated lymphoproliferative disorder (MTX-LPD) can present as a benign lymphoid proliferation or a malignant lymphoma in patients taking MTX. Almost 50% of MTX-LPD cases show spontaneous remission after withdrawal of MTX treatment. Studies have suggested that the hyper-immune state of rheumatoid arthritis, the immunosuppressive state associated with MTX, and the carcinogenicity of the Epstein-Barr virus might contribute to MTX-LPD development. Although most cases of MTX-LPD occur at extranodal sites, few cases of MTX-LPD affecting the stomach and duodenum have been reported. To our knowledge, no other study has reported on the endoscopic observations of dramatic withdrawal and appearance of multiple digestive tract lesions in a short period of time. Herein, we report the clinical course and imaging findings of our case, which may be useful for understanding the pathological condition of MTX-LPD.\n\nCase presentation\nWe describe the case of a 70-year-old woman with MTX-LPD of the stomach and duodenum. Disease regression was temporarily achieved after cessation of MTX treatment; however, it subsequently recurred, and complete response was only achieved after six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R-CHOP) chemotherapy.\n\nConclusions\nThe first-choice therapy for patients taking MTX who develop suspected MTX-LPD should be the withdrawal of MTX treatment. Even after remission is achieved, patients should be kept under careful observation, and if the disease recurs, chemotherapy should be commenced promptly.\n\nKeywords\nMethotrexate-associated lymphoproliferative disordersDiffuse large B-cell lymphomaRheumatoid arthritisissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nMethotrexate-associated lymphoproliferative disorder (MTX-LPD) can present as a benign lymphoid proliferation or a malignant lymphoma in patients taking MTX. In 1991, Ellman and colleagues reported the first case of lymphomas in a patient with rheumatoid arthritis (RA) treated with MTX [1]. The World Health Organization categorizes MTX-LPD under “other iatrogenic immunodeficiency-associated lymphoproliferative disorders.” MTX-LPD consists mainly of diffuse large B-cell lymphoma (DLBCL; 35–60% of cases) and classical Hodgkin’s lymphoma (12–25% of cases) [2]. Approximately 40–50% of MTX-LPD cases occur at extranodal sites, such as the skin, salivary glands, lungs, digestive tract, liver, and spine [3]. Although spontaneous remission of MTX-LPD after MTX withdrawal occurs in approximately 50% of cases [4], chemotherapy may be needed to treat lymphoma recurring or persisting after stopping MTX treatment.\n\nHere, we describe a case of MTX-LPD in the stomach and duodenum that temporarily resolved after the cessation of MTX treatment. In order to achieve complete response after recurrence of disease, prompt chemotherapy was required. To our knowledge, there are no other reports on the endoscopic observations of dramatic withdrawal and the appearance of multiple digestive tract lesions within a short period. The imaging findings along with the patient’s clinical course in this case may prove useful for understanding the pathological condition of MTX-LPD.\n\nCase presentation\nA 70-year-old woman presented to the clinic with a history of epigastric distress. Her medical history was significant for Helicobacter pylori infection, which was resolved five years prior; and RA, for which she had been taking MTX (6 mg per week) for the past 6 months. Her symptoms were investigated with esophagogastroduodenoscopy (EGD), which initially revealed no abnormality apart from atrophic gastritis. Following a two-month course of acid-suppressing drugs, she remained symptomatic; therefore, a repeat EGD was conducted, which revealed the emergence of multiple elevated lesions. As a result, she was referred to our hospital.\n\nPhysical examination at that time revealed the abdomen to be soft and flat, with no hepatosplenomegaly or lymphadenopathy. Laboratory tests showed elevated levels of lactate dehydrogenase (312 IU/L; reference range, 120–250 IU/L) and soluble interleukin-2 receptor (sIL-2R) (1430 IU/mL, reference range, 145–520 IU/mL). The lymphocyte count was 2375/μl (19%, reference range, 19–61%).\n\nEGD performed at the time of admission to our hospital revealed multiple “dish-like” lesions in the stomach and duodenum (Fig. 1a, d). Indigo carmine spraying revealed that the lesion elevation was relatively steep, the surface structure was equivalent to that of the background mucosa, and ulceration with white coat was observed in the central part of the lesion (Fig. 1b). Narrow band imaging revealed meandering irregular microvessels without loops (Fig. 1c). These results suggest that a solid tumor growing from the submucosa was ulcerated and exposed at the central part of the lesion. The histology of biopsy specimens obtained from the ulcerated lesions showed infiltration of large atypical lymphocytes. Immunohistochemical studies revealed the expression of cluster of differentiation (CD)5, CD20, and Ki-67 antigen, but the absence of cyclin D1, CD10, CD30, B-cell lymphoma (BCL)-2; Epstein–Barr virus (EBV)-encoded small RNA in situ hybridization (ISH) demonstrated that the EBV was absent (Fig. 2a–i). We carried out positron emission tomography–computed tomography (PET–CT) to evaluate the extent of disease. PET–CT showed abnormal uptake of radioactive tracers in the stomach, duodenum, and a few adjacent nodes, with a maximum standardized uptake value of 21.0 (Fig. 3). Based on these findings, and along with the patient’s history of RA treated with MTX, she was diagnosed with MTX-LPD showing features of stage II1 diffuse large B-cell lymphoma (DLBCL) (Lugano classification).Fig. 1 Endoscopic images of the stomach and duodenum affected by MTX-LPD. a, Before the withdrawal of MTX treatment, there were multiple dish-like lesions in the stomach. b, Indigo carmine spraying revealed that the lesion rise was relatively steep, the surface structure was equivalent to that of the background mucosa, and ulceration with white coat was observed in the central part of the lesion. c, Narrow band imaging revealed meandering irregular microvessels without loops. d, There were dish-like lesions also in the duodenum\n\nFig. 2 a, Histology of biopsy specimens from ulcerated stomach lesions showing infiltration of large atypical lymphocytes (H&E × 400). b, Immunohistochemical studies revealing the expression of CD5 (× 400), c, CD20 (× 400), d, and Ki-67 antigen (× 400), but the absence of e, cyclin D1 (× 400), f, CD10 (× 400), g, CD30 (× 400), h, BCL-2 (× 400), and i, the EBV (using EBER-ISH) (× 400)\n\nFig. 3 Clinical causes: We observed changes in MTX-LPD symptoms in the stomach and duodenum with regard to the levels of sIL-2R, and EGD and PET-CT findings\n\n\n\nInitial management consisted of the discontinuation of MTX, which resulted in symptom improvement and reduction of sIL-2R level. Two weeks after the withdrawal of MTX, the lymphocyte count increased from 2375/μl to 5616/μl (52%). EGD conducted 1 month after discontinuation revealed a reduction in the number of lesions with some scarring (Fig. 3). Pathological findings confirmed residual tumor cells. Three months after discontinuation, epigastric distress worsened and the sIL-2R level reached 1973 IU/mL. A third EGD showed the recurrence of multiple lesions. PET–CT showed abnormal uptake of radioactive tracers with a maximum standardized uptake value of 44.6 in the stomach (Fig. 3). We suspected MTX-LPD relapse and started six courses of rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R-CHOP) chemotherapy. After starting chemotherapy, her symptoms and the sIL-2R level improved rapidly. We carried out EGD and PET–CT 1 month from chemotherapy commencement that revealed the disappearance of the lesions and no evidence of lymphoma on pathological evaluation. One year after the cessation of chemotherapy, she remained asymptomatic, and the complete response of MTX-LPD was confirmed on the EGD, pathological examination, and PET–CT (Fig. 3).\n\nDiscussion and conclusions\nWe described the case of a 70-year-old woman with MTX-LPD of the stomach and duodenum. In this case, disease regression was temporarily achieved after the cessation of MTX treatment, but it subsequently recurred and complete response was only achieved after chemotherapy.\n\nRA patients have a twofold to fourfold increased risk of developing lymphoma compared to that of the general population [5]. MTX, the “anchor drug” for RA, is considered to be a major cause of lymphoproliferative disorders. The pathogenesis of MTX-LPD is incompletely understood, but studies have suggested that the “hyper-immune” state of RA and the immunosuppressive state associated with MTX might contribute to MTX-LPD development. For patients taking MTX, a shorter interval between the diagnosis of RA and LPD in MTX-LPD than in non-MTX-LPD (median, 132 vs. 240 months, respectively) has been documented [6], and the withdrawal of MTX treatment results in the spontaneous remission of LPD in 25–60% of patients taking MTX [2, 4, 6]. In an observational study about 102 cases of MTX-LPD, 47 patients were only withdrawn MTX without any additional treatment of LPD. In 28 of 47 (60%) patients, spontaneous remission occurred and continued for 3–84 months (median, 17). 13 of 28 (46%) patients required chemotherapy because of recurrence or residual disease [7].\n\nA large observational cohort study of 18,572 patients with RA [8] suggested that MTX contributed to a small increased risk of LPD development, with a standardized incidence ratio (SIR) of 1.7 (95% confidence interval (CI), 0.9–3.2). In a nested case–control study in Japan involving 5753 RA patients (28 patients in the MTX-LPD group and 125 patients in the MTX non-LPD group), Kameda et al. [9] reported that the mean dose of MTX was higher in the MTX-LPD group (8.4 [range, 5.9–10.0] mg/week) than in the non-LPD group (7.0 [5.0–8.6] mg/week). They suggested that a higher mean MTX dose is an independent risk factor for LPD development in RA patients. Studies have suggested that immunosuppressants other than MTX and biological preparations (e.g., infliximab, etanercept) can also induce LPD. In a 5-year cohort study of 1252 patients with severe psoriasis patients treated with cyclosporine, Paul et al. reported [10] that the incidence of leukemia was significantly elevated in the cohort compared to that in the general population (SIR; 7.3, 95% CI: 1.5–21.5). Hasserjian et al. reported 18 cases of lymphoproliferative disorders caused by biological preparations (e.g., Infliximab, Adalimumab, Etanercept) for autoimmune diseases (e.g., RA, psoriasis, inflammatory bowel disease) [11]. Only 6 patients had received prior treatment with MTX among them.\n\nEBV positivity might also contribute to MTX-LPD development. EBV has been implicated in Hodgkin’s lymphoma, Burkitt’s lymphoma, gastric carcinoma, and nasopharyngeal carcinoma [12]. Studies have shown that the monoclonal proliferation of host cells by EBV involves 3 steps: expression of the oncogenes of EBV, genetic/epigenetic changes in the host, and dysfunction of the immune system [13]. Hoshida and co-workers [6] found that the prevalence of EBV in RA patients with LPD was significantly higher than that in sporadic LPD (27.6% vs. 9.9%).\n\nAlmost 50% of MTX-LPD cases show remission merely by the withdrawal of MTX treatment [4]; thus, the first-choice treatment of MTX-LPD is the rapid cessation of MTX. However, subsequent recurrence of MTX-LPD has been reported in 18–45% of patients, and chemotherapy is indicated in cases of recurrence or in those not reaching remission after > 3 months [7, 14, 15]. Recent studies suggest that the pattern of lymphocyte count transition during withdrawal of MTX is associated with the spontaneous regression of MTX-LPD. Saito et al. reported that the lymphocyte count increased more than 220/μl in the regressive group compared to less than 150/μl in the persistent group at 2 weeks after the withdrawal of MTX [16]. Inui et al. reported the lymphocyte count increased 600/μl on an average at 2 weeks after the withdrawal of MTX in 20 cases of MTX-LPD [17]. Even our case was consistent with the findings that the lymphocyte count increased from 2375/μl to 5616/μl in 2 weeks, and that the spontaneous remission of MTX-LPD was observed.\n\nOther studies have shown a high prevalence of spontaneous remission to be associated with EBV-positivity and a non-DLBCL histology type. Older age (> 70 years) and a DLBCL histology type are predictive factors of shorter survival [7]. In MTX-LPD patients with a DLBCL histology type, five-year survival is 74%, and five-year progression-free survival is 65% [14]. CD5-positive DLBCL is closely associated with aggressive clinical features and parameters; thus, the overall International Prognostic Index score of CD5-positive DLBCL is significantly higher than that of CD5-negative DLBCL [18].\n\nFew reports have focused on the endoscopic features of gastric or duodenal lesions in MTX-LPD. Ikeda et al. [19] reported MTX-LPD of the stomach as DLBCL, which featured multiple elevated lesions with dish-like ulcers in the lower body of the stomach. Satoh et al. [20] reported MTX-LPD as DLBCL, presenting as a single ulcerative lesion resembling a Borrmann type-II advanced gastric cancer. The endoscopic pattern of gastric DLBCL varies; in most cases, a single or multiple dish-like ulcerative lesions at the gastric body or fundus are noted [21]. Characteristic features of MTX-LPD include prompt disappearance of lesions after discontinuing MTX, and achievement of spontaneous remission.\n\nOur case was classified as carrying a low rate of spontaneous remission and aggressive characteristics because of the patient’s advanced age, DLBCL histology type, CD5-positivity and EBV-negativity. In only a month after cessation of MTX treatment, her symptoms improved, and EGD showed that most lesions had disappeared. Subsequently, however, the symptoms exacerbated and the sIL-2R level increased. Repeat EGD revealed regrowth of lesions, and she was started on R-CHOP chemotherapy, which resulted in complete response.\n\nVarious new drugs with high efficacy, such as biological preparations, have been developed for treating RA. However, these drugs are very expensive, and it is highly likely that MTX—which is inexpensive and highly effective—will remain the first-line drug. Hence, future studies must examine the mechanism underlying the development of MTX-LPD, and the elucidation of this mechanism will help in preventing the occurrence of MTX-LPD.\n\nIn lymphoma patients treated with MTX, the first-choice therapy is the withdrawal of MTX treatment if MTX-LPD is suspected. Even after the remission of MTX-LPD, careful observation is important, and if the disease recurs, chemotherapy should be commenced promptly.\n\nAbbreviations\nBCLB-cell lymphoma\n\nCDcluster of differentiation\n\nCIconfidence interval\n\nDLBCLdiffuse large B-cell lymphoma\n\nEBVEpstein–Barr virus\n\nEGDesophagogastroduodenoscopy\n\nISHin situ hybridization\n\nMTX-LPDMethotrexate-associated lymphoproliferative disorder\n\nPET-CTpositron emission tomography–computed tomography\n\nRArheumatoid arthritis\n\nR-CHOPrituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone\n\nsIL-2Rsoluble interleukin-2 receptor\n\nSIRstandardized incidence ratio\n\nWe thank Arshad Makhdum, PhD, from Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript.\n\nFunding\nNo funding support was received for this manuscript.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nHT and MF wrote the paper; MF, NS and TI contributed to the paper design and coordination. All authors have read and approved the manuscript.\n\nEthics approval and consent to participate\nWritten consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ellman MH Hurwitz H Thomas C Kozloff M Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate J Rheumatol 1991 18 1741 1743 1787499 \n2. Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H World Health Organization classification of Tumours of Haematopoietic and lymphoid tissues 2017 Lyon IARC Press 462 464 \n3. Gion Y Iwaki N Takata K Takeuchi M Nishida K Orita Y Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types Cancer Sci 2017 108 1271 1280 10.1111/cas.13249 28380678 \n4. Takanashi S Aisa Y Ito C Arakaki H Osada Y Amano Y Clinical characteristics of methotrexate-associated lymphoproliferative disorders: relationship between absolute lymphocyte count recovery and spontaneous regression Rheumatol Int 2017 37 1629 1633 10.1007/s00296-017-3764-8 28676912 \n5. Anderson LA Gadalla S Morton LM Landgren O Pfeiffer R Warren JL Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies Int J Cancer 2009 125 398 10.1002/ijc.24287 19365835 \n6. Hoshida Y Xu JX Fujita S Nakamichi I Ikeda JI Tomita Y Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication J Rheumatol 2007 34 322 331 17117491 \n7. Ichikawa A Arakawa F Kiyasu J Sato K Miyoshi H Niino D Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein–Barr virus, and clonality are important predictors of disease progression and regression Eur J Haematol 2013 91 20 28 10.1111/ejh.12116 23560463 \n8. Wolfe F Michaud K Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients Arthritis Rheum 2004 50 1740 1751 10.1002/art.20311 15188349 \n9. Kameda T Dobashi H Miyatake N Inoo M Onishi I Kurata N Association of higher methotrexate dose with lymphoproliferative disease onset in rheumatoid arthritis patients Arthritis Care Res 2014 66 1302 1309 10.1002/acr.22306 \n10. Paul CF Ho VC McGeown C Christophers E Schmidtmann B Guillaume JC Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study J Invest Dermatol 2003 120 211 216 10.1046/j.1523-1747.2003.12040.x 12542524 \n11. Hasserjian RP Chen S Perkins SL De Leval L Kinney MC Barry TS Immunomodulator agent-related lymphoproliferative disorders Mod Pathol 2009 22 1532 1540 10.1038/modpathol.2009.131 19767727 \n12. Raab-Traub N Epstein–Barr virus in the pathogenesis of NPC Semin Cancer Biol 2002 12 431 441 10.1016/S1044579X0200086X 12450729 \n13. Raab-Traub N Novel mechanisms of oncogenesis by the Epstein–Barr virus Curr Opin Virol 2012 2 453 458 10.1016/j.coviro.2012.07.001 22858118 \n14. Niitsu N Okamoto M Nakamine H Hirano M Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate Cancer Sci 2010 101 1309 1313 10.1111/j.1349-7006.2010.01517.x 20210795 \n15. Rizzi R Curci P Delia M Rinaldi E Chiefa A Specchia G Spontaneous remission of “methotrexate-associated lymphoproliferative disorders” after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature Med Oncol 2009 26 1 9 10.1007/s12032-008-9069-8 18461290 \n16. Saito S Kaneko Y Yamaoka K Tokuhira M Takeuchi T Distinct patterns of lymphocyte count transition in lymphoproliferative disorder in patients with rheumatoid arthritis treated with methotrexate Rheumatol. 2017 56 940 946 10.1093/rheumatology/kex002 \n17. Inui Y Matsukoka H Yakushijin K Okamura A Shimada T Yano S Methotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early lymphocyte recovery after methotrexate withdrawal Leuk Lymphoma 2015 56 3045 3051 10.3109/10428194.2015.1022769 25721751 \n18. Yamaguchi M Seto M Okamoto M Ichinohasama R Nakamura N Yoshino T De novo CD5+ diffuse large B-cell lymphoma: a clinicopathologic study of 109 patients Blood. 2002 99 815 821 10.1182/blood.V99.3.815 11806981 \n19. Ikeda K Nakamura T Kinoshita T Fujiwara M Uose S Someda H Methotrexate-related lymphoproliferative disorder of the stomach in a patient with rheumatoid arthritis: a case of disease regression after methotrexate cessation Clin J Gastroenterol 2016 9 17 21 10.1007/s12328-015-0624-5 26733461 \n20. Satoh K Yoshida N Imaizumi K Komatsuda A Reversible methotrexate-associated lymphoproliferative disorder resembling advanced gastric cancer in a patient with rheumatoid arthritis Am J Med Sci 2009 338 334 335 10.1097/MAJ.0b013e3181acbb49 19745701 \n21. Vetro C Romano A Amico I Conticello C Motta G Figuera A Endoscopic features of gastro-intestinal lymphomas: from diagnosis to follow-up World J Gastroenterol 2014 20 12993 13005 10.3748/wjg.v20.i36.12993 25278693\n\n",
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"journal": "BMC gastroenterology",
"keywords": "Diffuse large B-cell lymphoma; Methotrexate-associated lymphoproliferative disorders; Rheumatoid arthritis",
"medline_ta": "BMC Gastroenterol",
"mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D003520:Cyclophosphamide; D004317:Doxorubicin; D004378:Duodenal Diseases; D016145:Endoscopy, Digestive System; D005260:Female; D006801:Humans; D008232:Lymphoproliferative Disorders; D008727:Methotrexate; D011241:Prednisone; D012008:Recurrence; D000069283:Rituximab; D013272:Stomach Diseases; D014750:Vincristine; D028761:Withholding Treatment",
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"pmid": "31023238",
"pubdate": "2019-04-25",
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"title": "Methotrexate-associated lymphoproliferative disorder in the stomach and duodenum: a case report.",
"title_normalized": "methotrexate associated lymphoproliferative disorder in the stomach and duodenum a case report"
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"abstract": "OBJECTIVE\nFew studies have examined clinical signs of aspiration in infants <51 weeks post-menstrual age (PMA) for whom the laryngeal cough reflex is not fully developed. This retrospective study explored 1) the association between signs of aspiration on a clinical feeding evaluation (CFE) and/or comorbid conditions with aspiration (silent or overt) on a modified barium swallow study (MBS) for infants in this age range, 2) the association between lower respiratory infection (LRI) and aspiration on MBS, and 3) the sensitivity and specificity of detecting aspiration according to signs on CFE and the evaluating speech-language pathologist's (SLP) years of experience.\n\n\nMETHODS\nA retrospective review of charts of patients with MBS completed January 1, 2012-December 31, 2014 was performed. Patients were included if they were <51-weeks PMA at the time of MBS and had a CFE conducted no more than seven days prior to the MBS. Patient age, comorbidities, and MBS and CFE details were collected. The impact of CFE findings, patient age, comorbid syndromes/associations, and aerodigestive diagnoses on the odds of demonstrating silent aspiration (SA) or overt aspiration during MBS with thin liquids was determined using logistic regression, and the sensitivity and specificity of CFE for identifying SA was calculated.\n\n\nRESULTS\nResults from 114 patients indicated that 46 (40 %) of the infants had SA and nine (8 %) had overt aspiration on MBS. Notable signs on CFEs were cough (36 %), oxygen desaturations (33 %), and chest congestion (32 %). On multiple regression analysis there was increased odds of SA on MBS with at least one clinical sign on CFE (OR: 24.3, p = 0.02), chronic lung disease, (OR: 18.2, p = 0.01), and airway abnormalities (OR: 2.94, p = 0.01). Cough on CFE was associated with increased odds of overt aspiration on MBS (OR: 5.69, p = 0.04). Neither SA nor overt aspiration were significantly associated with LRI. Sensitivity and specificity of CFE for correctly identifying the presence of SA were 98 % and 15 %, respectively; experience of the SLP was not a contributing factor.\n\n\nCONCLUSIONS\nFurther study is required to determine if specific signs on CFE are predictive of aspiration.",
"affiliations": "UPMC Children's Hospital of Pittsburgh, Department of Pediatrics, Division of Neonatology, USA. Electronic address: Arcangela.balest@chp.edu.;University of Pittsburgh Communication Science and Disorders, 3600 Atwood Street, Forbes Tower, Pittsburgh, PA, 15260, USA.;UPMC Children's Hospital of Pittsburgh, Department of Otolaryngology, USA.;UPMC Children's Hospital of Pittsburgh, Department of Audiology and Communication Disorders, USA.;University of Pittsburgh, School of Medicine, Present Address Allegheny General Hospital, Pittsburgh, PA, USA.;University of Pittsburgh Communication Science and Disorders, 3600 Atwood Street, Forbes Tower, Pittsburgh, PA, 15260, USA; UPMC Children's Hospital of Pittsburgh, Department of Otolaryngology, USA.",
"authors": "Balest|Arcangela L|AL|;Mahoney|Amanda S|AS|;Shaffer|Amber D|AD|;White|Katherine E|KE|;Theiss|Robert|R|;Dohar|Joseph|J|",
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"journal": "International journal of pediatric otorhinolaryngology",
"keywords": "Aspiration; Clinical feeding evaluation; Cough; Deglutition; Dysphagia; Feeding; Infant; Modified barium swallow study; Swallowing",
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": "D002675:Child, Preschool; D003679:Deglutition; D003680:Deglutition Disorders; D006801:Humans; D007223:Infant; D007830:Larynx; D053120:Respiratory Aspiration; D012189:Retrospective Studies",
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"publication_types": "D016428:Journal Article",
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"title": "Infant aspiration and associated signs on clinical feeding evaluation.",
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"abstract": "Whilst surgical resection is traditionally used for the successful eradication of locally aggressive osseous tumors, it is often hazardous or unachievable, particularly in complex anatomic sites, such as the pelvis and spine. The authors present the use of microwave ablation in combination with Zoledronic acid (ZA) administration, alone and with the use of ZA-loaded polymethyl methacrylate (PMMA) to percutaneously treat unresectable bone tumors in 4 patients with giant cell tumors (GCT), multiple myeloma (MM) and breast cancer metastasis.",
"affiliations": "Russell H. Morgan Department of Radiology and Radiological Science, Division of Neuroradiology and Neuro-Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, USA.;Russell H. Morgan Department of Radiology and Radiological Science, Division of Neuroradiology and Neuro-Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, USA.;Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, USA.;Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, USA.;Russell H. Morgan Department of Radiology and Radiological Science, Division of Neuroradiology and Neuro-Interventional Radiology, The Johns Hopkins University School of Medicine, Baltimore, USA. Electronic address: mkhan9@jhmi.edu.",
"authors": "Luna|Licia Pacheco|LP|;Sankaran|Nisha|N|;Ehresman|Jeff|J|;Sciubba|Daniel M|DM|;Khan|Majid|M|",
"chemical_list": "D000077211:Zoledronic Acid; D019904:Polymethyl Methacrylate",
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"issue": "76()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Breast cancer metastasis; Cementoplasty; Giant cell tumor; Multiple myeloma; Percutaneous; Zoledronic acid",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001859:Bone Neoplasms; D060826:Cementoplasty; D005260:Female; D006801:Humans; D008297:Male; D008872:Microwaves; D009101:Multiple Myeloma; D010388:Pelvis; D019904:Polymethyl Methacrylate; D000078702:Radiofrequency Therapy; D013131:Spine; D000077211:Zoledronic Acid",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "219-225",
"pmc": null,
"pmid": "32265080",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful percutaneous treatment of bone tumors using microwave ablation in combination with Zoledronic acid infused PMMA cementoplasty.",
"title_normalized": "successful percutaneous treatment of bone tumors using microwave ablation in combination with zoledronic acid infused pmma cementoplasty"
} | [
{
"companynumb": "US-AMGEN-USASP2020139501",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Bevacizumab has shown benefit in the first-line setting in combination with interferon; however, data on use as monotherapy are limited. In this retrospective analysis of 71 patients we assessed the efficacy of bevacizumab monotherapy in patients whose disease progressed during treatment with other targeted drugs. Bevacizumab monotherapy resulted in prolonged disease control and few discontinuations for adverse events, including for patients who were heavily pretreated.\n\n\nBACKGROUND\nBevacizumab has shown benefit in the first-line treatment of metastatic clear cell renal cell carcinoma (ccRCC) in combination with interferon α. In this retrospective analysis we assessed the efficacy of bevacizumab monotherapy in patients whose disease progressed during treatment with vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, and/or mammalian target of rapamycin inhibitors.\n\n\nMETHODS\nA retrospective analysis was performed on metastatic ccRCC patients who received bevacizumab monotherapy after their disease progressed during treatment with previous targeted therapies. The primary objective was to assess overall survival (OS) and the secondary objectives includes progression-free survival (PFS), therapy duration, and incidence of serious adverse events assessed during visits to the Memorial Sloan Kettering Cancer Center (MSKCC) urgent care center.\n\n\nRESULTS\nSeventy-one patients were treated with bevacizumab as monotherapy in the salvage setting. Most patients were heavily pretreated with 36 patients (51%) who received bevacizumab as a fourth-line or later agent, and 33 patients (46%) who received at least 2 previous VEGF targeted agents. Eighteen patients (25%) had a Karnofsky Performance Status (KPS) < 80%, and 20 patients (28%) were classified as poor risk according to MSKCC criteria. Median OS was 11.5 months (95% confidence interval [CI], 6.4-17.4), and median PFS was 1.9 months (95% CI, 1.7-4.1). Nine patients (13%) had a prolonged time of therapy of > 12 months. Four patients (6%) discontinued therapy because of adverse events. Poor KPS (< 80%) and MSKCC poor-risk classification were prognostic for poor OS with hazard ratios of 4.09 (P < .001) and 2.84 (P = .021), respectively.\n\n\nCONCLUSIONS\nBevacizumab monotherapy resulted in prolonged disease control and few discontinuations because of adverse events in patients whose disease had progressed during treatment with other targeted therapies, including patients who were heavily pretreated.",
"affiliations": "Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.;Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.;Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.;Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.;Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: motzerr@mskcc.org.",
"authors": "Lee|Chung-Han|CH|;Hötker|Andreas M|AM|;Voss|Martin H|MH|;Feldman|Darren R|DR|;Woo|Kaitlin M|KM|;Patil|Sujata|S|;Coskey|Devyn T|DT|;Akin|Oguz|O|;Hsieh|James J|JJ|;Motzer|Robert J|RJ|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1558-7673",
"issue": "14(1)",
"journal": "Clinical genitourinary cancer",
"keywords": "Kidney cancer; Retrospective analysis; TKI; VEGF; mTOR",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016879:Salvage Therapy; D016896:Treatment Outcome",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "56-62",
"pmc": null,
"pmid": "26404107",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": "17215529;17876014;16757724;20368558;17538086;22056247;23335087;19451442;19171708;18156031;23321547;12890841;18653228;24206640;23684421;20100962;11753085;23041453",
"title": "Bevacizumab Monotherapy as Salvage Therapy for Advanced Clear Cell Renal Cell Carcinoma Pretreated With Targeted Drugs.",
"title_normalized": "bevacizumab monotherapy as salvage therapy for advanced clear cell renal cell carcinoma pretreated with targeted drugs"
} | [
{
"companynumb": "US-ROCHE-1692433",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Hypertrophic cardiomyopathy in the newborn is a rare entity with heterogeneous etiology. Transient forms have been described in children of mothers with gestational diabetes and in preterm infants exposed both to prenatal and postnatal corticosteroids. We report a case of a preterm infant son of a mother who received renal transplant in whom hypertrophic cardiomyopathy was detected. He had been prenatally exposed to corticosteroids and tacrolimus that received the mother as immunosuppressive therapy. Both drugs cross the placental barrier and, on reaching the fetus, could have favored its development. Hypertrophic cardiomyopathy may be an uncommon side effect of treatment with tacrolimus in adults and children and it is reversible upon withdrawal. To our knowledge, it is the first published case of transient hypertrophic cardiomyopathy after fetal exposure to both corticosteroids and tacrolimus in the son of a renal transplanted mother.",
"affiliations": "Servicio de Neonatología, Hospital Universitario Puerta del Mar, Cádiz, España. pmendezab@gmail.com.;Servicio de Neonatología, Hospital Universitario Puerta del Mar, Cádiz, España.",
"authors": "Méndez-Abad|Paula|P|;Zafra-Rodríguez|Pamela|P|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "Argentina",
"delete": false,
"doi": "10.5546/aap.2018.e749",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0325-0075",
"issue": "116(6)",
"journal": "Archivos argentinos de pediatria",
"keywords": "Hypertrophic cardiomyopathy; Infant newborn; Tacrolimus; Transplantation",
"medline_ta": "Arch Argent Pediatr",
"mesh_terms": "D002312:Cardiomyopathy, Hypertrophic; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D007234:Infant, Premature; D016030:Kidney Transplantation; D008297:Male; D009035:Mothers; D010920:Placenta; D011247:Pregnancy; D016559:Tacrolimus",
"nlm_unique_id": "0372460",
"other_id": null,
"pages": "e749-e752",
"pmc": null,
"pmid": "30457729",
"pubdate": "2018-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypertrophic cardiomyopathy in preterm newborn with kidney transplanted mother.",
"title_normalized": "hypertrophic cardiomyopathy in preterm newborn with kidney transplanted mother"
} | [
{
"companynumb": "ES-TEVA-2018-ES-993456",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.",
"affiliations": "Pediatric Department, Centre Intercommunal de Créteil, Créteil, France; Inserm, Unité 955, Equipe 5, Créteil, France; DHU Ageing Thorax Vessel Blood, Créteil, France.;Pediatric Department, Centre Hospitalier Universitaire de Lille, Lille, France.;Pediatric Department, Centre Hospitalier Universitaire Timone Enfants, Marseille, France.;Pulmonology Department, AP-HP, Hôpital Bichat, Paris, France.;Pediatric Department, Centre Hospitalier Universitaire de Tours, France.;Hospital de Niños Ricardo Gutierrez, Buenos Aires, Argentina.;Pediatric Pulmonary Department, AP-HP, Hôpital Trousseau, Paris, France; Centre des Maladies Respiratoires Rare, Respirare(®), Paris, France.;Pulmonology Department, Centre Hospitalier Universitaire de Tours, France.;Pediatric Department, Centre Hospitalier Universitaire de Lille, Lille, France.;Pediatric Noninvasive Ventilation and Sleep Unit, Hôpital Necker Enfants-Malades, Paris Descartes Faculty, Paris, France.;Pediatric Department, Centre Hospitalier Universitaire Timone Enfants, Marseille, France.;Centre des Maladies Respiratoires Rare, Respirare(®), Paris, France; Pediatric Pulmonary Department, Hôpital Robert Debré, Paris, France.;Pediatric Department, Centre Intercommunal de Créteil, Créteil, France; Inserm, Unité 955, Equipe 5, Créteil, France; DHU Ageing Thorax Vessel Blood, Créteil, France; Centre des Maladies Respiratoires Rare, Respirare(®), Paris, France; Université Paris-Est, Faculté de Médecine, Créteil, France.;Biochemistry Department, AP-HP, Hôpital Trousseau, Paris, France.;Biochemistry Department, AP-HP, Hôpital Trousseau, Paris, France.;Inserm, Unité 955, Equipe 5, Créteil, France; DHU Ageing Thorax Vessel Blood, Créteil, France; Genetic Department, AP-HP, Hôpital Henri Mondor, Créteil, France.;Inserm, Unité 955, Equipe 5, Créteil, France; DHU Ageing Thorax Vessel Blood, Créteil, France; Centre des Maladies Respiratoires Rare, Respirare(®), Paris, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Genetic Department, AP-HP, Hôpital Henri Mondor, Créteil, France.;Université Paris-Est, Faculté de Médecine, Créteil, France; Genetic Department, AP-HP, Hôpital Henri Mondor, Créteil, France.;Pulmonology Department, AP-HP, Hôpital Bichat, Paris, France.;Pediatric Department, Centre Hospitalier Universitaire de Lille, Lille, France; Centre des Maladies Respiratoires Rare, Respirare(®), Paris, France.;Pediatric Department, Centre Hospitalier Universitaire de Lille, Lille, France; Centre des Maladies Respiratoires Rare, Respirare(®), Paris, France.;Pediatric Department, Centre Intercommunal de Créteil, Créteil, France; Inserm, Unité 955, Equipe 5, Créteil, France; DHU Ageing Thorax Vessel Blood, Créteil, France; Centre des Maladies Respiratoires Rare, Respirare(®), Paris, France; Université Paris-Est, Faculté de Médecine, Créteil, France. Electronic address: ralph.epaud@chicreteil.fr.",
"authors": "Nattes|Elodie|E|;Lejeune|Stephanie|S|;Carsin|Ania|A|;Borie|Raphael|R|;Gibertini|Isabelle|I|;Balinotti|Juan|J|;Nathan|Nadia|N|;Marchand-Adam|Sylvain|S|;Thumerelle|Caroline|C|;Fauroux|Brigitte|B|;Bosdure|Emmanuelle|E|;Houdouin|Veronique|V|;Delestrain|Celine|C|;Louha|MaleK|M|;Couderc|Remy|R|;De Becdelievre|Alix|A|;Fanen|Pascale|P|;Funalot|Benoit|B|;Crestani|Bruno|B|;Deschildre|Antoine|A|;Dubus|Jean-Christophe|JC|;Epaud|Ralph|R|",
"chemical_list": "D037701:Pulmonary Surfactant-Associated Protein B; D011663:Pulmonary Surfactants; D000074482:Thyroid Nuclear Factor 1",
"country": "England",
"delete": false,
"doi": "10.1016/j.rmed.2017.05.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6111",
"issue": "129()",
"journal": "Respiratory medicine",
"keywords": "Interstitial lung disease; NKX2-1; Prognosis; Steroids; Surfactant; Treatment",
"medline_ta": "Respir Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001264:Athetosis; D001992:Bronchoalveolar Lavage Fluid; D002648:Child; D002819:Chorea; D003409:Congenital Hypothyroidism; D005260:Female; D005602:France; D005801:Genes, Homeobox; D006801:Humans; D008171:Lung Diseases; D017563:Lung Diseases, Interstitial; D008297:Male; D009154:Mutation; D011379:Prognosis; D011649:Pulmonary Alveolar Proteinosis; D037701:Pulmonary Surfactant-Associated Protein B; D011663:Pulmonary Surfactants; D012127:Respiratory Distress Syndrome, Newborn; D012129:Respiratory Function Tests; D012189:Retrospective Studies; D000074482:Thyroid Nuclear Factor 1; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8908438",
"other_id": null,
"pages": "16-23",
"pmc": null,
"pmid": "28732825",
"pubdate": "2017-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Heterogeneity of lung disease associated with NK2 homeobox 1 mutations.",
"title_normalized": "heterogeneity of lung disease associated with nk2 homeobox 1 mutations"
} | [
{
"companynumb": "FR-CONCORDIA PHARMACEUTICALS INC.-GSH201707-004005",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
... |
{
"abstract": "BACKGROUND\nSome long-term nicotine gum users are addicted to nicotine and may need assistance to stop. There is no published evidence on the use of nicotine patches for this purpose.\n\n\nMETHODS\nA 45-year old man presented with a 30-year history of high-dose nicotine gum use (up to 200mg nicotine per day). He was highly nicotine dependent and had failed repeatedly to stop using nicotine gum use in the past. Within a week of commencing nicotine patches he was able to cease nicotine gum with minimal discomfort and has remained nicotine-free for 6 months, with abstinence confirmed biochemically. His severe sweating disorder rapidly resolved with cessation of the gum.\n\n\nCONCLUSIONS\nNicotine patches may be an effective treatment for long-term nicotine gum addiction.",
"affiliations": "The Sydney Clinic, Bronte, Australia mendel@bigpond.net.au.",
"authors": "Mendelsohn|Colin P|CP|",
"chemical_list": "D009538:Nicotine",
"country": "England",
"delete": false,
"doi": "10.1093/ntr/ntv124",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2203",
"issue": "18(5)",
"journal": "Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco",
"keywords": null,
"medline_ta": "Nicotine Tob Res",
"mesh_terms": "D000279:Administration, Cutaneous; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine; D012907:Smoking; D016540:Smoking Cessation; D013997:Time Factors; D061485:Tobacco Use Cessation Devices; D014029:Tobacco Use Disorder",
"nlm_unique_id": "9815751",
"other_id": null,
"pages": "1220-1",
"pmc": null,
"pmid": "26045253",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three Decades of High-Dose Nicotine Gum Dependence Treated With Nicotine Patches.",
"title_normalized": "three decades of high dose nicotine gum dependence treated with nicotine patches"
} | [
{
"companynumb": "AU-GLAXOSMITHKLINE-AU2016073356",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TESTOSTERONE"
},
"drugadditional": nul... |
{
"abstract": "Rabbit anti-thymocyte globulin (rATG) is an infusion of polyclonal rabbit-derived antibodies against human thymocyte markers, which can be used to prevent and treat acute rejection following organ transplantation. However, the product monograph issued by the manufacturer (Sanofi Canada) reports that serious immune-mediated reactions have been observed following the use of rATG, consisting of anaphylaxis or severe cytokine release syndrome (CRS), which is a form of vasoplegic syndrome (VS), in which distributive shock occurs refractory to norepinephrine (NE) and vasopressin (VP). Severe infusion-associated reactions are consistent with CRS and can cause serious cardiac or respiratory problems, or in certain cases, mortality. CRS is a form of systemic inflammatory response syndrome (SIRS). In SIRS, the substantial activation of endothelial inducible nitric oxide synthase (iNOS) and smooth muscle guanylate cyclase (GC) is observed, which can produce severe hypotension that is unresponsive to conventional vasopressors. Methylene blue (MB) is a direct inhibitor of iNOS and GC and has been used as an effective treatment for VS following cardiothoracic surgery. In the present study, the successful use of MB as a rescue therapy for CRS in a patient receiving rATG following a renal transplant was reported. Following an uneventful cadaveric kidney transplant involving the intravenous (IV) administration of rATG for the induction of immunological tolerance, the patient became markedly hypotensive and tachycardic. The patient required high doses of VP and NE infusions. Following the protocol described for treating refractory VS in post-cardiac surgery patients, the decision was made to initiate the patient on an IV MB infusion. This treatment protocol was shown to improve the hemodynamic status of the patient, which enabled the withdrawal of vasopressors and suggests an important role for methylene blue in the management of refractory VS.",
"affiliations": "Department of Anesthesia, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.;Department of Anesthesia, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.;Virtua Memorial Hospital, Department of Anesthesia, Mount Holly, NJ 08060, USA.;Department of Anesthesia, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.;Department of Anesthesia, New York University Medical Center, New York, NY 10016, USA.;Department of Anesthesia, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.",
"authors": "Denny|John T|JT|;Burr|Andrew T|AT|;Balzer|Fred|F|;Tse|James T|JT|;Denny|Julia E|JE|;Chyu|Darrick|D|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2015.2349",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-0981",
"issue": "9(5)",
"journal": "Experimental and therapeutic medicine",
"keywords": "cytokine release syndrome; cytokines; distributive shock; rabbit anti-thymocyte globulin; renal transplant complications; shock; thymoglobulin; vasoplegia; vasoplegic shock; vasoplegic syndrome",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "1915-1920",
"pmc": null,
"pmid": "26136914",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": "11015622;16886062;1340777;12209078;8993292;10567301;11529214;8465415;19217797;16143539;1378338;11383777;18473936;23678006;16434757;12830064;8651772;22772515;17095500;17387132;12472415;8465429;12226053;10512533;12394955;7678341;14759425;15985820;12768118;8651756;11146694;9833722;7505803;11427637;9366923;22982035;21092891;20150766;19756505;23353941;20145575",
"title": "Methylene blue treatment for cytokine release syndrome-associated vasoplegia following a renal transplant with rATG infusion: A case report and literature review.",
"title_normalized": "methylene blue treatment for cytokine release syndrome associated vasoplegia following a renal transplant with ratg infusion a case report and literature review"
} | [
{
"companynumb": "US-SA-2015SA040781",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizati... |
{
"abstract": "OBJECTIVE\nThere are no reports examining the safety of taking both topiramate and aripiprazole together with alcohol. The ultimate aim for this research is to determine whether this combination is safe and is superior to either drug taken alone in reducing alcohol use in alcohol dependent patients.\n\n\nMETHODS\nThis was an open-label trial. Thirteen heavy drinking participants not seeking treatment for alcoholism were randomized. Participants were titrated up to 300 mg of topiramate and 30 mg of aripiprazole a day over 35 days. Participants reported adverse events (AEs) daily alcohol use and participated in an alcohol challenge session (ACS).\n\n\nRESULTS\nThe eight participants who completed the study achieved the maximum doses of drugs. The AEs of the drugs would suggest that the AEs profile is broader but not additive. Alcohol use from the 28 days before screening to the seven days before the ACS was reduced (p = 0.08).\n\n\nCONCLUSIONS\nThere was no evidence that AEs of aripiprazole and topiramate are additive and can, therefore, be administered safely together with a modest amount of alcohol. There was also a trend for a reduction of alcohol use by participants. This finding has implications for further investigation of this combination of drugs for alcohol dependence.",
"affiliations": "Department of Psychiatry and the Center for Alcohol and Addiction Studies, Brown University, Providence, Rhode Island, USA. George_Kenna@Brown.edu",
"authors": "Kenna|George A|GA|;Leggio|Lorenzo|L|;Swift|Robert M|RM|",
"chemical_list": "D014150:Antipsychotic Agents; D018696:Neuroprotective Agents; D010879:Piperazines; D015363:Quinolones; D000077236:Topiramate; D005632:Fructose; D000068180:Aripiprazole",
"country": "England",
"delete": false,
"doi": "10.1002/hup.1042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-6222",
"issue": "24(6)",
"journal": "Human psychopharmacology",
"keywords": null,
"medline_ta": "Hum Psychopharmacol",
"mesh_terms": "D000328:Adult; D000428:Alcohol Drinking; D000437:Alcoholism; D014150:Antipsychotic Agents; D000068180:Aripiprazole; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005632:Fructose; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents; D010879:Piperazines; D015363:Quinolones; D000077236:Topiramate; D055815:Young Adult",
"nlm_unique_id": "8702539",
"other_id": null,
"pages": "465-72",
"pmc": null,
"pmid": "19551762",
"pubdate": "2009-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "A safety and tolerability laboratory study of the combination of aripiprazole and topiramate in volunteers who drink alcohol.",
"title_normalized": "a safety and tolerability laboratory study of the combination of aripiprazole and topiramate in volunteers who drink alcohol"
} | [
{
"companynumb": "US-JNJFOC-20130610422",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "A lumboperitoneal shunt facilitates dynamic flow of cerebrospinal fluid into the peritoneum. Consequently, neuraxial technique placement in the parturient with a lumboperitoneal shunt can result in unexpected levels of blockade. We present the case of a parturient with a lumboperitoneal shunt who experienced symptoms consistent with high blockade after epidural administration of 450 mg chloroprocaine. This report emphasizes potential mechanisms for high neuraxial blockade and strategies to decrease risks in this unique patient population.",
"affiliations": "From the Department of Anesthesiology and Critical Care.;From the Department of Anesthesiology and Critical Care.;Neurosurgery, Tufts Medical Center, Boston, Massachusetts.;From the Department of Anesthesiology and Critical Care.;From the Department of Anesthesiology and Critical Care.",
"authors": "Moreno-Duarte|Ingrid|I|;Hall|Robert R|RR|;Shutran|Max S|MS|;Radhakrishnan|Manga G|MG|;Drzymalski|Dan M|DM|",
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"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000779:Anesthetics, Local; D002557:Cerebrospinal Fluid Shunts; D002585:Cesarean Section; D005260:Female; D006801:Humans; D011247:Pregnancy; D011343:Procaine",
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"title": "Epidural Anesthesia for Cesarean Delivery in a Parturient With Lumboperitoneal Shunt: A Case Report.",
"title_normalized": "epidural anesthesia for cesarean delivery in a parturient with lumboperitoneal shunt a case report"
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"abstract": "Clonal cytogenic evolution with the development of additional chromosomal abnormalities (ACAs) in chronic myelogenous leukemia (CML) is a marker for disease progression and is known to impact therapy and survival. The presence of ACAs has been shown to affect the responses to tyrosine kinase inhibitors (TKI) in patients with newly diagnosed CML in accelerated phase (CML-AP). We report a rare case of a CML patient who presented in CML-AP and was found to have multiple ACAs including monosomy 7, deletion 7p, trisomy 8, and an extra Philadelphia chromosome (Ph) in separate Ph-positive cell line, respectively. Six months after combined chemotherapy with TKI, the patient achieved a major cytogenetic response with disappearance of monosomy 7/deletion 7p with no major molecular response.",
"affiliations": "Department of Pathology, University of Arizona, Tucson, AZ USA. Electronic address: alswied@pathology.arizona.edu.;Department of Pathology, University of Arizona, Tucson, AZ USA.;Department of Pathology, University of Arizona, Tucson, AZ USA.;Department of Pathology, University of Arizona, Tucson, AZ USA.;Division of Hematology and Medical Oncology, Department of Medicine, University of Arizona, Tucson, AZ USA.;Department of Pathology, University of Arizona, Tucson, AZ USA.",
"authors": "Alswied|Abdullah|A|;Rehman|Aseeb|A|;Lai|Li-Wen|LW|;Duran|Juanita|J|;Sardar|Muhammad|M|;Proytcheva|Maria A|MA|",
"chemical_list": "D000970:Antineoplastic Agents",
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"issue": "252-253()",
"journal": "Cancer genetics",
"keywords": "Additional chromosomal abnormalities; Chronic myelogenous leukemia; Clonal cytogenic evolution; Deletion 7p; Monosomy 7; Philadelphia chromosome",
"medline_ta": "Cancer Genet",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D006801:Humans; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male",
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"title": "Rare monosomy 7 and deletion 7p at diagnosis of chronic myeloid leukemia in accelerated phase.",
"title_normalized": "rare monosomy 7 and deletion 7p at diagnosis of chronic myeloid leukemia in accelerated phase"
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"abstract": "Adefovir dipivoxil, an oral prodrug of adefovir, is used in the treatment of lamivudine-resistant hepatitis B virus (HBV) infection. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN) were commonly reported in the past, when higher doses were used for the treatment of human immunodeficiency virus infection. However, nephrotoxicity is rare at lower doses that are currently recommended for the treatment of HBV infection. A 31-year-old female was detected to be hepatitis B surface antigen positive months after a kidney transplant. The patient was initiated on lamivudine, but developed resistance after 1 year of treatment, at which time low-dose adefovir was added. The patient developed renal allograft dysfunction after 10 months of starting adefovir. Serum creatinine increased from 1.1 mg/dl to 1.9 mg/dl, along with progressively increasing sub-nephrotic proteinuria. Renal allograft biopsy revealed features of ATN. After discontinuation of adefovir, proteinuria resolved and renal dysfunction improved slowly over the next 2 years. Adefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods.",
"affiliations": "Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Clinical Virology, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India.;Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India.",
"authors": "George|N|N|;Basu|G|G|;Mohapatra|A|A|;Zachariah|U|U|;Abraham|P|P|;Korula|A|A|;Varughese|S|S|;Jacob|C K|CK|;Tamilarasi|V|V|",
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"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-25-18010.4103/0971-4065.144423Case ReportAdefovir nephrotoxicity in a renal allograft recipient George N. Basu G. Mohapatra A. Zachariah U. 1Abraham P. 2Korula A. 3Varughese S. Jacob C. K. Tamilarasi V. Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India1 Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India2 Department of Clinical Virology, Christian Medical College, Vellore, Tamil Nadu, India3 Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, IndiaAddress for correspondence: Dr. Gopal Basu, Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India. E-mail: drbasug@yahoo.co.inMay-Jun 2015 25 3 180 183 Copyright: © Indian Journal of Nephrology2015This 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.Adefovir dipivoxil, an oral prodrug of adefovir, is used in the treatment of lamivudine-resistant hepatitis B virus (HBV) infection. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN) were commonly reported in the past, when higher doses were used for the treatment of human immunodeficiency virus infection. However, nephrotoxicity is rare at lower doses that are currently recommended for the treatment of HBV infection. A 31-year-old female was detected to be hepatitis B surface antigen positive months after a kidney transplant. The patient was initiated on lamivudine, but developed resistance after 1 year of treatment, at which time low-dose adefovir was added. The patient developed renal allograft dysfunction after 10 months of starting adefovir. Serum creatinine increased from 1.1 mg/dl to 1.9 mg/dl, along with progressively increasing sub-nephrotic proteinuria. Renal allograft biopsy revealed features of ATN. After discontinuation of adefovir, proteinuria resolved and renal dysfunction improved slowly over the next 2 years. Adefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods.\n\nAdefovirhepatitis Blamivudine-resistantnephrotoxicityrenaltransplant.\n==== Body\nIntroduction\nEffective treatment of hepatitis B virus (HBV) in renal transplant recipients is required to prevent active viral replication and progression of liver damage.[12] Lamivudine has traditionally been considered to be the drug of choice for post-transplant HBV infection due to its efficacy and safety.[3] However, there is an increasing incidence of lamivudine resistance due to selection of tyrosine-methionine-aspartate-aspartate (YMDD) mutants after long term therapy with lamivudine.[4] Adefovir dipivoxil, an oral prodrug of adefovir, is one of the agents effective against lamivudine-resistant HBV. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN) were commonly reported, when higher doses (60–120 mg/day) of adefovir were used for the treatment of human immunodeficiency virus (HIV) infection in the past.[5] However, nephrotoxicity is quite rare at lower doses (10 mg/day) currently recommended for the treatment of HBV infection. In this report, we describe the occurrence of adefovir-induced ATN in a renal allograft recipient who was treated with adefovir 10 mg daily for lamivudine-resistant HBV infection.\n\nCase Report\nA 31-year-old female with end-stage renal disease due to immunoglobulin A nephropathy underwent living-related kidney transplantation in May 2006, with mother as voluntary kidney donor. The human leukocyte antigen was haplomatch and pre-transplant complement-dependent cytotoxicity cross-match was negative. Her pre-transplant HIV enzyme-linked immunosorbent assay, hepatitis B surface antigen (HbsAg) and anti-hepatitis C virus serology was negative. She did not receive induction immunosuppression. There were no intraoperative or postoperative complications. She did not require blood transfusion during surgery. She was on prednisolone, cyclosporine and azathioprine for maintenance immunosuppression and reached a nadir serum creatinine of 0.7 mg/dl on the 5th postoperative day. She was detected to have BK viremia 1 month after the transplantation without graft dysfunction and was initiated on leflunomide 20 mg once daily. Her cyclosporine dose was gradually reduced from an initial dose of 150 mg twice daily in 2006 to 75 mg twice a day in 2007 and 25 mg twice daily in 2008. The same dose of cyclosporine was continued henceforth along with 7.5 mg of prednisolone, 100 mg azathioprine and 20 mg leflunomide. She had a stable graft function with serum creatinine of 1.1 mg/dl on this immunosuppression.\n\nFifteen months after the transplantation, she was incidentally detected to have deranged liver enzymes with aspartate aminotransferase and alanine aminotransferase levels of 60 IU/ml and 87 IU/ml, respectively. On further evaluation, she was detected to be HbsAg positive with HBV deoxyribonucleic acid titers of 2 × 108 IU/ml. She was initiated on lamivudine 100 mg once daily. The HBV DNA titers decreased to 466 IU/ml after 6 months. But on repeat evaluation a year later, HBV titers had rebounded to 1 × 107 IU/ml despite good compliance. In view of lamivudine resistance, she was advised to change to entecavir. However due to financial constraints, adefovir 10 mg once daily was added to lamivudine in August 2008. Her serum creatinine then was 1.1 mg/dl, with normal 24-h urine protein excretion. Her other medications included calcium carbonate, calcitriol, amlodipine, atorvastatin and leflunomide, apart from maintenance triple immunosuppression.\n\nAfter the addition of adefovir, her HBV DNA titers decreased to 79 IU/ml. However, there was slow deterioration of renal allograft function with serum creatinine increasing to 1.5 mg/dl after 10 months of adefovir and then to 1.9 mg/dl after 26 months of adefovir therapy. Simultaneously, there was progressive increase in 24-h urine protein excretion to 847 mg/dl. Her serum phosphorus was 3.1 mg/dl (normal range: 2.5–4.6 mg/dl) and serum bicarbonate was 24 meq/L. The urine pH was 7.0 with no glycosuria on dipstick analysis. BK virus polymerase chain reaction in blood was negative. No changes in immunosuppression were made during this period.\n\nA renal biopsy was performed, which revealed a core of renal tissue with 12 glomeruli, of which 3 were obsolescent. The remaining glomeruli displayed mild increase in mesangial cellularity. There were focal areas of ATN with regenerative changes of tubular lining epithelium, along with interstitial edema and mild interstitial infiltrates of mononuclear cells [Figure 1]. There was no evidence of rejection. Immunofluorescence staining did not reveal any immune deposits. C4d staining of peritubular capillaries was negative.\n\nFigure 1 Renal allograft biopsy revealing features of acute tubular necrosis. Biopsy showing tubular cell swelling (arrow head), cell necrosis with denudation of the basement membrane (thin arrows), and thinning of the brush-border (thick arrow)\n\nThe possibility of adefovir-induced ATN was considered and adefovir was replaced with entecavir. At the subsequent visit 6 months later, proteinuria had resolved completely to 89 mg/day, while serum creatinine improved to 1.4 mg/dl. Over the next 18 months, renal function continued to improve with serum creatinine reaching the baseline of 1.2 mg/dl [Figure 2]. However, since the patient did not achieve adequate viral suppression with entecavir at doses recommended in the setting of lamivudine resistance and due to lack of safer alternatives, tenofovir disoproxil fumarate was added to entecavir, with close monitoring of serum creatinine and tubular function. At the last follow-up, the patient is having stable renal allograft function with negative HBV DNA titers.\n\nFigure 2 Timeline of renal dysfunction and urinary protein excretion in relation to adefovir initiation. (Adef: Adefovir; ATN: Acute tubular necrosis; Ente: Entecavir; Lam: Lamivudine; Ten: Tenofovir)\n\nDiscussion\nAdefovir dipivoxil is an oral prodrug of adefovir that is effective against lamivudine-resistant HBV mutants. Adefovir was originally developed as an antiretroviral agent for HIV at a dosage of 60–120 mg daily, but was not preferred later due to high incidence of nephrotoxicity, occurring in 22–50% of patients.[5] Subsequently it was found that adefovir was effective against HBV in much lower dosages and was approved for treatment of the same in 2002 at a dosage of 10 mg daily. The active intracellular metabolite, adefovir diphosphate causes inhibition of both reverse transcriptase and HBV DNA polymerase and is incorporated into DNA causing chain termination, accounting for its therapeutic effects.\n\nThe drug gets concentrated within the renal proximal tubular cells due to active uptake from the blood by the human organic anion transporter-1.[6] It is then secreted into the urine by multi-drug resistant protein located at the apical side of proximal tubular cells. Adefovir acts as a mitochondrial toxin due to its ability to inhibit the human mitochondrial DNA polymerase gamma.[7] This can lead to impaired mitochondrial replication with mitochondrial loss and dysfunction, with resultant impairment of oxidative phosphorylation and cellular damage.\n\nIn the initial 1-year registration trials for HBV infection, the frequency of grade I nephrotoxicity (defined as serum creatinine 0.5 mg/dl above baseline values) was similar in adefovir-treated and placebo-treated patients (0% vs. 0%).[89] However, long-term studies reported that adefovir-induced nephrotoxicity occurred in a small proportion of patients even at lower dosages. For example, in a cohort of 125 patients with chronic hepatitis B e antigen (HBeAg)-negative hepatitis B treated with adefovir for 5 years, the frequency of serum creatinine elevations that were 0.5 mg/dl above baseline was 3%.[10] Similarly, 8% of the 65 patients who were HBeAg-positive and receiving adefovir for 5 years had reversible creatinine elevations, 5% had albuminuria, and 3% developed hypophosphatemia.[11]\n\nFrom these observations, it is clear that the nephrotoxicity of adefovir is both dose- and time-dependent. The typical clinical pattern of adefovir nephrotoxicity is characterized by slow rises in serum creatinine and decreases in serum phosphate levels, occurring 4–12 months after starting therapy. This can be associated with Fanconi-like renal tubular acidosis. The nephrotoxicity is usually reversible if therapy is stopped promptly.\n\nIn our patient, the pattern of nephrotoxicity was similar, as characterized by a gradual and progressive rise in serum creatinine along with tubular-range proteinuria over a period of 2 years. The renal biopsy revealed characteristic features of ATN such as thinning of the brush-border, tubular cell swelling and cell necrosis with denudation of the basement membrane. The other findings noted such as mild increase in mesangial cellularity, interstitial edema and mild interstitial infiltrates were not significant enough to suggest an alternative diagnosis. There was no evidence of tubulitis or peritubular capillaritis to merit a diagnosis of graft rejection. A review of the patient's medications did not reveal any confounding agent. The serum level of cyclosporine was < 25 ng/ml, thus making calcineurin nephrotoxicity highly unlikely.\n\nOn withdrawal of adefovir, there was prompt resolution of proteinuria and improvement in serum creatinine to 1.4 mg/dl. However, the serum creatinine reached baseline only after a period of around 2 years. Delay in recovery of renal function following withdrawal of adefovir has been described previously.[512] For example, in a randomized, double-blind, placebo-controlled multicenter trial with 12 months' follow-up among HIV-infected patients, 253 patients were assigned to adefovir 120 mg once daily.[5] Among 17.2% patients who developed adefovir nephrotoxicity, the median time to resolution of proximal renal tubular dysfunction was 15 weeks and in 16% of patients, the renal function did not recover completely even at 41 weeks after onset of nephrotoxicity.[5] Considering that the above study was conducted in patients with native kidneys, further delay in recovery of ATN can be expected in renal allograft recipients. For instance, in a report of adefovir-induced ATN in a renal allograft recipient, the renal function continued to worsen after discontinuation of adefovir, even though other markers of proximal tubular dysfunction resolved at 4 months after discontinuation.[12] Delay in recovery of ATN following delayed graft function has also been reported in renal allograft recipients.[13]\n\nOur patient did not have features of proximal renal tubular acidosis or hypophosphatemia, illustrating that all features of nephrotoxicity need not manifest in a particular patient. Thus, a high index of suspicion is required to diagnose adefovir nephrotoxicity.\n\nThe occurrence of adefovir nephrotoxicity in renal allograft recipients has been reported rarely. In a series of 11 renal transplant recipients who received adefovir for lamivudine-resistant chronic HBV infection, at 2 years after starting adefovir, there was a significant increase in serum creatinine from 125 (±35) to 141 (±32) μmol/l, (P = 0.02) and a significant increase in 24-hour proteinuria.[14] In another case series involving 14 renal transplant recipients who were on adefovir, four patients (29%) developed renal dysfunction due to presumed adefovir nephrotoxicity.[15]\n\nConclusion\nAdefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Fabrizi F Martin P Dixit V Kanwal F Dulai G HBsAg seropositive status and survival after renal transplantation: Meta-analysis of observational studies Am J Transplant 2005 5 2913 21 16303005 \n2 Mathurin P Mouquet C Poynard T Sylla C Benalia H Fretz C Impact of hepatitis B and C virus on kidney transplantation outcome Hepatology 1999 29 257 63 9862875 \n3 Fabrizi F Dulai G Dixit V Bunnapradist S Martin P Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation: Meta-analysis of clinical trials Transplantation 2004 77 859 64 15077027 \n4 Chayama K Suzuki Y Kobayashi M Kobayashi M Tsubota A Hashimoto M Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild type after cessation of therapy Hepatology 1998 27 1711 6 9620347 \n5 Fisher EJ Chaloner K Cohn DL Grant LB Alston B Brosgart CL The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: A randomized, placebo-controlled trial AIDS 2001 15 1695 700 11546945 \n6 Ho ES Lin DC Mendel DB Cihlar T Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1 J Am Soc Nephrol 2000 11 383 93 10703662 \n7 Tanji N Tanji K Kambham N Markowitz GS Bell A D'agati VD Adefovir nephrotoxicity: Possible role of mitochondrial DNA depletion Hum Pathol 2001 32 734 40 11486172 \n8 Marcellin P Chang TT Lim SG Tong MJ Sievert W Shiffman ML Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B N Engl J Med 2003 348 808 16 12606735 \n9 Hadziyannis SJ Tassopoulos NC Heathcote EJ Chang TT Kitis G Rizzetto M Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B N Engl J Med 2003 348 800 7 12606734 \n10 Hadziyannis SJ Tassopoulos NC Heathcote EJ Chang TT Kitis G Rizzetto M Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years Gastroenterology 2006 131 1743 51 17087951 \n11 Marcellin P Chang TT Lim SG Sievert W Tong M Arterburn S Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B Hepatology 2008 48 750 8 18752330 \n12 Izzedine H Kheder-Elfekih R Housset P Sarkozy C Brocheriou I Deray G Adefovir dipivoxil-induced acute tubular necrosis and Fanconi syndrome in a renal transplant patient AIDS 2009 23 544 5 19165085 \n13 Huraib S Al Khudair W Al Ghamdi G Iqbal A Post transplant acute tubular necrosis - How long you can wait. A case report? Saudi J Kidney Dis Transpl 2002 13 50 4 18209413 \n14 Kamar N Huart A Tack I Alric L Izopet J Rostaing L Renal side effects of adefovir in hepatitis B virus-(HBV) positive kidney allograft recipients Clin Nephrol 2009 71 36 42 19203548 \n15 Lai HW Chang CC Chen TH Tsai MC Chen TY Lin CC Safety and efficacy of adefovir therapy for lamivudine-resistant hepatitis B virus infection in renal transplant recipients J Formos Med Assoc 2012 111 439 44 22939662\n\n",
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"issue": "25(3)",
"journal": "Indian journal of nephrology",
"keywords": "Adefovir; hepatitis B; lamivudine-resistant; nephrotoxicity; renal; transplant.",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
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"pages": "180-3",
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"pmid": "26060371",
"pubdate": "2015",
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"title": "Adefovir nephrotoxicity in a renal allograft recipient.",
"title_normalized": "adefovir nephrotoxicity in a renal allograft recipient"
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"abstract": "We discuss the case of a 50-year-old nulliparous woman who conceived after in vitro fertilisation. She had multiple medical comorbidities and presented an obstetric and medical challenge. She was carefully managed through pregnancy and had a successful outcome. In this report, we explore the medical complexity, as well as ethical and logistic issues involved.",
"affiliations": "Obstetrics and Gynaecology, The Royal Free Hospital, London, UK.;Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, London, UK.;Obstetrics and Gynaecology, The Royal Free Hospital, London, UK.",
"authors": "Balachandran Nair|Deepa|D|http://orcid.org/0000-0002-3790-9256;Gopal|Dipesh P|DP|;Singh|Vinita|V|",
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"keywords": "diabetes; ethics; migration and health; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002585:Cesarean Section; D015897:Comorbidity; D003922:Diabetes Mellitus, Type 1; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008423:Maternal Age; D057193:Medical Tourism; D008875:Middle Aged; D009774:Obstetrics; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011254:Pregnancy in Diabetics; D018566:Pregnancy, High-Risk; D011295:Prenatal Care; D016216:Ultrasonography, Prenatal",
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"references": "25105982;24172695;25559311;25156070;22915663;24104771;25639706;28177512;25706069;28604169;26487769;28711075;28740618",
"title": "21st century obstetrics: a 50-year-old nullip-walk in the park?",
"title_normalized": "21st century obstetrics a 50 year old nullip walk in the park"
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"abstract": "OBJECTIVE\nThe objective of this exposed-unexposed study was to evaluate potential effects of dopamine agonists during pregnancy.\n\n\nMETHODS\nData from EFEMERIS, a cohort of 57,408 pregnant women living in South West France, were used to compare exposed and unexposed women. The exposed group included 183 women (0.3 %) who received at least one prescription for one dopamine agonist during pregnancy. These women were individually matched with two unexposed women from the cohort for age and the month-and-year of the start of pregnancy. Pregnancy losses, birth defects, preterm births, low birth weight and psychomotor development were studied.\n\n\nRESULTS\nBromocriptine was the most frequently prescribed dopamine agonist, followed by cabergoline and quinagolide. Most (75 %) of the dopamine agonists were prescribed at the beginning of pregnancy (first trimester). There was no difference between the two groups concerning pregnancy history and demographic data. After adjustment for potential confounders, prescription and dispensation of dopamine agonists was associated with an increased risk of pregnancy loss [PORa = 3.7; 95 % confidence interval (CI) 1.8-7.4] and preterm birth (PORa = 3.6; 95 % CI 1.5-8.3). The prevalence of birth defects and low birth weight was not significantly different between the two groups. No difference in psychomotor development at either 9 or 24 months was observed between the two groups.\n\n\nCONCLUSIONS\nThis study suggests that prenatal exposure to dopamine agonists may be associated with an increased risk of pregnancy loss and preterm birth.",
"affiliations": "Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de PharmacoVigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, INSERM UMR 1027, Faculté de Médecine, Université Toulouse 3, Centre Hospitalier Universitaire, 37 allées Jules Guesde, 31000, Toulouse, France, caroline.delarue-hurault@univ-tlse3.fr.",
"authors": "Hurault-Delarue|Caroline|C|;Montastruc|Jean-Louis|JL|;Beau|Anna-Belle|AB|;Lacroix|Isabelle|I|;Damase-Michel|Christine|C|",
"chemical_list": "D018491:Dopamine Agonists",
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"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D015331:Cohort Studies; D016208:Databases, Factual; D018491:Dopamine Agonists; D005260:Female; D005602:France; D006801:Humans; D007223:Infant; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D047928:Premature Birth; D012306:Risk",
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"title": "Pregnancy outcome in women exposed to dopamine agonists during pregnancy: a pharmacoepidemiology study in EFEMERIS database.",
"title_normalized": "pregnancy outcome in women exposed to dopamine agonists during pregnancy a pharmacoepidemiology study in efemeris database"
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"abstract": "OBJECTIVE\nTo compare the safety and regression rates of conservative treatments for complex atypical hyperplasia (CAH) between pre- and postmenopausal women.\n\n\nMETHODS\nHistorical cohort study of pre- and postmenopausal women with CAH managed conservatively at one center (Royal Women's Hospital, Melbourne, Australia) between September 1999 to June 2012.\n\n\nRESULTS\nOf the 153 women with CAH, 92 (60%) underwent hysterectomy and the remaining 61 were managed conservatively with oral or intrauterine progestogen: 42 were premenopausal and 19 were postmenopausal. Within 12 months, 32 (76%) premenopausal women demonstrated regression of CAH and none developed endometrial cancer. In contrast, only 4 (21%) postmenopausal women showed disease regression and 4 (21%) progressed to endometrial cancer. Over a median of 24 months, 3 premenopausal women relapsed with CAH and 2 developed endometrial cancer. Four premenopausal women had successful pregnancies.\n\n\nCONCLUSIONS\nConservative treatment with progestogen in premenopausal women with CAH leads to high regression rates within the first 12 months. In contrast, postmenopausal women have high rates of ongoing disease and cancer progression and conservative therapy should be avoided.",
"affiliations": "Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia fbrownfoot@student.unimelb.edu.au.;Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia.;Department of Gynaecology, Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia.;Department of Gynaecological Oncology, Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia.;Department of Gynaecological Oncology, Royal Women's Hospital, Parkville, Melbourne, Victoria, Australia.",
"authors": "Brownfoot|Fiona C|FC|;Hickey|Martha|M|;Ang|W Catarina|WC|;Arora|Vivek|V|;McNally|Orla|O|",
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"keywords": "complex atypical hyperplasia; menopause; progestogen",
"medline_ta": "Reprod Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D019468:Disease Management; D004714:Endometrial Hyperplasia; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007044:Hysterectomy; D008875:Middle Aged; D017698:Postmenopause; D017697:Premenopause; D011372:Progestins; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"references": null,
"title": "Complex atypical hyperplasia of the endometrium: differences in outcome following conservative management of pre- and postmenopausal women.",
"title_normalized": "complex atypical hyperplasia of the endometrium differences in outcome following conservative management of pre and postmenopausal women"
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"abstract": "Systemic lupus erythematosus is an autoimmune disease associated with mild valvular regurgitation. However, there have been no detailed reports of infective endocarditis in patients with systemic lupus erythematosus. Here, we describe a case of a 55-year-old woman without any cardiac abnormalities who was diagnosed with lupus nephritis by renal biopsy; she contracted infective endocarditis while receiving immunosuppressive therapy. Our case emphasizes that special consideration of the occurrence of infective endocarditis, and its early diagnosis and treatment are mandatory for patient survival. We propose that echocardiography should be performed before treating patients with systemic lupus erythematosus who have an uncertain cardiac status.",
"affiliations": "Department of Nephrology, Tsuchiura Kyodo General Hospital, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tsuchiura Kyodo General Hospital, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tsuchiura Kyodo General Hospital, Japan.",
"authors": "Ihara|Katsuhito|K|;Rai|Tatemitsu|T|;Naito|Shotaro|S|;Toda|Takayuki|T|;Sasaki|Sei|S|;Uchida|Shinichi|S|;Matsui|Noriaki|N|",
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"doi": "10.2185/jrm.2936",
"fulltext": "\n==== Front\nJ Rural MedJ Rural MedJRMJournal of Rural Medicine : JRM1880-487X1880-4888The Japanese Association of Rural Medicine 293610.2185/jrm.2936Case ReportInfective endocarditis in a patient with lupus nephritis who was undergoing\nimmunosuppressive therapy: A case of survival Ihara Katsuhito \n1\nRai Tatemitsu \n2\nNaito Shotaro \n2\nToda Takayuki \n1\nSasaki Sei \n2\nUchida Shinichi \n2\nMatsui Noriaki \n1\n1 Department of Nephrology, Tsuchiura Kyodo General Hospital,\nJapan2 Department of Nephrology, Tokyo Medical and Dental\nUniversity, JapanCorrespondence: Katsuhito Ihara, MD, Department of Nephrology, Tsuchiura Kyodo General Hospital, 4-1-1 Otsuno, Tsuchiura City, Ibaraki 300-0028, Japan. E-mail: ctngt512@yahoo.co.jp30 11 2017 11 2017 12 2 139 145 31 5 2017 07 7 2017 ©2017 The Japanese Association of Rural Medicine2017This is an open-access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0:\n\nhttp://creativecommons.org/licenses/by-nc-nd/4.0/）. Systemic lupus erythematosus is an autoimmune disease associated with mild valvular\nregurgitation. However, there have been no detailed reports of infective endocarditis in\npatients with systemic lupus erythematosus. Here, we describe a case of a 55-year-old\nwoman without any cardiac abnormalities who was diagnosed with lupus nephritis by renal\nbiopsy; she contracted infective endocarditis while receiving immunosuppressive therapy.\nOur case emphasizes that special consideration of the occurrence of infective\nendocarditis, and its early diagnosis and treatment are mandatory for patient survival. We\npropose that echocardiography should be performed before treating patients with systemic\nlupus erythematosus who have an uncertain cardiac status.\n\nsystemic lupus erythematosuslupus nephritisinfective endocarditisimmunosuppressive therapy\n==== Body\nIntroduction\nSystemic lupus erythematosus (SLE) is an autoimmune disease that can damage the heart,\nkidneys, joints, skin, lungs, blood vessels, liver, and nervous system. One major\ncomplication of SLE is valvular thickening and valve vegetation, commonly involving the\nmitral valve1), which can lead\nto mild valvular regurgitation that is clinically irrelevant in most patients2). Among patients with SLE, the\nprevalence of valvular abnormalities ranges from 18% to 61%, with a median prevalence of\n33%3,4,5). The co-occurrence of valvular disease and abnormalities in\nthe reticuloendothelial system and complement pathway in SLE can place patients at a risk\nfor developing infective endocarditis (IE)1, 6). However, the prevalence of IE among patients with SLE who\nreceive immunosuppressive therapy is unknown.\n\nHere, we describe the case of a middle-aged woman with SLE complicated by IE who survived\nowing to early detection and proper treatment of IE. Similar strategies could be employed to\neffectively treat other patients in the future.\n\nCase Report\nA 55-year-old Japanese woman was admitted to our hospital for suspected glomerulonephritis.\nProteinuria, as shown by a urine protein/creatinine ratio of 1.8 g, was identified 4 months\nbefore admission, which was confirmed by the subsequent findings of abnormal leukocyte and\ngranular casts by renal biopsy. The patient had previously been diagnosed with mixed\nconnective tissue disease (MCTD) 17 years ago. Echocardiography performed at that time had\nshown pulmonary hypertension, with an estimated right ventricle pressure of 51 mmHg, without\nany valvular abnormalities. In addition, autoimmune hepatitis had been identified by liver\nbiopsy 14 years prior to the present admission. Thus, a daily dose of 8-mg oral\nglucocorticoids (GC) had been administered for MCTD and autoimmune hepatitis in the\nrheumatology department. Positive anti-Smith antibody and a high titer of anti-double strand\n(ds) DNA antibody (920 IU/mL) at the present admission indicated a more likely diagnosis of\nSLE than MCTD. The patient was admitted to the nephrology department for evaluation and\ncontrol of disease activity.\n\nThe medical history of the patient consisted of hypertension and positive hepatitis C virus\nantibody. No remarkable family history, alcohol use, smoking, or allergy was noted.\nCandesartan cilexetil/hydrochlorothiazide, famotidine, alendronate sodium hydrate, and\nloxoprofen sodium hydrate had been administered. Upon admission, the patient had a blood\npressure of 126/80 mmHg, pulse rate of 99 beats per minute, body temperature of 36.7°C, and\noxygen saturation of 99% at room air. Physical examination revealed the absence of heart\nmurmur, crackles in lungs, edema, cutaneous, or articular findings. Findings of the head,\nneck, chest, abdomen, and extremities were unremarkable. The results of laboratory exams are\nshown in Table 1Table 1 Laboratory tests on admission\nBlood tests\tValues\turinalysis\tvalues\t\nRBC\t397 × 104 /μL\tprotein\t2+\t\nHb\t11 g/dL\toccult blood\t±\t\nHt\t35%\tglucose\t–\t\nPlt\t24.8 × 104 /μL\tRBC\t10–19 /hpf\t\nWBC\t3,550 /μL\tWBC\t10–19 /hpf\t\nSt\t0%\tprotein (collection)\t3.87 g/day\t\nSg\t75.2%\tNAG\t29.6 U/gCr\t\nMono\t2.5%\tβ2MG\t6.4 mg/gCr\t\nLym\t22%\thyaline casts\t2+\t\nEosi\t0.3%\tepithelial casts\t1+\t\nBaso\t0%\tleukocyte casts\t1+\t\nTP\t7.1 g/dL\tgranulocyte casts\t1+\t\nAlb\t2.2 g/dL\t\t\t\nBUN\t19 mg/dL\t\t\t\nCr\t0.72 mg/dL\t\t\t\neGFR\t65 mL/min/1.73 m2\t\t\t\nUA\t6.8 mg/dL\t\t\t\nNa\t141 mEq/L\t\t\t\nCl\t109 mEq/L\t\t\t\nK\t3.8 mEq/L\t\t\t\nCa\t8.1 mg/dL\t\t\t\niP\t3.2 mg/dL\t\t\t\nCK\t31 IU/L\t\t\t\nAST\t37 IU/L\t\t\t\nALT\t17 IU/L\t\t\t\nLDH\t174 IU/L\t\t\t\nALP\t424 IU/L\t\t\t\nγGTP\t156 IU/L\t\t\t\nHbA1c\t6% (NGSP)\t\t\t\nFBS\t121 mg/dL\t\t\t\nT-C\t119 mg/dL\t\t\t\nLDL-C\t71 mg/dL\t\t\t\nTG\t178 mg/dL\t\t\t\nCRP\t2.43 mg/dL\t\t\t\nIgG\t2,470 mg/dL\t\t\t\nIgM\t66.4 mg/dL\t\t\t\nIgA\t892 mg/dL\t\t\t\nIgE\t177.8 IU/mL\t\t\t\nC3\t36.2 mg/dL\t\t\t\nC4\t3.2 mg/dL\t\t\t\nCH50\t< 12.0 U/mL\t\t\t\nANA\t≥ 1,280 fold\t\t\t\nRF\t≤ 5 IU/mL\t\t\t\nC1q\t< 1.5 μg/mL\t\t\t\nanti-dsDNA Ab\t920 IU/mL\t\t\t\nanti CCP Ab\t< 0.6 U/mL\t\t\t\nanti GBM Ab\t< 10 EU\t\t\t\nMPO-ANCA\t< 10 EU\t\t\t\nPR3-ANCA\t< 10 EU\t\t\t\nASL\t77 IU/mL\t\t\t\nKL-6\t275 U/mL\t\t\t\nHb: hemoglobin, Ht: hematocrit, Plt: platelet, St: stab neutrophils, Seg: segmented\nneutrophils, Mono: monocytes, Lym: lymphocytes, Eosi: eosinophils, Baso: basophils,\nTP: total protein, Alb: albumin, BUN: blood urea nitrogen, Cr: serum creatinine, eGFR:\nestimated glomerular filtration rate, CK: creatine kinase, AST: aspartate\naminotransferase, ALT: alanine aminotransferase, LDH: lactic acid dehydrogenase, ALP:\nalkaline phosphatase, γGTP: γ-glutamyl transpeptidase, FBS: fasting blood sugar, T-C:\ntotal cholesterol, LDL-C: low-density lipoprotein cholesterol, TG: triglyceride, CRP:\nC-reactive protein, ANA: antinuclear antibody, RF: rheumatoid factor, Ab: antibody,\nCCP : cyclic citrullinated peptide, GBM: glomerular basement membrane, MPO-ANCA:\nmyeloperoxidase anti-neutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3\nanti-neutrophil cytoplasmic antibody, ASL: antistreptolysin, UP: urinary protein, UOB:\nurinary occult blood, UG: urinary glucose, NAG: N-acetyl-β-D-glucosaminidase,\nβ2MG: β2 microglobulin.\n\n. The cardiothoracic ratio of the patient was 58% by chest radiography, and\nreticular shadows in both lower lung fields were visualized on computed tomography (CT). No\nabnormalities were indicated on electrocardiogram, and echocardiography detected no valvular\nabnormalities, dysfunction, or right ventricular load. The size of the kidneys was normal\n(right: 8.8 × 4.2 cm, left: 9.2 × 5.1 cm). A diagnosis of lupus nephritis (LN) with\nnephrotic syndrome was made based on the clinical course and the results of laboratory\ntests, and intravenous pulse GC therapy (1,000 mg methylprednisolone daily for 3 doses) was\nstarted, followed by daily oral administration of 60 mg of GC (1 mg/kg/day). The patient\nunderwent renal biopsy on Day 7 and was classified as IV-S (A) + V type according to the\nInternational Society of Nephrology/Renal Pathology Society classification. She was\nprescribed 1 g of trimethoprim-sulfamethoxazole per day for prophylaxis of pneumocystis\npneumonia; however, owing to a decline in platelets and an elevation in hepatic-cystic\nenzymes, trimethoprim-sulfamethoxazole was changed to pentamidine inhalation once a month.\nAlthough we planned to administer intravenous pulse cyclophosphamide (CYC) along with GC, as\nrecommended by the American College of Rheumatology guidelines for LN, we postponed its\nadministration owing to esophageal candidiasis confirmed by upper endoscopy, which emerged\nduring GC treatment. After treatment of the candidiasis by 200 mg of fluconazole per day,\nhigh-dose (800 mg) CYC (500–1,000 mg/m2 IV once a month scheduled for six doses)\nwas administered from Day 64. Estimated glomerular filtration rate was maintained above 60\nmL/min/1.73 m2 throughout the treatment course. LN activity was well managed, as\njudged by urine protein levels < 0.5 g per day, a decrease in anti-ds DNA antibody\ntiters, and an increase in C3/C4 ratio (Figure\n1Figure 1 Clinical course. Changes in urinary protein levels and estimated glomerular\nfiltration rate are indicated in parallel with clinical events. anti-ds DNA,\nanti-double-stranded DNA; GC, glucocorticoids; m-PSL, methylprednisolone; IVYC,\nintravenous pulse cyclophosphamide; IE, infective endocarditis; MSSA,\nmethicillin-sensitive Staphylococcus aureus; TMP-SMX, trimethoprim-sulfamethoxazole;\nPM, pentamidine; FCZ, fluconazole; CTRX, ceftriaxone; AMPC/CVA,\namoxicillin-clavulanate; ABPC/SBT, ampicillin-sulbactam; GM, gentamycin; CHF,\ncongestive heart failure.\n\n). Therefore, the GC dose was gradually decreased, without subsequent administration\nof CYC.\n\nHowever, before her planned hospital discharge, the patient developed a fever owing to a\nurinary tract infection and bacteremia. Methicillin-sensitive Staphylococcus aureus (MSSA)\nwas detected in four bottles from two sets of blood culture on Day 81. Administration of 1 g\nof ceftriaxone per day following amoxicillin-clavulanate for 2 weeks led to improvement;\nhowever, after the antibiotics were stopped, fever relapsed and MSSA was detected in four\nbottles from two sets of blood culture on Day 105. As IE was suspected as the possible cause\nof the consecutive bacteremia, antibiotic therapy was started with 4.5 g of\nampicillin-sulbactam four times per day, and echocardiography was performed on Day 107,\nafter excluding other foci of infections. Transthoracic echocardiography revealed an\naneurysm in the chordae tendineae of the mitral valve and backward flow from the left\nventricle, indicating new mitral valve regurgitation (Figures 2a, b, c, dFigure 2 a)–(d) Transthoracic echocardiography on Day 107. Aneurysm in the chordae tendineae\nof the mitral valve and backward flow from the left ventricle indicated new mitral\nvalve regurgitation. (e)–(f) Transesophageal echocardiography on Day 108.\n\n). Transesophageal echocardiography performed the next day showed findings consistent\nwith IE (Figures 2e, f). Although the patient had no abnormal neurological findings,\ndiffusion-weighted magnetic resonance imaging revealed multiple fresh microinfarctions in\nthe brain (Figures 3a, b, c, d, eFigure 3 (a)–(e) Diffusion-weighted magnetic resonance imaging on Day 108 confirmed multiple\nfresh microinfarctions. (f) Brain CT on Day 110 showed no cerebral hemorrhage.\n\n). The patient did not have impaired vision, hemorrhage or Roth spots in the fundus of\nthe eye, or Janeway lesions or Osler’s nodes in her body. Brain CT did not detect cerebral\nhemorrhage on Day 110 (Figure 3f). A diagnosis of\nIE was made according to the Duke criteria, and administration of 60 mg of gentamycin twice\nper day was started in addition to 1.5 g of ampicillin-sulbactam three times per day. From\nDay 110, symptoms of congestive heart failure emerged, and the cardiorespiratory state of\nthe patient worsened over time (Figures 4a, bFigure 4 Chest radiograph on Day 61 (a) and Day 110 (b) confirmed exacerbation of\ncardiopulmonary congestion.\n\n). Although the temporary use of dobutamine, dopamine, and oxygen, and consecutive use\nof diuretics were partially effective in controlling the congestive heart failure, the\ncondition of the patient worsened, with an exacerbation of mitral valve regurgitation. When\nit became obvious that the IE could not be controlled with conservative therapy alone,\nmitral valve surgery was deemed necessary. Replacement of the mitral valve with an\nartificial valve was performed in the cardiovascular surgery department after tapering the\nGC dose to 5 mg daily. The surgical findings were consistent with IE (Figures 5a, b, cFigure 5 The mitral valve surgical findings in the mitral valve were consistent with infective\nendocarditis. (a) Intraoperative findings; (b) the mitral valve destroyed, and\nexhibiting infiltration of neutrophils and adhesion of vegetation; and (c) mitral\nvalve with adhesion of vegetation removed.\n\n). The postoperative clinical course was favorable, without worsening of renal\nfunction or LN activity, and the maintenance of adequate cardiac function with the\nartificial valve. The patient was discharged from the hospital with daily administration of\n5 mg of GC, and warfarin as anticoagulant therapy (Figure\n1).\n\nDiscussion\nOur case highlights two important clinical issues: (1) special consideration of the\noccurrence of IE is required among patients with SLE, and (2) early diagnosis and treatment\nof IE are necessary for patient survival.\n\nA previous study by Miller et al. reported that IE occurs in 3.3–4.4% of\npatients with SLE, regardless of valvular abnormalities and immunosuppression1). However, there have been no\ninvestigations regarding the prevalence of IE among patients with SLE who receive\nimmunosuppressive therapy. Most patients with SLE do not have their cardiac status evaluated\nby transthoracic echocardiography. Asymptomatic cardiac diseases often remain undiagnosed,\nwhich increases the risk for and potentially results in a higher prevalence of IE1). Although the prevalence of\nLibman–Sacks endocarditis, a well-known valvular abnormality, is reported to be 40–60% by\nautopsy, it is diagnosed in only 4–6% of patients with SLE, because the majority of patients\nare asymptomatic7). In addition,\na previous study has reported that the presence of high levels of IgG anticardiolipin\nantibodies is associated with the development of severe valvular regurgitation, a high\nincidence of thromboembolic events, and the need for valvular surgery in patients with\nSLE2). In the present case,\nantiphospholipid antibodies were not detected throughout the clinical course of the patient.\nHowever, in addition to the potential risk of IE among patients with SLE who have\nundiagnosed valvular abnormalities, major treatment for SLE (e.g., steroids) can increase\nthe risk of IE with valvular dysfunction progressing to valvular fibrosis and\natrophy1, 6). It was previously reported that IE\nhas a prevalence of 3.9% among patients with SLE who develop valvular abnormalities during\nsteroid therapy1). In the\npresent case, immunosuppressive therapy probably produced a compromised state that caused\nMSSA bacteremia from a urinary tract infection, which contributed to the development of IE.\nIn addition, steroid use can increase the risk of IE through hemodynamic changes due to\nvalvular dysfunction, and a previous study has reported an association between steroid use\nand IE8). Although we did not\ndetect any valvular abnormalities by echocardiography before treatment of LN, we strongly\nrecommend that echocardiography be performed in patients with SLE who show an uncertain\ncardiac status before treatment, considering the risk of IE owing to the prevalence of\nvalvular abnormalities, and the risk of the treatment itself.\n\nAlthough no studies have specifically focused on IE among patients with SLE, a Swedish\nstudy conducted from 1997 to 2007 reported a 30-day mortality rate of 10.4%, with a sudden\ndecline in survival rate a few months after onset and a gradual stabilization of mortality\nrate over 5 years9). The same\nstudy also reported a 6.3-fold higher risk of mortality among patients aged under 65\nyears9). In addition to a\nsudden increase in mortality, embolus complications occur in 24–44% of patients with IE, 65%\nof which involve the central nervous system, often leading to death by cerebral\nhemorrhage9). A 7%\nprevalence of Staphylococcus aureus infection in the mitral valve is frequently associated\nwith embolization, which is usually observed during the first 2–4 weeks after initiation of\nantibiotic treatment6). In our\ncase, as there was no pathological state predisposing to thrombosis, such as vasculitis or\nantiphospholipid syndrome, we believe that embolization resulted from IE. No previously\npublished reports have indicated that SLE is likely to cause infectious embolization. We\nconfirmed that MSSA infection in the mitral valve was the cause of embolization and cerebral\nmicroinfarction at a very early phase, leading us to promptly initiate proper treatment and\nprevent further severe embolus complications. Surgery for valvular dysfunction due to IE\nshould be considered in patients in whom IE cannot be cured or inactivated by conventional\ntreatment. Ternhag et al. report that patients who underwent surgery had\nreduced mortality than that of patients who did not undergo surgery, across a 1-year\nfollow-up after the onset of IE. Further, the 30-day mortality rate was significantly lower\nin the surgery group (6.3%) than in the non-surgery group (11.0%)9). When valve replacement is performed in patients who\nhave been prescribed steroids for a long period of time, anticoagulant therapy should be\nconsidered owing to the instability of platelet function and coagulability. Our patient\nsuccessfully recovered from IE and exhibited favorable cardiac function after mitral valve\nreplacement. Hence, we strongly recommend surgical intervention for any cases involving\ncongestive heart failure, treatment-resistant infection, or infectious embolization, as\nrecommended by the Japanese clinical guidelines for IE.\n\nIn conclusion, special consideration of the possibility of IE, and its early diagnosis and\ntreatment are required for reducing mortality among patients with SLE. We propose that\nechocardiography should be performed before treating patients with SLE who have an uncertain\ncardiac status. Future studies should determine whether IE occurs more frequently in\npatients on SLE who receive immunosuppressive therapy, and whether routine echocardiography\ncan successfully detect the occurrence of IE.\n\nConflict of interest: The authors declare no conflicts of interest.\n==== Refs\nReferences\n1 Miller CS Egan RM Falace DA \nPrevalence of infective endocarditis in patients with\nsystemic lupus erythematosus . J Am Dent\nAssoc 1999 ; 130 :\n387 –392 . doi: 10.14219/jada.archive.1999.0209 10085662 \n2 Perez-Villa F Font J Azqueta M \nSevere valvular regurgitation and antiphospholipid\nantibodies in systemic lupus erythematosus: a prospective, long-term, followup\nstudy . Arthritis Rheum 2005 ;\n53 : 460 –467 . doi: 10.1002/art.21162 15934103 \n3 Roldan CA Shively BK Crawford MH \nAn echocardiographic study of valvular heart disease\nassociated with systemic lupus erythematosus . N Engl J\nMed 1996 ; 335 :\n1424 –1430 . doi: 10.1056/NEJM199611073351903 8875919 \n4 Galve E Candell-Riera J Pigrau C \nPrevalence, morphologic types, and evolution of cardiac\nvalvular disease in systemic lupus erythematosus . N Engl J\nMed 1988 ; 319 :\n817 –823 . doi: 10.1056/NEJM198809293191302 3412413 \n5 Klinkhoff AV Thompson CR Reid GD \nM-mode and two-dimensional echocardiographic abnormalities\nin systemic lupus erythematosus . JAMA 1985 ;\n253 : 3273 –3277 . doi: 10.1001/jama.1985.03350460073024 3999313 \n6 Liao CH Yao TC Chung HT \nStaphylococcal endocarditis and multiple emboli in a\npatient with systemic lupus erythematosus . J\nRheumatol 2004 ; 31 :\n2305 –2306 . 15517650 \n7 Taniyasu N Koh Y Hiramatsu T \nAortic valve replacement due to Libman-Sacks endocarditis\ncombined with infectious endocarditis . Nippon Kyobu Geka Gakkai\nZasshi 1996 ; 44 :\n1193 –1197 (in Japanese, Abstract in\nEnglish) . 8828383 \n8 Armstrong D Wright S McVeigh C \nInfective endocarditis complicating rituximab (anti-CD20\nmonoclonal antibody) treatment in an SLE patient with a past history of Libman-Sacks\nendocarditis: a case for antibiotic prophylaxis? Clin\nRheumatol 2006 ; 25 :\n583 –584 . doi: 10.1007/s10067-005-0031-2 16222410 \n9 Ternhag A Cederström A Törner A \nA nationwide cohort study of mortality risk and long-term\nprognosis in infective endocarditis in Sweden . PLoS\nONE 2013 ; 8 : e67519 . doi: 10.1371/journal.pone.0067519 23861768\n\n",
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"issue": "12(2)",
"journal": "Journal of rural medicine : JRM",
"keywords": "immunosuppressive therapy; infective endocarditis; lupus nephritis; systemic lupus erythematosus",
"medline_ta": "J Rural Med",
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"references": "8828383;15934103;23861768;15517650;3999313;10085662;8875919;16222410;3412413",
"title": "Infective endocarditis in a patient with lupus nephritis who was undergoing immunosuppressive therapy: A case of survival.",
"title_normalized": "infective endocarditis in a patient with lupus nephritis who was undergoing immunosuppressive therapy a case of survival"
} | [
{
"companynumb": "JP-PFIZER INC-2017543271",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Amiodarone is an antiarrhythmic agent which is commonly used to treat both supraventricular and ventricular arrhythmias. This iodine containing compound has been associated with several adverse events like it tends to accumulate in several organs. Among those, the most serious is Amiodarone Pulmonary Toxicity (APT). While the incidence of this complication has decreased with the use of lower doses of amiodarone but it can occur with any dose. Pulmonary complications usually present as an acute or subacute pneumonitis. On chest X-ray and high-resolution Computed Tomography (CT), diffuse infiltrates were found. Here, we present a case in which acute respiratory distress syndrome like features were detected which got subsided after stopping tablet amiodarone. The patient was a known case of atrial fibrillation for which she was taking tablet amiodarone for the last six months.",
"affiliations": "Assistant Professor, Department of Anaesthesia, King George's Medical University, Lucknow, Uttar Pradesh, India.;Senior Resident, Department of Anaesthesia, King George's Medical University, Lucknow, Uttar Pradesh, India.",
"authors": "Singh|Vipin Kumar|VK|;Maheshwari|Vijeta|V|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2017/24710.9674",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "11(4)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Arrhythmia; Pulmonary toxicity; Upper respiratory tract infection",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "UD01-UD02",
"pmc": null,
"pmid": "28571241",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports",
"references": "20623129;17329700;18460037;17170505;17878423;12576397;9066469;17895560;19924000",
"title": "Acute Respiratory Distress Syndrome Complicated by Amiodarone Induced Pulmonary Fibrosis: Don't Let Your Guard Down.",
"title_normalized": "acute respiratory distress syndrome complicated by amiodarone induced pulmonary fibrosis don t let your guard down"
} | [
{
"companynumb": "IN-FRESENIUS KABI-FK201703992",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.",
"affiliations": "Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.;Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.;Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.;Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.;Internal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT.",
"authors": "Esteves|Alexandra|A|;Teixeira da Silva|Francisco|F|;Carvalho|José|J|;Carvoeiro|Ana|A|;Felgueiras|Paula|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.12903",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12903\nFamily/General Practice\nInternal Medicine\nHematology\nDiclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature\nMuacevic Alexander Adler John R Esteves Alexandra 1 Teixeira da Silva Francisco 1 Carvalho José 1 Carvoeiro Ana 1 Felgueiras Paula 1 \n1 \nInternal Medicine, Unidade Local de Saúde do Alto Minho, Viana do Castelo, PRT \n\nAlexandra Esteves amoreiraesteves@gmail.com\n25 1 2021 \n1 2021 \n13 1 e1290325 1 2021 Copyright © 2021, Esteves et al.2021Esteves 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/50858-diclofenac-induced-immune-hemolytic-anemia-a-case-report-and-review-of-literatureNon-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death.\n\nA 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia.\n\nHere, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.\n\ndiclofenachemolysisimmune hemolytic anemiaanemiadrug-induced immune hemolytic anemiaThe 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\nAutoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].\n\nDiclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].\n\nWe present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.\n\nCase presentation\nA 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.\n\nThree weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.\n\nOn the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.\n\nDespite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.\n\nPhysical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.\n\nBlood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.\n\nThe hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.\n\nThe hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.\n\nDuring hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.\n\nTable 1 Laboratory data during hospitalization.\nALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity\n\n \t \tResults\t\nVariable\tReference range (adults)\tDay 1\tDay 2\tDay 5\tDay 7\tDay 9\tDay 13\t\nHemoglobin (g/dL)\t11.8-15.8\t7.9\t7.8\t8.2\t9.1\t10.3\t11\t\nHematocrit (%)\t36.0-46.0\t21.9\t22.1\t24.4\t26.7\t30.6\t33\t\nRed blood cells (106/µL)\t4.2-5.4\t2.47\t2.42\t2.48\t2.63\t2.97\t3.14\t\nMCV (fL)\t80.4-96.4\t88.7\t91.3\t98.4\t101.5\t103\t105.1\t\nWhite cell count (103/µL)\t4.0-10.0\t13.88\t12.49\t18.09\t15.62\t11.43\t11.82\t\nDifferential cell count (103/L)\t \t \t \t \t \t \t \t\nNeutrophils\t1.5-8.0\t9.1\t8.3\t11.448\t9.4\t5.9\t7.2\t\nLymphocytes\t0.8-4.0\t3.3\t2.7\t5.5\t5.2\t4.7\t3.8\t\nPlatelet count (103/µL)\t150-400\t353\t353\t381\t377\t392\t362\t\nReticulocytes (%)\t0.5-1.5\t9.22\t \t \t \t \t \t\nSedimentation rate (mm)\t4-10\t103\t \t \t \t \t9\t\nC-reactive protein (mg/dL)\t<0.51\t3.23\t2.67\t0.69\t0.41\t0.23\t0.14\t\nUrea (mg/dL)\t17.0-43.0\t40\t31\t39\t35\t29\t33\t\nCreatinine (mg/dL)\t0.6-1.0\t0.84\t0.78\t0.8\t0.78\t0.84\t0.79\t\nSodium (mmol/L)\t136-145\t140\t141\t138\t143\t141\t142\t\nPotassium (mmol/L)\t3.5-5.1\t4.2\t4.2\t3\t3.7\t4\t3.9\t\nCalcium (mg/dL)\t8.6-10.3\t \t8.7\t \t \t \t \t\nUric acid (mg/dL)\t2.6-6\t \t7\t \t \t \t \t\nBilirubin (mg/dL)\t \t \t \t \t \t \t \t\nTotal\t0.3-1.2\t4.09\t4.01\t2.16\t2.29\t2.27\t1.28\t\nDirect\t<0.5\t0.07\t0.82\t0.71\t0.75\t0.75\t0.46\t\nLDH (UI/L)\t125-220\t805\t632\t467\t436\t388\t309\t\nALP (UI/L)\t30-120\t152\t135\t96\t93\t90\t76\t\nGGT (UI/L)\t<38\t83\t70\t55\t56\t54\t43\t\nALT (UI/L)\t7-45\t44\t \t19\t23\t30\t31\t\nAST (UI/L)\t8-35\t30\t22\t15\t21\t21\t23\t\nIron (µ/dL)\t70-180\t124\t \t \t \t \t \t\nTIBC (µ/dL)\t250-245\t300\t \t \t \t \t \t\nFolic acid (ng/mL)\t2.34-17.56\t5.8\t \t \t \t \t \t\nVitamin B12 (pg/mL)\t187-883\t414\t \t \t \t \t \t\nHaptoglobin (mg/dL)\t35-250\t<8\t \t \t \t \t \t\nDirect antiglobulin test\t \tPositive for IgG\t \t \t \t \t\nProtein electrophoresis\t \t \tNo monoclonal spikes\t \t \t\nTotal proteins (g/dL)\t6.4-8.2\t \t6.1\t \t \t \t \t\nAlbumin (g/dL)\t3.5-5.2 \t \t3.6\t \t \t \t \t\nImmunoglobulins\t \t \t \t \t \t \t \t\nIgA (mg/dL)\t60-400\t \t192\t \t \t \t \t\nIgG (mg/dL)\t70-1,600\t \t1,008\t \t \t \t \t\nIgM (mg/dL)\t40-230\t \t131\t \t \t \t \t\nANA\t \t \tNegative\t \t \t \t \t\nANCA\t \tNegative\t \t \t \t \t\nRheumatoid factor\t \t \t \tNegative\t \t \t \t\nanti-CCP\t \t \tNegative\t \t \t \t\nSerology\t \t \t \t \t \t \t \t\nHIV\t \t \tNegative\t \t \t \t \t\nHBV\t \t \tNegative\t \t \t \t \t\nHCV\t \t \tNegative\t \t \t \t \t\nGiven the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.\n\nDiscussion\nDrugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].\n\nWAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].\n\nPatients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].\n\nDIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].\n\nDrugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].\n\nSigns and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].\n\nThe DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].\n\nAs there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].\n\nIf DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].\n\nIn acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].\n\nApplying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.\n\nConclusions\nAs a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained or waived by all participants in this study\n\nAppendices\nTable 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.\nWHO-UMC, World Health Organization-Uppsala Monitoring Centre\n\nCausality term\tAssessment criteria\t\nCertain\t• Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary\t\nProbable/Likely\t• Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required\t\nPossible\t• Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear\t\nUnlikely\t• Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations\t\nConditional/Unclassified\t• Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination\t\nUnassessable/Unclassifiable\t• Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified\n==== Refs\nReferences\n1 Immune hemolytic anemia associated with drug therapy Blood Rev Garratty G 143 150 24 2010 20650555 \n2 Warm autoimmune hemolytic anemia N Engl J Med Brodsky RA 647 654 381 2019 31412178 \n3 Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia Br J Haematol Hill QA Stamps R Massey E Grainger JD Provan D Hill A British Society for Haematology Guidelines 208 220 177 2017 28369704 \n4 Risk of cardiovascular events associated with selective COX-2 inhibitors JAMA Mukherjee D Nissen SE Topol EJ 954 959 286 2001 11509060 \n5 Nonsteroidal antiinflammatory drugs - differences and similarities N Engl J Med Brooks PM Day RO 25 324 1991 \n6 Misdiagnosis in patients with diclofenac-induced hemolysis: new cases and a concise review Am J Hematol Ahrens N Genth R Kiesewetter H Salama A 128 131 81 2006 16432863 \n7 Autoimmune hemolytic anemia induced by diclofenac Ann Pharmacother López A Linares M Sánchez H Blanquer A 787 29 1995 \n8 Diclofenac-induced antibodies against RBCs and platelets: two case reports and a concise review Transfusion Meyer O Hoffmann T Aslan T Ahrens N Kiesewetter H Salama A 345 349 43 2003 12675720 \n9 Diclofenac-induced immune haemolytic anaemia: simultaneous occurrence of red blood cell autoantibodies and drug-dependent antibodies Br J Haematol Salama A Kroll H Wittmann G Mueller-Eckhardt C 640 644 95 1996 8982039 \n10 Drug-induced immune hemolytic anemia Expert Opin Drug Saf Salama A 73 79 8 2009 19236219 \n11 Drug-induced immune hemolytic anemia: the last 30 years of changes Immunohematology Arndt PA 44 54 30 2014 https://www.redcrossblood.org/content/dam/redcrossblood/immunohematology-journal/Immuno%202014%20No.%202.pdf#page=6 25247622 \n12 The changing spectrum of drug-induced immune hemolytic anemia Semin Hematol Arndt PA Garratty G 137 144 42 2005 16041663 \n13 Drugs that have been shown to cause drug-induced immune hemolytic anemia or positive direct antiglobulin tests: some interesting findings since 2007 Immunohematology Garratty G Arndt PA 66 79 30 2014 https://www.redcrossblood.org/content/dam/redcrossblood/immunohematology-journal/Immuno%202014%20No.%202.pdf#page=28 25247621 \n14 Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study Br J Haematol Garbe E Andersohn F Bronderet E 644 653 154 2011 21749359 \n15 One center's experience: the serology and drugs associated with drug-induced immune hemolytic anemia - a new paradigm Transfusion Johnson ST Fueger JT Gottschall JL 697 702 47 2007 17381629 \n16 Variability of findings in drug-induced immune haemolytic anaemia: experience over 20 years in a single centre Transfus Med Hemother Mayer B Bartolmäs T Yürek S 333 339 42 2015 26696803 \n17 The use of the WHO-UMC system for standardized case causality assessment. Uppsala Monitoring Centre 1 2021 https://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(1)",
"journal": "Cureus",
"keywords": "anemia; diclofenac; drug-induced immune hemolytic anemia; hemolysis; immune hemolytic anemia",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e12903",
"pmc": null,
"pmid": "33654588",
"pubdate": "2021-01-25",
"publication_types": "D002363:Case Reports",
"references": "25247622;21749359;12675720;8520100;28369704;16432863;31412178;19236219;16041663;20650555;2034249;11509060;25247621;17381629;26696803;8982039",
"title": "Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.",
"title_normalized": "diclofenac induced immune hemolytic anemia a case report and review of literature"
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"abstract": "CD8 encephalitis is a relatively recently described condition in the setting of HIV infection. It is becoming increasingly recognised in recent years though is still likely underdiagnosed.\nWe present three cases of encephalitis in HIV-positive black African females initially presenting with neurological pathology. Two cases concern recent presentations of patients attending HIV services at a large tertiary referral hospital and the third case involves a retrospective analysis of an archived case.\nMRI brain demonstrated periventricular white matter changes in 2 cases and a cerebellar lesion in the third case. CSF examination revealed lymphocytosis and elevated protein levels. CSF HIV viral load analysis showed viral escape along with new antiretroviral drug resistance mutations. CSF flow cytometry studies demonstrated a reversed CD4:CD8 ratio with a high CD8+ cells percentage. All patients had EBV DNA detected in their CSF. Brain biopsy in two patients confirmed CD8 encephalitis and also revealed isolated cells demonstrating EBV positivity by in-situ hybridization using EBER (Epstein-Barr virus-encoded small RNAs). Treatment with steroids and ART optimisation led to significant clinical and radiological improvements in all cases.\nCD8 encephalitis should be considered as a cause of neurological symptoms and confusion in the HIV-positive patient, particularly if poor ART adherence or viral resistance are suspected. Brain biopsy should be considered in HIV-positive patients with encephalopathy of uncertain cause. Early treatment with high-dose corticosteroids when suspecting this diagnosis is essential for a favourable outcome. The prognosis is variable but can be favourable even following severe encephalopathy. The presence of new INSTI mutations in the CSF but absent peripherally in two INSTI-era patients is a novel finding for this case series in the context of CD8 encephalitis. The role played by EBV in this disease remains unclear and warrants further investigation.",
"affiliations": "Department of GU Medicine and Infectious Diseases (GUIDe), St. James's Hospital, Dublin, Ireland.;Université de Paris, NeuroDiderot, Inserm, F-75019 Paris, France.;Department of Neurology, St. James's Hospital, Dublin, Ireland.;Department of Neurology, St. James's Hospital, Dublin, Ireland.;Department of Neuropathology, Beaumont Hospital, Dublin, Ireland.;Department of GU Medicine and Infectious Diseases (GUIDe), St. James's Hospital, Dublin, Ireland.;Department of GU Medicine and Infectious Diseases (GUIDe), St. James's Hospital, Dublin, Ireland.;Department of GU Medicine and Infectious Diseases (GUIDe), St. James's Hospital, Dublin, Ireland.",
"authors": "Kerr|C|C|;Adle-Biassette|H|H|;Moloney|P B|PB|;Hutchinson|S|S|;Cryan|J B|JB|;Clarke|S|S|;Mulcahy|F|F|;Devitt|E|E|",
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"fulltext": "\n==== Front\nBrain Behav Immun Health\nBrain Behav Immun Health\nBrain, Behavior, & Immunity - Health\n2666-3546\nElsevier\n\nS2666-3546(20)30129-0\n10.1016/j.bbih.2020.100164\n100164\nShort Communication\nCD8 encephalitis with CSF EBV viraemia and HIV drug resistance, a case series\nKerr C. colmkerr@gmail.com\ncokerr@tcd.ie\nab∗\nAdle-Biassette H. homa.adle@aphp.fr\ncde\nMoloney P.B. patrickmoloney7@gmail.com\nf\nHutchinson S. shutchinson@stjames.ie\nf\nCryan J.B. janecryan@beaumont.ie\ng\nClarke S. sclarke@stjames.ie\na\nMulcahy F. fmulcahy@stjames.ie\na\nDevitt E. emdevitt@stjames.ie\na\na Department of GU Medicine and Infectious Diseases (GUIDe), St. James’s Hospital, Dublin, Ireland\nb Department of Clinical Medicine, School of Medicine, St. James’s Hospital, Trinity College Dublin, Ireland\nc Université de Paris, NeuroDiderot, Inserm, F-75019 Paris, France\nd Service d’Anatomie Pathologique, Hôpital Lariboisière, APHP, Paris, France\ne Biobank BB, 0033-00064, Hôpital Lariboisière, Paris, France\nf Department of Neurology, St. James’s Hospital, Dublin, Ireland\ng Department of Neuropathology, Beaumont Hospital, Dublin, Ireland\n∗ Corresponding author. Department of GU Medicine and Infectious Diseases (GUIDe), St. James’s Hospital, Dublin, 01 4103000, Ireland. colmkerr@gmail.comcokerr@tcd.ie\n23 10 2020\n12 2020\n23 10 2020\n9 10016414 9 2020\n21 10 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nCD8 encephalitis is a relatively recently described condition in the setting of HIV infection. It is becoming increasingly recognised in recent years though is still likely underdiagnosed.\n\nMethods\n\nWe present three cases of encephalitis in HIV-positive black African females initially presenting with neurological pathology. Two cases concern recent presentations of patients attending HIV services at a large tertiary referral hospital and the third case involves a retrospective analysis of an archived case.\n\nResults and discussion\n\nMRI brain demonstrated periventricular white matter changes in 2 cases and a cerebellar lesion in the third case. CSF examination revealed lymphocytosis and elevated protein levels. CSF HIV viral load analysis showed viral escape along with new antiretroviral drug resistance mutations. CSF flow cytometry studies demonstrated a reversed CD4:CD8 ratio with a high CD8+ cells percentage. All patients had EBV DNA detected in their CSF. Brain biopsy in two patients confirmed CD8 encephalitis and also revealed isolated cells demonstrating EBV positivity by in-situ hybridization using EBER (Epstein–Barr virus-encoded small RNAs). Treatment with steroids and ART optimisation led to significant clinical and radiological improvements in all cases.\n\nDiscussion\n\nCD8 encephalitis should be considered as a cause of neurological symptoms and confusion in the HIV-positive patient, particularly if poor ART adherence or viral resistance are suspected. Brain biopsy should be considered in HIV-positive patients with encephalopathy of uncertain cause. Early treatment with high-dose corticosteroids when suspecting this diagnosis is essential for a favourable outcome. The prognosis is variable but can be favourable even following severe encephalopathy. The presence of new INSTI mutations in the CSF but absent peripherally in two INSTI-era patients is a novel finding for this case series in the context of CD8 encephalitis. The role played by EBV in this disease remains unclear and warrants further investigation.\n\nKeywords\n\nCD8\nEncephalitis\nHIV\nAfrican\nSteroid\nEBV\n==== Body\npmc1 Introduction\n\nCD8 encephalitis is an under-recognised condition that forms part of the spectrum of HIV neurocognitive disorders (Le and Spudich, 2016). It appears to be more prevalent among HIV-positive black African individuals (Lescure et al., 2013). Several triggers have been identified, including HIV viral escape in the CSF. Patients typically present with headaches, confusion and/or seizures. The condition is characterised by a high CD8:CD4 cell ratio on CSF flow cytometry and the presence of inflammation and CD8 lymphocyte infiltration on brain biopsy (Gray et al., 2013). Clinical suspicion for the disorder, the prompt administration of corticosteroids and ensuring HIV viral suppression in CSF and serum is essential to a favourable outcome (Zarkali et al., 2017).\n\n2 Methods\n\n2.1 Case 1\n\nA 39-year-old HIV-positive black African female presented to hospital following a seizure. She had a history of poor ART adherence with acquired NNRTI resistance mutations (V106M and F227L) since diagnosis but had good viraemic control in recent years. Her medical history was significant for multiple episodes of aseptic meningitis presenting as headaches and episodes of confusion over the preceding years, one of which was treated empirically as TB meningitis. At an outpatient clinic 3 months prior to her admission she reported good adherence to her ART regimen of tenofovir alfenamide/emtricitabine and dolutegravir. Her HIV viral load was undetectable.\n\nThe patient became progressively more obtunded post-admission and required intubation. CT brain imaging revealed extensive low-density changes throughout the white matter of both cerebral hemispheres. A lumbar puncture revealed clear CSF with WBC of 42 per cm2 (100% lymphocytes), elevated protein 121 mg/dL (normal range 15–45 mg/dL) and glucose 2.5 mmol/L (normal range 2.22–3.89 mmol/L). No acid-fast bacilli were identified and no organisms were identified on Gram staining. GeneXpert TB and cryptococcal antigen testing were negative. The patient was treated empirically with intravenous antimicrobials to cover a possible meningoencephalitis and was commenced on anti-epileptics while further test results were awaited.\n\nAn MRI brain demonstrated bilateral periventricular deep white matter changes involving both temporal lobes (left > right) (Fig. 1A). The patient’s CD4 count was 125 (19%) and serum HIV viral load was <40 copies/ml. A serum vasculitic screen was non-contributory. Syphilis and toxoplasma serology were negative. CSF PCR testing for JC virus, CMV, VZV, enterovirus, HSV 1&2, Listeria monocytogenes, Streptococcus pneumonia, Neisseria meningitidis and Haemophilus influenza were negative and cultures were sterile. EBV DNA was detected at a low level in the CSF but was not detected in serum. Autoimmune encephalitis antibodies were negative in serum and CSF. Further testing of the CSF sample revealed an elevated HIV viral load of 13,085 copies/ml and new resistance mutations: M184V and K219N and, on a further CSF sample, an integrase strand transfer inhibitor mutation, R263RK. This latter mutation confers intermediate resistance to dolutegravir. No malignant cells were seen in the CSF, but flow cytometry studies demonstrated a reversed CD4:CD8 ratio with 81% of the lymphocytes comprising of CD8+ cells.Fig. 1 (A&B)A: MRI brain of patient 1 demonstrating bilateral periventricular deep white matter changes with high signal involving both temporal lobes on axial T2 FLAIR sequences.B: MRI brain axial T2 FLAIR sequences of patient 2 revealing diffuse non-restricting T2 hyperintensities throughout the white matter involving the pons, temporal poles, insulae and periventricular white matter.\n\nFig. 1\n\nThe patient deteriorated further, developing diminished lower limb reflexes and mute plantars. An EEG showed diffuse generalised slowing without evidence of epileptiform activity. As the CSF flow cytometry results raised the possibility of CD8 encephalitis, a brain biopsy was performed. This demonstrated meningeal, grey and white matter inflammation characterised by lymphocytes, predominantly T-cells, with CD8 cells substantially outnumbering CD4 cells at a ratio of 5:1 (Fig. 2A–C). This confirmed a diagnosis of CD8 encephalitis. Interestingly, in-situ hybridization (ISH) of the brain biopsy using EBER (Epstein–Barr virus-encoded small RNAs) also showed 3 positive nuclei (Fig. 2D).Fig. 2 (A-D) Brain biopsy showing inflammation (A) characterised by lymphocytes, predominantly T cells (B), with CD8 cells predominant (C). ISH using EBER displayingpositive nuclei (D).\n\nFig. 2\n\nIntravenous methyl prednisolone was commenced. Within 48 h, the patient’s level of consciousness returned to normal allowing for successful extubation. Her ART regimen was optimised to take account of her new CSF resistance mutations (tenofovir alfenamide/emtricitabine/darunavir/cobicistat, dolutegravir 50 mg BD and rilpivirine). Repeat MRI brain imaging prior to discharge demonstrated a stable appearance of the extensive signal abnormality in the subcortical white matter. A repeat lumbar puncture prior to discharge revealed 1 WBC/cm2 and a protein of 59 m/dL. HIV viral load was now undetectable in the CSF. EBV DNA was again detected but at a low level (1815 copies/ml). The patient was discharged after 3 weeks on suppressive valaciclovir therapy, a decreasing dose of steroids and optimised ART. Subsequent serum and convalescent CSF revealed HIV viral suppression. The patient remains well at 18 months of follow up.\n\n3 Case 2\n\nOur second case involves a 42-year-old black African female with a history of HIV infection who presented with collapse. She had a history of ART adherence issues with archived M184V mutation. Her ART regimen consisted of raltegravir BD, darunavir and ritonavir. She had been last seen as an outpatient 2 months prior where her CD4 count was 234 cells/mm3 (19%) and her HIV viral load was undetectable.\n\nOn admission she was disorientated and exhibited slurred speech. MRI brain imaging revealed diffuse periventricular and subcortical non-restricting T2 hyperintensities (Fig. 1B). CSF showed a WBC count of 33 per cm2 (100% lymphocytes) and an elevated protein of 219 mg/dL. Anti-epileptics and meningoencephalitis treatment were commenced.\n\nAn EEG demonstrated abnormal bilateral slowing without epileptiform activity. CSF PCR testing for JC virus, CMV, VZV, enterovirus, HSV 1&2, Listeria monocytogenes, Streptococcus pneumonia, Neisseria meningitidis and Haemophilus influenza was negative. Further CSF investigations showed HIV viral load of 1240 copies/ml. A new INSTI mutation, N155H, was found in this sample which conferred high-level resistance to raltegravir. EBV DNA was also detected in the CSF at a low level. CSF flow cytometry revealed a reversed CD8:CD4 ratio with CD8+ cells at 70% and CD4+ at 30%.\n\nThese clinical, radiological and laboratory findings suggested a diagnosis of CD8 encephalitis. The patient started on high-dose intravenous steroids and completed 21 days of intravenous acyclovir. Her ART was broadened to tenofovir alfenamide/emtricitabine/darunavir/cobicistat, zidovudine and BD dolutegravir, reflecting the new HIV mutations. She responded excellently to this treatment, returning to her premorbid baseline after 2 weeks with complete HIV suppression in her CSF. Her steroids were weaned to zero and the patient had no further episodes of confusion or collapse after 9 months of follow up.\n\n4 Results and discussion\n\nCD8 encephalitis is a relatively recently described condition in the setting of HIV infection. It is becoming increasingly recognised in recent years though is still likely underdiagnosed (Langford and Letendre, 2013).\n\nPresenting signs and symptoms of CD8 encephalitis can include headache, confusion and seizures (Lescure et al., 2013), though ataxia and slurred speech have also been described (Salam et al., 2016). Triggers for the condition have been postulated to include infection, immune reconstitution inflammatory syndrome (IRIS) and HIV viral escape in the CSF as a result of poor ART adherence, viral mutation or other causes (Lescure et al., 2013; Morioka et al., 2016). A genetic component is believed to play a role as the condition seems to predominantly affect black Africans (Lescure et al., 2013; Miller et al., 2004).\n\nImaging features associated with the condition include high-intensity signal in the white and grey matter on T2 MRI brain imaging as well as multiple gadolinium-enhancing perivascular lesions that exhibit restriction on diffusion-weighted imaging (Lescure et al., 2013). Flow cytometry results of Lescure’s 14 patient CD8 encephalitis case series revealed a high percentage of CD8+ lymphocytes in the CSF with a high CD8:CD4 ratio (Lescure et al., 2013). Histopathological hallmarks of the condition include diffuse infiltration of the perivascular space by CD8+ lymphocytes, with a much lower ratio of CD4+ T cells (Lescure et al., 2013; Gray et al., 2013) in the context of perivascular contrast enhancement on T1 weighted imaging and in the absence of alternate, particularly infectious, cause.\n\nAnother feature of CD8 encephalitis is its responsiveness to steroids (Lescure et al., 2013; Zarkali et al., 2017; Moulignier et al., 2013). Several case reports and series have demonstrated that patients respond well to early treatment with steroids and can relapse if steroids are withdrawn or tapered too quickly (Salam et al., 2016). Long term immunosuppression with steroid sparing agents has been used in other cases (Salam et al., 2016) but a steroid taper and ART optimisation was sufficient in our patients to lead to clinical remission. If the condition is unrecognised and steroids are not administered promptly, the prognosis can be very poor with a high mortality rate (Lescure et al., 2013).\n\nOur patients initially presented with some of the classic phenotypic, symptomatic and diagnostic hallmarks of CD8 encephalitis. Both patients had histories of poor ART adherence and resistance issues. CSF findings revealed CSF HIV viral escape with new drug-resistant HIV mutations, not present in their serum, requiring ART regimen optimisation. CSF flow cytometry established clinical suspicion for CD8 encephalitis, and the subsequent initiation of high dose corticosteroids led to a dramatic clinical improvement. The presence of new INSTI mutations in the CSF that was not detected peripherally is a novel finding for this case series in the context of CD8 encephalitis.\n\nThe presence of EBV at low levels in the CSF of these patients, as well as the presence of positive nuclei on brain biopsy, were interesting findings. This prompted us to consult international colleagues, a collaboration which led to the revisiting of an archived case that had similar histological findings.\n\n5 Archived case\n\nIn 2001, a 33-year-old African woman presented with a several month-long history of ataxia. The patient tested positive for HIV, with a CD4 count of 71 cells/mm3, and a HIV viral load of 609,000 copies/ml. An MRI displayed a non-contrast enhancing focal cerebellar lesion with low T1 and T2 high signal intensities, predominantly in the cortex, accompanied by severe cerebellar atrophy involving the hemispheres and the vermis. CSF PCR for HSV1&2, VZV, CMV, JCV and BK virus were negative. The patient was commenced on didanosine, lamivudine and nelfinavir.\n\nDespite improvement in CD4 and viral load, repeat MRI imaging displayed T2 high signal intensities extending to mid cerebellar peduncles and the posterior pons. CSF analysis revealed raised WBC 39 per cm2 (80% lymphocytes) and elevated protein (114 mg/dL). EBV was detected in the CSF. A brain biopsy was performed (Fig. 3). This demonstrated lymphocytic infiltrate composed of CD8+ T-cells. ISH using EBER displayed numerous positive nuclei. A diagnosis of EBV cerebellitis was made. A HIV resistance profile demonstrated new ART resistance. The patient commenced treatment with ganciclovir, steroids (1 mg/kg) and her ART regimen was optimised, leading to a dramatic clinical improvement.Fig. 3 (A-I).These figures demonstrate cerebellitis characterised by meningoencephalitis with severe ischemic parenchymal loss (A). Dense meningeal and parenchymal lymphocytic infiltrates with vasculitis (arrows) and loss of Purkinje cells (B, C) are shown. The infiltrates were composed of B (D, H), CD8+ T cells (E, G) and macrophages (F). Note the parenchymal loss (asterisk in A, D, E, F). ISH using EBER displayed numerous positive nuclei (I). (A, D, E x 25; B HE x 100; C, F, G x 200; H, I x 400).\n\nFig. 3\n\nWith hindsight, we believe that this patient presented with all the symptomatic, radiological and histological features of EBV-related CD8+ encephalitis. The brain biopsy was characterized by massive CD8+ infiltrates and vasculitis. We hypothesise that this patient too had a diagnosis of CD8+ encephalitis that responded to high dose steroids and ART optimisation. EBV was detected in the CSF of this patient just as it was in the two previously described cases, and positive nuclei were seen on brain biopsy.\n\nIn the literature, Raman and Nelson (2014) describe a case of EBV-associated cerebral vasculitis complicating HIV infection where CD8 infiltration and EBV positivity is seen on brain biopsy of a patient with an insidious course of neurological symptomatology. This patient responded to valganciclovir and steroids. Trevillyan et al. (2013) discuss a case of EBV encephalitis in a patient presenting with HIV associated neurocognitive disorder, a different presentation to that of our patients. This patient had known archived HIV ART resistance and responded to valganciclovir and ART optimisation. However, it remains unclear to us in the case of our patients if EBV plays a role in triggering this pathology or if it is merely an innocent bystander in the disease process of CD8 encephalitis.\n\n6 Conclusion\n\nCD8 encephalitis should be considered as a cause of confusion or neurological deficit in HIV-positive patients. MR imaging and CSF parameters may be helpful in the diagnostic work-up but brain biopsy should be pursued for a definitive diagnosis in patients exhibiting an encephalopathy of uncertain cause. Early treatment with high-dose corticosteroids is essential for a favourable outcome. The prognosis is variable but can be favourable even following severe encephalopathy. The presence of new INSTI mutations in the CSF but not detected peripherally in two INSTI-era patients is a novel finding for this case series in the context of CD8 encephalitis. A further novel finding includes the presence of EBV DNA in the CSF of all patients, and the presence of EBER positive nuclei on brain biopsy, in the context of HIV viral escape. Whether EBV reactivation is a trigger for, or a consequence of, the patients’ CD8 encephalitis is unknown and warrants further investigation.\n\n7 Authors contributions\n\nCK, HAB, ED, SC, and FM contributed to the writing and the conceptualisation of the manuscript. JCB, PBM and SH contributed to the editing of the manuscript and the provision of figures included in the manuscript.\n\nPatient consent\n\nOur case series contains details of three patients. Two cases concern patients who have provided written consent for the use of their clinical details and imaging in this case series. One case refers to archived samples from a patient who has since been lost to follow up. Brain biopsy images of this patient are used in this case series. The patient provided verbal consent at the time (2001) for her images to be used for future publication.\n\nFunding\n\nThis research did not receive any funding.\n\nDeclaration of competing interest\n\nNone of the authors have any competing interests to declare.\n\nAcknowledgements\n\nWe would like to firstly thank the patients featured in this case series for providing their consent that allowed for this case series to be written. We would also like to thank all the medical, nursing and ancillary health care staff involved in the care of these patients.\n==== Refs\nReferences\n\nGray F. Lescure F.X. Adle-Biassette H. Polivka M. Gallien S. Pialoux G. Encephalitis with infiltration by CD8+ lymphocytes in HIV patients receiving combination antiretroviral treatment Brain Pathol. 23 5 2013 525 533 23347174\nLangford D. Letendre S. Editorial Commentary: Severe HIV-Associated CD8+ T-Cell Encephalitis: Is it the Tip of the Iceberg? Clinical Infectious Diseases vol. 57 2013 an official publication of the Infectious Diseases Society of America 109 111 1\nLe L.T. Spudich S.S. HIV-associated neurologic disorders and central nervous system opportunistic infections in HIV Semin. Neurol. 36 4 2016 373 381 27643907\nLescure F.X. Moulignier A. Savatovsky J. Amiel C. Carcelain G. Molina J.M. CD8 Encephalitis in HIV-Infected Patients Receiving cART: a Treatable Entity Clinical infectious diseases : an official publication of the Infectious Diseases Society of America vol. 57 1 2013 101 108 23515205\nMiller R.F. Isaacson P.G. Hall-Craggs M. Lucas S. Gray F. Scaravilli F. Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART Acta Neuropathol. 108 1 2004 17 23 15085359\nMorioka H. Yanagisawa N. Sasaki S. Sekiya N. Suganuma A. Imamura A. CD8 encephalitis caused by persistently detectable drug-resistant HIV Internal medicine (Tokyo, Japan) 55 10 2016 1383 1386\nMoulignier A. Savatovsky J. Polivka M. Boutboul D. Depaz R. Lescure F.X. CD8 T lymphocytes encephalitis mimicking brain tumor in HIV-1 infection J. Neurovirol. 19 6 2013 606 609 24277438\nRaman L. Nelson M. Cerebral vasculitis and encephalitis due to Epstein-Barr virus in a patient with newly diagnosed HIV infection J. Clin. Virol. : the official publication of the Pan American Society for Clinical Virology 59 4 2014 264 267\nSalam S. Mihalova T. Ustianowski A. McKee D. Siripurapu R. Relapsing CD8+ encephalitis-looking for a solution BMJ Case Rep. 2016 2016\nTrevillyan J.M. Mahony A.A. McLean C. Hoy J.F. Successful treatment of Epstein-Barr virus encephalitis in the setting of HIV-associated neurocognitive disorder: a diagnostic and therapeutic challenge Antivir. Ther. 18 2 2013 257 261 23475078\nZarkali A. Gorgoraptis N. Miller R. John L. Merve A. Thust S. CD8+ encephalitis: a severe but treatable HIV-related acute encephalopathy Practical Neurol. 17 1 2017 42 46\n\n",
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"keywords": "African; CD8; EBV; Encephalitis; HIV; Steroid",
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"title": "CD8 encephalitis with CSF EBV viraemia and HIV drug resistance, a case series.",
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"abstract": "BACKGROUND\nExtensive use of novel therapies for multiple myeloma has been accompanied by intriguing toxic side effects affecting various organs and organ systems. Although skin effects with some of these medications have been well-documented, hair changes are fairly rare.\n\n\nMETHODS\nWe report herein a unique case of a patient with myeloma who developed multidirectional pattern of scalp hair growth starting at 14 months into treatment with cafilzomib. This pattern of hair growth had not previously been described in the literature.Management and outcome: The patient had a near-complete response to caflizomib, and continues on this maintenance treatment regimen to the present day. There has not been any change in the unusual hair appearance and texture.\n\n\nCONCLUSIONS\nA score of 5 on the Naranjo nomogram makes the causality relationship between carfilzomib use and the multidirectional hair growth probable. The mechanism by which carfilzomib causes this hair change remains to be elucidated.",
"affiliations": "Department of Medicine, Eisenhower Health, Rancho Mirage, CA, USA.;Department of Medicine, Eisenhower Health, Rancho Mirage, CA, USA.;Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, CA, USA.;Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, CA, USA.",
"authors": "Tuler|Shahaf|S|https://orcid.org/0000-0002-2695-6153;Kaur|Jaspreet|J|https://orcid.org/0000-0002-4125-5355;Delaware|Suzette|S|;Dasanu|Constantin A|CA|https://orcid.org/0000-0003-0425-8394",
"chemical_list": "D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib",
"country": "England",
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"doi": "10.1177/1078155220964544",
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"issue": "27(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Carflizomib; dermatological toxicities; hair; multiple myeloma; proteasome inhibitor",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D005260:Female; D006197:Hair; D006801:Humans; D009101:Multiple Myeloma; D009842:Oligopeptides; D061988:Proteasome Inhibitors",
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"title": "Multidirectional pattern of hair growth with carflizomib use for multiple myeloma.",
"title_normalized": "multidirectional pattern of hair growth with carflizomib use for multiple myeloma"
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"abstract": "Multiple myeloma survival has significantly improved in recent years, due to novel agents that are available for treatment. The anti-CD38 monoclonal antibody Daratumumab is particularly efficient for patients with relapse/refractory disease, and many studies have shown its unprecedented efficacy also as a first treatment. However, to avoid the incidence of infusion reactions, long infusion schedules of 8 h at first dose and 4 h in the following doses are required, which can reduce the compliance of patients and health care professionals. A reduced infusion time of 90 min has been reported previously, but data are missing on the prolonged safety of this over time as well as the efficacy of this approach. In this work, we investigate the safety of 484 rapid Daratumumab infusions given early after the second dose over a 22 months period in 39 myeloma patients.",
"affiliations": "Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.;Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.",
"authors": "Gozzetti|Alessandro|A|;Bacchiarri|Francesca|F|;Sammartano|Vincenzo|V|;Defina|Marzia|M|;Sicuranza|Anna|A|;Mecacci|Bianca|B|;Zappone|Elisabetta|E|;Cencini|Emanuele|E|;Fabbri|Alberto|A|;Raspadori|Donatella|D|;Bocchia|Monica|M|",
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"doi": "10.3389/fonc.2020.570187",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.570187\nOncology\nBrief Research Report\nLong-Term Safety of Rapid Daratumumab Infusions in Multiple Myeloma Patients\nGozzetti Alessandro * Bacchiarri Francesca Sammartano Vincenzo Defina Marzia Sicuranza Anna Mecacci Bianca Zappone Elisabetta Cencini Emanuele Fabbri Alberto Raspadori Donatella Bocchia Monica Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy\nEdited by: María-Victoria Mateos, University Hospital of Salamanca, Spain\n\nReviewed by: Elena Zamagni, University of Bologna, Italy; Alessandra Larocca, University Hospital of the City of Health and Science of Turin, Italy\n\n*Correspondence: Alessandro Gozzetti, gozzetti@unisi.itThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n\n21 12 2020 \n2020 \n21 12 2020 \n10 57018706 6 2020 13 11 2020 Copyright © 2020 Gozzetti, Bacchiarri, Sammartano, Defina, Sicuranza, Mecacci, Zappone, Cencini, Fabbri, Raspadori and Bocchia2020Gozzetti, Bacchiarri, Sammartano, Defina, Sicuranza, Mecacci, Zappone, Cencini, Fabbri, Raspadori and BocchiaThis 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.Multiple myeloma survival has significantly improved in recent years, due to novel agents that are available for treatment. The anti-CD38 monoclonal antibody Daratumumab is particularly efficient for patients with relapse/refractory disease, and many studies have shown its unprecedented efficacy also as a first treatment. However, to avoid the incidence of infusion reactions, long infusion schedules of 8 h at first dose and 4 h in the following doses are required, which can reduce the compliance of patients and health care professionals. A reduced infusion time of 90 min has been reported previously, but data are missing on the prolonged safety of this over time as well as the efficacy of this approach. In this work, we investigate the safety of 484 rapid Daratumumab infusions given early after the second dose over a 22 months period in 39 myeloma patients.\n\nDaratumumabmultiple myelomarapid infusionsafetyefficacy\n==== Body\nIntroduction\nMultiple myeloma (MM) is a plasma cell disorder, the prognosis of which has dramatically improved in the last years thanks to new immunomodulatory drugs (IMIDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs), in relapsed/refractory disease and at diagnosis (1–6). Daratumumab, a CD38 antagonist, is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds CD38 expressed on the cell surface in a variety of hematological malignancies, including myeloma, lymphomas, and leukemias, as well as on other cell types and tissues with various expression levels. Daratumumab acts through different mechanisms of action including an immune-mediated effect: i) antibody-dependent cytotoxicity (ADC), ii) complement-dependent cytotoxicity (CDC), and iii) antibody-dependent cellular phagocytosis (ADCP). It can also cause apoptosis through a direct antitumor effect or it can act as an immune modulator to decrease immunosuppression or infuence CD38 enzymatic inhibition. When Daratumumab was used as a single drug in relapsed/refractory MM patients who previously received a median of four lines of therapy, it led to an unprecedented response of 31% (ORR) and a median OS of 20.1 months (7). CASTOR and POLLUX studies demonstrated that the addition of Daratumumab to bortezomib and lenalidomide, respectively, prolonged PFS and OS in the relapsed refractory setting (8, 9). Daratumumab combinations with pomalidomide and carfilzomib have been used for relapsed refractory disease, and other combinations are now approved also at diagnosis (10–14). In particular, the combination with pomalidomide and dexamethasone has been tested in a cohort of heavily pretreated patients, giving an ORR of 60% (17% CR or better), while Daratumumab combined with carfilzomib and dexamethasone did not reach PFS at a median follow-up of 17 months. In the Alcyone trial (12) Daratumumab–VMP (velcade, melphalan, prednisone) compared to VMP alone showed a superior PFS (36.4 vs 19.3 months, respectively) and OS (78% vs 68.9%, respectively, at 40 months of follow up) in newly diagnosed MM patients (NDMM) that were not eligible for transplantation. Furthermore, the MAIA study (13) showed the superiority of Daratumumab in NDMM patients when comparing Dara–Rd (Daratumumab, Revlimid, Dexamethasone) with Rd alone. PFS was superior for Dara–Rd vs Rd (not reached vs 31.9 months), with 24% of minimal residual disease (MRD) showing negativity in the Dara–Rd group. Finally, the Cassiopeia study (14) evaluated Daratumumab–VTD (velcade, thalidomide, Dexamethasone) vs VTD in NDMM patients in pre-transplant induction therapy and post-transplant consolidation. Dara–VTD was superior in terms of the depth of response (MRD negativity of 64% vs 44%) and PFS (93% vs 85% at 18 months). These studies showed the good tolerability of daratumumab; however, due to the expression of CD38 on airway smooth muscle cells, infusion-related reactions (IRRs) are very common at the first dose, accounting for about 40% of patients and presenting with symptoms (cough, wheezing, rhinorrhea) similar to those of allergic rhinitis. Daratumumab as a monotherapy or when combined with revlimid dexamethasone is given intravenously (IV), every week for 8 weeks, then every 2 weeks for 16 weeks, and then every month, while the Dara–Velcade regimen (DVd) is given weekly with 9 doses, then every 3 weeks with 5 doses, and then every 4 weeks (15). It is worthy of note that the infusion duration is particularly long for the first infusion (7 h), with median durations of 4.3 and 3.5 h for second and other infusions, respectively. Moreover, if an infusion-related reaction presents, the infusion may take longer, worsening the patient’s quality of life and also affecting the planning of daily practice for physicians and nurses. Splitting the first dose over two days reduces the length of each infusion (4 h each), although the patient has to come to the hospital twice. Strategies to reduce the infusion time have been reported (16): in one study, the authors showed safety in 28 patients with MM with an infusion time of 90 min starting from a dose >10 in the majority of cases. In 11 out of 28 patients, a 90 min infusion was given from the third dose. No report, however, has been made regarding the prolonged safety of rapid Daratumumab infusions over time, nor regarding the efficacy of the drug with this modified schedule. It is worthy of note that the subcutaneous formulation has been tested in many trials and is about to be introduced in clinical practice (17).\n\nMaterials and Methods\nPatient Characteristics\nFrom December 2018 to October 2020, we performed an observational prospective single-arm, single-center study, with the twofold aim of reducing the time of infusion and the stay of the patient in the day hospital. The primary endpoint of the study was the safety of rapid Daratumumab infusions. The secondary endpoint was the safety of the first Daratumumab infusions. Patients receiving Daratumumab as standard clinical practice at relapse and patients enrolled in clinical trials at diagnosis could be enrolled. Patient characteristics are reported in Table 1. Nineteen patients were affected by RRMM and received Daratumumab alone or in combination with other agents (lenalidomide, bortezomib, pomalidomide), and 20 patients received Daratumumab as consolidation therapy in the protocol DART4MM (this trial was registered at ClinicalTrials.gov with the number NCT039922170; EUDARACT N. 2018-000386-36: Daratumumab as consolidation therapy in patients who already achieved >VGPR/MRD positivity during first line therapy). Ethical approval was obtained locally, and DART4MM was also approved by the Italian Dug Regulatory Agency (AIFA, with a specific approval amendment for rapid Daratumumab infusions).\n\nTable 1 Patient characteristics.\n\nN\tM/F\tAge\tType\tFISH:S/H\tN.Previous lines\tDara-therapy\tN.Dara previous infusions\tIRR1 dose\tN.Rapid infusions\tIRR in Rapid infusions\tDisease status before Dara\tBestresponse\tPD:Y/N\tFUO/infection\tA/D\t\n1\tM\t68\tIgA κ\tS\t3\tDVd\t16\tNo\t4\tNone\tRR\tPR\tY\tYes\tDead\t\n2\tM\t84\tIgG κ\tS\t6\tDRd\t3\tNo\t28\tNone\tRR\tPR\tN\tYes\tAlive\t\n3\tM\t57\tIgG κ\tND\t4\tDVd\t5\tNo\t18\tNone\tRR\tPR\tN\tYes\tAlive\t\n4\tM\t60\tBJ.κ\tH\t6\tDRd\t3\tNo\t24\tNone\tRR\tPR\tY\tYes\tDead\t\n5\tM\t53\tIgG κ\tH\t2\tDPd\t2\tYes\t12\tNone\tRR\tSD\tY\tYes\tDead\t\n6\tM\t71\tIgG κ\tN\t1\tDRd\t2\tNo\t21\tNone\tRR\tCR\tN\tNo\tAlive\t\n7\tM\t58\tBJ.λ\tS\t1\tDRd\t2\tYes\t19\tNone\tRR\tPR\tN\tYes\tAlive\t\n8\tF\t62\tIgG λ\tN\t6\tDara alone\t13\tNo\t1\tNone\tRR\tPR\tY\tYes\tDead\t\n9\tM\t57\tIgG λ\tN\t3\tDRd\t5\tYes\t7\tNone\tRR\tSD\tY\tNo\tDead\t\n10\tM\t65\tIgG λ\tN\t1\tDRd\t2\tYes\t4\tNone\tRR\tVGPR\tN\tYes\tAlive\t\n11\tM\t63\tBJ λ\tN\t1\tDara alone\t2\tNo\t19\tNone\tRR\tVGPR\tN\tYes\tAlive\t\n12\tM\t63\tIgG λ\tND\t1\tDara alone\t12\tNo\t18\tNone\tRR\tPR\tN\tNo\tAlive\t\n13\tM\t49\tIgG/k\tH\t6\tDara Alone\t13\tNo\t4\tNone\tRR\tPR\tY\tNo\tDead\t\n14\tF\t55\tIgG/k\tH\t2\tDVd\t2\tNo\t11\tNone\tRR\tPR\tN\tNo\tAlive\t\n15\tF\t63\tIgG/k\tS\t6\tDRd\t2\tNo\t9\tNone\tRR\tVGPR\tN\tNo\tAlive\t\n16\tM\t64\tBJ/λ\tS\t2\tDRd\t2\tNo\t7\tNone\tRR\tVGPR\tN\tNo\tAlive\t\n17\tM\t45\tIgG/k\tS\t1\tDRd\t2\tNo\t1\tNone\tRR\tNA\tN\tNo\tAlive\t\n18\tM\t61\tIgG/k\tS\t4\tDVd\t2\tNo\t1\tNone\tRR\tNA\tN\tNo\tAlive\t\n19\tF\t63\tBJ/λ\tS\t1\tDRd\t2\tYes\t1\tNone\tRR\tNA\tN\tNo\tAlive\t\n20\tF\t51\tIgG κ\tS\t1\tDART4MM\t2\tNo\t21\tNone\tCR-MRD pos\tCR\tN\tNo\tAlive\t\n21\tF\t63\tIgG κ\tS\t1\tDART4MM\t2\tNo\t14\tNone\tCR-MRD pos\tCR\tN\tNo\tAlive\t\n22\tM\t71\tIgA λ\tS\t1\tDART4MM\t2\tNo\t14\tNone\tVGPR\tsCR-MRD neg\tN\tNo\tAlive\t\n23\tM\t62\tIgG k\tS\t1\tDART4MM\t2\tNo\t16\tNone\tCR-MRD pos\tCR\tN\tNo\tAlive\t\n24\tF\t65\tIgG k\tS\t1\tDART4MM\t2\tNo\t16\tNone\tVGPR\tVGPR\tN\tNo\tAlive\t\n25\tF\t72\tIgG λ\tH\t1\tDART4MM\t3\tYes\t26\tNone\tVGPR\tVGPR\tY\tNo\tAlive\t\n26\tF\t78\tIgG κ\tN\t1\tDART4MM\t2\tYes\t30\tNone\tVGPR\tCR\tN\tNo\tAlive\t\n27\tM\t71\tIgG κ\tS\t1\tDART4MM\t2\tNo\t14\tNone\tVGPR\tsCR-MRD neg\tN\tNo\tAlive\t\n28\tM\t66\tIgG λ\tND\t1\tDART4MM\t2\tNo\t14\tNone\tVGPR\tCR-MRD neg\tN\tNo\tAlive\t\n29\tF\t65\tIgG λ\tS\t1\tDART4MM\t2\tYes\t14\tNone\tCR-MRD pos\tCR-MRD neg\tN\tNo\tAlive\t\n30\tM\t55\tBJ λ\tND\t1\tDART4MM\t2\tNo\t14\tNone\tCR-MRD pos\tCR-MRD neg\tN\tNo\tAlive\t\n31\tM\t58\tIgG κ\tS\t1\tDART4MM\t2\tYes\t14\tNone\tVGPR\tCR-MRD neg\tN\tNo\tAlive\t\n32\tM\t48\tIgG λ\tS\t1\tDART4MM\t2\tNo\t14\tNone\tCR-MRD pos\tCR-MRD neg\tN\tNo\tAlive\t\n33\tM\t70\tIgG/k\tS\t1\tDART4MM\t2\tNo\t18\tNone\tVGPR\tVGPR\tN\tNo\tAlive\t\n34\tF\t66\tIgG/k\tS\t1\tDART4MM\t2\tNo\t12\tNone\tVGPR\tCR\tN\tNo\tAlive\t\n35\tM\t65\tIgG/k\tS\t1\tDART4MM\t2\tYes\t15\tNone\tVGPR\tVGPR\tN\tNo\tAlive\t\n36\tM\t66\tIgG k\tS\t1\tDART4MM\t2\tNo\t5\tNone\tVGPR\tNA\tN\tNo\tAlive\t\n37\tM\t62\tIgG/k\tS\t1\tDART4MM\t2\tYes\t2\tNone\tCR-MRD pos\tNA\tN\tNo\tAlive\t\n38\tM\t52\tIgG/k\tS\t1\tDART4MM\t2\tYes\t1\tNone\tVGPR\tNA\tN\tNo\tAlive\t\n39\tF\t59\tIgG/k\tS\t1\tDART4MM\t2\tYes\t1\tNone\tVGPR\tNA\tN\tNo\tAlive\t\nFISH : ND, not done; H = high risk (t 4;14-t14;16-del 17p); S, standard risk (all other anomalies); N, normal; DVd, dara, velcade, dexamethasone; DRd, Dara, Revlimid, dexamethasone; DPd, Dara, Pomalidomide, dexamethasone; NA, not applicable (too early for assessment); IRR, infusion-related reaction; FUO, fever of unknown origin.\n\nN Rapid infusions and IRRR in Rapid infusions columns are evidenced in bold.\n\nTreatment Schedule\nThe infusion schedule is reported in Table 2. The first dose of daratumumab was split into day 1 and day 2 with a median infusion duration of 4 h each. Rapid infusion could start from the third dose if no IRR was seen in the previous infusion (second). A rapid infusion rate was calculated to deliver 20% of the dose over 30 min (200 ml/h), and then the rate was increased to deliver the remaining 80% over 60 min (450 ml/h). This resulted in a 90 min estimated infusion time (total volume 550 ml). Premedication drugs, according to the current clinical practice, were corticosteroids (IV dexamethasone 20 mg), antipyretic (oral paracetamol 1.000 mg), and antihistamine (IV chlorphenamine maleate 10 mg); a two-puff inhalation of β-adrenergic bronchodilator (salbutamol) given 20 min before the first infusion was chosen instead of montelukast after a referral with a local pneumologist. All patients received antiviral and antibacterial prophylaxis (Acyclovir 400 mg twice daily, trimethoprim–sulfamethoxazole, 160 + 800 mg twice daily twice/week). All patients treated with lenalidomide or pomalidomide received thromboprophylaxis with low-dose aspirin (18). Safety assessments included any adverse events (AEs), physical examinations, clinical laboratory parameters, vital signs measurement, and Eastern Cooperative Oncology Group performance status. AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (19). Responses were defined according to IMWG criteria (20). Minimal residual disease (MRD) was evaluated by next-generation flow on bone marrow aspirate with a sensitivity of 10-6 (Euroflow criteria) (21).\n\nTable 2 Infusions schedule.\n\nDaratumumab\tTotal volume\tInitial infusion rate\tIncrements of infusion rate\tMaximum infusion rate\tTotal infusion time\t\nI infusion:\t\t\t\t\t\t\nDay 1\n+\nDay 2\t500 ml\n+\n500 ml\t50 ml/h\t50 ml/h every hour\t200 ml/h\t4 h\t\nII infusion\t500 ml\t50 ml/h\t50 ml/h every hour\t200 ml/h\t4 h\t\n>III infusion\t550 ml\t200 ml/h\nfor 30 min\t450 ml/h\nfor 60 min\t450 ml/h\t1,5 h\t\nResults\nA total of 39 consecutive patients (27 M/12 F) with a median age of 64 years (range 48–84 years) were referred to our Hematology center and received a rapid infusion of daratumumab, leading to a total of 484 rapid infusions (median number 14, range 1–30) over a 22 month observational period (Table 1). No serious adverse event was recorded in all patients during rapid infusion. Six out of 39 (15%) patients (one with associated renal amyloidosis) had been previously treated with Daratumumab on entry to the study. They had already received a median of 12 infusions (range 5–16), and no IRRs were registered during subsequent rapid infusions (Table 3). Pre-existing chronic obstructive pulmonary disease or asthma were absent in previous patient history in 38 out of 39 patients. One patient reported smoking activity in their past history; they were then referred to the pneumologist, and a therapy with β−adrenergic bronchodilator was administered three days before the first infusion.\n\nTable 3 Summary of main patient characteristics and results.\n\nPatients N\t39\t\nM/F\t27/12\t\nAge median (range)\t64 (48–84)\t\nStudy period\tDecember 2018–October 2020\t\nDisease status:\t\t\nRelapse\t19\t\n Dara Schedule:\t\t\n DRd\t10\t\n DVd\t4\t\n Dara alone\t4\t\n DPd\t1\t\nConsolidation (DART4MM)\t20\t\nIRR at first infusion\t13/39 (33%)\t\nGrade 1–2\t13 (100%)\t\n Allergic rhinitis/nasal congestion\t7 (54%)\t\n Dyspnoea\t3 (13%)\t\n Chills\t3 (13%)\t\nTotal N. Rapid infusions\t484\t\nMedian N. rapid infusions per patient (range)\t14 (1-30)\t\nN. Patients starting Dara Rapid since Third infusion\t30/39\t\nIRR in rapid infusions\t0/484\t\nInfusion-Related Reactions at First Dose During Daratumumab Long-Infusion Treatment\nIRRs at the first Daratumumab split infusion were seen in 13 of 39 patients (33%): five were in RR MM patients, while the other 8 patients were included in the DART4MM study. All IRRs at the first dose happened on day 1; they were mild and of grades 1–2: (seven showed allergic rhinitis, three showed dyspnea, and three exhibited chills), and the drug was temporarily stopped in all cases. Allergic rhinitis was treated with IV hydrocortisone hemisuccinate at 100/200 mg, chlorphenamine maleate, and salbutamol. All bronchospasms were treated with salbutamol aerosol: in one case, IV chlorphenamine maleate at 10 mg was also added, and in two cases, hydrocortisone hemisuccinate at 200 mg was also added. Chills were treated with corticosteroids IV in all cases. The median time to recovery after IRRs was 30 min. All patients who had an IRR during the first split dose did not have other reactions during subsequent infusions, regardless of the infusion time.\n\nInfusion-Related Reactions at Rapid Infusions\nThirty-three of 39 (79%) patients received Daratumumab as a rapid infusion upfront (30 at the third infusion, day 15, cycle 1; and three patients at the fourth infusion, day 22, cycle 1). No subsequent IRRs were seen. Premedication was reduced after dose >10, when Daratumumab was used as a monotherapy or in the DART4MM study, with oral antihistamine (loratadine 10 mg), dexamethasone 10 mg (IV), and paracetamol 500 mg (oral) in all patients. Moreover, in 6 patients, corticosteroids were reduced to 4 mg dexamethasone after dose >14.\n\nAdverse Events That Were Not Infusion Related\nTreatment-emergent adverse events (TEAEs) during therapy and that were not infusion-related were similar to other populations of patients treated with daratumumab, all of grades 1–2 (Hematological TEAEs: lymphopenia in 12 patients, 31%; anemia in 9, 23%; thrombocytopenia in 9, 23%; neutropenia in 9, 23%. Non-hematological TEAEs: arthralgia in 8 patients, 20%; fever of unknown origin (FUO) in 8 patients, 20%). Two patients who received Daratumumab in combination with lenalidomide had pneumonia/infection and stopped treatment: one patient had a septic shock requiring emergency care unit admission—at last follow-up, they are alive and in VGPR—the other patient had bacterial pneumonia (staphylococcus aureus), maintaining a stable response. Both patients had grade 3 neutropenia at the time of hospitalization.\n\nResponse to Treatment\nDuring Daratumumab therapy, 23 of 32 evaluable patients had a response improvement (72%). In particular, in the DART4MM protocol, 9 of 16 patients showed an improved response, from a VGPR or CR-MRD pos to a CR or CR-MRD neg by next-generation flow, while in the evaluable RRMM patients, 14 of 16 had at least a PR. Six of 39 patients exhibited a halted progression: three patients were treated at line 6, two at line 3 and one patient at line 2 of therapy, respectively. The latter maintained an SD for 6 months with Daratumumab before progressing (who received Daratumumab for 6 months while maintaining a SD).\n\nDiscussion\nIn this study, we describe the largest population of MM patients so far reported to receive rapid infusions of Daratumumab from cycle 1 day 15 (n = 30) with the longest follow-up to evaluate safety. In fact, the long follow-up period reported of 22 months makes the study quite reliable to evaluate both short and long-term safety. The availability of Daratumumab has revolutionized treatment practice for MM, leading to a marked improvement in outcomes for the treatment of MM patients. However, the current administration schedules can negatively impact patient’s compliance and out-patient care system organization. The rapid infusion Daratumumab schedule here reported provides a practical and safe solution that has a positive impact on resource utilization. Another point of interest is that rapid infusion was revealed to be particularly convenient during the Covid-19 emergency, reducing patients’ time spent in hospitals and reducing social contacts for patients and staff. Rapid infusions have been tested with other monoclonal antibodies in the past; for example, rapid 60 min infusions of rituximab (IgG1 chimeric anti CD20 antibody) for B cell lymphoproliferative disorders have been adopted at our institution and many others since 2006 (22, 23). The efficacy of rituximab was maintained and patients were rapidly dismissed from the clinic. Rapid Daratumumab infusion has very recently been reported in another trial (24) in which 53 MM patients received rapid infusions and no difference was seen in terms of IRRs with respect to 47 patients receiving long infusions (1.9% vs 4.3%). The latter study compared rapid infusions vs standard IV infusions: 53 patients received rapid infusions of Daratumumab, but only 18 received the rapid infusion starting from cycle 1 day 15 upfront (as in our study). Importantly, the authors showed a cost saving for rapid infusions: the total costs estimated for a 52 week regimen of Daratumumab infused at standard and rapid rates were $137,200 and $122,200 (P <.001), respectively. However, in comparison to our study, there is no report on the safety of the method in long-term follow-up, nor regarding the efficacy of the drug. Recent studies have also shown the good safety and efficacy of the subcutaneous (SC) infusion with a dose of 1,800 mg with recombinant human hyaluronidase PH20 (rHuPH20)(concentration 30,000 U; in 15 ml) in a single, premixed vial that was administered over 3 to 5 min, and this formulation will be available soon (12, 25). The serum pharmacokinetic (PK) concentrations and efficacy achieved with an 1800 mg SC dose were consistent with what has been observed for Daratumumab 16 mg/kg IV in patients with RRMM. Certainly, SC administration will be more utilized in the near future, but we have to consider that, despite the reduced number of IRRs during SC therapy compared to the IV formulation, almost all reactions happened during the first 6 h after injection. Although PK was not performed in the present study, efficacy was maintained in our study. To our knowledge, no study has so far reported on the efficacy of rapid infusions; however, even considering the small number of patients treated, the treatment efficacy appeared to be quite in line with that expected after the standard infusion length. In conclusion, our study demonstrates that a rapid infusion of Daratumumab after the second dose is safe and well tolerated. As such, while waiting for the SC formulation, this schedule can be adopted by many hematological centers to improve MM patients’ quality of life and allow more sustainable out-patient care infusion planning.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Comitato Etico Regionale-Regione toscana, area vasta sud est; Agenzia Italiana del Farmaco. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nAG designed the study and wrote the manuscript. MD, EZ, AF, and EC were involved in the patient treatment. AS and DR performed the laboratory analysis. FB, VS, and BM collected the data and helped to write the manuscript. MB supervised the study and revised the manuscript. All authors contributed to the article and approved the submitted version.\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\nThe handling Editor declared a past co-authorship with one of the authors AG.\n\nAcknowledgments\nWe thank patients and staff. We thank the Italian Association against Lymphoma, Myeloma, and Leukemia (Siena section) for patient support. This work has been presented in part as a poster at the International Myeloma Workshop in Boston, 12–15 September 2019.\n==== Refs\nReferences\n1 \nGozzetti A Candi V Papini G \nBocchia. Therapeutic advancements in multiple myeloma\n. Front Oncol (2014 ) 4 :241. 10.3389/fonc.2014.00241 \n25237651 \n2 \nMohty M Terpos E Mateos MV Cavo M Lejniece S Beksac M \nEMMOS Investigators. 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N Engl J Med (2016 ) 375 :754–66. 10.1056/NEJMoa1606038 \n\n10 \nChari A Suvannasankha A Fay JW Arnulf B Kaufman JL Ifthikharuddin JJ \nDaratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma\n. Blood (2017 ) 130 :974–81. 10.1182/blood-2017-05-785246 \n\n11 \nDimopoulos M Quach H Mateos MV Landgren O Leleu X Siegel D \nCarfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study\n. Lancet (2020 ) 396 :186–97. 10.1016/S0140-6736(20)30734-0 \n\n12 \nMateos MV Cavo M Blade J Dimopoulos MA Suzuki K Jakubowiak A \nOverall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial\n. Lancet (2020 ) 395 :132–41. 10.1016/S0140-6736(19)32956-3 \n\n13 \nFacon T Kumar S Plesner T Orlowski RZ Moreau P Bahlis N \nMAIA Trial Investigators. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma\n. N Engl J Med (2019 ) 380 (22 ):2104–15. 10.1056/NEJMoa1817249 \n\n14 \nMoreau P Attal M Hulin C Arnulf B Belhadj K Benboubker L \nBortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study\n. Lancet (2019 ) 394 (10192 ):29 –38\n. 10.1016/S0140-6736(19)31240-1 \n31171419 \n15 \nDARZALEX® (daratumumab) injection, for intravenous use. May 2020 (2019 ). Available at: http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf.\n\n16 \nBarr H Dempsey J Waller A Huang Y Williams N Sharma N \nNinety-minute daratumumab infusion is safe in multiple myeloma\n. Leukemia (2018 ) 32 :2495–518. 10.1038/s41375-018-0120-2 \n\n17 \nUsmani SZ Nahi H Mateos MV van de Donk NWCJ Chari A Kaufman JL \nSubcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma\n. Blood (2019 ) 134 :668–77. 10.1182/blood.2019000667 \n\n18 \nCini M Zamagni E Valdré L Palareti G Patriarca F Tacchetti P \nThalidomide-dexamethasone as up-front therapy for patients with newly diagnosed multiple myeloma: thrombophilic alterations, thrombotic complications, and thromboprophylaxis with low-dose warfarin\n. Eur J Haematol (2010 ) 84 :484–92. 10.1111/j.1600-0609.2010.01434.x \n\n19 \nCommon terminology criteria for adverse events (CTCAE) (2010): Version 4.03 (2020 ). Available at: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03, US Department of Health and Human Services, National Institutes of Health, National Cancer Institute.\n\n20 \nKumar S Paiva B Anderson KC Durie B Landgren O Moreau P \nInternational Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma\n. Lancet Oncol (2016 ) 17 :e328–46. 10.1016/S1470-2045(16)30206-6 \n\n21 \nFlores-Montero J Sanoja-Flores L Paiva B Puig N García-Sánchez O Böttcher S \nNext Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma\n. Leukemia (2017 ) 31 :2094–103. 10.1038/leu.2017.29 \n\n22 \nSehn LH Donaldson J Filewich A Fitzgerald C Gill KK Runzer N \nRapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting\n. Blood (2007 ) 109 :4171–3. 10.1182/blood-2006-11-059469 \n\n23 \nFabbri A Gozzetti A Lazzi S Lenoci M D’Amuri A Leoncini L \nActivity of rituximab monotherapy in refractory splenic marginal zone lymphoma complicated with autoimmune hemolytic anemia\n. Clin Lymphoma Myeloma (2006 ) 6 :496–9. 10.3816/CLM.2006.n.033 \n\n24 \nHamadeh IS Reese ES Arnall JR Kachur E Martin AL Schneider M \nSafety and Cost Benefits of the Rapid Daratumumab Infusion Protocol\n. Clin Lymphoma Myeloma Leuk (2020 ) 7 :S2152 –2650(20)30105-1\n. 10.1016/j.clml.2020.02.014 \n\n25 \nMateos MV Nahi H Legiec W Grosicki S Vorobyev V Spicka I \nSubcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial\n. Lancet Haematol (2020 ) 7 :e370–80. 10.1016/S2352-3026(20)30070-3\n\n",
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"journal": "Frontiers in oncology",
"keywords": "Daratumumab; efficacy; multiple myeloma; rapid infusion; safety",
"medline_ta": "Front Oncol",
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"pubdate": "2020",
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"title": "Long-Term Safety of Rapid Daratumumab Infusions in Multiple Myeloma Patients.",
"title_normalized": "long term safety of rapid daratumumab infusions in multiple myeloma patients"
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"abstract": "BACKGROUND\nCetuximab is registered for use in colorectal cancer (CRC) patients with RAS wild-type tumours only. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification (prenylation) of KRAS. We hypothesize that the activated KRAS pathway in KRAS mutant tumors can be inhibited by simvastatin rendering these tumors sensitive to the EGFR inhibitor cetuximab.\n\n\nMETHODS\nA Simon two-stage, single-arm, phase II study was performed to test the efficacy and safety of the addition of simvastatin to cetuximab in patients with a KRAS mutation in their CRC tumour who were previously treated with fluoropyrimidine, oxaliplatin and irinotecan based regimens. The primary endpoint was to test the percentage of patients alive and free from progression 12.5 weeks after the first administration of cetuximab. Our hypothesis was that at least 40% was free from progression, comparable to, though slightly lower than in KRAS wild-type patients.\n\n\nRESULTS\nFour of 18 included patients (22.2%) were free from progression at the primary endpoint time. The time to progression in these 4 patients ranged from 20.3 to 47 weeks.\n\n\nCONCLUSIONS\nBased on the current study we conclude that the theoretical concept of KRAS modulation with simvastatin was not applicable in the clinic, as we were not able to restore sensitivity to cetuximab in CRC patients harbouring a somatic KRAS mutation.",
"affiliations": "Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. j.m.baas@lumc.nl.;Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.;Department of Clinical Oncology, Amphia Hospital, Langendijk 75, 4819 EV, Breda, The Netherlands.;Department of Clinical Oncology, Orbis Medical Center, Dr. H. van der Hoffplein 1, 6162 BG, Sittard-Geleen, The Netherlands.;Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.;Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.;Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.;Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.",
"authors": "Baas|J M|JM|;Krens|L L|LL|;ten Tije|A J|AJ|;Erdkamp|F|F|;van Wezel|T|T|;Morreau|H|H|;Gelderblom|H|H|;Guchelaar|H J|HJ|",
"chemical_list": "C117307:KRAS protein, human; D019821:Simvastatin; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab",
"country": "United States",
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"doi": "10.1007/s10637-015-0285-8",
"fulltext": "\n==== Front\nInvest New DrugsInvest New DrugsInvestigational New Drugs0167-69971573-0646Springer US New York 28510.1007/s10637-015-0285-8Phase II StudiesSafety and efficacy of the addition of simvastatin to cetuximab in previously treated KRAS mutant metastatic colorectal cancer patients Baas J. M. +31 (0)71 526 3486j.m.baas@lumc.nl Krens L. L. ten Tije A. J. Erdkamp F. van Wezel T. Morreau H. Gelderblom H. Guchelaar H. J. Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands Department of Clinical Oncology, Amphia Hospital, Langendijk 75, 4819 EV Breda, The Netherlands Department of Clinical Oncology, Orbis Medical Center, Dr. H. van der Hoffplein 1, 6162 BG Sittard–Geleen, The Netherlands Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands 19 9 2015 19 9 2015 2015 33 6 1242 1247 4 5 2015 27 8 2015 © The Author(s) 2015\nOpen Access This 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.Summary\nIntroduction Cetuximab is registered for use in colorectal cancer (CRC) patients with RAS wild-type tumours only. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification (prenylation) of KRAS. We hypothesize that the activitated KRAS pathway in KRAS mutant tumors can be inhibited by simvastatin rendering these tumors sensitive to the EGFR inhibitor cetuximab. Methods A Simon two-stage, single-arm, phase II study was performed to test the efficacy and safety of the addition of simvastatin to cetuximab in patients with a KRAS mutation in their CRC tumour who were previously treated with fluoropyrimidine, oxaliplatin and irinotecan based regimens. The primary endpoint was to test the percentage of patients alive and free from progression 12.5 weeks after the first administration of cetuximab. Our hypothesis was that at least 40 % was free from progression, comparable to, though slightly lower than in KRAS wild-type patients. Results Four of 18 included patients (22.2 %) were free from progression at the primary endpoint time. The time to progression in these 4 patients ranged from 20.3 to 47 weeks. Conclusion Based on the current study we conclude that the theoretical concept of KRAS modulation with simvastatin was not applicable in the clinic, as we were not able to restore sensitivity to cetuximab in CRC patients harbouring a somatic KRAS mutation.\n\nKeywords\nKRASColorectal cancerCetuximabStatinissue-copyright-statement© Springer Science+Business Media New York 2015\n==== Body\nIntroduction\nEach year over 940.000 patients are diagnosed with colorectal cancer (CRC) world-wide and over 500.000 people die of this disease [1]. In patients with advanced or metastatic colorectal treatment with monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), cetuximab and panitumumab are proven to be active after failing fluoropyrimidine, oxaliplatin and irinotecan based regimens, though only in patients with tumours without a mutation in the KRAS [2, 3] or more recently RAS gene [4]. This led to the question whether increased activation of KRAS signaling by KRAS mutations can be modulated, thereby making KRAS mutated tumours sensitive to EGFR inhibitor therapy. One possible target for modulation is the mevalonate pathway, as we have previously discussed [5].\n\nThe mevalonate pathway is a metabolic cascade with various end-products including cholesterol. Other end-products are farnesyl and geranylgeranyl moieties (C15 and C17), both essential for posttranslational prenylation of the RAS protein and its association with the cytoplasmic membrane, and thereby activation of the RAS protein. By using HMG-CoA reductase inhibitors not only the synthesis of cholesterol is inhibited, but also the formation of C15 and C17, thereby inhibiting posttranslational modification of RAS [5, 6]. By blocking the mevalonate pathway in CRC patients with KRAS mutated tumours, the activated KRAS pathway might be inhibited. This would theoretically lead to increased sensitivity to cetuximab, potentially comparable to tumours with wild-type KRAS.\n\nThis single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to cetuximab in patients with a KRAS mutation in their tumour who were previously treated with fluoropyrimidine, oxaliplatin and irinotecan based regimens.\n\nMethods\nPatients\nEligible patients had advanced or metastatic colorectal cancer with a mutation in codon 12, 13 or 61 of the KRAS gene (either on tissue of the primary tumour or of a metastasis), after failing fluoropyrimidine, oxaliplatin and irinotecan based regimens, or after failure of oxaliplatin based therapy in patients who cannot be treated with irinotecan.\n\nOther eligibility criteria included age 18 years or older, written informed consent, World Health Organisation (WHO) performance score of 0 to 2 and progression of disease in the past 3 months prior to inclusion. Exclusion criteria included symptomatic brain metastases, previous treatment with EGFR inhibitors and history of toxicity during statin.\n\nThe study protocol was approved by the Ethics Committees of all participating hospitals.\n\nStudy design\nThis phase II, single-arm, multi-center study was performed using a Simon two-stage design [7]. In the first stage, 15 patients were included, followed by an interim analysis. Results of this analysis would determine whether the combination of simvastatin and cetuximab may have clinical benefit in this group of CRC patients, thus justifying the second stage and including up to 41 patients.\n\nTreatment schedule\nCetuximab was first administered at least one week after start of simvastatin therapy. The initial cetuximab dose was 400 mg/m2 with subsequent weekly infusions of 250 mg/m2. Pretreatment with an antihistamine and a corticosteroid was mandatory before the first infusion of cetuximab and recommended for all subsequent infusions.\n\nSimvastatin 80 mg orally once daily was started at start of study participation. This dose was chosen taken into consideration the need for continuous administration of the statin during the entire study, inhibitory effect on the mevalonate pathway and tolerability. Statins in cancer therapy have been studied in clinical trials in solid [8–18] and haematologic [19–21] malignancies, both as monotherapy as well as additional to chemotherapy. Statin doses from 20 mg/day up to 35 mg/kg/day were used, with only continuous use of statins when dosed at a maximum of 80 mg/day. Since the aim of this study is to modulate KRAS during the entire treatment with cetuximab and therefore a continuous exposure to simvastatin is needed, a dose of 80 mg/day was selected in order to obtain maximum effect while minimizing the risk of toxicity.\n\nTreatment was continued until progression of disease, clinical signs of progression, unacceptable toxicity or cetuximab toxicity requiring withholding of more than 2 subsequent infusions.\n\nTumour response was every 6 weeks using CT-scans and according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Scans of patients free from progression at time of primary endpoint were centrally reviewed.\n\nEndpoints\nPrimary objective was to test the percentage of patients alive and free from progression and alive at 12.5 weeks after the first administration of cetuximab. Our hypothesis was that at least 40 % of patients was free from progression, comparable to though slightly lower than in KRAS wild-type patients [2].\n\nSecondary objectives were to investigate overall survival (OS), objective response rate (ORR), progression free survival (PFS), and safety of simvastatin combined with cetuximab in this population and to evaluate the correlation between skin toxicity and response to treatment. Exploratory endpoints were to investigate the role of cholesterol as a biomarker during this treatment and whether PIK3CA status correlates with response to cetuximab in this population.\n\nMutational analysis\nKRAS mutational status was reconfirmed centrally, testing for the 7 most frequent mutations in codon 12 and 13 as described in detail elsewhere [22]. In addition, we tested for the 3 most common mutation in the PIK3CA gene; in exon 9 (c.1624G>A (p.E542K) and c.1633G>A (pE545K)) and exon 20 (c.3140A>G (p.H1047R)). Though KRAS and BRAF mutations are known to be mutually exclusive [23], we did test for the activating hotspot mutation p.V600E.\n\nStatistics\nSample size was chosen based on previous published data of CRC patients with KRAS wild-type tumours treated with cetuximab [2], aiming for a at least 40 % of patients free from progression at 12.5 weeks after start of cetuximab treatment in patients with KRAS mutant type tumours (i.e., slightly lower than the effect in KRAS wild-type patients). Combined with an alpha of 0.05 and a power of 0.80, an interim size of 15 and a total sample size of 46 patients were required. An interim analysis was to be performed after the inclusion of 15 evaluable patients. Only when at least 40 % (i.e., 6 patients) were free from progression at the 12.5 weeks, another 31 patients would be enrolled during the second stage of the study.\n\nResults\nPatients\nDuring the first stage of the study 18 instead of 15 patients were enrolled to account for patients that were thought to unevaluable for the primary endpoint. Baseline characteristics are listed in Table 1. None of the patients were using statins prior to inclusion.Table 1 Baseline characteristics\n\nAge – years\t\n Mean\t62\t\n Range\t52–75\t\nGender – n (%)\t\n Male\t13 (72)\t\n Female\t5 (18)\t\nWHO performance score – n (%)\t\n 0\t13 (72)\t\n I\t5 (18)\t\nSite of primary tumour – n (%)\t\n Colon\t12 (67)\t\n Rectum\t6 (33)\t\nPrior lines of chemotherapy – n (%)\t\n 1\t2\t\n 2\t15\t\n 3\t1\t\nPrior surgery – n (%)\t13 (72)\t\nPrior radiotherapy – n (%)\t4 (22)\t\n\n\nEfficacy\nFour of 18 patients were free from progression at the primary endpoint time, therefore the percentage of patients alive and free from progression 12.5 weeks after the first administration of cetuximab was 22 %. The time to progression in these 4 patients ranged from 20.3 to 47 weeks. Drug exposure to simvastatin and cetuximab was equal for all patients.\n\nFigure 1 shows progression free (panel A) and overall survival (panel B). Median PFS was 9 weeks (mean 12.9 weeks, range 3.9–47 weeks). Median OS was 31.5 weeks (mean 36.3, range 8–138.1). The ORR was 6 % (partial remission in 1 patient). A true relation between skin toxicity and efficacy of treatment was not observed in this study though this may (partly) be due to the low number of patients and due to the improved knowledge of the efficacy of pre-emptive skin toxicity management.Fig. 1 \na Progression free survival in weeks for the addition of simvastatin to cetuximab in CRC patients failing standard therapy. b Overall survival in weeks for the addition of simvastatin to cetuximab in CRC patients failing standard therapy\n\n\n\nSafety\nMain symptoms and adverse events reported on study reported were fatigue (n = 11), acne (n = 10) and rash (n = 6). Myopathy was not reported. Three patients had elevation of creatine kinase (CK) levels on study (grade 4 in one patient). Skin toxicity occurred in 10 patients; the worst grade of acneiform rash was grade 3 in one patient, grade 2 in 4 patients and grade 1 in the remaining 5 patients. One patient experienced a severe (i.e., grade 3) allergic reaction during the first infusion of cetuximab. One of the serious adverse events did precede the death of a participant. Upon the scheduled laboratory examination severe elevation of liver enzymes were observed. Rhabdomyolysis was considered, (though on study CK levels were below 3.000 U/l) and so was progression of liver metastases. Study medication was interrupted immediately, however the patient’s situation did not improve and it was decided to terminate study participation permanently. Specific SNPs associated with increased risk of statin-induced myopathy (i.e., SLCO1B1 variants [24]) were considered though none were identified in this patient. The patient deceased few weeks later. Post-mortem examination did not occur.\n\nExploratory endpoints\nAll patients showed cholesterol reduction, ranging from a maximum reduction of 0.8 to 64.4 %. The percentage of cholesterol reduction did not correlate with progression free survival.\n\nTumour tissue of 15 patients was available for central review. Table 2 shows mutational status of KRAS and PIK3CA per patient. Of the 4 patients responding to treatment, 3 had a KRAS mutation in codon 12 and 1 had a PIK3CA mutation. As expected all patients were BRAF wild-type.Table 2 \nKRAS and PIK3CA mutational status per patient\n\nStudy number\t\nKRAS mutation\t\nPIK3CA mutational status\t\n1\tG12D\tWild-type\t\n2\tG12V\tWilde-type\t\n3\tG12V\tWild-type\t\n4\tG12C\tWild-type\t\n5\tG12V\tWild-type\t\n6\tG12S\tWild-type\t\n7\t\nmissing\n\t\nMissing\n\t\n8\tG12V\tWild-type\t\n9\tG13D\tWild-type\t\n10\tG13D\tWild-type\t\n11\tG12D\tWild-type\t\n12\tG12D\tWild-type\t\n13\t\nmissing\n\t\nMissing\n\t\n14\tG12V\tWild-type\t\n15\tG12A\tWild-type\t\n16\tG12A\tWild-type\t\n17\tG13D\tMutation in exon 9\t\n18\tG12D\tMutation in exon 9\t\n\n\nDiscussion\nTo our knowledge, this is the first clinical trial testing the addition of simvastatin to cetuximab monotherapy in CRC patients harbouring a KRAS mutation in tumour tissue as an attempt to restore cetuximab sensitivity. While it was remarkable to notice a durable progression free survival in 4 patients, the interim analysis showed that the predefined criteria to proceed to the second stage of this study were not reached. Therefore, the current study suggests that high dose simvastatin does not render cetuximab sensitivity in KRAS mutant CRC.\n\nStatines are one of several potential agents to modulate KRAS signaling, as we have previously reviewed [5]. The current study is not the first to hypothesize on statins and their inhibitory effect on the activity of RAS and its downstream pathway. However, all but one previous reports include only preclinical data. For example, lovastatin and simvastatin inhibit downstream activity in breast cells with mutated HRAS, possibly by inhibiting membrane localization of HRAS. The effect was reversed when adding farnesyl pyrophosphate, indicating the effect was related to prenylation of RAS [25]. More recently, simvastatin was shown to restore cetuximab resistance in vitro and in vivo [26]. Based on these results, one might wonder whether the negative outcome of the current study would have been different if using higher doses of simvastatin. However, preclinical data showed a significant reduction in cell growth of KRAS mutant CRC cell lines using 0.2 μM simvastatin, the equivalent of 2 mg/kg/day in humans [26]. Moreover, in cardiovascular disease the registered dose of 80 mg of simvastatin is significantly lowers cholesterol serum levels. It is reasonable that this dose will also affect the formation of the C15 and C17 groups and subsequently the prenylation of the KRAS protein. Furthermore, we question whether higher doses will be feasible in terms of safety.\n\nA recent study of Lee et al. tested the efficacy of the addition of the same dose of simvastatin (i.e., 80 mg once daily) to cetuximab and irinotecan in KRAS mutant CRC patients failing prior oxaliplatin, fluoropyrimidine and irinotecan based therapy [27]. The initially reported PFS and OS (median 7.6 months and 12.8 months respectively) were considerably higher than historical results in chemotherapy refractory CRC patients with KRAS mutated tumours [28] and chemotherapy refractory CRC patients in general [29–31]. Moreover, these results were in contrast with our findings. However, a recent erratum published by this group showed that initial survival data were incorrect [32]. The corrected PFS and OS are in line with our results, providing no evidence for a modulating effect of simvastatin on the KRAS mutant phenotype.\n\nThe majority of patients had a KRAS mutation in codon 12 and only 3 in codon 13. It has been reported that tumours harbouring a G13D mutation in the KRAS gene might be sensitive to EGFR-inhibitors [33]. Moreover, none of our patients had a PIK3CA mutation in exon 20, while these might also be more likely to be sensitive to EGFR-inhibitors, contrary to mutations in exon 9 [34]. However, of the 4 patients who were free from progression at time of the primary endpoint only one patients had a G13D mutation in the KRAS gene and none had a PIK3CA mutation in exon 20.\n\nConclusion\nBased on the current study we conclude that the concept of KRAS modulation with simvastatin was not applicable in the clinic. Similar results were recently demonstrated in this population treated with panitumumab and simvastatin [35]. Better treatment strategies are needed for this patient population.\n\nJ. M. Baas and L. L. Krens contributed equally to this work.\n\nCompliance with ethical standards\nConflict of interest\nJara M, Baas: none; Lisanne L. Krens: none; A.J. ten Tije: none; F. Erdkamp: none; Tom van Wezel: none; Hans Morreau: none; Henk-Jan Guchelaar: research funding by Amgen Inc and Merck BV; Hans Gelderblom: research funding by Amgen Inc en Merck BV.\n\nInformed consent\nThe informed consent form was signed by the patient (and physician) prior to inclusion and according to the ICH guidelines on Good Clinical Practice.\n\nFunding\nThis was an Investigator Initiated Study, made possible by a research grant offered by Merck Serono.\n==== Refs\nReferences\n1. Denters MJ Deutekom M Fockens P Bossuyt PM Dekker E Implementation of population screening for colorectal cancer by repeated fecal occult blood test in the Netherlands BMC Gastroenterol 2009 9 28 10.1186/1471-230X-9-28 19393087 \n2. Karapetis CS Khambata-Ford S Jonker DJ K-ras mutations and benefit from cetuximab in advanced colorectal cancer N Engl J Med 2008 359 1757 1765 10.1056/NEJMoa0804385 18946061 \n3. Amado RG Wolf M Peeters M Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer J Clin Oncol 2008 26 1626 1634 10.1200/JCO.2007.14.7116 18316791 \n4. Sorich MJ Wiese MD Rowland A Kichenadasse G McKinnon RA Karapetis CS Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials Ann Oncol 2014 26 13 21 10.1093/annonc/mdu378 25115304 \n5. Krens LL Baas JM Gelderblom H Guchelaar HJ Therapeutic modulation of k-ras signaling in colorectal cancer Drug Discov Today 2010 15 502 516 10.1016/j.drudis.2010.05.012 20594936 \n6. Swanson KM Hohl RJ Anti-cancer therapy: targeting the mevalonate pathway Curr Cancer Drug Targets 2006 6 15 37 10.2174/156800906775471743 16475974 \n7. Simon R Optimal two-stage designs for phase II clinical trials Control Clin Trials 1989 10 1 10 10.1016/0197-2456(89)90015-9 2702835 \n8. Hong JY Nam EM Lee J Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients Cancer Chemother Pharmacol 2014 73 125 130 10.1007/s00280-013-2328-1 24162380 \n9. Manoukian GE Tannir NM Jonasch E Qiao W Haygood TM Tu SM Pilot trial of bone-targeted therapy combining zoledronate with fluvastatin or atorvastatin for patients with metastatic renal cell carcinoma Clin Genitourin Cancer 2011 9 81 88 10.1016/j.clgc.2011.07.001 21958521 \n10. Han JY Lim KY Yu SY Yun T Kim HT Lee JS A phase 2 study of irinotecan, cisplatin, and simvastatin for untreated extensive-disease small cell lung cancer Cancer 2011 117 2178 2185 10.1002/cncr.25790 21523731 \n11. Han JY Lee SH Yoo NJ A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer Clin Cancer Res 2011 17 1553 1560 10.1158/1078-0432.CCR-10-2525 21411446 \n12. Konings IR van der Gaast A van der Wijk LJ de Jongh FE Eskens FA Sleijfer S The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial Eur J Cancer 2010 46 3200 3204 10.1016/j.ejca.2010.07.036 20727735 \n13. Lee J Jung KH Park YS Simvastatin plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as first-line chemotherapy in metastatic colorectal patients: a multicenter phase II study Cancer Chemother Pharmacol 2009 64 657 663 10.1007/s00280-008-0913-5 19169686 \n14. Graf H Jungst C Straub G Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma Digestion 2008 78 34 38 10.1159/000156702 18797167 \n15. Knox JJ Siu LL Chen E A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix Eur J Cancer 2005 41 523 530 10.1016/j.ejca.2004.12.013 15737556 \n16. Lersch C Schmelz R Erdmann J Treatment of HCC with pravastatin, octreotide, or gemcitabine—a critical evaluation Hepatogastroenterology 2004 51 1099 1103 15239254 \n17. Kim WS Kim MM Choi HJ Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma Invest New Drugs 2001 19 81 83 10.1023/A:1006481423298 11291836 \n18. Kawata S Yamasaki E Nagase T Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial Br J Cancer 2001 84 886 891 10.1054/bjoc.2000.1716 11286466 \n19. Ahmed TA Hayslip J Leggas M Pharmacokinetics of high-dose simvastatin in refractory and relapsed chronic lymphocytic leukemia patients Cancer Chemother Pharmacol 2013 72 1369 1374 10.1007/s00280-013-2326-3 24162379 \n20. Hus M Grzasko N Szostek M Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma Ann Hematol 2011 90 1161 1166 10.1007/s00277-011-1276-2 21698395 \n21. van der Spek E Bloem AC Sinnige HA Lokhorst HM High dose simvastatin does not reverse resistance to vincristine, adriamycin, and dexamethasone (VAD) in myeloma Haematologica 2007 92 e130 e131 10.3324/haematol.12071 18055977 \n22. van Eijk R Licht J Schrumpf M Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non-small-cell lung cancer using allele-specific qPCR PLoS One 2011 6 e17791 10.1371/journal.pone.0017791 21408138 \n23. Tol J Nagtegaal ID Punt CJ BRAF mutation in metastatic colorectal cancer N Engl J Med 2009 361 98 99 10.1056/NEJMc0904160 19571295 \n24. Link E Parish S Armitage J SLCO1B1 variants and statin-induced myopathy—a genomewide study N Engl J Med 2008 359 789 799 10.1056/NEJMoa0801936 18650507 \n25. Kang S Kim ES Moon A Simvastatin and lovastatin inhibit breast cell invasion induced by H-Ras Oncol Rep 2009 21 1317 1322 19360310 \n26. Lee J Lee I Han B Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations J Natl Cancer Inst 2011 103 674 688 10.1093/jnci/djr070 21398618 \n27. Lee J Hong YS Hong JY Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab Invest New Drugs 2014 32 535 541 10.1007/s10637-014-0065-x 24468885 \n28. De Roock W Claes B Bernasconi D Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis Lancet Oncol 2010 11 753 762 10.1016/S1470-2045(10)70130-3 20619739 \n29. Grothey A van Cutsem E Sobrero A Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial Lancet 2013 381 303 312 10.1016/S0140-6736(12)61900-X 23177514 \n30. Jonker DJ O’Callaghan CJ Karapetis CS Cetuximab for the treatment of colorectal cancer N Engl J Med 2007 357 2040 2048 10.1056/NEJMoa071834 18003960 \n31. van Cutsem E Peeters M Siena S Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer J Clin Oncol 2007 25 1658 1664 10.1200/JCO.2006.08.1620 17470858 \n32. Lee J, Hong YS, Hong JY et al (2014) Erratum to: effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab. Invest New Drugs\n33. Tejpar S Celik I Schlichting M Sartorius U Bokemeyer C Van CE Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab J Clin Oncol 2012 30 3570 3577 10.1200/JCO.2012.42.2592 22734028 \n34. Karapetis CS Jonker D Daneshmand M PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer—results from NCIC CTG/AGITG CO.17 Clin Cancer Res 2014 20 744 753 10.1158/1078-0432.CCR-13-0606 24218517 \n35. Baas JM Krens LL Bos MM Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients Anticancer Drugs 2015 26 872 877 10.1097/CAD.0000000000000255 26053280\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0167-6997",
"issue": "33(6)",
"journal": "Investigational new drugs",
"keywords": "Cetuximab; Colorectal cancer; KRAS; Statin",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D005076:Exanthema; D005221:Fatigue; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras); D019821:Simvastatin; D016896:Treatment Outcome",
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"pages": "1242-7",
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"pmid": "26386973",
"pubdate": "2015-12",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "20594936;19169686;19571295;20619739;20727735;21408138;21411446;21398618;21523731;21698395;19360310;22734028;23177514;24162379;24162380;24218517;24468885;25115304;26053280;19393087;11286466;11291836;21958521;2702835;15737556;16475974;17470858;18003960;18055977;18316791;18797167;18946061;18650507;15239254",
"title": "Safety and efficacy of the addition of simvastatin to cetuximab in previously treated KRAS mutant metastatic colorectal cancer patients.",
"title_normalized": "safety and efficacy of the addition of simvastatin to cetuximab in previously treated kras mutant metastatic colorectal cancer patients"
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"abstract": "ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.",
"affiliations": "AbbVie Inc., North Chicago, IL.",
"authors": "Badri|P|P|;Dutta|S|S|;Coakley|E|E|;Cohen|D|D|;Ding|B|B|;Podsadecki|T|T|;Bernstein|B|B|;Awni|W|W|;Menon|R|R|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D016572:Cyclosporine; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; C585405:paritaprevir; D016559:Tacrolimus",
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"fulltext": "\n==== Front\nAm J TransplantAm. J. Transplant10.1111/(ISSN)1600-6143AJTAmerican Journal of Transplantation1600-61351600-6143John Wiley and Sons Inc. Hoboken 10.1111/ajt.13111AJT13111Original ArticleOriginal ArticlesClinical SciencePharmacokinetics and Dose Recommendations for Cyclosporine and Tacrolimus When Coadministered With ABT‐450, Ombitasvir, and Dasabuvir Cyclosporine and Tacrolimus Drug InteractionsBadri et alBadri P. \n1\nDutta S. \n1\nCoakley E. \n1\nCohen D. \n1\nDing B. \n1\nPodsadecki T. \n1\nBernstein B. \n1\nAwni W. \n1\nMenon R. \n1\n1 AbbVie Inc.North ChicagoIL* Corresponding author: Prajakta Badri, prajakta.badri@abbvie.com5 2015 23 2 2015 15 5 10.1111/ajt.v15.51313 1322 03 10 2014 16 11 2014 16 11 2014 © 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.The authors describe the drug–drug interaction profile of the he patitis C direct‐acting antiviral agents ABT‐450, ombitasvir, and dasabuvir with cyclosporine A and tacrolimus, and use pha rmacokinetic simulations to develop recommendations for reduced doses of cyclosporine A and tacrolimus in posttransplant patients with recurrent hepatitis C infection.\n\nABT‐450, ombitasvir, and dasabuvir are direct‐acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT–450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady‐state concentrations of all 3 DAAs, dose‐normalized cyclosporine concentration at 24 hours (C24), and area under the concentration‐time curve from time 0 to infinity (AUC∞) were 15.8‐fold and 5.8‐fold, respectively, and dose‐normalized tacrolimus C24 and AUC∞ were 17‐fold and 57‐fold, respectively, of either agent alone. Cyclosporine and tacrolimus half‐lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV‐infected posttransplant patients being treated with this 3‐DAA regimen.\n\nclinical research/practiceinfectious diseaseliver transplantation/hepatologypharmacologyimmunosuppressantcalcineurin inhibitor: cyclosporine A (CsA)immunosuppressantcalcineurin inhibitor: tacrolimusinfection and infectious agentsviral: hepatitis Cpharmacokinetics/pharmacodynamicsAbbVie, Inc. Interpretation source-schema-version-number2.0component-idajt13111cover-dateMay 2015details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:15.09.2016\n==== Body\nAbbreviations\n3D regimenABT‐450/ritonavir, ombitasvir, and dasabuvir\n\nABT‐450/rABT‐450 administered with ritonavir\n\nAUCarea under the concentration‐time curve\n\nAUC∞area under the concentration‐time curve from time 0 to infinity\n\nBMIbody mass index\n\nC12 or C24concentration at 12 or 24 h\n\nCIconfidence interval\n\nCmaxmaximal concentration\n\nCtroughtrough concentration\n\nCVcoefficient of variation\n\nCYPcytochrome P450\n\nDAAdirect‐acting antiviral agent\n\nHCVhepatitis C virus\n\nLLOQlower limit of quantitation\n\nNSnonstructural protein\n\nOATP1B1organic anion transporting polypeptide 1B1\n\nP‐gpP‐glycoprotein\n\nSVR12sustained virologic response 12 weeks post‐treatment\n\nTmaxtime to maximum observed concentration (Cmax)\n\nt1/2terminal phase elimination half‐life\n\nIntroduction\nHepatitis C virus (HCV) infection affects approximately 170 million individuals worldwide 1. Chronic HCV infection can result in cirrhosis or hepatocellular carcinoma, both of which are leading causes of liver transplantation 2. Recurrence of HCV infection after liver transplantation is universal, and may lead to allograft loss 3. The course of HCV infection after liver transplantation is accelerated compared with that in the pretransplant setting, with 10% to 30% of patients developing cirrhosis only 5 years posttransplantation 4. Thus, safe and effective treatment of HCV in the posttransplant setting, in which patients receive immunosuppressive agents to prevent allograft rejection, is an important consideration in the development of new HCV therapies.\n\nABT‐450, ombitasvir (ABT‐267), and dasabuvir (ABT‐333) are direct‐acting antiviral agents (DAAs) developed for interferon‐free, all‐oral combination treatment of chronic HCV infection. These DAAs have distinct, nonoverlapping mechanisms of action against HCV. ABT‐450 is a nonstructural (NS) protein 3/4A protease inhibitor identified by AbbVie and Enanta as a lead compound for clinical development. ABT‐450 is metabolized primarily by cytochrome P450 (CYP) 3A and is administered with a low dose of the CYP3A inhibitor ritonavir as a pharmacokinetic enhancer (coadministration denoted ABT‐450/r) to allow for once daily administration and lower ABT‐450 doses. Ombitasvir is an NS5A inhibitor and dasabuvir is an NS5B nonnucleoside polymerase inhibitor. Results from Phase 3 trials in over 2000 HCV genotype 1‐infected subjects demonstrated that treatment with this combination of 3 DAAs (3D regimen) with ribavirin produced sustained virologic response 12 weeks after the end of treatment (SVR12) in 92% of patients with cirrhosis and 96% of patients without cirrhosis 5, 6. In addition, in the CORAL I study in liver transplant recipients with recurrent HCV genotype 1 infection and no cirrhosis (Metavir ≤ F2) at least 12 months after transplantation, 33 of 34 patients (97.1%; 95% confidence interval [CI], 91.4% to 100%) who were treated with the 3D regimen plus ribavirin for 24 weeks achieved SVR12 and no graft rejection events occurred 7. The calcineurin inhibitors cyclosporine A (cyclosporine) and tacrolimus are key immunosuppressants administered to liver transplant recipients. The dosing recommendations for cyclosporine and tacrolimus in the CORAL I study were derived from pharmacokinetic simulations based on drug interaction data described in the current report.\n\nThe metabolic and transporter profiles of the DAAs and cyclosporine and tacrolimus show considerable overlap. Cyclosporine and tacrolimus are metabolized by CYP3A and transported by the transmembrane protein P‐glycoprotein (P‐gp) and both agents are inhibitors of organic anion transporting polypeptide 1B1 (OATP1B1), an uptake transporter in the liver 8, 9, 10, 11. CYP3A, P‐gp, and OATP1B1 are all involved in ABT‐450 disposition and CYP3A is involved in dasabuvir metabolism. Ritonavir is a substrate and inhibitor of CYP3A 12 and it affects multiple drug transporters 13. Additionally, P‐gp is involved in ombitasvir and dasabuvir disposition and OATP1B1 is involved in dasabuvir metabolite (M1) disposition 14. Thus, interactions between the 3D regimen and cyclosporine or tacrolimus might be expected to alter drug exposures for all of these agents.\n\nTwo studies were conducted to evaluate the pharmacokinetics of coadministration of the 3D regimen with cyclosporine or tacrolimus in healthy volunteers to inform dosing recommendations prior to initiation of trials in transplant patients. Using data from these studies, pharmacokinetic simulations were performed to compare the time‐concentration profiles of cyclosporine and tacrolimus alone or in the presence of the 3D regimen to further inform dosing recommendations in transplant recipients.\n\nSubjects and Methods\nTwo Phase 1 studies evaluated the pharmacokinetics of the DAAs administered with cyclosporine or tacrolimus. Both studies were conducted at the same site (PPD Development, Austin, TX) in accordance with Good Clinical Practice guidelines and ethical principles that have their origin in the Declaration of Helsinki. The protocols for the cyclosporine and tacrolimus studies (Protocols M13‐103 and M13‐491, respectively) were approved by the institutional review board (RCRC, now known as Salus IRB, Austin, TX; registration numbers IRB00006834 and IRB00006833) and written informed consent was obtained from each subject before any study‐related procedures were performed.\n\nSubjects\nEnrollment criteria were similar for both studies. Males and females between the ages of 18 and 55 years with body mass index (BMI) between 18 and 30 kg/m2 and in general good health were enrolled. Subjects must not have used any of the following prior to study drug administration: tobacco or nicotine‐containing products within 6 months; known inhibitors or inducers of CYP3A or OATP1B1 within 1 month; or alcohol within 72 h.\n\nStudy design\nThe studies were open‐label, sequential, multiple‐dose designed to evaluate the safety, tolerability, and pharmacokinetic interactions of coadministration of the 3D regimen (ABT‐450/r, ombitasvir, and dasabuvir) or 2‐DAA regimens (ABT‐450/r plus dasabuvir or ABT‐450/r plus ombitasvir) and cyclosporine or tacrolimus. In each study, eligible subjects were enrolled into one of three groups (N = 12 per group), each consisting of two periods (Fig. 1). The 3D regimen is the proposed regimen for treatment of HCV genotype 1; therefore, pharmacokinetic results from subjects who received the 3D regimen plus cyclosporine or tacrolimus are the focus of this report.\n\nFigure 1 \nCyclosporine and tacrolimus study designs.\n\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsCyclosporine study\nIn Period 1, subjects received a single 100 mg dose of cyclosporine capsule (Neoral®, Novartis Pharmaceuticals Corporation, East Hanover, NJ) in the morning. In Period 2, subjects received the following oral regimens: a single 30 mg dose of cyclosporine solution (Neoral®, Novartis Pharmaceuticals Corporation, East Hanover, NJ) in the morning on Day 1 and Day 15, and ABT‐450/r 150/100 mg once daily, ombitasvir 25 mg once daily, and dasabuvir 400 mg twice daily on Days 1 through 21. The 30 mg dose of cyclosporine was chosen based on the magnitude of interaction observed in the two groups that received the 2‐DAA regimens and cyclosporine. The 400 mg dasabuvir formulation is bioequivalent to the 250 mg tablet (administered twice daily) evaluated in Phase 3 studies of the 3D regimen. Cyclosporine and the DAAs were coadministered at the same time in the morning. This study design permitted evaluation of the effect of single‐dose and steady‐state 3D regimen on a single dose of cyclosporine and the effect of a single dose of cyclosporine on steady‐state 3D regimen.\n\nTacrolimus study\nIn Period 1, subjects received a single 2 mg dose of tacrolimus capsule (Prograf®, Astellas Pharma US, Inc., Deerfield, IL) in the morning. In Period 2, subjects received the following oral regimens: a single 2 mg dose of tacrolimus capsule in the morning on Day 15, and ABT–450/r 150/100 mg once daily, ombitasvir 25 mg once daily, and dasabuvir 400 mg twice daily on Days 1 through 28. Tacrolimus and the DAAs were coadministered at the same time in the morning. This study design permitted evaluation of the effect of steady‐state 3D regimen on a single dose of tacrolimus and the effect of a single dose of tacrolimus on steady‐state 3D regimen.\n\nCyclosporine and tacrolimus are administered without food to maximize absorption 8, 9; therefore, on Study Day 1, cyclosporine and tacrolimus were administered after a minimum 10‐h fast to mimic typical dosing. However, the 3D regimen is administered with food. In the current studies, cyclosporine and tacrolimus were coadministered with the 3D regimen in the presence of food to enable dose recommendations for further clinical development of the 3D regimen in HCV‐infected patients receiving these agents.\n\nSample collection and bioanalytical methods\nBlood samples for the determination of drug concentrations were collected by venipuncture at multiple timepoints throughout each study (Fig. 1).\n\nPlasma concentrations of ABT‐450, ritonavir, ombitasvir, dasabuvir, and dasabuvir M1 (dasabuvir metabolite) and whole blood concentrations of cyclosporine and tacrolimus were determined using a validated liquid chromatography and tandem mass spectrometric detection method. The lower limits of quantitation (LLOQ) for ABT‐450, ritonavir, ombitasvir, dasabuvir, dasabuvir M1, cyclosporine, and tacrolimus were 0.595 ng/mL, 4.91 ng/mL, 0.424 ng/mL, 4.53 ng/mL, 4.72 ng/mL, 5.0 ng/mL, and 0.250 ng/mL, respectively.\n\nPharmacokinetic evaluations\nNoncompartmental methods were used to estimate the maximum observed concentration (Cmax) and time to Cmax (peak time, Tmax), predose trough concentration (Ctrough) (C12 for dasabuvir and dasabuvir M1 and C24 for all others), apparent terminal phase elimination rate constant (β), terminal phase elimination half‐life (t1/2), and area under the concentration‐time curve from time 0 to 12 h (dasabuvir and dasabuvir M1), 24 h (all others) (AUC12 or AUC24), or infinite time (AUC∞). Dose‐normalized pharmacokinetic parameters were calculated by dividing parameters by the administered dose.\n\nSafety and tolerability\nSafety and tolerability were evaluated based on adverse event monitoring, vital signs measurements, physical examinations, 12‐lead electrocardiogram assessments, and laboratory tests.\n\nStatistical analysis\nTo assess the effect of the 3D regimen on cyclosporine or tacrolimus, a repeated measures analysis was performed for the natural logarithms of dose‐normalized cyclosporine or tacrolimus Cmax, AUC, and C24. Similarly, to assess the effect of cyclosporine or tacrolimus on the 3D regimen, a repeated measures analysis was performed for the natural logarithms of ABT‐450, ritonavir, ombitasvir, dasabuvir, and dasabuvir M1 Cmax, AUC, and C24 (C12 for dasabuvir and dasabuvir M1). The 90% CIs for ratio estimates were obtained by taking the antilogarithm of the upper and lower limits of the CIs for the difference of the least squares means on the logarithmic scale obtained within the framework of the repeated measures analysis model.\n\nIn each study, complete data from 12 subjects per group would have provided at least 81.5% power for the test on ABT‐450 AUC if the ratio of the central values was twofold (assuming the error term variance of 0.2929 for the natural logarithm of AUC). Based on previous studies, the variability in other drugs is lower than that of ABT‐450.\n\nPharmacokinetic simulations\nMean concentration‐time profiles for 3D plus cyclosporine or tacrolimus were used to simulate concentration‐time profiles for different regimens (cyclosporine 100 mg once daily plus 3D, and tacrolimus 0.5 mg every 7 days, 0.5 mg every 14 days, or 0.2 mg every 72 h plus 3D) using nonparametric super‐positioning (Phoenix™ WinNonlin®, Version 6.3, Pharsight Corporation, St. Louis, MO). Simulated concentration‐time profiles for 3D plus cyclosporine or tacrolimus were compared with the simulated concentration‐time profiles for cyclosporine alone (250 mg twice daily) or tacrolimus alone (2 mg twice daily) to provide dosing recommendations for coadministration of cyclosporine or tacrolimus with the 3D regimen.\n\nResults\nSubjects and baseline demographics\nIn each study, 12 subjects were enrolled in the group that evaluated interaction of cyclosporine or tacrolimus with the 3D regimen. Two subjects in the cyclosporine study were excluded from statistical analyses of pharmacokinetic parameters for Period 2 Day 15; one who withdrew due to a family emergency and one who had no measurable blood cyclosporine concentrations.\n\nIn each study, the mean age of subjects was 33 years and the mean BMI was 26 kg/m2. All subjects but one were male and the majority (75%) was white.\n\nEffect of the 3D regimen on cyclosporine and tacrolimus pharmacokinetics\nCyclosporine\nThe dose‐normalized mean blood concentration‐time profiles for cyclosporine administered alone (Period 1, Day 1) or with the 3D regimen (Period 2, Days 1 and 15) are presented in Fig. 2. The mean (% coefficient of variation, CV) pharmacokinetic parameters of cyclosporine, with and without dose normalization, and dose‐normalized geometric mean ratios and 90% CIs are presented in Table 1. The effect of 3D on cyclosporine exposures was greater when the DAAs were at steady state than after 1 day of dosing. In the presence of a single dose of the 3D regimen, dose‐normalized cyclosporine C24 and AUC∞ were 7.0‐fold and 3.0‐fold of the cyclosporine values when administered alone, respectively, whereas cyclosporine dose‐normalized Cmax was 36% lower. Cyclosporine half‐life increased from 7.3 to 16 h and Tmax was delayed by 2.2 h. In the presence of the 3D regimen at steady state, dose‐normalized cyclosporine C24 and AUC∞ were 16‐fold and 5.8‐fold of the cyclosporine values when administered alone, respectively, whereas cyclosporine dose‐normalized Cmax was similar. Cyclosporine half‐life increased from 7.3 to 25 h and Tmax was delayed by 3.1 h.\n\nFigure 2 \nMean dose‐normalized concentration‐time profile (log‐linear scale) of a single dose of cyclosporine with or without coadministration of the 3D regimen. Note: 3D, ABT‐450/ritonavir 150/100 mg once daily, ombitasvir 25 mg once daily, and dasabuvir 400 mg twice daily.\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsTable 1 Cyclosporine pharmacokinetic parameters\n\n\tCsA 100 mg\tCsA 30 mg + 3D\tCsA 30 mg + 3D\t\n\tPeriod 1, Day 1 (N = 12)\tPeriod 2, Day 1 (N = 12)\tPeriod 2, Day 15 (N = 10)\t\nParameter\tMean (%CV)\tMean (%CV)\tGeometric Mean Ratio (90% CI)\tMean (%CV)\tGeometric Mean Ratio (90% CI)\t\nCmax/D (ng/mL/mg)\t6.4 (22)\t4.3 (44)\t0.64 (0.54–0.75)\t6.5 (25)\t1.0 (0.85–1.2)\t\nAUC∞/D (ng·h/mL/mg)\t21 (21)\t72 (60)\t3.0 (2.5–3.7)\t125 (25)\t5.8 (4.7–7.1)\t\nC24/D (ng/mL/mg)\t0.08 (29)\t0.61 (42)\t7.0 (6.2–7.9)\t1.4 (23)\t16 (14–18)\t\nC12/D (ng/mL/mg)\t0.27 (32)\t1.8 (39)\t–\t3.3 (23)\t–\t\nCmax (ng/mL)\t635 (22)\t128 (44)\t–\t194 (25)\t–\t\nTmax (h)\t1.8 (33)\t4.0 (41)\t–\t4.9 (24)\t–\t\nAUC∞ (ng·h/mL)\t2110 (21)\t2170 (60)\t–\t3750 (25)\t–\t\nt1/2 (h)\n1\n\n\t7.3 (22)\t16 (78)\t–\t25 (43)\t–\t\nC24 (ng/mL)\t8.5 (29)\t18 (42)\t–\t41 (23)\t–\t\nC12 (ng/mL)\t27 (32)\t53 (39)\t–\t98 (23)\t–\t\nCsA, cyclosporine A; 3D, ABT‐450/ritonavir 150/100 mg once daily, ombitasvir 25 mg daily, and dasabuvir 400 mg twice daily; D, dose.\n\n1 Harmonic mean ± pseudo‐CV%.\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsTacrolimus\nThe dose‐normalized mean blood concentration‐time profiles for tacrolimus administered alone (Period 1, Day 1) or with the 3D regimen (Period 2, Day 15) are presented in Fig. 3. The mean (%CV) pharmacokinetic parameters of tacrolimus, with and without dose normalization, and dose‐normalized geometric mean ratios and 90% CIs are presented in Table 2. In the presence of the 3D regimen at steady state, dose‐normalized tacrolimus Cmax, C24, and AUC∞ were 4.0‐, 17‐, and 57‐fold of the tacrolimus values when administered alone, respectively. Tacrolimus half‐life increased from 32 to 232 h and Tmax was delayed by 3.2 h.\n\nFigure 3 \nMean dose‐normalized concentration‐time profile (log‐linear scale) of a single dose of tacrolimus with or without coadministration of the 3D regimen. Note: 3D = ABT‐450/ritonavir 150/100 mg once daily, ombitasvir 25 mg once daily, and dasabuvir 400 mg twice daily.\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsTable 2 Tacrolimus pharmacokinetic parameters\n\n\tTacrolimus 2 mg\tTacrolimus 2 mg + 3D\t\n\tPeriod 1, Day 1 (N = 12)\tPeriod 2, Day 15 (N = 12)\t\nParameter\tMean (%CV)\tMean (%CV)\tGeometric Mean Ratio (90% CI)\t\nCmax/D (ng/mL/mg)\t5.7 (39)\t22 (23)\t4.0 (3.2–5.0)\t\nAUC∞/D (ng·h/mL/mg)\t59 (34)\t3290 (25)\t57 (46–72)\t\nC24/D (ng/mL/mg)\t0.53 (32)\t8.5 (23)\t17 (13–21)\t\nC12/D (ng/mL/mg)\t0.78 (31)\t11 (29)\t–\t\nCmax (ng/mL)\t11 (39)\t43 (23)\t–\t\nTmax (h)\t1.8 (37)\t5.0 (38)\t–\t\nAUC∞ (ng·h/mL)\t118 (34)\t6590 (25)\t–\t\nt1/2 (h)\n1\n\n\t32 (26)\t232 (30)\t–\t\nC24 (ng/mL)\t1.1 (32)\t17 (23)\t–\t\nC12 (ng/mL)\t1.6 (31)\t23 (29)\t–\t\n3D, ABT‐450/ritonavir 150/100 mg once daily, ombitasvir 25 mg once daily, and dasabuvir 400 mg twice daily; D, dose.\n\n1 Harmonic mean ± pseudo‐CV%.\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsProjected cyclosporine and tacrolimus Ctrough values for reduced dosing regimens\nIllustrations of timelines from the time a patient undergoes transplant through the first several days of 3D treatment, and comparisons of the pharmacokinetic simulations of expected cyclosporine and tacrolimus concentration‐time profiles before and after 3D treatment are shown in Fig. 4 and Fig. 5. The expected Ctrough values in posttransplant patients who initiate 3D treatment are provided in Table 3. A reduction in cyclosporine dose and dosing frequency from 250 mg twice daily (total daily dose of 500 mg) to 100 mg once daily (fivefold reduction in total daily dose) is projected to maintain Ctrough values similar to values observed before 3D treatment. Similarly, a reduction in tacrolimus dose and dosing frequency from 2 mg twice daily to 0.5 mg every 7 days is expected to maintain Ctrough levels within the range observed before initiation of 3D treatment at 12 months after transplantation. Administration of 0.2 mg strength of tacrolimus, available in some countries, every 72 h is also expected to maintain acceptable Ctrough levels (Table 3).\n\nFigure 4 \nSimulated concentration‐time profile for coadministration of cyclosporine 100 mg once daily with the 3D regimen. QD, once daily; BID, twice daily. Note: The plot illustrates the timeline from the time a patient undergoes transplant through the first several days of 3D (ABT‐450/ritonavir 150/100 mg once daily, ombitasvir 25 mg once daily, and dasabuvir 400 mg twice daily) treatment. The mean concentration‐time profile for cyclosporine is shown (black and blue lines). The grey lines illustrate the cyclosporine profile in the absence of 3D treatment. Subjects were assumed to have a stable cyclosporine Ctrough of 100 ng/mL when initiating 3D treatment. Further modifications in cyclosporine dose or dosing frequency should be guided by trough levels measured during coadministration with the 3D regimen.\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsFigure 5 \nSimulated concentration‐time profile for coadministration of tacrolimus 0.5 mg every 7 days with the 3D regimen. QD, once daily; BID, twice daily. Note: The plot illustrates the timeline from the time a patient undergoes transplant through the first 2 weeks of 3D (ABT‐450/ritonavir 150/100 mg once daily, ombitasvir 25 mg once daily, and dasabuvir 400 mg twice daily) treatment. The mean concentration‐time profile for tacrolimus is shown (black and blue lines). The grey lines illustrate the tacrolimus profile in the absence of 3D treatment. Subjects were assumed to have a stable tacrolimus Ctrough of 5 ng/mL when initiating 3D treatment. Further modifications in tacrolimus dose or dosing frequency should be guided by trough levels measured during coadministration with the 3D regimen.\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsTable 3 Projected cyclosporine (CsA) and tacrolimus Ctrough (C24) values for posttransplant patients who initiate 3D treatment\n\n\tCtrough before 3D treatment1 (ng/mL)\tCtrough during 3D treatment (ng/mL)\t\n\nCsA dose\n\t\n250 mg BID (500 mg daily)\n\t\n100 mg QD (1/5th total daily dose)\n\t\n70–90\t90–120\t\n100–120\t100–120\t\n\nTacrolimus dose\n\t\n2 mg (BID)\n\t\n0.5 mg every 7 days\n\t\n5–7\t6–12\t\n8–10\t8–12\t\n\n2 mg (BID)\n\t\n0.5 mg every 14 days\n\t\n5–7\t3–4\t\n8–10\t3–6\t\n\n2 mg (BID)\n\t\n0.2 mg\n2\nevery 72 h\n\t\n5–7\t5–8\t\n8–10\t8–9\t\n3D, ABT‐450/ritonavir 150/100 mg once daily, ombitasvir 25 mg once daily, and dasabuvir 400 mg twice daily; Ctrough, predose morning concentration; QD, once daily; BID, twice daily.\n\n 1Assumes the Ctrough concentration is stable.\n\n 2Strength approved in some countries.\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsEffect of cyclosporine and tacrolimus on DAA steady‐state pharmacokinetics\nThe geometric mean ratios and 90% CIs of DAA steady‐state pharmacokinetic parameters in the presence of cyclosporine or tacrolimus compared to those of the DAAs alone are presented in Fig. 6. In the presence of cyclosporine or tacrolimus, steady‐state ombitasvir exposures (Cmax and AUC) were generally similar (≤15% change) to those in the absence of cyclosporine or tacrolimus, whereas ABT‐450 exposures (Cmax and AUC) were 44% to 72% higher, respectively, in the presence of cyclosporine and 34% to 43% lower, respectively, in the presence of tacrolimus. Ritonavir, dasabuvir, and dasabuvir M1 pharmacokinetic parameters were only slightly affected (≤34% change) by cyclosporine and tacrolimus.\n\nFigure 6 \nGeometric mean ratios and 90% confidence intervals for DAA pharmacokinetic parameters in the presence of a single dose of cyclosporine or tacrolimus compared to those of the DAAs alone. Note: Ctrough (C24) and AUC24 for ABT‐450, ritonavir, and ombitasvir; Ctrough (C12) and AUC12 for dasabuvir and dasabuvir M1.\n\n© 2015 The Authors. American Journal of Transplantation Published by The American Society of Transplantation and the American Society of Transplant SurgeonsSafety and tolerability\nCoadministration of the 3D regimen with cyclosporine was well tolerated in the 12 subjects in the study. Adverse events were infrequent and were mild in severity except for one moderate event of syncope assessed as unrelated to the DAAs or cyclosporine in the opinion of the investigator. Coadministration of the 3D regimen with tacrolimus was also well tolerated in the 12 subjects in the study. Adverse events were mild in severity except for moderate nausea in one subject and vomiting in two subjects. One of the adverse events of vomiting was assessed by the investigator as possibly related to tacrolimus, but not to the 3D regimen.\n\nNo deaths, serious adverse events, adverse events that led to discontinuation, or clinically meaningful abnormal laboratory values were reported in either study. No clinically significant electrocardiogram abnormalities were observed.\n\nDiscussion\nEffects of the 3D regimen of ABT‐450/r, ombitasvir, and dasabuvir on cyclosporine and tacrolimus pharmacokinetics were evaluated in healthy volunteers to inform dosing recommendations for studies in posttransplant patients receiving immunosuppressive therapy. Because the immunosuppressants have metabolic and transporter profiles that overlap with those of DAAs, particularly for CYP3A, coadministration may cause drug interactions that affect drug exposures 15. Results from the current studies suggest that the dose and dosing frequency of these agents should be reduced upon initiation of 3D therapy.\n\nCyclosporine total exposure (AUC) and C24 values increased significantly, but peak exposure (Cmax) did not, suggesting the drug interaction was mediated by reduced clearance rather than increased oral bioavailability. Reduced clearance was also reflected in the longer cyclosporine elimination half‐life, which increased from 7 to 25 h in the presence of the 3D regimen. This result is consistent with the known effect of ritonavir on CYP3A substrates 12 and the inhibitory effect of ABT‐450 on OATP1B1. This result is also consistent with effects of other CYP3A inhibitors on cyclosporine 8, 16, 17, 18.\n\nCyclosporine dose‐normalized C24 values in the presence of single and multiple doses of the 3D regimen were sevenfold to 16‐fold of the dose‐normalized C24 values when cyclosporine was administered alone. In addition, cyclosporine dose‐normalized C24 values in the presence of the 3D regimen were approximately twofold to fivefold of the dose‐normalized C12 values when cyclosporine was administered alone. Higher cyclosporine exposure following multiple doses of the 3D regimen is likely due to higher ritonavir exposures at steady state compared to those after a single dose 19. These results suggest that a typical cyclosporine twice‐daily dose should not be used in posttransplant patients. Pharmacokinetic simulations indicate that after initiation of 3D therapy, posttransplant patients should receive a once‐daily cyclosporine dose that is one‐fifth of the pre‐3D treatment total daily dose to achieve cyclosporine trough levels comparable to those observed prior to administration of the 3D regimen. The one‐fifth dose is consistent with the fivefold to 20‐fold dose reduction required when cyclosporine is given with lopinavir/ritonavir 20. Subsequent cyclosporine dose and dosing frequency modifications during 3D therapy should be informed by the individual's cyclosporine trough concentrations. Upon completion of 3D treatment, the pre‐3D dose of cyclosporine may be resumed the following day and the dose modified thereafter based on cyclosporine trough levels.\n\nCoadministration of the 3D regimen with tacrolimus caused an increase in tacrolimus exposures that was greater than the increase in cyclosporine exposures. Similar to cyclosporine, effects of the 3D regimen on tacrolimus AUC and C24 were greater than the effect on Cmax, indicating the primary mechanism of interaction is through inhibition of elimination and reduced clearance rather than increased bioavailability. The reduction in tacrolimus clearance resulted in an increase in tacrolimus elimination half‐life from 32 h (1.3 days) to 232 h (approximately 10 days). Because tacrolimus is a CYP3A and OATP1B substrate, the drug interaction is likely mediated by CYP3A inhibition by ritonavir and OATP1B inhibition by ABT‐450. The effect of the 3D regimen on tacrolimus is similar to the effect of other CYP3A inhibitors on tacrolimus 9, 17, 18, 21.\n\nThe tacrolimus dose‐normalized C24 value in the presence of steady‐state 3D regimen was 17‐fold of the dose‐normalized C24 value when tacrolimus was administered alone. In addition, the dose‐normalized C24 value in the presence of steady‐state 3D regimen was 11‐fold of the dose‐normalized C12 value when tacrolimus was administered alone. These results suggest that a typical twice‐daily dose of tacrolimus should not be used in posttransplant patients. Pharmacokinetic simulations indicate that posttransplant patients should receive a tacrolimus dose of 0.5 mg (lowest strength available in the U.S.) every 7 days upon initiation of 3D therapy. This dose is consistent with the expected tacrolimus dose for patients being treated with lopinavir/ritonavir (22). Subsequent tacrolimus dose and dosing frequency modifications during 3D therapy should be informed by the individual's tacrolimus trough concentrations. Upon completion of 3D treatment, the pre‐3D dose of tacrolimus may be resumed 2 days later (due to the greater effect of the 3D regimen on tacrolimus pharmacokinetics and assuming acceptable tacrolimus trough levels determined on that day) and the dose modified thereafter based on further testing of tacrolimus trough levels.\n\nDosing recommendations for cyclosporine and tacrolimus are based on the assumption that the typical target trough concentration is a reasonable surrogate for total exposure, which is directly related to clinical outcome 20, 23. This strategy has been used in posttransplant patients on boceprevir, telaprevir, or HIV protease inhibitors without a marked increase in hepatic rejection events 22, 24, 25, and in the CORAL I study, in which there were no episodes of rejection 7.\n\nIt should be noted that a lower dose of cyclosporine was administered in Period 2 based on anticipated interaction. Hence, dose‐normalized parameters were compared to estimate the drug interaction. Additionally, the C24 value following a single dose of cyclosporine and tacrolimus is not the same as the Ctrough level following steady‐state dosing of cyclosporine and tacrolimus. However, the increase in C24 values following coadministration of a single dose of cyclosporine and tacrolimus with the 3D regimen provides an approximation of the anticipated increase in Ctrough at steady state. For this reason, pharmacokinetic simulations were performed to guide‐dosing recommendations.\n\nFigures 4 and 5 illustrate the timeline from the time a patient undergoes transplant through the first several days of 3D treatment. A fivefold reduction in the total cyclosporine dose administered once daily with the 3D regimen is projected to maintain Ctrough values similar to values observed before 3D treatment, while blunting peak‐to‐trough fluctuations due to increased cyclosporine half‐life. Similarly, a tacrolimus dose of 0.5 mg every 7 days is expected to maintain Ctrough levels within the range observed before initiation of the 3D regimen. If lower Ctrough levels are desired, a tacrolimus dose of 0.5 mg every 14 days could be considered.\n\nOmbitasvir, dasabuvir, dasabuvir M1, and ritonavir exposures were not affected by cyclosporine or tacrolimus to a clinically meaningful extent. Steady‐state ABT‐450 exposures (Cmax and AUC) increased by 44% to 72% in the presence of 30 mg cyclosporine, but this increase is not likely to affect the safety of the 3D regimen in transplant recipients. This is supported by results from a Phase 2 study in HCV‐infected patients in which ABT‐450 doses of 200 mg and 250 mg administered for 12 to 24 weeks, which resulted in ABT‐450 exposures at least twofold greater than those observed in the current studies, were safe and well tolerated 26, 27. Likewise, the ≤ 43% decreases in steady‐state ABT‐450 exposures in the presence of tacrolimus are not expected to affect the safety or efficacy of the 3D regimen in transplant recipients. The effect of tacrolimus on ABT–450 appears to be absorption‐related because the effect is observed after a single dose; however, confirmation of this hypothesis requires further testing. Tacrolimus has also been shown to reduce telaprevir concentrations during coadministration in a limited number of patients 28. Overall, coadministration of cyclosporine or tacrolimus with the 3D regimen was well tolerated in the healthy volunteers in these studies.\n\nIn conclusion, the results suggest that initiation of 3D therapy in posttransplant patients should be accompanied by reduced doses and dosing frequencies of cyclosporine or tacrolimus. On average, posttransplant patients who initiate 3D treatment should reduce their total daily cyclosporine dose to one‐fifth of the pre‐3D dose and administer it once daily to achieve cyclosporine Ctrough levels comparable to pre‐3D treatment levels. Similarly, the tacrolimus dose should be reduced to 0.5 mg every 7 days or 0.2 mg every 72 h in posttransplant patients who initiate 3D treatment. Subsequent dose and dosing frequency modifications for cyclosporine or tacrolimus while receiving 3D treatment should be further informed by individual drug level data. These dosing recommendations for cyclosporine and tacrolimus have been successfully employed in the CORAL I study in HCV genotype 1‐infected posttransplant subjects treated with the 3D regimen plus ribavirin for 24 weeks, in which 97.1% of subjects achieved SVR12 and no graft rejections occurred 7.\n\nDisclosure\nThe authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. All authors are AbbVie, Inc. employees and may hold AbbVie stock or options. This manuscript contains information on the investigational products ABT‐450/r, ombitasvir, and dasabuvir.\n\nAcknowledgments\nThis work was funded by AbbVie, Inc. Interpretation of data and review and approval of the manuscript were performed by AbbVie. The authors would like to thank Leimin Fan, Jun Zhang, and Jill Polzin of AbbVie for analytical support and Lisa Hernandez and Pam Watson of AbbVie and Allison Kitten (freelance writer under contract with AbbVie) for medical writing support. 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Accessed September 09, 2014.\n\n13 \n\nZhang \nL \n, \n\nStrong \nJM \n, \n\nQiu \nW \n, \n\nLesko \nLJ \n, \n\nHuang \nS‐M. \n\nScientific perspectives on drug transporters and their role in drug interactions . \nMol. Pharm. \n2006 ; \n3 : 62 –66 .\n16686370 \n14 \n\nBow \nDAJ \n, \n\nLiu \nJ \n, \n\nKavetskaia \nO \n, et al. A mechanistic non‐clinical assessment of drug‐drug interactions (metabolism and transporters) with the hepatitis C virus (HCV) regimen: ABT‐450/r, ombitasvir and dasabuvir. Poster presented at: 2014 American Association for the Study of Liver Diseases/European Association for the Study of the Liver Special Conference on Hepatitis C; 2014; Sept. 12—13; New York, NY.\n\n15 \n\nBerenguer \nM. \n\nManagement of hepatitis C virus in the transplant patient . \nClin Liver Dis. \n2007 ; \n11 : 355 –376 .\n17606212 \n16 \n\nCampana \nC \n, \n\nRegazzi \nMB \n, \n\nBuggia \nI \n, \n\nMolinaro \nM. \n\nClinically significant drug interactions with cyclosporin. An update . \nClin Pharmacokinet. \n1996 ; \n30 : 141 –179 .\n8906896 \n17 \n\nAmundsen \nR \n, \n\nÅsberg \nA \n, \n\nOhm \nIK \n, \n\nChristensen \nH. \n\nCyclosporine A‐ and tacrolimus‐mediated inhibition of CYP3A4 and CYP3A5 in vitro . \nDrug Metab Dispos. \n2012 ; \n40 : 655 –661 .\n22205779 \n18 \n\nNara \nM \n, \n\nTakahashi \nN \n, \n\nMiura \nM \n, et al. \nEffect of itraconazole on the concentrations of tacrolimus and cyclosporine in the blood of patients receiving allogeneic hematopoietic stem cell transplants . \nEur J Clin Pharmacol. \n2013 ; \n69 : 1321 –1329 .\n23354810 \n19 \n\nBernstein \nB \n, \n\nMenon \nR \n, \n\nKlein \nCE \n, et al. \nPharmacokinetics, safety and tolerability of the HCV protease inhibitor ABT‐450 with ritonavir following multiple ascending doses in healthy adult volunteers [abstract 58] . \nGlobal Antiviral J. \n2009 ; \n5 ; 53 Available at: http://www.informedhorizons.com/hepdart2009/pdf/AbstractBook_HEPDART09_sent.pdf. Accessed September 17, 2014.\n\n20 \n\nVogel \nM \n, \n\nVoigt \nE \n, \n\nMichaelis \nHC \n, et al. \nManagement of drug‐to‐drug interactions between cyclosporine A and the protease‐inhibitor lopinavir/ritonavir in liver‐transplanted HIV‐infected patients . \nLiver Transpl. \n2004 ; \n10 : 939 –944 .\n15237382 \n21 \n\nChristians \nU \n, \n\nJacobsen \nW \n, \n\nBenet \nLZ \n, \n\nLampen \nA. \n\nMechanisms of clinically relevant drug interactions associated with tacrolimus . \nClin Pharmacokinet. \n2002 ; \n41 : 813 –851 .\n12190331 \n22 \n\nJain \nAB \n, \n\nVenkataramanan \nR \n, \n\nEghtesad \nB \n, et al. \nEffect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients . \nLiver Transpl. \n2003 ; \n9 : 954 –960 .\n12942457 \n23 \n\nUndre \nNA. \n\nPharmacokinetics of tacrolimus‐based combination therapies . \nNephrol Dial Transplant. \n2003 ; \n18 : i12 –15 .\n12738758 \n24 \n\nCoilly \nA \n, \n\nRoche \nB \n, \n\nDumortier \nJ \n, et al. \nSafety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience . \nJ Hepatol. \n2014 ; \n60 : 78 –86 .\n23994384 \n25 \n\nKwo \nPY \n, \n\nGhabril \nM \n, \n\nLacerda \nMA \n, \n\nJoseph Tector \nA \n, \n\nFridell \nJA \n, \n\nVianna \nR. \n\nTelaprevir with peginterferon/ribavirin for retreatment of null responders with advanced fibrosis post‐orthotopic liver transplant . \nClin Transplant. \n2014 ; \n28 : 722 –727 .\n24708229 \n26 \n\nKowdley \nKV \n, \n\nLawitz \nE \n, \n\nPoordad \nF \n, et al. \nSafety and efficacy of interferon‐free regimens of ABT‐450/r, ABT‐267, ABT‐333 +/− ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study [abstract 3] . \nJ Hepatol. \n2013 ; \n58 : S2 .\n\n27 \n\nPoordad \nF \n, \n\nLawitz \nE \n, \n\nKowdley \nKV \n, et al. \nExploratory study of oral combination antiviral therapy for hepatitis C . \nN Engl J Med. \n2013 ; \n368 : 45 –53 .\n23281975 \n28 \n\nFarnik \nH \n, \n\nZimmermann \nT \n, \n\nHerrmann \nE \n, et al. \nTelaprevir drug monitoring during antiviral therapy of hepatitis C graft infection after liver transplantation . \nLiver Int. \n2014 ; Mar 20. doi: 10.1111/liv.12532. [Epub ahead of print].\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1600-6135",
"issue": "15(5)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "calcineurin inhibitor: cyclosporine A (CsA); calcineurin inhibitor: tacrolimus; clinical research/practice; immunosuppressant; infection and infectious agents; infectious disease; liver transplantation/hepatology; pharmacokinetics/pharmacodynamics; pharmacology; viral: hepatitis C",
"medline_ta": "Am J Transplant",
"mesh_terms": "D015081:2-Naphthylamine; D000293:Adolescent; D000328:Adult; D000813:Anilides; D000998:Antiviral Agents; D019540:Area Under Curve; D002219:Carbamates; D003521:Cyclopropanes; D016572:Cyclosporine; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D013449:Sulfonamides; D016559:Tacrolimus; D014498:Uracil; D014633:Valine; D055815:Young Adult",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "1313-22",
"pmc": null,
"pmid": "25708713",
"pubdate": "2015-05",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12190331;12942457;24649882;17244767;23354810;23281975;16686370;12362293;16234060;17606212;22205779;21984985;24720703;8906896;19785645;23994384;24725237;12738758;15237382;24708229;15036326",
"title": "Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir.",
"title_normalized": "pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with abt 450 ombitasvir and dasabuvir"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2015SP001219",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nAmoxicillin (AX) is the ß-lactam most often involved in IgE-mediated reactions. Diagnosis is based mainly on skin testing, although sensitivity is not optimal. We produced a new AX derivative, amoxicilloyl-poly-L-lysine (APL), and analyzed its recognition of IgE using the passive histamine release test (pHRT).\n\n\nMETHODS\nThe study population comprised patients (n=19) with confirmed AX allergy and specific IgE to AX and controls (n=10) with good tolerance to AX. pHRT was performed using \"IgE-stripped\" blood from a single donor that was sensitized in vitro by patient sera and incubated with AX or APL. Histamine release was determined and expressed as nanograms of histamine released per milliliter of blood.\n\n\nRESULTS\nThe clinical symptoms were anaphylaxis (n=9), urticaria (n=7), erythema (n=2), and nondefined immediate reactions (n=1). The median (IQR) time interval between reaction and study was 90 (60-240) days and between drug intake and development of symptoms 24 (10-60) minutes. The median sIgE level was 3.37 (0.95-5.89) kUA/L. The sensitivity of pHRT to APL was 79% and the specificity 100%, which were higher than data obtained with pHRT to AX (63% sensitivity and 90% specificity). There was a positive correlation between maximal histamine release levels obtained with AX and APL (r=0.63).\n\n\nCONCLUSIONS\nIn patients with immediate hypersensitivity reactions to AX, APL showed higher sensitivity and specificity than the culprit drug, AX, when tested in vitro by pHRT. This indicates that APL can improve the in vitro diagnostic accuracy of allergic reactions to AX. Further assessment of skin testing is necessary.",
"affiliations": "Diater Laboratorios, Madrid, Spain.;Department of Dermatology, University Hospital of Odense, Denmark and Charité, Berlin, Germany.;Allergy Service, Ramon y Cajal Hospital, Madrid, Spain.;Departament of Pharmacology, University Complutense of Madrid, Spain.;Allergy Unit, Cruz Roja Hospital, Madrid, Spain.;Allergy Unit, IBIMA-Regional University Hospital of Malaga UMA, Málaga, Spain.;Allergy Unit, IBIMA-Regional University Hospital of Malaga UMA, Málaga, Spain.;Diater Laboratorios, Madrid, Spain.;Diater Laboratorios, Madrid, Spain.;Department of Dermatology, University Hospital of Odense, Denmark and Charité, Berlin, Germany.;Allergy Unit, IBIMA-Regional University Hospital of Malaga UMA, Málaga, Spain.;Allergy Unit, IBIMA-Regional University Hospital of Malaga UMA, Málaga, Spain.",
"authors": "Arribas|F|F|;Falkencrone|S|S|;Sola|J|J|;Gomez-Serranillos|M P|MP|;Laguna|J J|JJ|;Montañez|M I|MI|;Fernandez|T D|TD|;Rodríguez|D|D|;Pineda|F|F|;Skov|P S|PS|;Mayorga|C|C|;Torres|M J|MJ|",
"chemical_list": "D015415:Biomarkers; D011107:Polylysine; D007073:Immunoglobulin E; D000658:Amoxicillin",
"country": "Spain",
"delete": false,
"doi": "10.18176/jiaci.0180",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-9068",
"issue": "27(6)",
"journal": "Journal of investigational allergology & clinical immunology",
"keywords": "Allergy; Amoxicillin; Amoxicilloyl-poly-L-lysine; Basophil histamine release; Immediate reactions",
"medline_ta": "J Investig Allergol Clin Immunol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000658:Amoxicillin; D000707:Anaphylaxis; D000918:Antibody Specificity; D001491:Basophils; D015415:Biomarkers; D004342:Drug Hypersensitivity; D005260:Female; D006636:Histamine Release; D006801:Humans; D007073:Immunoglobulin E; D008297:Male; D008875:Middle Aged; D011107:Polylysine; D012372:ROC Curve; D012882:Skin Tests; D055815:Young Adult",
"nlm_unique_id": "9107858",
"other_id": null,
"pages": "356-362",
"pmc": null,
"pmid": "28628008",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Basophil Histamine Release Induced by Amoxicilloyl-poly-L-lysine Compared With Amoxicillin in Patients With IgE-Mediated Allergic Reactions to Amoxicillin.",
"title_normalized": "basophil histamine release induced by amoxicilloyl poly l lysine compared with amoxicillin in patients with ige mediated allergic reactions to amoxicillin"
} | [
{
"companynumb": "ES-TEVA-2018-ES-844240",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors.\n\n\nMETHODS\nWe conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM.\n\n\nRESULTS\nA total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0-21.9 months) and median overall survival was 51 months (95% CI, 42.8-59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed.\n\n\nCONCLUSIONS\nThe CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.",
"affiliations": "1Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;1Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;1Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;1Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.;1Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.",
"authors": "Al-Toubah|Taymeyah|T|;Pelle|Eleonora|E|;Valone|Tiffany|T|;Haider|Mintallah|M|;Strosberg|Jonathan R|JR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": null,
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": null,
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "1-8",
"pmc": null,
"pmid": "34433130",
"pubdate": "2021-08-24",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and Toxicity Analysis of Capecitabine and Temozolomide in Neuroendocrine Neoplasms.",
"title_normalized": "efficacy and toxicity analysis of capecitabine and temozolomide in neuroendocrine neoplasms"
} | [
{
"companynumb": "US-APOTEX-2022AP007780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": "4",
... |
{
"abstract": "Opiate intoxication has been associated with life-threatening effects of sympathetic suppression and respiratory depression, but current literature is limited in describing its neurotoxic effects on the central nervous system. Here, we present the case of an otherwise high-functioning adolescent male who was found unresponsive after ingestion of approximately 3-4 fake oxycodone 10-325 mg pills laced with fentanyl. Magnetic resonance imaging showed evidence of diffuse T2 hyperintensities in the corpus callosum and bilateral frontal, parietal, and cerebellum indicative of diffuse white matter injury. In addition, there were distinct areas of restricted diffusion in the bilateral basal ganglia concerning for oxidative stress-mediated neuronal loss. His neurological exam improved with supportive treatment over the course of his hospitalization. Although limited literature has shown leukoencephalopathy to be associated with opioid overdose, we present a case of additional involvement of subcortical gray matter.",
"affiliations": "Department of Neurology, University of California Irvine (UCI), USA.;Department of Neurology, University of California Irvine (UCI), USA.;Department of Neurology, CHOC Children's Specialists, Orange, USA.",
"authors": "Dinicu|Andreea I|AI|https://orcid.org/0000-0002-4390-5083;Chaudhari|Amit|A|;Kayyal|Simon|S|",
"chemical_list": "D009294:Narcotics; D010098:Oxycodone; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1177/1971400920927878",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1971-4009",
"issue": "33(3)",
"journal": "The neuroradiology journal",
"keywords": "Leukoencephalopathy; adolescent; opioid overdose; white matter injury",
"medline_ta": "Neuroradiol J",
"mesh_terms": "D001921:Brain; D005283:Fentanyl; D006801:Humans; D056784:Leukoencephalopathies; D008297:Male; D009294:Narcotics; D009474:Neurons; D000083682:Opiate Overdose; D010098:Oxycodone; D066127:White Matter; D055815:Young Adult",
"nlm_unique_id": "101295103",
"other_id": null,
"pages": "267-270",
"pmc": null,
"pmid": "32508271",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19892815;22582355;18440072;28865531;31328634;25433910;28424016;26653341;19116698;20440598",
"title": "Diffuse subcortical white matter injury and bilateral basal ganglia neuronal loss after acute opioid overdose.",
"title_normalized": "diffuse subcortical white matter injury and bilateral basal ganglia neuronal loss after acute opioid overdose"
} | [
{
"companynumb": "US-PFIZER INC-2020265042",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL CITRATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThrombocytopenia, not associated with bone marrow primary disease, is a common clinical problem. The possibility of drug-induced thrombocytopenia must be considered, especially in hospitalized patients. Drugs can cause thrombocytopenia by several mechanisms including direct bone marrow or other organ toxicity, and immune reactions.\n\n\nMETHODS\nWe describe a patient presenting with thrombocytopenia likely related to bisoprolol.\n\n\nCONCLUSIONS\nWe report a case of bisoprolol-induced thrombocytopenia which resolved with drug discontinuation and steroid therapy. We review the mechanisms involved in drug-induced immune thrombocytopenia.",
"affiliations": "Hematology Department, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Hematology Department, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Hematology Department, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Clinical Pathology Department, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;ImunoHemotherappy Department, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal.;Portuguese Institute of Blood and Transplantation, Centro de Sangue e da Transplantação de Lisboa, Lisboa, Portugal.;Pharmaceutical Services, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Pharmaceutical Services, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Pharmaceutical Services, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Hematology Department, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.;Hematology Department, Hospital São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal.",
"authors": "Mousinho|F|F|;Mendes|T|T|;Sousa E Santos|P|P|;Azevedo|A P|AP|;Mousinho|G|G|;Malcata|C|C|;Viegas|E|E|;Madureira|B|B|;Falcão|F|F|;Gomes|A P|AP|;Lima|F|F|",
"chemical_list": "D000959:Antihypertensive Agents; D017298:Bisoprolol",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12614",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(2)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "antibodies; bisoprolol; case report; thrombocytopenia",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000959:Antihypertensive Agents; D017298:Bisoprolol; D006801:Humans; D008297:Male; D008875:Middle Aged; D013921:Thrombocytopenia",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "280-283",
"pmc": null,
"pmid": "28868658",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Bisoprolol-induced thrombocytopenia: A case report.",
"title_normalized": "bisoprolol induced thrombocytopenia a case report"
} | [
{
"companynumb": "PT-TEVA-2018-PT-877250",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": "1",
... |
{
"abstract": "Neuroleptic malignant syndrome (NMS) is a life-threatening idiosyncratic reaction that usually occurs after the administration of antipsychotic drugs. Antidepressants, benzodiazepines, and antiepileptic drugs are also suggested to be associated with NMS. It is believed to result from a dopaminergic blockade in the central nervous system. NMS is manifested by hyperthermia, muscle rigidity, autonomic dysfunction, altered mental status, leukocytosis, and elevated serum creatinine phosphokinase. Valproate is commonly used in the treatment of many psychiatric and neurologic disorders. Valproate can precipitate NMS, especially when used with antipsychotic drugs concurrently. A 17-year-old male patient, who presented with fever, muscular rigidity, confusion, sweating, and tachycardia was admitted to the emergency room. He had been taking only valproate for the last two months for bipolar disorder. His laboratory analyses revealed raised serum hepatic enzymes, creatinine phosphokinase, and myoglobin levels. Considering fever, rigidity, autonomic dysfunction, cognitive alteration, and high creatinine phosphokinase levels, the patient was diagnosed with NMS. In this paper, we aim to discuss the association between valproate and NMS.",
"affiliations": "Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey.;Department of Pediatric Neurology, Mersin University School of Medicine, Mersin, Turkey.;Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey.;Department of Pediatric Neurology, Mersin University School of Medicine, Mersin, Turkey.;Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey.",
"authors": "Yıldırım|Veli|V|;Direk|Meltem Çobanogulları|MÇ|;Güneş|Serkan|S|;Okuyaz|Çetin|Ç|;Toros|Fevziye|F|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.9758/cpn.2017.15.1.76",
"fulltext": "\n==== Front\nClin Psychopharmacol NeurosciClin Psychopharmacol NeurosciClinical Psychopharmacology and Neuroscience1738-10882093-4327Korean College of Neuropsychopharmacology 2813811710.9758/cpn.2017.15.1.76cpn-15-076Case ReportNeuroleptic Malignant Syndrome Associated with Valproate in an Adolescent Yıldırım Veli 1Direk Meltem Çobanogulları 2Güneş Serkan 1Okuyaz Çetin 2Toros Fevziye 11 Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, \nTurkey2 Department of Pediatric Neurology, Mersin University School of Medicine, Mersin, \nTurkeyAddress for correspondence: Serkan Güneş, MD, Department of Child and Adolescent Psychiatry, Mersin University School of Medicine, Çiftlikköy Kampüsü, Yenişehir, Mersin, Turkey, Tel: +90-5542587368, Fax: +90-3242410092, E-mail: dr_sgunes@hotmail.com2 2017 28 2 2017 15 1 76 78 12 2 2016 16 3 2016 15 4 2016 Copyright © 2017, Korean College of Neuropsychopharmacology2017This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Neuroleptic malignant syndrome (NMS) is a life-threatening idiosyncratic reaction that usually occurs after the administration of antipsychotic drugs. Antidepressants, benzodiazepines, and antiepileptic drugs are also suggested to be associated with NMS. It is believed to result from a dopaminergic blockade in the central nervous system. NMS is manifested by hyperthermia, muscle rigidity, autonomic dysfunction, altered mental status, leukocytosis, and elevated serum creatinine phosphokinase. Valproate is commonly used in the treatment of many psychiatric and neurologic disorders. Valproate can precipitate NMS, especially when used with antipsychotic drugs concurrently. A 17-year-old male patient, who presented with fever, muscular rigidity, confusion, sweating, and tachycardia was admitted to the emergency room. He had been taking only valproate for the last two months for bipolar disorder. His laboratory analyses revealed raised serum hepatic enzymes, creatinine phosphokinase, and myoglobin levels. Considering fever, rigidity, autonomic dysfunction, cognitive alteration, and high creatinine phosphokinase levels, the patient was diagnosed with NMS. In this paper, we aim to discuss the association between valproate and NMS.\n\nNeuroleptic malignant syndromeValproateAdolescentChild\n==== Body\nINTRODUCTION\nNeuroleptic malignant syndrome (NMS) was first recognized in 1956 by Ayd but was only defined in 1960 by Delay and Deniker.1) NMS is a rarely encountered, life threatening complication that usually appears within the first two weeks of antipsychotic therapy.2) Moreover, NMS cases due to certain antidepressants, benzodiazepines, antiepileptic drugs, metoclopramide, and lithium have also been reported.3) Its incidence ranges from 0.02% to 3% with a mortality rate around 10%.4) The most common causes of death include rhythm disorders, respiratory failure, and renal or cardiovascular insufficiency.5)\n\nNMS is clinically characterized by fever, muscular rigidity, autonomic dysfunction, and altered mental state, whereas its laboratory features are comprised of elevated serum hepatic enzymes, creatinine phosphokinase, and white blood cell count.6) Dopamine receptor blockage is thought to play a role in the pathogenesis of NMS.7) The risk factors for NMS include high-dose antipsychotic use, rapid dose titration, using the parenteral form of anti-psychotic drugs, advanced age, male sex, malnutrition, dehydration, traumatic or organic cerebral injury, iron deficiency, infections, and concurrent use of lithium, anti-cholinergic agents, and certain antidepressants.5)\n\nThe present paper aims to discuss NMS developed in an adolescent, who had been diagnosed with bipolar disorder and receiving valproate. Informed consent was obtained from the patient’s parents for publication of this case report.\n\nCASE\nA 17-year-old male patient was admitted to the emergency room with complaints of fever, sweating, sore throat, loss of appetite, weakness, lethargy, and reduced speech. He was diagnosed with type I bipolar disorder two years ago and valproate, haloperidol, and biperiden therapies were commenced. Haloperidol and biperiden therapies were tapered two months prior to the emergency room visit and that only valproate therapy continued for the last two months. He had been taking 500 mg valproate per day for two years. The patient’s body temperature was high for the last week and remained high all day long. His mental state was completely altered and he was not eating, speaking, sleeping, or leaving his room. There was no substance or other drug use or surgical intervention in his history.\n\nExamination of the patient revealed moderate general status. His heart rate was 110 beats/minute, respiratory rate was 22 times/minute, blood pressure was 110/70 mmHg, and axillary body temperature was 38.5°C. Confusion, distractibility, and extensive muscular rigidity were evident on his neurological examination. Mental examination revealed incorrect orientation. His affect was dysphoric, anxious, and irritable. He had visual and hearing hallucinations. Other system examinations were unremarkable.\n\nResults of laboratory analyses were as follows: glucose, 154 mg/dl (60–100 mg/dl); urea, 78 mg/dl (10.7–38.5 mg/dl); creatinine, 1.08 mg/dl (0–0.9 mg/dl); ammonium, 84 μmol/L (36–85 μmol/L); lactate, 13.1 mg/dl (4.5–19.8 mg/dl); Na, 149 mEq/L (132–145 mEq/L); K, 4.7 mEq/L (3.1–5.1 mEq/L); Cl, 116 mEq/L (96–111 mEq/L); Ca, 8.9 mg/dl (8.4–10.9 mg/dl); creatinine phosphokinase, >4,267 U/L (0–145 U/L); alanine aminotransferase, 70 U/L (0–39 U/L); aspartate aminotransferase, 240 U/L (0–47 U/L); gamma-glutamyl transferase, 20 U/L (0–17 U/L); lactate dehydrogenase, 759 U/L (0–580 U/L); myoglobin, >1,000 ng/ml (25–58 ng/ml); thyroid stimulating hormone, 1.59 μIU/ml (0.15–3.5 μIU/ml); free T4, 15.34 pmol/L (10–25 pmol/L). In complete blood count, leukocyte count was 9,610/mm3 (4,500–13,000/mm3), hemoglobin was 15.2 g/dl (12–15 g/dl) and hematocrit was 44.6% (34–43%). Serum valproate concentration was <12.5 μg/ml (50–100 μg/ml).\n\nThe patient was admitted to the pediatric neurology clinic for further investigation. Peripheral blood, throat, and urine cultures were performed; there was no growth. Procalcitonin and C-reactive protein were studied and found to be within the normal limits. Computed cranial tomography was reported to be normal, and no abnormality in arterial blood gas analysis was observed. Cerebrospinal fluid examination, complete urinalysis, and chest X-ray were unremarkable. Electrocardiogram showed sinus tachycardia.\n\nThe patient was diagnosed with NMS, because it was the only diagnosis by which all the clinical and laboratory findings could be explained.\n\nDISCUSSION\nAlthough NMS is usually observed within the first ten days of antipsychotic drug use, NMS may appear at any phase of treatment, independent of duration and dose.2) Many late-onset NMS cases have been reported in the literature.8–10) There was a case of a patient developing NMS after ten years of antipsychotic drug use.11)\n\nAlthough the clinical signs are variable, muscular rigidity, autonomic dysfunction, and cognitive changes are the main symptoms. Frequent laboratory findings include elevated creatinine phosphokinase, leukocytosis, and myoglobulinuria.6) The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria, which are created by the American Psychiatry Association, can be used to diagnose NMS. Diagnosis of NMS according to the DSM-IV can be made in the presence of both of major symptoms (high fever and muscular rigidity) and at least two or more of minor symptoms (sweating, dysphagia, chilling, incontinence, cognitive alteration, mutism, tachycardia, elevated or variable blood pressure, leukocytosis, or laboratory findings suggestive of muscular injury).6) In the present case, the patient met the two major (fever and rigidity) and five of the minor (confusion, sweating, tachycardia, mutism, and elevated creatinine phosphokinase) criteria.\n\nHead trauma, malignant hyperthermia, drug intoxication, central nervous system diseases, central anticholinergic syndrome, pheochromocytoma, thyroid storm, and sepsis should be considered in the differential diagnosis of NMS.6) In the present case, other intracranial pathologies were excluded based on anamnesis, physical examination, and computed tomography. Malignant hyperthermia was not considered since PaCO2 was not elevated in the arterial blood gas analysis and there was no anesthetic or neuromuscular blocking agent use in the patient’s history. Serum valproate level was <12.5 μg/ml; hence, drug intoxication was excluded. Anticholinergic syndrome was excluded because of the absence of anticholinergic drug use and sepsis was excluded because of absence of growth in blood, throat, or urine cultures. Thyroid pathologies were eliminated due to normal thyroid hormone concentrations.\n\nIn general, typical antipsychotic drugs cause NMS due to their high antidopaminergic effects (D2 receptor blockade). However, even an atypical antipsychotic with low antidopaminergic effects may cause NMS.12) Moreover, it has been reported that many drugs without known anti-dopaminergic effects have also caused NMS. Therefore, some factors, besides D2 receptor blockade, are considered to be responsible for the pathogenesis of NMS.7) Benzodiazepines, tricyclic antidepressants, serotonin reuptake inhibitors, metoclopramide, amphetamine, lithium, and tetrabenazine may also cause NMS.3) Antiepileptic drugs such as carbamazepine, oxcarbazepine, and lamotrigine were also demonstrated to be associated with NMS.13–15)\n\nValproate is commonly used as an anticonvulsant and mood stabilizer in neurologic and psychiatric disorders.16) Studies of valproate have mostly focused on its mechanisms of action on the GABAergic system. Specifically, valproate has been shown to increase whole-brain GABA levels and potentiate response by inhibiting GABA-transaminase and activating glutamic acid decarboxylase. Valproate blocks voltage-dependent sodium channels, and it is also known to function as a weak blocker of T-type calcium channels.17) In a case report, Verma et al.3) reported that NMS developed following the addition of valproate in the treatment of a patient receiving anti-psychotic drugs for two years, without remarkable complication. Tanii et al.18) reported a case, in which a patient developed NMS due to withdrawal of levomepromazine from their treatment, while continuing treatment with valproate. In many studies stating that antipsychotics cause NMS, patients had been receiving concurrent valproate therapy.7,19,20)\n\nWe hypothesized that valproate might induce NMS via the GABA system in our patient. Although the exact mechanism of how NMS is connected with the GABA system is not yet entirely understood, it is known that the GABAergic medications, baclofen, and lamotrigine may cause symptoms of NMS.15,21) It was also reported that chronic treatment of rodents with valproate increased the brain dopamine levels in some areas and decreased it in other brain areas.17) Changes in the dopaminergic system due to chronic valproate therapy might be another mechanism that induced NMS symptoms in our case. In addition, when the patient in the present case used haloperidol two month ago, it constituted hypodopaminergic and D2 supersensitive statement. This statement might be induced by the addition of valproate via one of the possible mechanisms, and predispose the patient to NMS.\n\nAlthough valproate does not directly cause NMS, it seems to be an agent associated with NMS development in the present case. To our knowledge, this is the first case of NMS, in an adolescent, associated with valproate treatment.\n\nAcknowledgments\nThis article was conducted at the Mersin University Medical Faculty.\n==== Refs\nREFERENCES\n1 Védie C Poinso F Hemmi F Rivet B Major symptoms and differential diagnosis of neuroleptic malignant syndrome: three case reports Eur Psychiatry 2000 15 334 337 10.1016/S0924-9338(00)00403-X 10954878 \n2 Fekadu A Bisson JI Neuroleptic malignant syndrome: diagnostic and therapeutic dilemmas Behav Neurol 2005 16 9 13 10.1155/2005/471260 16082075 \n3 Verma R Junewar V Rathaur BPS An atypical case of neuroleptic malignant syndrome precipitated by valproate BMJ Case Rep 2014 10.1136/bcr-2013-202578 \n4 Sarkar P Natarajan C Gode N Prevalence of neuroleptic malignant syndrome in 672 consecutive male in-patients Indian J Psychiatry 2009 51 202 205 10.4103/0019-5545.55089 19881049 \n5 Rasmussen KG Risk factors for neuroleptic malignant syndrome Am J Psychiatry 1998 155 1639 1640 10.1176/ajp.155.11.1626v 9812150 \n6 Strawn JR Keck PE Jr Caroff SN Neuroleptic malignant syndrome Am J Psychiatry 2007 164 870 876 10.1176/ajp.2007.164.6.870 17541044 \n7 Ananth J Parameswaran S Gunatilake S Burgoyne K Sidhom T Neuroleptic malignant syndrome and atypical antipsychotic drugs J Clin Psychiatry 2004 65 464 470 10.4088/JCP.v65n0403 15119907 \n8 Kern JL Cernek PK Delayed risperidone-induced neuroleptic malignant syndrome Ann Pharmacother 1996 30 300 10.1177/106002809603000321 8833573 \n9 Lee MS Lee HJ Kim L A case of delayed NMS induced by risperidone Psychiatr Serv 2000 51 254 255 10.1176/appi.ps.51.2.254-a 10655017 \n10 Kunz M Gomes FA Tramontina JF Kapczinski F Late-onset neuroleptic malignant syndrome in a patient using olanzapine J Clin Psychopharmacol 2007 27 303 304 10.1097/01.jcp.0000270093.39909.a9 17502780 \n11 Oglodek E Szota A Araszkiewicz A Olanzapine-induced neuroleptic malignant syndrome after 10 years of treatment Aust N Z J Psychiatry 2013 47 972 10.1177/0004867413487230 23630396 \n12 Chakraborty N Johnston T Aripiprazole and neuroleptic malignant syndrome Int Clin Psychopharmacol 2004 19 351 353 10.1097/00004850-200411000-00007 15486522 \n13 Nisijima K Kusakabe Y Ohtuka K Ishiguroa T Addition of carbamazepine to long-term treatment with neuroleptics may induce neuroleptic malignant syndrome Biol Psychiatry 1998 44 930 931 10.1016/S0006-3223(98)00025-0 9807653 \n14 Angelopoulos P Markopoulou M Kyamidis K Bobotas K Neuroleptic malignant syndrome without fever after addition of oxcarbazepine to long-term treatment with amisulpride Gen Hosp Psychiatry 2008 30 482 484 10.1016/j.genhosppsych.2008.03.007 18774435 \n15 Ishioka M Yasui-Furukori N Hashimoto K Sugawara N Neuroleptic malignant syndrome induced by lamotrigine Clin Neuropharmacol 2013 36 131 132 10.1097/WNF.0b013e318294799a 23783003 \n16 Bae KY Jang JE Kim YH Kim JM Yoon JS Valproate-induced hyperammonemic encephalopathy caused by free carnitine deficiency in a patient with bipolar disorder: a case report Clin Psychopharmacol Neurosci 2009 7 57 62 \n17 Johannessen CU Johannessen SI Valproate: past, present, and future CNS Drug Rev 2003 9 199 216 10.1111/j.1527-3458.2003.tb00249.x 12847559 \n18 Tanii H Saka K Inoue K Okada M Neuroleptic malignant syndrome following levomepromazine discontinuation J Neuropsychiatry Clin Neurosci 2010 22 E16 10.1176/jnp.2010.22.2.247.e16 20463130 \n19 Gortney JS Fagan A Kissack JC Neuroleptic malignant syndrome secondary to quetiapine Ann Pharmacother 2009 43 785 791 10.1345/aph.1L371 19299325 \n20 Ladds B Thomas P Mejia C Hauser D Extreme elevation of creatinine phosphokinase levels in neuroleptic malignant syndrome associated with atypical antipsychotics Am J Psychiatry 2009 166 114 115 10.1176/appi.ajp.2008.08101485 19122020 \n21 Samson-Fang L Gooch J Norlin C Intrathecal baclofen withdrawal simulating neuroleptic malignant syndrome in a child with cerebral palsy Dev Med Child Neurol 2000 42 561 565 10.1017/S0012162200001055 10981935\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-1088",
"issue": "15(1)",
"journal": "Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology",
"keywords": "Adolescent; Child; Neuroleptic malignant syndrome; Valproate",
"medline_ta": "Clin Psychopharmacol Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101207332",
"other_id": null,
"pages": "76-78",
"pmc": null,
"pmid": "28138117",
"pubdate": "2017-02-28",
"publication_types": "D002363:Case Reports",
"references": "23783003;23630396;15119907;8833573;16082075;18774435;9807653;19299325;20463130;12847559;17502780;17541044;19881049;10655017;24604797;9812150;19122020;15486522;10981935;10954878",
"title": "Neuroleptic Malignant Syndrome Associated with Valproate in an Adolescent.",
"title_normalized": "neuroleptic malignant syndrome associated with valproate in an adolescent"
} | [
{
"companynumb": "TR-ORCHID HEALTHCARE-1064162",
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{
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"activesubstance": {
"activesubstancename": "DIVALPROEX SODIUM"
},
"drugadditional": "3... |
{
"abstract": "This study aimed to evaluate the feasibility and effect of triamcinolone acetonide (TA) injection for lateral malleolar (LM) bursitis.\n\n\n\nWe retrospectively reviewed data of 49 consecutive patients (49 ankles) who received TA injection between March 2016 and March 2019. All cases received 1 ml (40 mg) of TA injection after aspiration of fluid in the LM bursal sac. Subsequently, the ankle was compressed with an elastic cohesive bandage for 2 weeks. Treatment responses were assessed according to the degree of fluctuation, shrinkage of the bursal sac, and soft tissue swelling. We used the Medical Outcomes Study Short Form Health Survey (SF-36) and complications at 2 and 4 weeks and at 3 and 6 months after TA injection.\n\n\n\nForty-four patients (89.8%) experienced complete resolution, four (8.2%) had partial resolution, and one (2.0%) had no resolution after the first or second TA injection. The physical component scores of SF-36 improved from 72.8 ± 6.0 to 82.3 ± 6.5 at the last follow-up (p < 0.001). Associated complications included skin atrophy in three patients (6.1%) and transient hyperglycemia in four (8.2%).\n\n\n\nTA injection is an effective and safe procedure for LM bursitis. It should be considered as a primary treatment method.",
"affiliations": "Department of Orthopedic Surgery and Biomedical Research Institute, 220312Pusan National University Hospital, Seo-gu, Busan, Republic of Korea.;Department of Orthopedic Surgery and Biomedical Research Institute, 220312Pusan National University Hospital, Seo-gu, Busan, Republic of Korea.;Department of Orthopedic Surgery, 194197Pusan National University Yangsan Hospital, Mulgeum-eup, Yangsan, Republic of Korea.;Department of Orthopedic Surgery, 194197Pusan National University Yangsan Hospital, Mulgeum-eup, Yangsan, Republic of Korea.;Department of Orthopedic Surgery and Biomedical Research Institute, 220312Pusan National University Hospital, Seo-gu, Busan, Republic of Korea.;Department of Orthopedic Surgery, 194197Pusan National University Yangsan Hospital, Mulgeum-eup, Yangsan, Republic of Korea.",
"authors": "Goh|Tae Sik|TS|;Ahn|Tae Young|TY|;Kim|Kyeongbaek|K|;Shin|Won Chul|WC|0000-0002-6918-3015;Moon|Nam Hoon|NH|;Woo|Seung Hun|SH|0000-0002-9765-8057",
"chemical_list": "D005938:Glucocorticoids; D014222:Triamcinolone Acetonide",
"country": "England",
"delete": false,
"doi": "10.1177/2309499020952893",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-5536",
"issue": "28(3)",
"journal": "Journal of orthopaedic surgery (Hong Kong)",
"keywords": "ankle; lateral malleolar bursitis; nonoperative treatment; triamcinolone acetonide",
"medline_ta": "J Orthop Surg (Hong Kong)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002062:Bursitis; D058128:Compression Bandages; D005260:Female; D005360:Fibula; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D014222:Triamcinolone Acetonide",
"nlm_unique_id": "9440382",
"other_id": null,
"pages": "2309499020952893",
"pmc": null,
"pmid": "32873149",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcome of triamcinolone acetonide injection for lateral malleolar bursitis.",
"title_normalized": "outcome of triamcinolone acetonide injection for lateral malleolar bursitis"
} | [
{
"companynumb": "KR-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-264042",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"d... |
{
"abstract": "Most recent studies discussing tachycardias with alternating QRS polarity have referred to those known as torsade de pointes. This report, in contrast, deals with bidirectional tachycardia and the effects of lignocaine on 10 patients with this arrhythmia. Three of the patients also had digitalis-induced atrial tachycardia with block. In one patient, a single bolus of lignocaine was followed (five minutes later) by ventricular fibrillation, but the other nine patients received two boluses of 75 mg followed by a drip infusion of 3 mg/min. The drug terminated the episodes of atrial tachycardia with block and bidirectional tachycardia in all patients thus treated. Whereas the abolition of the bidirectional tachycardia was permanent in the seven patients with digitalis intoxication, it recurred after stopping the drip infusion in the two patients without digitalis toxicity. It is concluded that lignocaine can be useful in the treatment of digitalis-induced bidirectional tachycardia and atrial tachycardia with block. From this study no conclusions can be drawn, however, as to whether lignocaine is superior to other class I or class IV agents.",
"affiliations": null,
"authors": "Castellanos|A|A|;Ferreiro|J|J|;Pefkaros|K|K|;Rozanski|J J|JJ|;Moleiro|F|F|;Myerburg|R J|RJ|",
"chemical_list": "D004077:Digoxin; D008012:Lidocaine",
"country": "England",
"delete": false,
"doi": "10.1136/hrt.48.1.27",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0769",
"issue": "48(1)",
"journal": "British heart journal",
"keywords": null,
"medline_ta": "Br Heart J",
"mesh_terms": "D000328:Adult; D000368:Aged; D004077:Digoxin; D004334:Drug Administration Schedule; D005260:Female; D006327:Heart Block; D006801:Humans; D007263:Infusions, Parenteral; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D013610:Tachycardia",
"nlm_unique_id": "0370634",
"other_id": null,
"pages": "27-32",
"pmc": null,
"pmid": "7082511",
"pubdate": "1982-07",
"publication_types": "D016428:Journal Article",
"references": "7002302;5645715;4211199;13632881;4709543;5571473;4609637;1096787;4781244;920585;4415990;879008;4744795;4744783",
"title": "Effects of lignocaine on bidirectional tachycardia and on digitalis-induced atrial tachycardia with block.",
"title_normalized": "effects of lignocaine on bidirectional tachycardia and on digitalis induced atrial tachycardia with block"
} | [
{
"companynumb": "US-BAXTER-2021BAX016663",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXTROSE\\LIDOCAINE HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nThe taxanes docetaxel and cabazitaxel prolong overall survival for men with metastatic castration-resistant prostate cancer (mCRPC), with cabazitaxel approved in the postdocetaxel setting only. Recent data suggest they have similar efficacy but a different safety profile in the first-line mCRPC setting.\n\n\nOBJECTIVE\nTo assess patient preference between docetaxel and cabazitaxel among men who received one or more doses of each taxane and did not experience progression after the first taxane.\n\n\nMETHODS\nChemotherapy-naïve patients with mCRPC were randomized 1:1 to receive docetaxel (75 mg/m2 every 3 wk × 4 cycles) followed by cabazitaxel (25 mg/m2 every 3 wk × 4 cycles) or the reverse sequence. Randomization was stratified by prior abiraterone or enzalutamide use.\nThe primary endpoint was patient preference, assessed via a dedicated questionnaire after the second taxane. Secondary endpoints included reasons for patient preference, prostate-specific antigen response, radiological progression-free survival, and overall survival. This clinical trial is registered at ClinicalTrials.gov as NCT02044354.\n\n\nCONCLUSIONS\nOf 195 men randomized, 152 met the prespecified modified intent-to-treat criteria for analysis. Overall, 66 patients (43%) preferred cabazitaxel, 40 (27%) preferred docetaxel, and 46 (30%) had no preference (p = 0.004, adjusted for treatment period effect). More patients preferred treatment period 1 (43%, 95% confidence interval [CI] 36-52%) versus period 2 (27%, 95% CI 20-34%). Patient preference for cabazitaxel was mainly related to less fatigue (72%), better quality of life (64%), and other adverse events (hair loss, pain, nail disorders, edema). Adverse events were consistent with the known safety profile of each drug.\n\n\nCONCLUSIONS\nA significantly higher proportion of chemotherapy-naïve men with mCRPC who received both taxanes preferred cabazitaxel over docetaxel. Less fatigue and better quality of life were the two main reasons driving patient choice.\nMen with metastatic castration-resistant prostate cancer preferred cabazitaxel over docetaxel for chemotherapy, mainly because of less fatigue and better quality of life.",
"affiliations": "Department of Cancer Medicine, Gustave Roussy, University of Paris Saclay, Villejuif, France.;Institut de Cancerologie de l'Ouest, Angers, France.;Medical Oncology, Institut Paoli-Calmettes, Marseille, France.;Strasbourg Oncologie Libérale, Strasbourg, France.;Hospital Foch, Suresnes, France.;Oncology Department, Centre Hospitalier Universitaire Saint-Andre, Bordeaux, France.;Centre René Gauducheau, Nantes, France.;GINECO and Regional Centre Control Against Cancer Francois Baclesse, Caen, France.;GINECO-Centre Hospitalier Départemental Vendée Les Oudairies, La Roche-Sur-Yon, France.;Hôpital Jean Minjoz, Besancon, France.;Medical Oncology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.;Hospital Saint-Louis, Paris, France.;Clinique Sainte Marguerite, Hyères, France.;Institut de Cancerologie de Lorraine, Vandœuvre-Les-Nancy, France.;Hospital Foch, Suresnes, France.;Centre Léon Bérard, Lyon, France.;CHU Brest, Brest, France.;Department of Biostatistics and Epidemiology, Gustave Roussy, University Paris-Saclay, Univerity Paris-Sud, Villejuif, France.;Clinical Research Department, Institut Gustave Roussy, Villejuif, France.;Department of Biostatistics and Epidemiology, Gustave Roussy, University Paris-Saclay, Univerity Paris-Sud, Villejuif, France.;Department of Cancer Medicine, Gustave Roussy, University of Paris Saclay, Villejuif, France. Electronic address: karim.fizazi@gustaveroussy.fr.",
"authors": "Baciarello|Giulia|G|;Delva|Remy|R|;Gravis|Gwenaelle|G|;Tazi|Youssef|Y|;Beuzeboc|Philippe|P|;Gross-Goupil|Marine|M|;Bompas|Emmanuelle|E|;Joly|Florence|F|;Greilsamer|Charlotte|C|;Hon|Thierry Nguyen Tan|TNT|;Barthelemy|Philippe|P|;Culine|Stephane|S|;Berdah|Jean Francois|JF|;Deblock|Mathilde|M|;Ratta|Raffaele|R|;Flechon|Aude|A|;Cheneau|Caroline|C|;Maillard|Aline|A|;Martineau|Geraldine|G|;Borget|Isabelle|I|;Fizazi|Karim|K|;|||",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1016/j.eururo.2021.10.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0302-2838",
"issue": null,
"journal": "European urology",
"keywords": "Cabazitaxel; Castration-resistant; Chemotherapy; Docetaxel; Patient preference; Prostate cancer",
"medline_ta": "Eur Urol",
"mesh_terms": null,
"nlm_unique_id": "7512719",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34789394",
"pubdate": "2021-11-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patient Preference Between Cabazitaxel and Docetaxel for First-line Chemotherapy in Metastatic Castration-resistant Prostate Cancer: The CABADOC Trial.",
"title_normalized": "patient preference between cabazitaxel and docetaxel for first line chemotherapy in metastatic castration resistant prostate cancer the cabadoc trial"
} | [
{
"companynumb": "FR-MYLANLABS-2022M1043707",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
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