article dict | reports listlengths 1 3.97k |
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{
"abstract": "BACKGROUND\nMucormycosis is a severe infection in renal transplant recipients. Here, we report a case of maxillary sinus mucormycosis in a patient who presented with a facial pain complaint.\n\n\nMETHODS\nA 51-year-old female patient with renal transplantation due to autosomal dominant, polycystic kidney disease and diabetic nephropathy was admitted to our hospital with facial pain and minimal edema of the left half of her face on the 8th month of transplantation. On physical examination, there was only tenderness and slight edema on the left half of the face. On the paranasal computed tomography, extensive soft tissue densities involving septations, filling the left maxillary sinus, extending to the nasal cavity, and obliterating the left osteometeal unit were observed. Because facial pain was not relieved by antibiotics and several, potent analgesic drugs on the second day, mucormycosis infection with bone involvement was suspected. A left maxillary sinus excision was performed. Microscopic examination of the debridement specimen revealed necrotic bone interspersed with fungal hyphae, and culture isolated Rhizopus oryzae. Liposomal amphotericin B was started. The patient was on tacrolimus, prednisolone, and mycophenolate mofetil. Tacrolimus was switched to cyclosporine to regulate serum glucose levels. The left maxillary sinus was washed with liposomal amphoterin B daily and curetted with intervals. The patient started dialysis because of severe renal function loss. The patient was discharged on the 96th day of liposomal amphotericin B.\n\n\nCONCLUSIONS\nIt should be kept in mind that mucormycosis may be present in the sinuses even if there is no evidence for nasal, oral, and dental examination in renal transplant patients with facial pain.",
"affiliations": "Nephrology Department, Inonu University Medical Faculty, Malatya, Turkey.;Nephrology Department, Inonu University Medical Faculty, Malatya, Turkey. Electronic address: hulyataskapan@yahoo.com.;Department of Otorhinolaryngology, Inonu University Medical Faculty, Malatya, Turkey.;Department of Infectious Diseases, Faculty of Medicine, Nigde Omer Halisdemir University, Nigde, Turkey.;Radiology Department, Inonu University Medical Faculty, Malatya, Turkey.",
"authors": "Berktaş|Bayram|B|;Taşkapan|Hülya|H|;Bayindir|Tugba|T|;Kayabas|Uner|U|;Yildirim|Ismail Okan|IO|",
"chemical_list": "D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.02.048",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D005157:Facial Pain; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D015523:Maxillary Sinusitis; D008875:Middle Aged; D009091:Mucormycosis; D012233:Rhizopus",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2498-2500",
"pmc": null,
"pmid": "31405737",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mucormycosis Presented with Facial Pain in a Renal Transplant Patient: A Case Report.",
"title_normalized": "mucormycosis presented with facial pain in a renal transplant patient a case report"
} | [
{
"companynumb": "TR-ACCORD-152845",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nBiologic drugs (bDMARD), especially TNF-α-inhibitors (TNFi), are used in refractory Takayasu's arteritis (TAK) patients. Up to 23% of patients are switched to a different bDMARD because of inefficacy. No data are available on which strategy is more efficient after TNFi failure. The aim of our study is to evaluate whether a switch or swap strategy should be preferred in TAK patients failing TNFis.\n\n\nMETHODS\nTAK patients treated with a second bDMARD after the failure of the first TNFi were identified from 3 referral centres. Patients were classified as switch if treated with a different TNFi, and swap if treated with a non-TNFi bDMARD. Baseline features were evaluated. Efficacy and safety of the second bDMARD at 6 and 12 months were assessed and a comparison between switch and swap patients was made.\n\n\nRESULTS\nTwenty-four TAK patients were identified. Eleven patients (46%) were switched and 13 patients (54%) were swapped (12 to tocilizumab, 1 to ustekinumab). Baseline features of patients in the 2 groups were comparable. At 12 months, the second bDMARD was suspended in 4 switch (36%) and in 5 swap (42%) patients. Second biologic drug survival and relapse-free survival were equivalent between the two groups at 6 and 12 months. A vascular worsening was observed in 4 switch (40%) and 2 swap (25%) patients. Severe infections, myocardial infarction, ischemic stroke or cancer were recorded in no patient.\n\n\nCONCLUSIONS\nOur retrospective study suggests that in first-line TNFi failure TAK patients both switch and swap strategies can be considered suitable approaches.",
"affiliations": "Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy. campochiaro.corrado@hsr.it.;Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.;Unit of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, Italy.;Unit of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, and University of Genoa and IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.;Unit of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, Italy.;University of Genoa and IRCCS Istituto Giannina Gaslini, Genoa, Italy.;University of Genoa and IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Unit of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, Italy.;Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.;University of Genoa and IRCCS Istituto Giannina Gaslini, Genoa, Italy.;Unit of Rheumatology, Azienda USL-IRCCS di Reggio Emilia, Italy.;Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy.",
"authors": "Campochiaro|Corrado|C|;Tomelleri|Alessandro|A|;Galli|Elena|E|;Cocchiara|Emanuele|E|;Sartorelli|Silvia|S|;Muratore|Francesco|F|;Malattia|Clara|C|;Caorsi|Roberta|R|;Catanoso|Maria Grazia|MG|;Baldissera|Elena|E|;Ravelli|Angelo|A|;Salvarani|Carlo|C|;Dagna|Lorenzo|L|",
"chemical_list": "D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "39 Suppl 129(2)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D006801:Humans; D012189:Retrospective Studies; D013625:Takayasu Arteritis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "129-134",
"pmc": null,
"pmid": "33666154",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Failure of first anti-TNF agent in Takayasu's arteritis: to switch or to swap?",
"title_normalized": "failure of first anti tnf agent in takayasu s arteritis to switch or to swap"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020150516",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Acquired von Willebrand disease (aVWD) is rare disease and is associated with a variety of underlying diseases. We report a case of aVWD in the setting of multiple myeloma. The patient was a 63-year-old female with breast cancer in remission who was admitted for symptomatic anemia. She was diagnosed with multiple myeloma. She also had subcutaneous bleeding before admission. Laboratory studies revealed isolated prolongation of the activated partial thromboplastin time, which corrected in a mixing study. Her factor VIII activity, von Willebrand factor (VWF) Ag, and VWF activity were low. VWF multimer study confirmed the patient had aVWD. The treatment of aVWD is discussed in this article, including the treatment of underlying diseases, and acute management in emergent situations. An intriguing question in this case is whether the patient's multiple myeloma is a chemotherapy-induced hematological malignancy or a second primary malignancy.",
"affiliations": "Department of Medicine, MedStar Union Memorial Hospital, Baltimore, Maryland, USA.",
"authors": "Jin|Ning|N|;Salahuddin|Farah F|FF|;Nesbitt|John A|JA|",
"chemical_list": "D000970:Antineoplastic Agents; D014841:von Willebrand Factor; D005169:Factor VIII",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "25(8)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005169:Factor VIII; D005260:Female; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma; D010314:Partial Thromboplastin Time; D010950:Plasma Cells; D017741:Survivors; D016896:Treatment Outcome; D014842:von Willebrand Diseases; D014841:von Willebrand Factor",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "890-3",
"pmc": null,
"pmid": "24911454",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired von Willebrand disease and multiple myeloma: a case report of a breast cancer survivor.",
"title_normalized": "acquired von willebrand disease and multiple myeloma a case report of a breast cancer survivor"
} | [
{
"companynumb": "US-TEVA-563961USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"... |
{
"abstract": "With the aim of developing an effective therapy for heavily pretreated refractory MM outpatients, we evaluated the OPPEBVCAD regimen, a Hodgkin's disease-derived protocol that includes many drugs effective in MM administered in a sequential schedule. Twenty-two pts aged 42-72 years, with symptomatic highly-pretreated refractory (18 cases), or primary resistant MM (four cases. including two pts with plasma cell leukemia-PCL) received this therapy every 28 days (2-4 cycles, followed by a maintenance program). Therapeutic response (Chronic Leukemia-Myeloma Task Force criteria) and performance status (PS) and pain (W.H.O.) were evaluated. All of the pts were evaluable for response. There were 9 (40%) objective responses (OR: stabilization of blood counts and bone lesions, serum calcium normalization, 50% or more reduction in the concentration of serum monoclonal component (MC), 90% reduction in Bence-Jones proteinuria), 8 (36%) partial responses (PR: 25-50% reduction in serum MC), 1 no response or stable disease (NR), and 4 (18%) cases of progressive disease (PD). OR plus PR were 77%. Of the 4 primary resistant tumors (2 PCL and 2 MM), 2 achieved PR, 1 OR (a PCL case) and 1 progressed. Median survival was 15 months for responding pts (OR plus PR) and 4.5 months for non-responders (NR plus PD). PS and pain improved in 15 pts and did not change in 9. The most frequent side effects were cytopenias, with one drug related infective death. The OPPEBVCAD regimen proved to be an effective therapy for refractory relapsing or primary resistant MM: in responders (two-thirds of the pts), survival was prolonged by about 10 months. Its efficacy in anthracycline-treated pts, as well as the feasibility of using it on an outpatient basis without any continuous drug infusions, make this regimen a promising third line salvage therapy.",
"affiliations": "Servizio di Ematologia, Istituto di Scienze Mediche, Università di Milano, Ospedale Maggiore, I.R.C.C.S., Italy.",
"authors": "Colombi|M|M|;Guffanti|A|A|;Alietti|A|A|;Latargia|M L|ML|;Vener|C|C|;Maiolo|A T|AT|;Baldini|L|L|",
"chemical_list": "D001761:Bleomycin; D011344:Procarbazine; D015251:Epirubicin; D014750:Vincristine; D014747:Vinblastine; D008130:Lomustine; D008558:Melphalan; D014751:Vindesine; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.3109/10428190009054884",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "40(1-2)",
"journal": "Leukemia & lymphoma",
"keywords": null,
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000380:Agranulocytosis; D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D002423:Cause of Death; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin; D006801:Humans; D008130:Lomustine; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D011241:Prednisone; D011344:Procarbazine; D016879:Salvage Therapy; D015996:Survival Rate; D013921:Thrombocytopenia; D016896:Treatment Outcome; D014747:Vinblastine; D014750:Vincristine; D014751:Vindesine",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "87-94",
"pmc": null,
"pmid": "11426632",
"pubdate": "2000-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "OPP-EBV-CAD regimen as salvage treatment in advanced refractory or resistant multiple myeloma.",
"title_normalized": "opp ebv cad regimen as salvage treatment in advanced refractory or resistant multiple myeloma"
} | [
{
"companynumb": "IT-PFIZER INC-2020096544",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROCARBAZINE"
},
"drugadditional": "3",
... |
{
"abstract": "Catatonia is a syndrome of motor and behavioral disturbance. It is a poorly understood condition, which is underrecognized and may go untreated despite intensive medical workup and numerous unsuccessful medication trials. However, with treatments known to be effective, such as benzodiazepines and/or electroconvulsive therapy, patients may return to their baseline functioning. Autism and catatonia have been previously reported together. We report 2 patients with autism and mental retardation who developed catatonic symptoms at the onset of puberty. Both patients experienced persistent symptoms over several years and presented with a history of motor disturbance, functional decline, and episodic aggression. Both patients were treated with electroconvulsive therapy resulting in a positive response and functional improvement. Catatonia may persist as a chronic condition, lasting over several months or years, if not recognized and treated.",
"affiliations": "Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109-5734, USA. neerag@umich.edu",
"authors": "Ghaziuddin|Neera|N|;Gih|Daniel|D|;Barbosa|Virginia|V|;Maixner|Daniel F|DF|;Ghaziuddin|Mohammad|M|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D005473:Fluoxetine; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1097/YCT.0b013e3181de332e",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1095-0680",
"issue": "26(4)",
"journal": "The journal of ECT",
"keywords": null,
"medline_ta": "J ECT",
"mesh_terms": "D000293:Adolescent; D017668:Age of Onset; D000374:Aggression; D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D001321:Autistic Disorder; D002389:Catatonia; D002648:Child; D002659:Child Development Disorders, Pervasive; D004519:Education, Special; D004565:Electroconvulsive Therapy; D004569:Electroencephalography; D005473:Fluoxetine; D006319:Hearing Loss, Sensorineural; D006801:Humans; D008607:Intellectual Disability; D008279:Magnetic Resonance Imaging; D008297:Male; D011627:Puberty; D020280:Sertraline; D013177:Sports; D013239:Stereotyped Behavior",
"nlm_unique_id": "9808943",
"other_id": null,
"pages": "274-7",
"pmc": null,
"pmid": "20562645",
"pubdate": "2010-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Onset of catatonia at puberty: electroconvulsive therapy response in two autistic adolescents.",
"title_normalized": "onset of catatonia at puberty electroconvulsive therapy response in two autistic adolescents"
} | [
{
"companynumb": "US-APOTEX-2017AP021895",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "Peritoneal lymphomatosis represents a rare presentation of any type of non-Hodgkin's lymphoma, with relatively few cases reported in the literature. We present here the case of a 61-year-old man who originally presented with increased abdominal distention associated with shortness of breath and diaphoresis who was found to have evidence of peritoneal carcinomatosis on CT scan. Biopsy confirmed diffuse large B-cell lymphoma, and the working diagnosis was subsequently modified to peritoneal lymphomatosis. The patient was treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) therapy with initially good response. His course was complicated by tumour lysis syndrome. We review the limited literature discussing peritoneal lymphomatosis and discuss the importance of facilitating rapid and efficacious treatment.",
"affiliations": "MedStar Georgetown University Hospital, Washington, DC, USA.;MedStar Georgetown University Hospital, Washington, DC, USA.;Virginia Cancer Specialists, Arlington, Virginia, USA.",
"authors": "Kareff|Samuel|S|http://orcid.org/0000-0001-7431-1221;Yin|Chao|C|;Feigert|John|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231238",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(8)",
"journal": "BMJ case reports",
"keywords": "cancer intervention; malignant and benign haematology; oncology; radiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003924:Diabetes Mellitus, Type 2; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D006973:Hypertension; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D010534:Peritoneal Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31413062",
"pubdate": "2019-08-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27756028;27900846;25308238;27179155;19700895;25694630;31040529;29130007;24711934;25378847;22693400",
"title": "High-grade B-cell lymphoma masquerading as peritoneal lymphomatosis.",
"title_normalized": "high grade b cell lymphoma masquerading as peritoneal lymphomatosis"
} | [
{
"companynumb": "US-JNJFOC-20190907066",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"d... |
{
"abstract": "The use of antiretrovirals as pre-exposure prophylaxis (PrEP) is highly efficacious in HIV prevention. The World Health Organization recently recommended Truvada(®) (Gilead Sciences, Inc.) or tenofovir disoproxil fumarate (TDF) for high-risk individuals, with limited data for single-agent TDF PrEP in men who have sex with men (MSM). We report two cases of TDF PrEP failure in MSM who had received long-term TDF for hepatitis B infection and had therapeutic levels of drug immediately after HIV acquisition. Rapid antiretroviral intensification at diagnosis of acute HIV infection failed to limit immune dysfunction or prevent the establishment of a viral reservoir.",
"affiliations": "Department of Genitourinary Medicine and Infectious Disease, Guys and St Thomas' NHS Trust, London, UK. julie.fox@kcl.ac.uk.;Department of Sexual Health and HIV, Kings College Hospital, London, UK.;Department of Sexual Health and HIV, Kings College Hospital, London, UK.;Department of Genitourinary Medicine and Infectious Disease, Guys and St Thomas' NHS Trust, London, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.;Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.;Department of Infectious Diseases, Kings College London, London, UK.;Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.;Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.;Department of Infectious Diseases, Imperial College, London, UK.;Nuffield Department of Medicine, University of Oxford, Oxford, UK.",
"authors": "Fox|Julie|J|http://orcid.org/0000-0002-0583-8019;Brady|Michael|M|;Alexander|Hannah|H|;Davies|Olubanke|O|;Robinson|Nicola|N|;Pace|Mathew|M|;Else|Laura|L|;Cason|John|J|;Khoo|Saye|S|;Back|David|D|;Fidler|Sarah|S|;Frater|John|J|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40121-015-0102-x",
"fulltext": "\n==== Front\nInfect Dis Ther\nInfect Dis Ther\nInfectious Diseases and Therapy\n2193-8229\n2193-6382\nSpringer Healthcare Cheshire\n\n102\n10.1007/s40121-015-0102-x\nCase Report\nTenofovir Disoproxil Fumarate Fails to Prevent HIV Acquisition or the Establishment of a Viral Reservoir: Two Case Reports\nhttp://orcid.org/0000-0002-0583-8019\nFox Julie julie.fox@kcl.ac.uk\n\nBrady Michael\nAlexander Hannah\nDavies Olubanke\nRobinson Nicola\nPace Mathew\nElse Laura\nCason John\nKhoo Saye\nBack David\nFidler Sarah\nFrater John\nDepartment of Genitourinary Medicine and Infectious Disease, Guys and St Thomas’ NHS Trust, London, UK\nDepartment of Sexual Health and HIV, Kings College Hospital, London, UK\nNuffield Department of Medicine, University of Oxford, Oxford, UK\nOxford NIHR Biomedical Research Centre, Oxford, UK\nOxford Martin School, Oxford, UK\nDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK\nDepartment of Infectious Diseases, Kings College London, London, UK\nDepartment of Infectious Diseases, Imperial College, London, UK\n9 1 2016\n9 1 2016\n3 2016\n5 1 6571\n5 11 2015\n© The Author(s) 2015\nThe use of antiretrovirals as pre-exposure prophylaxis (PrEP) is highly efficacious in HIV prevention. The World Health Organization recently recommended Truvada® (Gilead Sciences, Inc.) or tenofovir disoproxil fumarate (TDF) for high-risk individuals, with limited data for single-agent TDF PrEP in men who have sex with men (MSM). We report two cases of TDF PrEP failure in MSM who had received long-term TDF for hepatitis B infection and had therapeutic levels of drug immediately after HIV acquisition. Rapid antiretroviral intensification at diagnosis of acute HIV infection failed to limit immune dysfunction or prevent the establishment of a viral reservoir.\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1007/s40121-015-0102-x) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nHIV\nPre-exposure prophylaxis\nTenofovir\nViral reservoir\nissue-copyright-statement© Springer Healthcare 2016\n==== Body\nIntroduction\n\nThe use of antiretrovirals (ARVs) as pre-exposure prophylaxis (PrEP) is highly efficacious at limiting HIV transmission [1–6]. Recent World Health Organization (WHO) guidelines recommend single-agent tenofovir disoproxil fumarate (TDF) or Truvada® [TDF/emtricitabine (FTC); Gilead Sciences, Inc.] for individuals at risk of HIV acquisition [7]. Single-agent TDF PrEP shows benefit over placebo and is comparable with Truvada in preventing HIV transmission in HIV serodiscordant heterosexual couples [2] and individuals who inject drugs [3]. Efficacy data for TDF in men who have sex with men (MSM) are limited [8] and it is not known whether drug level requirements are the same for both HIV treatment and prevention. However, animal model data suggest that TDF alone is less protective than Truvada [9, 10] and pharmacokinetic analysis of the partners PrEP study supports this [11].\n\nCases of PrEP failure mainly occur due to poor adherence [1–6, 11]. Early detection is essential to minimize monotherapy drug exposure and prevent drug resistance development [12]. Whether ARV therapy (ART) should be stopped or intensified at PrEP failure is unclear [13]. A recent case presentation reported an undetectable viral reservoir in an individual’s intensifying ART at PrEP failure [14]. This is supported by cohort data and data from macaques suggest that three-drug ARV at acute HIV infection can improve clinical outcome [15–17] by limiting viral reservoir [17–20] and immune dysfunction [21–23], and that these benefits are greater the earlier the ARVs are started [15–17].\n\nWe report two cases of PrEP failure amongst MSM receiving long-term TDF for hepatitis B treatment with therapeutic tenofovir levels around the time of HIV-1 acquisition. Despite continuing TDF and intensifying to combination ARV at acute HIV diagnosis, both cases had significant viral reservoirs and elevated markers of immune activation/exhaustion within 4 weeks of HIV-1 diagnosis consistent with established HIV-1 infection.\n\nCase reports\n\nPatients\n\nInformed consent was obtained from both patients for being included in this case report.\n\nTwo patients from separate HIV centers were diagnosed with acute HIV whilst receiving TDF monotherapy for hepatitis B infection. To allow case comparison, day 1 was defined as the day of estimated date of HIV seroconversion (EDSC, i.e., the mid-point date between HIV-negative and HIV-positive test or 14 days prior to p24 antigen-positive/HIV antibody-negative result).\n\nBoth patients had received TDF 300 mg/day for hepatitis B infection (hepatitis B s-antigen and e-antigen positive) and maintained a consistently undetectable hepatitis B DNA for 3+ years with no viral blips. In the 6 weeks prior to HIV acquisition both individuals reported condom-less receptive anal sex with casual male partners and denied any missed doses of TDF. Longstanding good adherence was further suggested by the regularity of pharmacy script provision and drug levels carried out at HIV diagnosis were within the therapeutic range (Fig. 1). No other sexually transmitted infections were detected at HIV diagnosis. ARV was intensified within 3 weeks of presumed HIV acquisition and blood taken for quantification of viral reservoir and immune function approximately 1 week later. The cases are summarized in Table 1.Fig. 1 Pharmacokinetic plot of tenofovir levels taken at HIV diagnosis. For patient A the tenofovir trough level 17 h post-dose was 48 ng/mL (between 10th and 25th centile) and for patient B the tenofovir trough concentration 7 h post-dose was 220 ng/mL (75th centile). TDF tenofovir disoproxil fumarate\n\nTable 1 Summary characteristics of cases of HIV-1 acquisition on TDF\n\nCharacteristics\tPatient A\tPatient B\t\nAcute HIV diagnosis\tHIV-positive test 12 days after HIV-negative test\tP24 antigen positive/HIV antibody negative\t\nHepatitis B history\t\n Duration known hepatitis B infection\t6 years\t7 years\t\n Duration TDF monotherapy\t4 years\t3 years\t\n No. hepatitis B VL blips on TDF\t0\t0\t\nHIV seroconversion symptoms\tMild fever\tHospitalized with severe sore throat, fever\t\nBlood results at acute HIV diagnosis\t\n Days from EDSC to blood test\t10\t14\t\n HIV VL (copies/mL)\t<50\t158,899\t\n CD4 T cell count\t584 (35%)\t550 (24%)\t\n CD4:CD8 ratio\t1.19\t0.49\t\n Hepatitis B VL\tUndetectable\tUndetectable\t\n HIV genotype\tNot possible\tWild type\t\nIntensified ART regime\t\n Days from EDSC to intensification\t15\t19\t\n Regime\tEviplera\tTruvada, raltegravir, darunavir, ritonavir\t\nReservoir quantification\t\n Days from EDSC to blood test\t12\t24\t\n HIV total DNA (copies/million CD4 cells)\t1381 (3.14)\t2746 (3.44)\t\n Integrated DNA (copies/million CD4 T cells)\t586.6 (2.77)\t1431.6 (3.16)\t\n RNA (copies/million CD4 T cells)\t116\t1236\t\nImmunology\t\n Days from EDSC to blood test\t15\t24\t\n CD4 + CD38 + (%)\t65.8\t42.2\t\n CD4 + HLA-DR + (%)\t3.12\t4.34\t\n CD8 + CD38 + (%)\t57\t38.8\t\n CD8 + HLA-DR + (%)\t14.4\t9.58\t\nART antiretroviral therapy, EDSC estimated date of HIV seroconversion, TDF tenofovir disoproxil fumarate, VL viral load\n\nLaboratory Results\n\nPatient A was diagnosed with acute HIV infection (HIV antibody positive 10 days after HIV antibody-negative test and by 3 bands on Western Blot) following a 4-day history of mild flu-like symptoms suggestive of seroconversion illness. Results 9 days after EDSC were: CD4 T cell count 584 cells/µL (35%), CD4:CD8 ratio 1.19, and HIV-1 plasma viral load <50 copies/mL. The ARV regimen was immediately intensified (12 days from EDCS) to Eviplera® (25 mg rilpivirine, 200 mg emtricitabine, and 245 mg TDF; Gilead Sciences International Ltd.) and the viral load remained undetectable thereafter. Viral genotype failed to amplify due to low viral load. Results 15 days after EDSC (3 days after ARV intensification) showed total HIV-1 DNA 1381 copies/million CD4 cells, integrated DNA 586.6 copies/million CD4 T cells, and unspliced intracellular HIV-1 RNA transcripts 116 copies/106 copies 18 s RNA.\n\nPatient B was diagnosed with acute HIV (p24 antigen-positive/antibody-negative antibody) following hospitalization with a severe seroconversion illness comprising severe flu-like symptoms, fatigue, and myalgia. Results 14 days after EDSC were: CD4 T cell count 550 cells/µL (24%), CD4:CD8 ratio 0.49, and HIV-1 plasma viral load 103,306 copies/mL. The regimen was intensified 19 days after EDSC to Truvada (one tablet once daily), raltegravir (400 mg twice daily), darunavir (800 mg once daily), and ritonavir (100 mg once daily). Viral genotype showed wild-type drug-sensitive virus. Blood taken 24 days after EDSC (5 days after ART intensification) showed total HIV-1 DNA 2746 copies/million CD4 cells, integrated DNA 1431.6 copies/million CD4 T cells, and unspliced intracellular HIV-1 RNA transcripts 1236 copies/106 copies 18 s RNA.\n\nImmune activation, defined as the percentage expression of CD38 and HLA-DR on CD4 and CD8 T cells, was 65.8 and 57% for patient A and 42.2 and 38.8% for patient B.\n\nMethods\n\nHIV Diagnosis, Viral Load, and Therapeutic Drug Level Monitoring\n\nHIV testing was carried out using the Abbott Architect HIV Ag/Ab combo assay and VIDAS quantitative HIV p24 11 assay. Confirmation occurred with Vidas HIV Duo Quick (HIV6) ELFA fourth-generation assay and Bispot Immunocomb third-generation assay.\n\nWestern blot was carried out using MP Diagnostics HIV Blot 2.2. HIV-1 plasma viral load was quantified by Roche COBAS V2.0, and viral genotype determined using Taqman sequencing. Tenofovir (TFV) drug levels were measured by a validated HPLC–MS/MS with a lower limit of quantification of 5 ng/mL [24]. The tenofovir concentration for each patient was plotted against a percentile plot derived from a published population pharmacokinetic model of tenofovir plasma concentrations in HIV-infected subjects (Fig. 1) [25].\n\nHIV Reservoir\n\nPurified CD4 T cells were analyzed by qPCR for HIV-1 DNA (total and integrated) and cell-associated HIV-1 RNA unspliced transcripts (CA-RNA) as reported elsewhere [19].\n\nImmune Activation and Exhaustion\n\nPBMC were stained with the anchor markers (CD3-VioBlue, CD4(VIT4)-VioGreen, CD8-APC) and a Live/Dead marker Near IR-APC-Cy7 plus either an activation panel (CD25(3G10)-PE, CD38-PE-Vio770, CD69-FITC, Anti-HLA-DR-PerCP) or an exhaustion panel (TIGIT-PE, TIM-3-FITC, LAG-3-PerCPeF710, PD1-PE-Cy7). Cells were run on a MACSQuant and analyzed with FlowJo software v10 (Miltenyi Biotec).\n\nDiscussion\n\nAs PrEP is becoming more widely available and uptake increasing, this is a timely reminder that TDF monotherapy PrEP in MSM has limited efficacy data and that HIV-1 acquisition can occur in the presence of TFV drug levels within the therapeutic range required to treat HIV [26]. These cases are instructive to providers and the field of PrEP, and highlight that patients with HBV receiving tenofovir for HBV should consider intensification to Truvada (TDF/FTC) if they meet guidelines (e.g., Centers for Disease Control and Prevention) for PrEP. The lack of resistance detected concurs with randomized control study data showing a very low incidence of resistance in cases of tenofovir failure [29].\n\nAlthough PrEP effectiveness is largely driven by adherence [1–8, 11, 26, 27], this was not implicated in these cases as evidenced by consistently undetectable hepatitis B DNA and therapeutic plasma levels of tenofovir at HIV diagnosis (a proxy for HIV acquisition). Whilst drug levels were high enough to treat both hepatitis B and HIV infection [26], the drug level required to protect from HIV infection is not known and, if higher, may explain the transmission events. Additionally, it is not known whether hepatitis B increases susceptibility to HIV and the presence of TDF-resistant mutations may need to be excluded by minor variant sequencing [12].\n\nThese cases also show that rapid intensification with ARVs did not prevent reservoir seeding or immune dysfunction. Indeed, the level of viral reservoir, immune activation, and immune exhaustion were comparable to those observed in untreated primary HIV cohorts [15]. Patient A is of additional interest as this occurred despite no evidence of on-going viral replication in plasma prior to ARV intensification. This suggests the importance of sanctuary sites for the establishment of viral reservoir and is consistent with primate models [27].\n\nConclusion\n\nSingle-drug TDF PrEP was not effective in preventing HIV infection and intensified ART post-infection did not reduce the viral reservoir in either patient. Whilst single-agent PrEP is not to be recommended as an HIV prevention strategy in MSM in European [28] and US [13] PrEP guidelines, it is by the WHO [7]. Close monitoring of outcomes of TDF usage in MSM needs to be carried out.\n\nElectronic supplementary material\n\nBelow is the link to the electronic supplementary material. Supplementary material 1 (PDF 197 kb)\n\nWe would like to thank the Kings College London Infectious Diseases Biobank. No funding was received for publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.\n\nDisclosures\n\nJulie Fox has received research grants from ViiV and Gilead and has done a Jansen BHIVA symposium. Saye Khoo has received research funding support from Merck, Gilead, Janssen, and ViiV. David Back has received an educational grant from Gilead, and honoraria from Gilead for lectures and Advisory Boards. Michael Brady, Hannah Alexander, Olubanke Davies, Nicola Robinson, Mathew Pace, Laura Else, John Cason, Sarah Fidler, and John Frater have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nInformed consent was obtained from both patients for being included in this case report.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nOn behalf of CHERUB Collaboration.\n\nJ. Frater and S. Fidler are joint senior authors and contributed equally.\n==== Refs\nReferences\n\n1. Grant RM Lama JR Anderson PL Pre-exposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men N Engl J Med 2010 363 2587 2599 10.1056/NEJMoa1011205 21091279\n2. Baeten JM Donnell D Ndase P Antiretroviral prophylaxis for HIV prevention in heterosexual men and women N Engl J Med 2012 367 5 399 410 10.1056/NEJMoa1108524 22784037\n3. Choopanya K Martin M Suntharasamai P Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial Lancet 2013 381 9883 2083 2090 10.1016/S0140-6736(13)61127-7 23769234\n4. Van Damme L Corneli A Ahmed K Pre-exposure prophylaxis for HIV infection among African women N Engl J Med 2012 367 5 411 422 10.1056/NEJMoa1202614 22784040\n5. McCormack S Dunn D, Gafos M, et al. Pragmatic Open-Label Randomised Trial of preexposure prophylaxis: the PROUD Study. 2015 conference on retroviruses and opportunistic infections (CROI), Seattle, USA, abstract 22LB; 2015.\n6. Molina J-M Capitant C, Spire B, et al. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS Ipergay Trial. 2015 conference on retroviruses and opportunistic infections (CROI), Seattle, USA, abstract 23LB; 2015.\n7. WHO: Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. September 2015. Available from: http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1. Accessed Nov 11, 2015.\n8. Grohskopf LA Chillag KL Gvetadze R Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate disoproxil fumarate among HIV-uninfected men who have sex with men in the United States J Acquir Immune Defic Syndr 2013 64 1 79 86 10.1097/QAI.0b013e31828ece33 23466649\n9. Subbarao S Otten RA Ramos A Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges J Infect Dis 2006 194 904 911 10.1086/507306 16960777\n10. Radzio J Aung W Holder A Prevention of vaginal SHIV transmission in macaques by a coitally-dependent Truvada regimen PLoS ONE 2012 7 12 2012 10.1371/journal.pone.0050632\n11. Baeten JM Donnell D Mugo NR Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial Lancet Infect Dis. 2014 14 11 1055 1064 10.1016/S1473-3099(14)70937-5 25300863\n12. Grant RM Liegler T Defechereux P Drug resistance and plasma viral RNA level after ineffective use of oral pre-exposure prophylaxis in women AIDS. 2015 29 3 331 337 10.1097/QAD.0000000000000556 25503265\n13. Preexposure Prophylaxis for the Prevention of HIV Infection in the United States—2014 Clinical Practice Guideline. Available from: http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf.\n14. Hatano H, et al. Lack of detectable HIV DNA in a PrEP study participant treated during “hyperacute” HIV infection. 21st CROI. 3–6 March 2014, Boston. Late breaker poster 397LB. http://croiconference.org/sites/all/abstracts/397LB.pdf (PDF). Accessed 1202015.\n15. Le T Wright EJ Smith DM Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy N Engl J Med 2013 368 3 218 230 10.1056/NEJMoa1110187 23323898\n16. Fidler S Porter K Ewings F Short-course antiretroviral therapy in primary HIV infection N Engl J Med 2013 368 3 207 217 10.1056/NEJMoa1110039 23323897\n17. Sáez-Cirión A Bacchus C Hocqueloux L Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study PLoS Pathog 2013 9 3 e1003211 10.1371/journal.ppat.1003211 23516360\n18. Ananworanich J Schuetz A Vandergeeten C Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection PLoS ONE 2012 7 3 e33948 10.1371/journal.pone.0033948 22479485\n19. Williams JP Hurst J Stöhr W HIV-1 DNA predicts disease progression and post-treatment virological control Elife. 2014 3 e03821 25217531\n20. Whitney JB Hill AL Sanisetty S Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys Nature 2014 512 7512 74 77 25042999\n21. Schuetz A Deleage C Sereti I Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation PLoS Pathog 2014 10 12 e1004543 10.1371/journal.ppat.1004543 25503054\n22. Rosenberg ES Altfeld M Poon SH Immune control of HIV-1 after early treatment of acute infection Nature 2000 407 523 526 10.1038/35035103 11029005\n23. Thornhill J Inshaw J, Oomeer S, et al. Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection. J Int AIDS Soc. 2014;17(4Suppl 3).\n24. Jackson A Moyle G Watson V Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for HIV treatment and prevention J Acquir Immune Defic Syndr 2013 62 3 275 281 10.1097/QAI.0b013e3182829bd0 23274933\n25. Baheti G Kiser JJ Havens PL Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients Antimicrob Agents Chemother 2011 55 11 5294 5299 10.1128/AAC.05317-11 21896913\n26. Donnell D Baeten JM Bumpus NN HIV protective efficacy and correlates of Tenofovir disoproxil fumarate blood concentrations in a clinical trial of PrEP for HIV prevention J Acquir Immune Defic Syndr 2014 66 3 340 348 10.1097/QAI.0000000000000172 24784763\n27. Baeten J Celum C Systemic and topical drugs for the prevention of HIV infection: antiretroviral pre-exposure prophylaxis Annu Rev Med 2013 64 219 232 10.1146/annurev-med-050911-163701 23020883\n28. European Guidelines for treatment of HIV-infected adults in Europe 2015. Available from: http://www.eacsociety.org/files/guidelines_8_0-english_web.pdf. Accessed Nov 11, 2015.\n29. Lehman DA Baeten JM McCoy CO Risk of drug resistance among persons acquiring HIV within a randomized clinical trial of single or dual agent preexposure prophylaxis J Infect Dis 2015 211 8 1211 1218 25587020\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "5(1)",
"journal": "Infectious diseases and therapy",
"keywords": "HIV; Pre-exposure prophylaxis; Tenofovir; Viral reservoir",
"medline_ta": "Infect Dis Ther",
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"other_id": null,
"pages": "65-71",
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"title": "Tenofovir Disoproxil Fumarate Fails to Prevent HIV Acquisition or the Establishment of a Viral Reservoir: Two Case Reports.",
"title_normalized": "tenofovir disoproxil fumarate fails to prevent hiv acquisition or the establishment of a viral reservoir two case reports"
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"abstract": "OBJECTIVE\nTo review the literature regarding the pharmacokinetic profiles, comparative safety and efficacy, and comparative costs of loop diuretics to evaluate the current clinical usefulness of furosemide.\n\n\nMETHODS\nA search of MEDLINE (1966-June 2009) was conducted using the terms furosemide, torsemide, bumetanide, ethacrynic acid, and loop diuretics. Articles were limited to those written in English.\n\n\nMETHODS\nAll English-language articles identified from the data sources were reviewed. Studies were eligible if they encompassed pharmacokinetics, comparative safety and efficacy, or comparative costs of the loop diuretics.\n\n\nRESULTS\nIn patients with heart failure (HF), torsemide demonstrated decreased mortality compared with furosemide in 1 study (2.2% vs 4.5% in the furosemide group; p < 0.05), decreased hospitalizations in 1 study (23 in the torsemide group vs 61 in the furosemide group; p < 0.01), and improved New York Heart Association functional classifications in 2 studies. In the first, 45.8% with torsemide versus 37.2% with furosemide demonstrated improvement in at least one functional class (p = 0.00017). In the second, 40.2% with torsemide and 30.7% with furosemide demonstrated improvement in at least one functional class (p = 0.014). In 2 of 3 studies of patients with cirrhosis, torsemide increased natriuresis and total volume diuresed compared with furosemide in patients with cirrhosis; however, no significant difference between the agents with respect to plasma renin and aldosterone concentrations was demonstrated. In patients with pulmonary hypertension, central venous pressure, capillary wedge pressure, and stroke volume significantly improved from baseline among patients who received torsemide, but not in those who received furosemide, although the intergroup analysis failed to reach statistical significance. Among patients with chronic kidney disease, no significant differences were noted with respect to natriuresis and blood pressure control between the 2 agents; however, in patients with acute kidney injury, patients who received furosemide had a significant improvement in urine output versus the torsemide group. Additionally, 2 trials comparing bumetanide with furosemide were identified, although the results were conflicting. In patients with nephrotic syndrome, bumetanide significantly improved weight loss in the first 4 weeks and in week 20, compared with furosemide. In patients with HF, significant improvement in dyspnea at rest and on exertion was exhibited in the bumetanide group, but not in the furosemide group; no significant difference was noted between the 2 groups when evaluating global assessment.\n\n\nCONCLUSIONS\nGrowing evidence demonstrates more favorable pharmacokinetic profiles of torsemide and bumetanide compared with furosemide. Furthermore, torsemide may be more efficacious and safer than furosemide in patients with HF. A trial comparing all 3 drugs would be required to confirm torsemide as the primary loop diuretic in patients with HF, but based upon limited current evidence, we recommend torsemide over furosemide. Currently, little evidence exists to support either torsemide or bumetanide as first-line treatment over furosemide in patients with other edematous disease states.",
"affiliations": "Division of Internal Medicine, Auburn University Harrison School of Pharmacy, University of Alabama at Birmingham Huntsville Regional Medical Campus, Huntsville, AL, USA. wargoka@auburn.edu",
"authors": "Wargo|Kurt A|KA|;Banta|William M|WM|",
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"mesh_terms": "D005665:Furosemide; D006333:Heart Failure; D006801:Humans; D007676:Kidney Failure, Chronic; D008103:Liver Cirrhosis; D049994:Sodium Potassium Chloride Symporter Inhibitors",
"nlm_unique_id": "9203131",
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"pubdate": "2009-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "A comprehensive review of the loop diuretics: should furosemide be first line?",
"title_normalized": "a comprehensive review of the loop diuretics should furosemide be first line"
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"abstract": "Mycobacterium tuberculosis is one of the most hard-to-treat bacterial pathogens with a high capacity to develop antibiotic resistance by mutations. Here we have performed whole genome sequencing of consecutive M. tuberculosis isolates obtained during nine years from a patient with pulmonary tuberculosis. The infecting strain was isoniazid resistant and during treatment it stepwise accumulated resistance mutations to eight additional antibiotics. Heteroresistance was common and sub-populations with up to three different resistance mutations to the same drug co-existed. Sweeps of different resistant clones dominated the population at different timepoints, always coupled to resistance mutations coinciding with changes in the treatment regimens. Resistance mutations were predominant and no hitch-hiking, compensatory or virulence increasing mutations were detected showing that the dominant selection pressure was antibiotic treatment. The results highlight the dynamic nature of M. tuberculosis infection, population structure and resistance evolution and the importance of rapid antibiotic susceptibility tests to battle this pathogen.",
"affiliations": "Department of Medical Biochemical and Microbiology, Uppsala University, Uppsala, Sweden.;Public Health Agency of Sweden, Solna, Sweden.;Public Health Agency of Sweden, Solna, Sweden.;Department of Global Public Health, Karolinska Institute, Stockholm, Sweden.;Department of Medical Biochemical and Microbiology, Uppsala University, Uppsala, Sweden.;Department of Medical Biochemical and Microbiology, Uppsala University, Uppsala, Sweden.",
"authors": "Hjort|Karin|K|;Jurén|Pontus|P|;Toro|Juan Carlos|JC|;Hoffner|Sven|S|;Andersson|Dan I|DI|;Sandegren|Linus|L|",
"chemical_list": null,
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"doi": "10.1093/infdis/jiaa625",
"fulltext": "\n==== Front\nJ Infect Dis\nJ Infect Dis\njid\nThe Journal of Infectious Diseases\n0022-1899\n1537-6613\nOxford University Press US\n\n33045067\n10.1093/infdis/jiaa625\njiaa625\nMajor Articles and Brief Reports\nBacteria\nAcademicSubjects/MED00290\nDynamics of Extensive Drug Resistance Evolution of Mycobacterium tuberculosis in a Single Patient During 9 Years of Disease and Treatment\nHjort Karin 1\nJurén Pontus 2\nToro Juan Carlos 2\nHoffner Sven 3\nAndersson Dan I 1\nSandegren Linus 1\n1 Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden\n2 Public Health Agency of Sweden, Solna, Sweden\n3 Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden\nCorrespondence: Linus Sandegren, PhD, Box 582, 751 23 Uppsala, Sweden (linus.sandegren@imbim.uu.se).\n15 3 2022\n12 10 2020\n12 10 2020\n225 6 10111020\n26 6 2020\n25 9 2020\n08 10 2020\n16 11 2020\n© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nMycobacterium tuberculosis is one of the hardest to treat bacterial pathogens with a high capacity to develop antibiotic resistance by mutations. Here we have performed whole-genome sequencing of consecutive M. tuberculosis isolates obtained during 9 years from a patient with pulmonary tuberculosis. The infecting strain was isoniazid resistant and during treatment it stepwise accumulated resistance mutations to 8 additional antibiotics. Heteroresistance was common and subpopulations with up to 3 different resistance mutations to the same drug coexisted. Sweeps of different resistant clones dominated the population at different time points, always coupled to resistance mutations coinciding with changes in the treatment regimens. Resistance mutations were predominant and no hitch-hiking, compensatory, or virulence-increasing mutations were detected, showing that the dominant selection pressure was antibiotic treatment. The results highlight the dynamic nature of M. tuberculosis infection, population structure, and resistance evolution and the importance of rapid antibiotic susceptibility tests to battle this pathogen.\n\nWhole-genome sequencing of Mycobacterium tuberculosis from a single patient during 9 years of disease and treatment showed that sequence evolution was mainly driven by antibiotic treatment, resulting in a stepwise accumulation of resistance mutations to (essentially) all used antibiotics.\n\nantibiotic resistance\nMycobacterium tuberculosis\nevolution\nSwedish Research Council 10.13039/501100004359 2017-01527 K2013-99X-22208-01-5\n==== Body\npmc Mycobacterium tuberculosis represents one of the most devastating human pathogens in history. Effective combination treatment regimens against tuberculosis extend for months or years and the drugs have severe side effects [1]. This reduces patient compliance leading to suboptimal treatment, transmission of resistant strains, and compromises complete eradication of the infection. The development of resistance among M. tuberculosis strains has resulted in multidrug resistant and extensively drug resistant bacteria [2]. There is no known horizontal transfer of resistance genes in M. tuberculosis; instead antibiotic resistance depends solely on selection of de novo mutations during treatment [3]. The subsequent evolutionary success of resistant mutants depends largely on the resistance level and fitness of the mutant, epistatic effects between genetic alleles, and selective sweeps due to antibiotic treatment [4, 5].\n\nBecause antibiotics target vital processes in the cell, resistance mutations that occur in genes responsible for these processes often confer a fitness cost to the cell, reducing the ability of the resistant mutant to be maintained in the population [4, 6]. However, following a costly mutation, compensating mutations may occur that mitigate the fitness cost of the original resistance mutation [7–10]. In the presence of an antibiotic, the mutation frequency of occurrence, together with level of resistance and fitness cost for each mutation, will therefore be the main determinants of mutation prevalence in the population [4, 6, 11, 12]. In the recommended M. tuberculosis treatment plan the antibiotic selection pressure comes from multiple antibiotics at the same time, creating a complex selection landscape in each individual patient [1]. To add to the complexity, epistatic effects between resistance mutations and the genetic background may also play a part in the evolutionary fate of mutations [7, 9, 13, 14].\n\nPrevious whole-genome sequencing (WGS) studies on the evolution of antibiotic resistance of M. tuberculosis during treatment in patients show somewhat contradictory results [5, 15–19]. Some conclude that a majority of fixed mutations in the population were associated with drug resistance [16, 18, 19] and that antibiotic selection was the dominating factor driving evolution under treatment [16, 18]. Other studies report a high degree of hitchhiking mutations and a large diversity of mutations unrelated to drug resistance between longitudinal samples [5, 15]. Most studies observed a stepwise evolution of antibiotic resistance [15, 16, 18]. Some reported coexistence of mutationally different clonal populations of the same resistance phenotype at the same time point during infection [15, 17, 19].\n\nHere we studied the evolution of extensive drug resistance in a M. tuberculosis strain belonging to the Beijing lineage in a single patient over 9 years (1991–1999). The infecting strain was initially resistant to isoniazid and during the course of infection further resistance developed to 8 additional compounds used for treatment, eventually leading to the death of the patient. To address the genetic composition of the infecting M. tuberculosis population over the course of infection and determine the evolutionary trajectories of resistant subpopulations, we performed WGS of both population samples and several single isolates from the populations at each sampling point. Genetic changes were compared with treatment regimens and changes in phenotypic resistance patterns to determine how resistance evolved in response to antibiotic treatment.\n\nMETHODS\n\nIsolates\n\nM. tuberculosis isolates were obtained from a previous collection of samples from 1 Swedish patient during 9 years (1991–1999) of pulmonary tuberculosis [20]. The high sequence similarity strongly suggests that the patient carried the same single clone during 9 years without reinfection. The samples (populations) were collected at 8 different time points before and during treatment. Each sample was grown on Löwenstein-Jensen slants at 37°C to subsequently isolate up to 10 single colonies. The isolates were analyzed for phenotypic drug susceptibility using the BACTEC 460TB system (Becton and Dickinson). Both populations and individual isolates were kept frozen at −70°C until used in this study.\n\nDNA Extraction\n\nDNA was isolated from 8 population samples and from 7–10 previously isolated colonies from each of the 8 different population samples, in total 77 samples (Figure 1). The population/isolate samples were cultured for 3 to 4 weeks on Löwenstein-Jensen slants at 37°C and DNA was isolated by chloroform-isoamyl alcohol extraction according to a protocol described earlier [21].\n\nFigure 1. Illustration of time points for sampling, antibiotic treatment, and phenotypic resistance. The sampling consisted of 8 time points (S91/222, S91/224, S912/263, S92/001, S92/031, S93/007, S93/021, and S99/293) from 0 to 95 months, as indicated with arrows and vertical dashed lines in the upper part of the figure. The patient was diagnosed with lung tuberculosis at time 0. The time line is drawn to scale only up to month 25. Each antibiotic has a time line where antibiotic (AB) treatment (striped), phenotypic resistance (red), intermediate resistance (orange), and susceptibility (green) from the patient records are indicated.\n\nWhole-Genome Sequencing and Bioinformatics\n\nThe genomic DNA was sequenced with Illumina HiSeq 2000 using 2 × 90 read length with an average of 50× coverage by the BGI sequencing facility (Hongkong, China). Reads were trimmed from adaptor sequences and by quality as listed in Supplementary Table 1. The isolate S91/222-1.4 was sequenced using a polymerase chain reaction (PCR)-free library preparation to obtain higher reference coverage of GC-rich regions. The S91/222-1.4 sequence data was used for de novo assembly (CLC Genomics Workbench v12) and the best matching complete M. tuberculosis genome was identified by BLASTn at the National Center for Biotechnology Information (NCBI) as CCDC5079 (CP002884). Reference assembly of S91/222-1.4 raw reads onto CCDC5079 was then used to identify variations and generate a reference genome to which all other isolates were assembled and sequence variation analyzed [22]. Single nucleotide polymorphisms (SNPs) and structural variations were identified using the respective tools in CLC Genomic Workbench v12 and the Microbial Genomics Plugin using the following criteria: (1) for the population samples a SNP frequency of at least 10% and 5 reads with the same mutation was used as cutoff to validate each mutation in the population; and (2) for the isolated clones a SNP frequency >70% was used as cutoff to validate each mutation. In addition, each validated mutation in a single clone or population sample was visually reconfirmed from the assemblies of WGS data. The Pro-Glu/Pro-Pro-Glu (PE/PPE) gene families were excluded from all analyses due to their repetitive abundance and high frequency of sequence errors reported [23]. All sequences including metadata were deposited at NCBI under BioProject number PRJNA641253.\n\nRESULTS\n\nTo elucidate the dynamics of genetic variation in a M. tuberculosis strain during disease and treatment of an infected patient, from diagnosis of pulmonary tuberculosis until her death 9 years later, we performed WGS of 8 population samples from different time points during infection and 7–10 clones isolated from each of the populations [20]. From the patient records it was clear that the infecting strain developed resistance to different drugs used in the treatment in a stepwise manner (Figure 1). The infecting strain belonged to the Beijing lineage and was genetically very similar to the previously sequenced isolate CCDC5079 (CP002884) [22] differing by only 242 SNPs and small indels and 21 structural variations mainly including the presence/absence of IS6110 elements (Supplementary Table 2). The resulting reference assembly comprised 4.4 mega base pairs and the fraction of reference coverage of each of the subsequent samples was >99%.\n\nTo identify preexisting resistance mutations in the infecting strain, all SNPs and indels (in total 242) that differed between the isolates from the initial sample and the susceptible CCDC5079 strain was subjected to a literature search to identify SNPs in genes previously determined to lead to antibiotic resistance [22]. Two mutations were found in genes previously linked to isoniazid resistance, katG S315T [24] and low-level ethambutol resistance, embB T1082A [25]. These findings are in accordance with the initial susceptibility test showing resistance to isoniazid and an early but varying presence of ethambutol resistance in an otherwise susceptible strain (Figure 1).\n\nTemporal Genetic Changes in the Infecting Population Show Strong Selection for Resistance Mutations in Response to Treatment\n\nThe index isolate was taken when the patient was first diagnosed with tuberculosis in March 1991. Treatment was then initiated with isoniazid, rifampicin, and pyrazinamide. After phenotypic antibiotic susceptibility testing the infecting strain was found to be resistant to isoniazid as could be explained by the katG S315T mutation [24] (Figure 1 and Figure 2). Isoniazid was therefore replaced with ethambutol.\n\nFigure 2. Illustration of the genetic composition and relatedness of the isolated clones at each sampling time point. Antibiotics used at each time point are listed at the top with + indicating treatment. Gray circles represent clonal populations and the area of the circle indicates the fraction of clones that showed identical sequence at each time point. Total number of clones are listed below for each time point. Resistance mutations are indicated by red dots inside the population circles and other mutations by black (nonsynonymous) and gray dots (synonymous) on the connecting branches to indicate when they arose. Only resistance mutations are indicated within the population circles at each time point for clarity. The antibiotic resistance mutations in the population sample at each time point are listed at the bottom of the figure. The first time a mutation was observed is indicated in bold. Striped lines indicate relatedness of clones that did not evolve directly from clones detected at the previous time point. Abbreviation: Fs, frame shift.\n\nThree months after initiation of treatment, the strain was phenotypically resistant against both isoniazid and ethambutol. The ethambutol resistance could be explained by the embB T1082A mutation present already in the initial sample [25]. Although the susceptibility testing showed no phenotypic resistance towards rifampicin, WGS revealed the presence of 3 different rpoB (β-subunit of RNA polymerase) mutations in the population, H526L (standard Escherichia coli nomenclature, M. tuberculosis nomenclature H445L, frequency 10%), D516V (M. tuberculosis nomenclature D435V, frequency 10%), and H526Y (M. tuberculosis nomenclature H445Y, frequency 83%) (Figure 3A and Supplementary Table 3). These mutations are commonly found among clinical rifampicin-resistant M. tuberculosis isolates [26–28]. In contrast to the population sequence, the dominating rpoB mutation in the clones was D516V (9 of 10 clones) and only 1 clone had the H526L mutation (Figure 3A).\n\nFigure 3. Clonal subpopulations of mutations connected to (A) rifampicin, (B) streptomycin, and (C) ethionamide resistance. The frequency (%) of each mutation is shown for both the population sample (P) and among the clonal samples (C). A, rifampicin resistance with mutations within the β-subunit of the bacterial RNA polymerase, rpoB. B, streptomycin resistance with mutations within 2 different genes, the ribosomal S12 protein rpsL and the 16S rRNA (rrs) gene. C, ethionamide resistance with mutations within the monooxygenase gene, ethA.\n\nAfter an additional 2 months (5 months after diagnosis) of treatment with rifampicin, ethambutol, pyrazinamide, streptomycin, and ciprofloxacin, the strain was phenotypically resistant also to rifampicin and the rpoB D516V mutation dominated the population sample and was present in all clones (Figure 2 and Figure 3A). From now on the rpoB D516V mutation was present in all samples and none of the other rpoB mutations were detected again. At this time point the strain was still considered phenotypically susceptible to streptomycin but in the WGS data known streptomycin resistance mutations in rpsL K88R (S12 ribosomal protein) and rrs C517T (16S rRNA) had emerged in the population sample (Figure 2, Figure 3B, and Supplementary Table 3) [29, 30].\n\nEight months after the diagnosis, treatment consisted of ciprofloxacin, amikacin, clofazimine, and ethionamide and the strain was phenotypically resistant to isoniazid, ethambutol, streptomycin, rifampicin, ciprofloxacin, and clarithromycin. Mutations associated with resistance were katG S315T (INH), embB T1082A (ETB), rpoB D516V (RIF), and there were 3 different mutations in genes associated with streptomycin resistance at frequencies of 26%–48% (rpsL K43R and K88R, and rrs C517T) in the population sample (Figure 2, Figure 3B, and Supplementary Table 2) [29, 30]. The variability in streptomycin resistance mutations was maintained at the fifth sampling point (10 months), with rpsL K88R and rrs (C517T) still present in the population sample (Figure 2). Two single clones were found to carry either the rpsL K43R or the rrs C517T mutations while the rest had the rpsL K88R mutation. The strain was now also phenotypically resistant to clofazimine, likely by mutations in the transcriptional repressor (rv0678) of the efflux pump MmpL5 (Figure 1 and Supplementary Table 3) [31].\n\nAfter an additional 10 months (20 months) of treatment with ciprofloxacin, amikacin, clofazimine, and ethionamide, and addition of rifabutin during the last 2 months, the rpsL K43R mutant had taken over the population and was present in all clones. A mutation in ethA (Q206fs), a monooxygenase involved in ethionamide and protionamide resistance, was also present in the population and in all clones (Figure 2 and Figure 3C) [32].\n\nOnly 2 months later (22 months), the spectrum of mutations associated with streptomycin resistance had once again changed and a new mutation in rrs (A514C) combined with a new ethA S251fs mutation dominated the clones and the population sample, except 1 clone that retained the rpsL K43R mutation together with ethA Q206fs (Figure 2 and Figure 3 and Supplementary Table 3) [32].\n\nBetween 22 and 95 months after the initial diagnosis there were no samples saved that could be sequenced. After 29 months of treatments all antibiotics were discontinued and the patient underwent sanatorium treatment for 2 months, after which antibiotic treatment was reinitiated (Figure 1). At 53 months after diagnosis the patient underwent a pneumonectomy of the right lung, which lead to a significant improvement. Antibiotic treatment was continued and no growth of bacilli in sputum samples was detected for a year and therefore all antibiotic treatment was discontinued.\n\nIn April 1999, 8 years after the tuberculosis diagnosis, the patient suffered a relapse with extensive bacterial growth in the left lung and the strain now tested resistant against 9 antibiotics: isoniazid, rifampicin, ethambutol, streptomycin, amikacin, ethionamide, rifabutin, capreomycin, and clarithromycin. All sequenced clones at this time point were related to the strain isolated after 20 months of treatment but now the clones contained between 13 and 14 nonsynonymous mutations (Figure 2 and Supplementary Tables 3 and 4). The katG S315T (INH), rpoB D516V (RIF), rpsL K43R (STR), and ethA Q206fs (ETH) were all present 6 years earlier. A second mutation in embB, G406D, previously associated with ethambutol resistance, was present in all clones [25]. Also, a new rrs A1401G mutation was present in all clones (Figure 2 and Supplementary Table 3), previously detected in clinical isolates resistant to amikacin, kanamycin, and capreomycin [33, 34].\n\nIn total, 50 mutations in 38 different genes were observed among all 77 samples during the infection period (Supplementary Tables 3 and 4). The average number of mutations (SNP, small deletions, and insertions) after 8 years of sampling was 13.5 per clone. The mutational spectrum was heavily dominated by nonsynonymous mutations with an average SNPs ratio of 8.5:1 of nonsynonymous to synonymous SNPs (1.54 mutations per genome and year) and more than a third were resistance mutations (0.63 mutations per genome and year). Mutations previously shown to be involved in antibiotic resistance were also the only mutations dominating the populations or clones at more than 1 time point (Figure 2 and Supplementary Table 3). Predicted resistance mutations also largely correlated with susceptibility test results and appeared in connection with treatment with the corresponding drug [20]. The level of similarity between clones from the same population was high and at the last time point 11 mutations were shared by all 10 clones with an additional 1 to 2 mutations/clone.\n\nPossible Compensatory Mutations and Virulence Mutations Did Not Persist in the Population\n\nIn addition to antibiotic selection, mutations that increase bacterial fitness by compensating for negative effects of other mutations or that increase bacterial virulence may increase in an infecting population over time. Mutations in gyrA R264L, rpoB R143C (M. tuberculosis nomenclature R167C), ribF (rv2786c), pitA (rv0545), ppsC (rv2933), ppsA (rv2931), rv3404c, recN (rv1696), and espK (rv3879) mutations that possibly could lead to compensation of fitness costs or changes in virulence were observed in clones (Supplementary Tables 3 and 4) [35–37]. However, none of these mutations were present at more than 1 time point. In contrast, a set of tandem duplications between IS6110 elements increased in frequency over the course of infection (Table 1 and Figure 4). The size of the duplications ranged from 132 579 bp to 360 499 bp with a minimum common overlapping region of 51 128 bp, including putative virulence-associated genes such as sapM and satS, the RNA polymerase sigma factor sigF, and the toxin-antitoxin system vapC44/vapB44. The duplications were observed sporadically in 1 clone at the first, second, and third time points but increased drastically in frequency at time points 7 and 8 (duplication frequencies of 43% and 90%, respectively). In the last sampled population amplifications with different end points were present, indicating that this is not just an expansion of a single clone but due to individual duplication events. Duplications in this region has been observed previously and implicated in decreased virulence in clinical isolates from the Beijing lineage [38].\n\nTable 1. Analysis of Genomic Duplications in Clones\n\nSampling, mo\tClones With Duplication/Total Clones\tIsolate Name\tDuplicated Region\tLength, Base Pairs\tIS6110 End Points\t\n0\t1/7\t1.2\t3 484 819–3 845 317\t360 499\tYes\t\n3\t1/10\t2.9\t3 484 819–3 708 206\t223 388\tYes\t\n5\t1/7\t3.4\t3 484 819–3 845 317\t360 499\tYes\t\n8\t0/7\t…\t…\t…\t…\t\n10\t0/10\t…\t…\t…\t…\t\n20\t0/9\t…\t…\t…\t…\t\n22\t3/9\t7.2\t3 484 819–3 845 317\t360 499\tYes\t\n\t\t7.5\t3 484 819–3 845 317\t360 499\tYes\t\n\t\t7.8\t3 484 819–3 845 317\t360 499\tYes\t\n95\t9/10\t8.1\t3 657 079–3 789 657\t132 579\tNo\t\n\t\t8.2\t3 544 002–3 708 206\t164 205\tYes\t\n\t\t8.3\t3 484 819–3 708 206\t223 388\tYes\t\n\t\t8.4\t3 544 002–3 845 317\t301 316\tYes\t\n\t\t8.5\t3 484 819–3 845 317\t360 499\tYes\t\n\t\t8.6\t3 544 002–3 845 317\t301 316\tYes\t\n\t\t8.7\t3 484 819–3 845 317\t360 499\tYes\t\n\t\t8.8\t3 544 002–3 708 206\t164 205\tYes\t\n\t\t8.10\t3 484 819–3 845 317\t360 499\tYes\t\n\nFigure 4. Tandem duplications. Clones with tandem duplications are shown including the length and position of the duplicated regions. The smallest common duplicated region is highlighted at the top including the genes within the region. IS6110 elements that serve as duplication end points are indicated with arrows on the dashed line.\n\nDISCUSSION\n\nA hallmark of M. tuberculosis is the ability to form persistent long-term infections that are difficult to treat with antibiotics. The population structure of M. tuberculosis in the infected lung is highly compartmentalized, generating differential exposure of antibiotics that may promote coexistance of different resistant subpopulations in different parts of the lung [11, 12]. The rapid population sweeps observed here for resistance mutations, the small number of other mutations found, and the fact that only mutations associated with antibiotic resistance were found at more than 1 time point in the population indicate antibiotic treatments to be the dominant force of selection. Other WGS studies of longitudinal intrapatient samples of M. tuberculosis isolates have also suggested antibiotic treatment to be the dominating force of selection [16, 18]. In contrast to some other studies, we found very few additional mutations and did not observe any hitchhiking mutations in addition to the resistance mutations [5, 15, 17]. A factor that can explain part of the observed differences between studies is differences in the selective factors, such as treatment regimens, between different patients as well as the compartmentalization of tuberculosis in the lungs, and the difficulty of retrieving representative samples that reflect the genetic variation in populations [11, 12]. In addition, whether genome sequence approaches are based on population samples or single-colony samples can also affect the results. Here, the level of sequence identity between clones from the same population was high and differences between population samples and clones from the same population was mainly observed in SNP frequencies for different genotypic resistant mutations for the same phenotypic susceptibility.\n\nWe never observed a mixture of resistant and susceptible genotypes for the same antibiotic among the clones and only once for the population samples (time point 7, rv0678 possible clofazimine resistance) indicating a strong selection by the treatments. However, multiple resistance mutations to the same drug existed simultaneously and varied over time for rifampicin, ethionamide, and streptomycin resistance. This could be due to longitudinal variability in the sampling of subpopulations of M. tuberculosis recovered from separate cavities of the lung [11, 12], complex genetics of resistance, variable selection by different treatments, or a combination of these factors. The 5 population switches of dominant subclones always matched the treatment regimens with additional resistance mutations mostly originating from the previous dominating clone. A likely explanation is therefore that selection for mutants with low fitness cost and high resistance generated the clonal variance and selective sweeps, as has been seen before for rifampicin and streptomycin resistance mutations [17, 18, 39, 40]. For example, variation in rifampicin resistance levels and degree of fitness cost between the 3 mutations rpoB H526Y, D516V, and H526L has been reported [28, 41–43]. In addition, previous experiments in E. coli and M. tuberculosis showed epistasis of rifampicin resistance mutations in rpoB with streptomycin and isoniazid resistance mutations [13, 14, 43, 44]. Stochastic appearance of resistance mutations to other antibiotics among the existing subpopulations may also contribute to clonal sweeps. For example, the clonal variation of streptomycin resistance at the last 3 sampling points was probably due to evolution of ethionamide and ethambutol resistance in different rpsL/rrs clones and maybe also clofazimine resistance. When the first ethionamide resistance mutation (ethA Q206fs) evolved at 20 months in a clone with a preexisting rpsL K43R mutation, the previously dominating rpsL K88R and rrs (517T) mutations disappeared completely. The rpsL K43R mutation also has no or low fitness cost compared to a drug-susceptible strain and it is one of the most common clinical streptomycin-resistant mutations [30, 39, 45]. The combination of an ethA S251fs mutation in a clone with an rrs C514T mutation dominated at 22 months with a temporary dip in the frequency of rpsL K43R mutations. The last sample was again dominated by the rpsL K43R mutation but this time in combination with an rrs A1401G mutation leading to high amikacin resistance and low-level capreomycin resistance [34].\n\nA general explanation for antibiotic-resistant phenotypes without specific target mutations, which was the case for ciprofloxacin in our study, could be increased expression of efflux pumps [46]. Mutations in pstB (rv0933), rv0678, and rv2326c coding for efflux pumps were observed and upregulation of the PstB efflux pump has been shown to be connected to fluoroquinolone resistance [47]. Given the long period of infection, it is also plausible that differences in susceptibility testing laboratory procedures between different samples affect the reporting of resistance, especially when the minimum inhibitory concentration is close to the clinical breakpoint.\n\nSeveral studies have shown that compensatory mutations can ameliorate fitness costs of resistance, often without loss of resistance [6, 7, 20, 48]. Previously described compensatory mutation in M. tuberculosis are mainly connected with mutations in the rpoA or rpoC genes compensating for rifampicin resistance, but no such mutations were found here [48]. At the later time points, possible compensatory mutations for rifampicin resistance were observed in pitA, ppsA, ppsC, and recN but they were only present at 1 sampling point [36, 37]. After the pneumonectomy, the patient improved in health and there were no detectable bacilli from sputum cultures. All antibiotic treatments were also discontinued but after 16 months without treatment the patient relapsed and the strain now contained additional resistance mutations. This is discouraging because it indicates that the combined resistance mutations did not confer a sufficiently high fitness cost for the patient’s immune system to clear the infection or that the patient was exposed to risk factors that increased the risk of a relapse.\n\nAn alternative explanation for the success of the last clonal population could be that some of the new mutations found in the population at that time caused an increased virulence and associated population expansion. However, all identified mutations instead point towards lowered virulence. The frame shift mutation found in espK, a gene previously described to be involved in virulence, would likely lead to inactivation of EspK and be predicted to lead to decreased virulence [35]. Also, the large tandem duplications within the same region that increased in frequency at the 2 last time points have previously been observed to reduce virulence in a mouse model [38]. Overall, there is no indication that virulence-increasing mutations were selected in the patient over a period of 9 years.\n\nIn conclusion, this patient case illustrates the fast and stepwise evolution of resistance even with the simultaneous use of multiple antibiotics, illustrating a remarkable adaptability of M. tuberculosis in the human lung and the dynamics of different emerging subpopulations during infection. Most importantly, this unique patient material demonstrates the need for rapid diagnostics of both bacterial genotype and phenotype before treatment is initiated. Thus, had it been known that the strain was isoniazid resistant and had reduced susceptibility to ethambutol, it is likely that the initial treatment regime could have been adjusted to provide a better outcome.\n\nSupplementary Data\n\nSupplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.\n\njiaa625_suppl_Supplementary_Table_S1 Click here for additional data file.\n\njiaa625_suppl_Supplementary_Table_S2 Click here for additional data file.\n\njiaa625_suppl_Supplementary_Table_S3 Click here for additional data file.\n\njiaa625_suppl_Supplementary_Table_S4 Click here for additional data file.\n\nNotes\n\nFinancial support. This work was supported by the Vetenskapsrådet (grant numbers 2017-01527 to D. I. A. and K2013-99X-22208-01-5 to L. S.).\n\nPotential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n\n1. Sotgiu G , CentisR, D’ambrosioL, MiglioriGB. Tuberculosis treatment and drug regimens. Cold Spring Harb Perspect Med 2015; 5 :a017822.25573773\n2. Gandhi NR , NunnP, DhedaK, et al Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis. Lancet 2010; 375 :1830–43.20488523\n3. Eldholm V , BallouxF. Antimicrobial resistance in Mycobacterium tuberculosis: the odd one out. Trends Microbiol 2016; 24 :637–48.27068531\n4. Gygli SM , BorrellS, TraunerA, GagneuxS. Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives. 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Sirgel FA , WarrenRM, BöttgerEC, KlopperM, VictorTC, van HeldenPD. The rationale for using rifabutin in the treatment of MDR and XDR tuberculosis outbreaks. PLoS One 2013; 8 :e59414.23527189\n28. Berrada ZL , LinSY, RodwellTC, et al Rifabutin and rifampin resistance levels and associated rpoB mutations in clinical isolates of Mycobacterium tuberculosis complex. Diagn Microbiol Infect Dis 2016; 85 :177–81.27036978\n29. Phelan J , CollF, McNerneyR, et al Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance. BMC Med 2016; 14 :31.27005572\n30. Sun H , ZhangC, XiangL, et al Characterization of mutations in streptomycin-resistant Mycobacterium tuberculosis isolates in Sichuan, China and the association between Beijing-lineage and dual-mutation in gidB. Tuberculosis (Edinb) 2016; 96 :102–6.26786661\n31. Hartkoorn RC , UplekarS, ColeST. Cross-resistance between clofazimine and bedaquiline through upregulation of MmpL5 in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2014; 58 :2979–81.24590481\n32. Morlock GP , MetchockB, SikesD, CrawfordJT, CookseyRC. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 2003; 47 :3799–805.14638486\n33. Maus CE , PlikaytisBB, ShinnickTM. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2005; 49 :3192–7.16048924\n34. Engström A , PerskvistN, WerngrenJ, HoffnerSE, JuréenP. Comparison of clinical isolates and in vitro selected mutants reveals that tlyA is not a sensitive genetic marker for capreomycin resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 2011; 66 :1247–54.21427106\n35. Forrellad MA , KleppLI, GioffréA, et al Virulence factors of the Mycobacterium tuberculosis complex. Virulence 2013; 4 :3–66.23076359\n36. Bisson GP , MehaffyC, BroecklingC, et al Upregulation of the phthiocerol dimycocerosate biosynthetic pathway by rifampin-resistant, rpoB mutant Mycobacterium tuberculosis. J Bacteriol 2012; 194 :6441–52.23002228\n37. Moura de Sousa J , SousaA, BourgardC, GordoI. Potential for adaptation overrides cost of resistance. Future Microbiol 2015; 10 :1415–31.26343510\n38. Domenech P , RogA, MooljiJU, et al Origins of a 350-kilobase genomic duplication in Mycobacterium tuberculosis and its impact on virulence. Infect Immun 2014; 82 :2902–12.24778110\n39. Spies FS , von GrollA, RibeiroAW, et al Biological cost in Mycobacterium tuberculosis with mutations in the rpsL, rrs, rpoB, and katG genes. Tuberculosis (Edinb) 2013; 93 :150–4.23276692\n40. Springer B , KidanYG, PrammanananT, EllrottK, BöttgerEC, SanderP. Mechanisms of streptomycin resistance: selection of mutations in the 16S rRNA gene conferring resistance. Antimicrob Agents Chemother 2001; 45 :2877–84.11557484\n41. Cavusoglu C , Karaca-DericiY, BilgicA. In-vitro activity of rifabutin against rifampicin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations. Clin Microbiol Infect 2004; 10 :662–5.15214882\n42. Brandis G , PietschF, AlemayehuR, HughesD. Comprehensive phenotypic characterization of rifampicin resistance mutations in Salmonella provides insight into the evolution of resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 2015; 70 :680–5.25362573\n43. Durão P , TrindadeS, SousaA, GordoI. Multiple resistance at no cost: rifampicin and streptomycin a dangerous liaison in the spread of antibiotic resistance. Mol Biol Evol 2015; 32 :2675–80.26130082\n44. Li Q , JiaoW, YinQ, et al Positive epistasis of major low-cost drug resistance mutations rpoB 531-TTG and katG 315-ACC depends on the phylogenetic background of Mycobacterium tuberculosis strains. Int J Antimicrob Agents 2017; 49 :757–62.28456705\n45. Jagielski T , IgnatowskaH, BakułaZ, et al Screening for streptomycin resistance-conferring mutations in Mycobacterium tuberculosis clinical isolates from Poland. PLoS One 2014; 9 :e100078.24937123\n46. Gupta AK , KatochVM, ChauhanDS, et al Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microb Drug Resist 2010; 16 :21–8.20001742\n47. Lu J , LiuM, WangY, PangY, ZhaoZ. Mechanisms of fluoroquinolone monoresistance in Mycobacterium tuberculosis. FEMS Microbiol Lett 2014; 353 :40–8.24822277\n48. Comas I , BorrellS, RoetzerA, et al Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nat Genet 2011; 44 :106–10.22179134\n\n",
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"title": "Dynamics of extensive drug resistance evolution of Mycobacterium tuberculosis in a single patient during 9 years of disease and treatment.",
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"abstract": "Postherpetic neuralgia (PHN) is common in the United States. Current treatment options for PHN are fairly limited. Spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) are considered mostly experimental and still rarely performed in patients with PHN.\n\n\n\nTwo case reports and a review of the literature.\n\n\n\nTertiary academic medical center.\n\n\n\n1) Pubmed, Ovid, and EBMR databases were searched for all reports that had the following key words: postherpetic neuralgia, spinal cord stimulation, and peripheral nerve stimulation. 2) A retrospective chart review was performed for all the patients that underwent PNS for PHN at Mayo Clinic Florida (MCF).\n\n\n\nThere were 20 original reports that described 309 patients with PHN who were treated with SCS. Sixteen reports had a permanent implantation of SCS, with a total of 255 patients, out of which 120 had long-term pain relief. There were six reports of subcutaneous PNS for PHN (in a thoracic area). Four reports provided data on success rates where all five patients received complete pain relief. In our practice, two patients underwent subcutaneous PNS for PHN (in the thoracic area) with good pain relief for 10 months and 2.5 years, respectively.\n\n\n\nBased on our review of the literature and the two cases at MCF, subcutaneous PNS seems to be a promising intervention in the treatment of PHN.",
"affiliations": "Departments of Pain Medicine.;Departments of Pain Medicine.;Anesthesiology, Mayo Clinic, Florida, USA.;Departments of Pain Medicine.",
"authors": "Kurklinsky|Svetlana|S|;Palmer|Scott C|SC|;Arroliga|Mack J|MJ|;Ghazi|Salim M|SM|",
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"mesh_terms": "D004599:Electric Stimulation Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D051474:Neuralgia, Postherpetic",
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"title": "Neuromodulation in Postherpetic Neuralgia: Case Reports and Review of the Literature.",
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"abstract": "BACKGROUND\nProsthetic joint infections are severe complications of joint implants. Further complications arise when polymicrobial and/or multidrug-resistant microorganisms are involved. Currently, there are limited data on the management of these infections and on the tolerability of long-term treatment with daptomycin, ceftazidime and colistin.\n\n\nMETHODS\nA 55-year-old Caucasian woman who had a right hip prosthesis removed 1 year prior because of infection was admitted for prosthesis reimplantation. On admission at our hospital, anamnesis regarding etiology and management of prosthesis infection was not available. On clinical, laboratory findings and imaging studies infection was not suspected. A hip prosthesis was reimplanted. At surgery, histopathological and microbiological investigations were not taken. Three weeks after reimplantation, surgical site infection due to Enterobacter cloacae was diagnosed and oral ciprofloxacin was prescribed. Four days later, a periprosthesis fluid collection was evidenced and a percutaneous needle aspirate grew Staphylococcus epidermidis and S. haemolyticus. Enterobacter genome was also detected from the same sample. Teicoplanin and meropenem were added to ciprofloxacin without clinical improvement. Moreover, acetabular cup dislocation was documented. She underwent prosthesis explantation, debridement, and positioning of an antimicrobial mixed spacer. From the intraoperatory cultures S. epidermidis and Acinetobacter baumannii were grown. Daptomycin, ceftazidime, colistin and rifampin were administered. Four days later, rifampin was stopped due to a suspected liver toxicity. While undergoing therapy she presented recurrent episodes of wound dehiscence and on the 22nd week of treatment a further surgical debridement was performed, upon which the spacer was removed. At this time, intraoperative cultures resulted negative. Three months later, after a total of 8 months, antimicrobials were interrupted. Subsequently, a femoral transcondylar traction was positioned, and 3 weeks later a new prosthesis was reimplanted. At over 1 year after reimplantation she is well.\n\n\nCONCLUSIONS\nOur findings suggest that microbiologic investigations are mandatory even when prosthetic joint infection is not suspected. Molecular methods for identification of microorganisms can be used in addition to conventional cultures especially when patients are under antibiotic treatment. Daptomycin, ceftazidime and colistin can be administered for several months without side effects. Guidelines specifically addressing the diagnosis and the management of polymicrobial, multidrug-resistant prosthetic joint infections need to be developed.",
"affiliations": "Infectious Disease Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06100 Perugia, Italy. mariabruna.pasticci@unipg.it.",
"authors": "Pasticci|Maria Bruna|MB|;Di Filippo|Paolo|P|;Pasqualini|Leonella|L|;Mencacci|Antonella|A|;Pallotto|Carlo|C|;Malincarne|Lisa|L|;Baldelli|Franco|F|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D017576:Daptomycin; D003091:Colistin",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-1862492370310.1186/1752-1947-8-186Case ReportTolerability and efficacy of long-term treatment with daptomycin, ceftazidime and colistin in a patient with a polymicrobial, multidrug-resistant prosthetic joint reinfection: a case report Pasticci Maria Bruna 1mariabruna.pasticci@unipg.itDi Filippo Paolo 2paolodifilippo@virgilio.itPasqualini Leonella 3leonella.pasqualini@unipg.itMencacci Antonella 4antonella.mencacci@unipg.itPallotto Carlo 1carlop85@hotmail.itMalincarne Lisa 1lisa.malincarne@unipg.itBaldelli Franco 1franco.baldelli@unipg.it1 Infectious Disease Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06100 Perugia, Italy2 Orthopedic Department, Ospedale Santa Maria, Terni, Italy3 Internal Medicine Section, Department of Medical Sciences, University of Perugia, Perugia, Italy4 Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy2014 12 6 2014 8 186 186 16 9 2013 1 4 2014 Copyright © 2014 Pasticci et al.; licensee BioMed Central Ltd.2014Pasticci et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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.Introduction\nProsthetic joint infections are severe complications of joint implants. Further complications arise when polymicrobial and/or multidrug-resistant microorganisms are involved. Currently, there are limited data on the management of these infections and on the tolerability of long-term treatment with daptomycin, ceftazidime and colistin.\n\nCase presentation\nA 55-year-old Caucasian woman who had a right hip prosthesis removed 1 year prior because of infection was admitted for prosthesis reimplantation. On admission at our hospital, anamnesis regarding etiology and management of prosthesis infection was not available. On clinical, laboratory findings and imaging studies infection was not suspected. A hip prosthesis was reimplanted. At surgery, histopathological and microbiological investigations were not taken. Three weeks after reimplantation, surgical site infection due to Enterobacter cloacae was diagnosed and oral ciprofloxacin was prescribed. Four days later, a periprosthesis fluid collection was evidenced and a percutaneous needle aspirate grew Staphylococcus epidermidis and S. haemolyticus. Enterobacter genome was also detected from the same sample. Teicoplanin and meropenem were added to ciprofloxacin without clinical improvement. Moreover, acetabular cup dislocation was documented. She underwent prosthesis explantation, debridement, and positioning of an antimicrobial mixed spacer. From the intraoperatory cultures S. epidermidis and Acinetobacter baumannii were grown. Daptomycin, ceftazidime, colistin and rifampin were administered. Four days later, rifampin was stopped due to a suspected liver toxicity. While undergoing therapy she presented recurrent episodes of wound dehiscence and on the 22nd week of treatment a further surgical debridement was performed, upon which the spacer was removed. At this time, intraoperative cultures resulted negative. Three months later, after a total of 8 months, antimicrobials were interrupted. Subsequently, a femoral transcondylar traction was positioned, and 3 weeks later a new prosthesis was reimplanted. At over 1 year after reimplantation she is well.\n\nConclusions\nOur findings suggest that microbiologic investigations are mandatory even when prosthetic joint infection is not suspected. Molecular methods for identification of microorganisms can be used in addition to conventional cultures especially when patients are under antibiotic treatment. Daptomycin, ceftazidime and colistin can be administered for several months without side effects. Guidelines specifically addressing the diagnosis and the management of polymicrobial, multidrug-resistant prosthetic joint infections need to be developed.\n==== Body\nIntroduction\nProsthetic joint infection (PJI) is one of the most severe complications of joint replacement [1]. Although this is a rare event [1], the overall burden is high as a consequence of an increased number of implanted prosthesis in the aging population, an increased number of patients with risk factors for infection and improved methods to detect these infections. PJIs are associated with high morbidity, a need of complex treatment, prolonged hospitalization and substantial healthcare costs. Moreover, PJIs can lead to impaired functioning or even permanent disability [1,2]. Further complications arise when polymicrobial, multi-drug-resistant (MDR) [3,4] or difficult to treat microorganisms are involved [5-10].\n\nHere, a complicated case of PJ reinfection is reported.\n\nCase presentation\nA 55-year-old Caucasian woman was admitted for a right hip prosthesis reimplantation. The first arthroplasty was performed 3 years earlier due to hip osteoarthritis. However, after 2 years her prosthesis had been explanted and a spacer positioned due to infection. After 1 month the spacer had also been removed. No further data on microbiological results and medical treatment were available at the time of her admission at our hospital. On admission, she was complaining of pain and was not taking antibiotic therapy. Her erythrocyte sedimentation rate (ESR) was 35mm 1°hour, her white blood cell count and differential were normal, C-reactive protein (C-RP) was not available and a leukocyte scan resulted normal. She underwent hip reimplantation. At surgery, histopathological and microbiological investigations were not taken. After arthroplasty, she was discharged. Two weeks later she was seen as an out-patient complaining of hip pain, motion impairment and dehiscence of the wound. Enterobacter cloacae was grown from the wound exudate. The isolate was an extended spectrum β-lactamase producer, resistant to gentamicin, and susceptible to ciprofloxacin, imipenem, and colistin, according to Clinical and Laboratory Standards Institute (CLSI) breakpoints [11]. She was started on a treatment with oral ciprofloxacin 500mg twice per day. Four days later, ultrasound evidenced periprosthesis fluid collection. Staphylococcus epidermidis and S. haemolyticus were cultured from the needle aspiration. Both coagulase-negative staphylococci (CoNS) isolates resulted oxacillin and ciprofloxacin resistant, teicoplanin susceptible [11]. The same sample was also examined with the commercial real-time polymerase chain reaction-based system, SeptiFast (Roche Molecular Diagnostics, Mannheim, Germany) which detected E. cloacae/aerogenes and CoNS genomes. At this point, the patient was readmitted. Teicoplanin intravenous 400mg per day and meropenem intravenous 2g three times per day (patient’s weight was 68kg) were added to ciprofloxacin without clinical improvement. After 2 weeks, E. cloacae with the same susceptibility pattern of the previous isolate and Acinetobacter baumannii were grown from the aspirated synovial fluid of her hip. A. baumannii isolate resistant to aztreonam, cefepime, cefotaxime, ciprofloxacin, imipenem, fosfomycin, gentamicin, and trimethoprim/sulfamethoxazole, but susceptible to ceftazidime and colistin [11] was obtained. Tigecycline minimal inhibitory concentration was 1.5mg/L, however, no breakpoints were available for this antimicrobial agent against A. baumannii, according to CLSI [11]. At this point, a standard radiograph evidenced acetabular cup dislocation, therefore her prosthesis was removed. During surgery, extensive debridement was performed and a spacer with vancomycin and gentamicin was inserted. From the periprosthesis tissue samples, and her prosthesis, S. epidermidis and A. baumannii were identified while from the synovial fluid only S. epidermidis was isolated. Susceptibility patterns of A. baumannii isolates did not differ. The susceptibility pattern of the two latter S. epidermidis isolates was different from that of the previous one in respect to erythromycin, clindamycin, and trimethoprim/sulfamethoxazole. Ceftazidime was added to the pre-existing therapy. When in vitro antimicrobial susceptibility [11] with synergism results (Figure 1) [12,13] were made available, therapy was modified as follows: daptomycin intravenous 500mg per day, ceftazidime intravenous 2g three times per day, colistin intravenous 3 million units three times per day, and rifampin 600mg daily administered orally. Four days later, rifampin was stopped due to a suspected liver toxicity. Overall, her condition improved despite recurrent episodes of wound dehiscence and purulence. After almost 12 weeks of antimicrobial treatment, she was accepted into a protected residence where she continued to undergo treatment of intravenous antimicrobial therapy with daptomycin 500mg per day, ceftazidime 2g three times per day, and colistin 3 million units three times per day. One month later, a computed tomography (CT) scan of her hip showed liquid around the spacer and femur inflammatory reaction (Figure 2). Two weeks later, another dehiscence of the wound manifested. She was readmitted for an ulterior debridement and this time the spacer was also removed. Prior to surgery antimicrobial therapy was not interrupted. Intraoperative microbiological investigations resulted negative including the molecular SeptiFast test. After surgery she returned to the protected residence and continued the same antimicrobial therapy. Three weeks later, colistin was reduced from 3 to 2 million units intravenous per day every 8 hours. After a total of 8 months, all antimicrobials were stopped. During the entire period antimicrobial therapy was administered, she was clinically monitored and, every 10 days, ESR, C-RP, blood count, creatine phosphokinase, liver and kidney function tests and electrolytes were obtained. No side effects were observed during treatment. When antimicrobials were discontinued, a further CT of her hip evidenced dislocation of her femur and inflammatory tissue surrounding her femur and the acetabular cavity. During the following 3-month period, she did not manifest clinical evidence of infection, and her ESR and C-RP were normal; then she was readmitted to another hospital to be reimplanted. A femoral transcondylar traction was first positioned for over 3 weeks in order to extend her muscles, thereafter a third prosthesis was implanted. At surgery, there was no evidence of purulence; however, there was necrotic tissue which underwent debridement. After several samples were collected for microbiologic investigations, she was administered daptomycin intravenous 500mg per day, ceftazidime intravenous 6g per day, and colistin intravenous 2 million units three times per day until microbiological results, including the SeptiFast test, were reported negative. For more than a year since her third prosthesis was reimplanted, she has been asymptomatic and has regained motility.\n\nFigure 1 Acinetobacter baumannii: E-test, interaction between colistin and rifampin. Fractional inhibitory concentration=1.37 [13].\n\nFigure 2 Computed tomography. a) Coronal and b) axial images showing fluid around the spacer, femoral inflammation, and spacer dislocation.\n\nDiscussion\nThere are several guidelines on the diagnosis and the management of PJIs; however, polymicrobial, MDR and difficult to treat PJIs [5,6] have not been thoroughly addressed.\n\nThis article reports a polymicrobial, MDR prosthesis reinfection successfully treated with a two-stage long interval reimplant and prolonged antimicrobial therapy.\n\nIn our case, E. cloacae, A. baumannii and CoNS were the more probable etiologies of the infection. In fact, all the microorganisms, even in different combinations and at different times, were identified from multiple intraoperative tissues, prosthesis, and periprosthesis and synovial fluid aspirates [14-16]. It is impossible to state if any of the isolated microorganisms had already been present in a nonreplicating phase in the involved articulation at the time of the first reimplantation at our hospital. Nonperforming intraoperative histopathological and microbiological examinations can lead to missed cases of prosthesis infections [2,5,14-16]. Improper sample collection, small colony variants [7,8], antimicrobial therapy before or during surgery and a lack of sonication [17-19] can also hinder diagnosis and etiology of PJIs [1,2,5,13-20]. Small colony variants as well can lead to problems in microorganism identification and antimicrobial susceptibility results [7,8]. However, in our case, it was not possible to verify if the observed differences for CoNS in respect to susceptibility and identification results were due to small colony variants.\n\nThe SeptiFast test has been commercialized for the diagnosis of sepsis from peripheral blood samples and identifies 25 different common pathogens [21]. This test has been suggested to have a potentiality in detecting pathogens also from specimens other than blood, like sonicated fluids from removed prosthesis and synovial fluids [19,22]. Its sensitivity was better than that of culture in patients under antibiotic treatment [22]. In our case Enterobacter cloacae/aerogenes and CoNS genomes were detected with the SeptiFast test in the aspirated periprosthetic fluid, and contemporary cultures grew S. epidermidis and S. haemolyticus. At that time, the patient had been diagnosed surgical site infection and was on oral ciprofloxacin, active in vitro against E. cloacae but not against CoNS. The clinical significance of deoxyribonucleic acid (DNA) in the blood of septic patients in the absence of microorganism growth is still not optimally defined [21] and there is limited data on other biological samples. However, in our case, the fact that, 8 days later, E. cloacae was isolated from the aspirated synovial fluid points to the clinical relevance of the molecular results. The absence of bacterial DNA and viable microorganisms in intraoperative samples at the time the prosthesis was implanted for the third time was used to further support the absence of residual infection. Culture has the ability to identify microorganisms not included in the SeptiFast panel and to allow susceptibility testing. Thus, it is reasonable to use a molecular test in adjunct to culture in patients with PJIs under antibiotic therapy.\n\nRegarding the most effective surgical strategy for PJIs and the best time of prosthesis reimplantation, the decision depends on the operating orthopedic surgeon, medical specialists, and the patient [16]. Concerning the use of spacers, some researchers recommend avoiding cement spacers when infections are due to MDR or difficult to treat microorganisms such as quinolone-resistant and rifampin-resistant staphylococci, quinolone-resistant Gram-negative microorganisms, small colony variants, or fungi [5-8,16,20]. However, other researchers suggest avoiding external fixations in the presence of bone infection, but instead perform debridement repeatedly and change spacers as necessary. Furthermore, antimicrobial impregnated spacers, either premixed or prepared by the surgeons, can cause systemic toxicity [16]. The optimal timing for prosthesis reimplantation is another issue lacking controlled randomized studies to support a specific recommendation [16]. In our patient, initially, a cement spacer was positioned, then, it was removed and for a 3-month interval our patient was left without a spacer, continuing intravenous antimicrobial therapy. Then, after a long interval without antimicrobials, clinical signs of infection and normal ESR and C-RP results, she was readmitted for reimplantation. Overall, in our patient there was a delay of 1 year between prosthesis explant and reimplantation, due to the fact that: 1) clinically, the infection was not fully controlled until the spacer was left in place, 2) the patient had undergone hip prosthesis surgery twice and was at high risk for further infective complications.\n\nIn our case, recovery from infection was obtained with surgical therapy and a combination of antimicrobial treatment with daptomycin, ceftazidime, and colistin that were finally efficacious and well tolerated. It is possible that initial antibiotic therapy with teicoplanin, ceftazidime and ciprofloxacin was not completely effective due to biofilm infection, suboptimal dosing of teicoplanin, and resulting CoNS ciprofloxacin resistance.\n\nConclusions\nOur findings suggest that microbiologic investigations are mandatory even when PJI is not suspected on clinical and laboratory findings and imaging studies. Molecular methods for identification of microorganisms can be used in addition to conventional cultures in patients with PJIs especially when they are under antibiotic treatment. Daptomycin, ceftazidime and colistin can be administered for several months without side effects. Guidelines specifically addressing the diagnosis and the management of polymicrobial, MDR PJIs need to be developed.\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\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nMBP enrolled the patient, acquired, analyzed and interpreted the patient’s data and was involve in drafting the manuscript; PDF reimplanted the joint prosthesis, reviewed the manuscript for important intellectual content; LP acquired, analyzed, interpreted the patient’s data and reviewed the manuscript for important intellectual content; AM was involved with microbiological investigations, acquired, analyzed, interpreted the patient’s data and reviewed the manuscript for important intellectual content; CP was involved in acquiring the patient’s data and in drafting the manuscript; LM was involved in acquiring the patient’s data and drafting the manuscript; FB reviewed the manuscript and gave the final approval of the version to be published. All authors read and approved the final manuscript.\n\nAcknowledgments\nWe would like to thank the patient for her consent to report the case and accompanying images.\n==== Refs\nZimmerli W Trampuz A Ochsner PE Prosthetic-joint infections N Engl J Med 2004 351 16 1645 1654 15483283 \nCorvec S Portillo ME Pasticci MB Borens O Trampuz A Epidemiology and new developments in the diagnosis of prosthetic joint infection Int J Artif Organs 2012 35 10 923 934 23138706 \nMartinez-Pastor JC Vilchez F Pitart C Sierra JM Soriano A Antibiotic resistance in orthopaedic surgery: acute knee prosthetic joint infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae Eur J Clin Microbiol Infect Dis 2010 29 1039 1041 20473541 \nMoran E Masters S Berendt AR McLardy-Smith P Byren I Atkins BL Guiding empirical antibiotic therapy in orthopaedics: the microbiology of prosthetic joint infection managed by debridement, irrigation and prosthesis retention J Infect 2007 55 1 7 17343916 \nBorens O Nussbaumer F Baalbaki R Trampuz A Update on implant related infections in orthopaedic surgery. Diagnosis and treatment Revue Medicale Suisse 2009 5 230 2563 2568 20085205 \nZimmerli W Widmer AF Blatter M Frei R Ochsner PE Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group JAMA 1998 279 1537 1541 9605897 \nProctor RA van LP Kristjansson M Maslow JN Arbeit RD Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus Clin Infect Dis 1995 20 95 102 7727677 \nSendi P Frei R Maurer TB Trampuz A Zimmerli W Graber P Escherichia coli variants in periprosthetic joint infection: diagnostic challenges with sessile bacteria and sonication J Clin Microbiol 2010 48 1720 1725 20335421 \nDel Pozo JL Patel R Clinical practice. Infection associated with prosthetic joints N Engl J Med 2009 361 787 794 19692690 \nTrebse R Pisot V Trampuz A Treatment of infected retained implants J Bone Joint Surg (Br) 2005 87 249 256 15736752 \nClinical and Laboratory Standards Institute Performance Standards for Antimicrobial Susceptibility Testing. Ninetheenth Informational Supplement, M100-S19. 29, 3 2009 PA: Wayne \nBassetti M Repetto E Righi E Boni S Diverio M Molinari MP Mussap M Artioli S Ansaldi F Durando P Orengo G Bobbio Pallavicini F Viscoli C Colistin and rifampicin in the treatment of multidrug-resistant Acinetobacter baumannii infections J Antimicrob Chemother 2008 61 417 420 18174197 \nFarina C Russello G Chinello P Pasticci MB Raglio A Ravasio V Rizzi M Scarparo C Vailati F Suter F Italian Infective Endocarditis Study Group (SEI): In vitro activity effects of twelve antibiotics alone and in association against twenty-seven Enterococcus faecalis strains isolated from Italian patients with infective endocarditis: high in vitro synergistic effect of the association ceftriaxone-fosfomycin Chemotherapy 2011 57 5 426 433 22122863 \nLeone S Borre S Monforte A Mordente G Petrosillo N Signore A Venditti M Viale P Nicastri E Lauria FN Carosi G Moroni M Ippolito G GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi), Working Group on Prosthetic Joint Infections: Consensus document on controversial issues in the diagnosis and treatment of prosthetic joint infections Int J Infect Dis 2010 14 Suppl 67 77 \nSociete de Pathologie Infectieuse de Langue Francaise Recommendations for bone and joint prosthetic device infections in clinical practice (prosthesis, implants, osteosynthesis) Med Mal Infect 2010 40 185 211 20303685 \nOsmon DR Berbari EF Berendt AR Zimmerli W Steckelberg JM Rao N Hanssen A Wilson WR Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Disease Society of America Clin Infect Dis 2013 56 1 25 23230301 \nTrampuz A Piper KE Jacobson MJ Hanssen AD Unni KK Osmon DR Mandrekar JN Cockerill FR Steckelberg JM Grenleaf JF Patel RP Sonication of removed hip and knee prosthesis for diagnosis of infection N Engl J Med 2007 357 7 654 663 17699815 \nNelson CL McLaren AC McLaren SG Johnson JW Smeltzer MS Is aseptic loosening truly aseptic? Clin Orthop Relat Res 2005 437 25 30 16056022 \nAchermann Y Vogt M Leunig M Wust J Trampuz A Improved diagnosis of periprosthetic joint infection by multiplex PCR of sonication fluid from removed implants J Clin Microbiol 2010 48 4 1208 1214 20164283 \nGiulieri SG Graber P Ochsner PE Zimmerli W Management of infection associated with total hip arthroplasty according to a treatment algorithm Infection 2004 32 222 228 15293078 \nChang S-S W-h H Liu T-S Lee S-H Wang C-H Chou H-C Yeo Y-H Tseng C-P Lee C-C Multiplex PCR system for rapid detection of pathogens in patients with presumed sepsis – a systemic review and meta-analysis PloS One 2013 8 e62323 23734173 \nMencacci A Leli C Cardaccia A Montagna P Moretti A Bietolini C Meucci M Perito S Cenci E Bistoni F Comparison of conventional culture with SeptiFast real-time PCR for microbial pathogen detection in clinical specimens other than blood J Med Microbiol 2011 60 1774 1778 21835970\n\n",
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"mesh_terms": "D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D060085:Coinfection; D003091:Colistin; D017576:Daptomycin; D024901:Drug Resistance, Multiple, Bacterial; D004359:Drug Therapy, Combination; D016972:Enterobacter cloacae; D004756:Enterobacteriaceae Infections; D005260:Female; D006622:Hip Prosthesis; D006801:Humans; D008875:Middle Aged; D016459:Prosthesis-Related Infections; D012008:Recurrence; D012086:Reoperation; D013203:Staphylococcal Infections; D013212:Staphylococcus epidermidis; D041162:Staphylococcus haemolyticus; D016896:Treatment Outcome",
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"title": "Tolerability and efficacy of long-term treatment with daptomycin, ceftazidime and colistin in a patient with a polymicrobial, multidrug-resistant prosthetic joint reinfection: a case report.",
"title_normalized": "tolerability and efficacy of long term treatment with daptomycin ceftazidime and colistin in a patient with a polymicrobial multidrug resistant prosthetic joint reinfection a case report"
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"abstract": "BACKGROUND\nWarm-antibody AIHA is known to complicate solid organ (SOT) and HSCT, the disease maybe refractory to standard therapy. Immunosuppressive therapies as well as IVIG, and rituximab have been the main stay of treatment. Over the past decade, B-lymphocyte targeted, anti-CD-20 antibody has been recognized in the treatment of autoimmune diseases and utilized in AIHA. Bortezomib, a proteasome inhibitor that causes apoptosis of plasma cells, is an appealing targeted therapy in secondary AIHA and has demonstrated efficacy in HSCT patients. From our experience, we advocate for early targeted therapy that combines B cell with plasma cell depletion.\n\n\nMETHODS\nWe describe a 4-year-old-girl with stage III neuroblastoma, complicated with intestinal necrosis needing multivisceral transplant developed warm AIHA 1-year after transplantation, and following an adenovirus infection. She received immunoglobulin therapy, rituximab, sirolimus, plasmapheresis, and long-term prednisolone with no sustained benefit while developing spinal fractures related to the latter therapy. She received bortezomib for intractable AIHA in combination with rituximab with no appreciable adverse effects. Three years later the child remains in remission with normal reticulocyte and recovered B cells. In the interim, she required chelation therapy for iron overload related to blood transfusion requirement during the treatment of AIHA.\n\n\nCONCLUSIONS\nWe propose early targeted anti-plasma cell therapy with steroid burst, IVIG, rituximab, and possible plasmapheresis may reduce morbidity in secondary refractory w-AIHA.",
"affiliations": "MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.;National Institute of Health, Bethesda, MD, USA.;MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.;MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.;MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.;MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.;MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.;MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.;MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.;MedStar Georgetown University Hospital, Transplant Institute, Washington, DC, USA.",
"authors": "Ghobrial|Shahira|S|https://orcid.org/0000-0003-2168-3878;Gonzalez|Corina Elena|CE|https://orcid.org/0000-0003-0169-9805;Kaufman|Stuart|S|https://orcid.org/0000-0002-5308-4565;Yazigi|Nada|N|;Matsumoto|Cal|C|;Fishbein|Thomas|T|;Hawksworth|Jason|J|;Ekong|Udeme D|UD|;Kroemer|Alexander|A|;Khan|Khalid|K|",
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"doi": "10.1111/petr.14045",
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"journal": "Pediatric transplantation",
"keywords": "anti-plasma cells; bortezomib; child; multivisceral transplant; refractory autoimmune hemolytic anemia",
"medline_ta": "Pediatr Transplant",
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"pmid": "34092010",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Anti-plasma cell treatment in refractory autoimmune hemolytic anemia in a child with multivisceral transplant.",
"title_normalized": "anti plasma cell treatment in refractory autoimmune hemolytic anemia in a child with multivisceral transplant"
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"abstract": "A 49-year-old male HIV positive patient on treatment failure presented with complaints of fever and dysphagia of three weeks duration and later on developed cervical lymphadenopathy along with severe vomiting and abdominal pain. Liver function tests were found to be worsening with severe drop in CD4 counts. An extensive workup for pyrexia was done. FNAC and biopsy of lymph node showed features suggestive of granulomatous lymphadenitis. CBNAAT of the lymph node aspirate was negative for MTB. Blood culture and lymph node cultures were negative for Mycobacterium Avium Complex (MAC). MAC was however, finally detected and reported positive on Fluorescence in Situ Hybridization (FISH) of the cervical lymph node aspirate. Prompt treatment for MAC was initiated with Ethambutol 800 mg OD and Azithromycin 500 mg OD following which fever spikes subsided and lymph node resolved. The Patient's condition gradually improved and was discharged shortly with a good recovery on subsequent follow ups. Fever is one of the common symptoms in patients with MAC infection. Some other clinical manifestations include weight loss, hepatosplenomegaly and intra-abdominal lymphadenopathy. Diagnostic evaluation should be aggressive. As there is a high risk for MAC infection in advanced HIV cases with poor HAART compliance, FISH can be a valuable and effective diagnostic tool in early detection and treatment of MAC.",
"affiliations": "Department of Internal Medicine, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.;Department of Community Medicine, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.;Department of Internal Medicine, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.;Department of Microbiology, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.;Department of Microbiology, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.;ID-FISH Technology Inc., Palo Alto, CA, USA.",
"authors": "Prabhu|Vikas|V|;Coelho|Steffi|S|;Achappa|Basavaprabhu|B|;Baliga|Shrikala|S|;Sharon|Leesha|L|;Shah|Jyotsna|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jctube.2020.100188",
"fulltext": "\n==== Front\nJ Clin Tuberc Other Mycobact Dis\nJ Clin Tuberc Other Mycobact Dis\nJournal of Clinical Tuberculosis and Other Mycobacterial Diseases\n2405-5794 Elsevier \n\nS2405-5794(20)30052-8\n10.1016/j.jctube.2020.100188\n100188\nArticle\nRole of fluorescence in situ hybridization in detecting mycobacterium avium complex presenting as fever in treatment failure HIV\nPrabhu Vikas vikas.vittal1@learner.manipal.edua⁎ Coelho Steffi b Achappa Basavaprabhu a Baliga Shrikala c Sharon Leesha c Shah Jyotsna d a Department of Internal Medicine, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India\nb Department of Community Medicine, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India\nc Department of Microbiology, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India\nd ID-FISH Technology Inc., Palo Alto, CA, USA\n⁎ Corresponding author at: Department of Internal Medicine, Kasturba Medical College, Mangalore 575001, Karnataka, India. vikas.vittal1@learner.manipal.edu\n10 9 2020 \n12 2020 \n10 9 2020 \n21 100188© 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 49-year-old male HIV positive patient on treatment failure presented with complaints of fever and dysphagia of three weeks duration and later on developed cervical lymphadenopathy along with severe vomiting and abdominal pain. Liver function tests were found to be worsening with severe drop in CD4 counts. An extensive workup for pyrexia was done. FNAC and biopsy of lymph node showed features suggestive of granulomatous lymphadenitis. CBNAAT of the lymph node aspirate was negative for MTB. Blood culture and lymph node cultures were negative for Mycobacterium Avium Complex (MAC). MAC was however, finally detected and reported positive on Fluorescence in Situ Hybridization (FISH) of the cervical lymph node aspirate. Prompt treatment for MAC was initiated with Ethambutol 800 mg OD and Azithromycin 500 mg OD following which fever spikes subsided and lymph node resolved. The Patient’s condition gradually improved and was discharged shortly with a good recovery on subsequent follow ups.\n\nFever is one of the common symptoms in patients with MAC infection. Some other clinical manifestations include weight loss, hepatosplenomegaly and intra-abdominal lymphadenopathy. Diagnostic evaluation should be aggressive.\n\nAs there is a high risk for MAC infection in advanced HIV cases with poor HAART compliance, FISH can be a valuable and effective diagnostic tool in early detection and treatment of MAC.\n\nKeywords\nTuberculosisMTBMACFISHHIVHAART\n==== Body\n1 Introduction\nFever in advanced HIV, although a common presenting complaint, can be a diagnostic conundrum [1]. The immune-compromised state predisposes one to an array of opportunistic infections. Mycobacterium Avium Complex infection (MAC) is one of the rare complications in the present era of HAART, worldwide. However, patients who have a poor compliance to HAART are at a high risk of developing MAC. The most important intervention in this setting is for early diagnosis and treatment of MAC. The identification of mycobacteria from cultures at the species level frequently relies on observing colony characteristics and growth [2]. FISH can distinguish closely related organisms by DNA sequencing [3]. FISH assays can be effective diagnostic tools for detecting Mycobacteria from solid and liquid cultures and for their identification\n\n2 Case presentation\nA 49-year-old male HIV positive patient for the last 15 years and driver by occupation presented with chief complaints of fever with chills and dysphagia since 3 weeks. Fever was insidious in onset, high grade associated with chills and rigors. Dysphagia was associated with throat pain. His CD4 T-cell as of 12/06/17 was 300. Patient was a known case of RVD for the last 15 years and was clinically stable on regular combination ART regimen of Zidovudine, Lamivudine and Efavirenz.\n\nHowever, due to complaints of fatigability and drowsiness during his regular night duties, he stopped taking Efavirenz and then gradually stopped ART one month back, following which he presented with the above mentioned complaints. He had history of pulmonary tuberculosis 15 years back for which he had taken a complete 6 monthly course of ATT. He was also diabetic since 3 years on regular medications. No history of any other comorbidities. On examination vitals were stable. Local examination of the oral cavity showed candidiasis and ulcer over posterior pharyngeal wall. Chest auscultation revealed vesicular breath sounds with no adventitious sounds. Other Systems examination did not reveal any abnormalities.\n\n3 Investigations\nRoutine blood investigations at the time of admission and subsequent ones during hospital stay are as shown in Table 1.Table 1 Investigations\tOn admission (12/07/17)\t(25/07/17)\t(27/07/17)\t\nHemoglobin (gm/dl)\t10.4\t10.2\t\t\nWhite blood cell count (cells/mm3)\t5200\t12,400\t\t\nPlatelet (cells/mm3)\t1.5 Lakhs\t1.22 Lakhs\t\t\nESR (mm/hr)\t52\t\t\t\nCreatinine (mg/dl)\t0.7\t\t\t\nUrea (mg/dl)\t19\t\t\t\nTotal bilirubin (mg/dl)\t0.33\t4.36\t5.09\t\nDirect bilirubin (mg/dl)\t0.15\t3.83\t4.67\t\nAspartate Transaminase (U/L)\t28\t206\t415\t\nAlanine Transaminase (U/L)\t45\t490\t450\t\nAlkaline Phosphatase (U/L)\t350\t402\t576\t\nGlycosylated Hemoglobin (%)\t11\t\t\t\nCD4 count (cells/mm3)\t64\t\t\t\n\n\nUpper gastrointestinal endoscopy done in view of dysphagia showed Grade B GERD along with duodenal erosions and esophageal ulcer. Biopsy was taken from the ulcer site and was reported to be active esophagitis, which was inconclusive. PAS stain was negative for fungus.\n\nUltrasonography of abdomen and pelvis showed hepatomegaly, borderline splenomegaly and few sub-centimetric iliac lymph nodes.\n\nThe patient continued to have persistent fever, and later on developed cervical lymphadenopathy along with vomiting and abdominal pain during the hospital stay. LFT was found to be worsening. Peripheral smear showed microcytic hypochromic anaemia with thrombocytopenia and reactive lymphocytosis.\n\nSputum culture showed no AFB and no growth on culture. CBNAAT was negative for MTB. Repeated Blood cultures showed no growth. Lymph node cultures showed no growth. Stool routine was negative for opportunistic pathogens\n\nLeft Cervical Lymph Node FNAC done showed granulomatous lymphadenitis as shown in Fig. 1.Fig. 1 Lymph node FNAC showing granulomas (red arrows) suggestive of granulomatous lymphadenitis. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\n\n\nLymph node biopsy was done which revealed Bacterial Infective lymphadenitis as shown in Fig. 2.Fig. 2 Giemsa stain showing bacterial aggregates (red arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\n\n\nFISH study was done and was reported positive for Atypical mycobacterium – Mycobacterium Avium Complex (MAC).\n\n4 Outcome and follow up\nPatient started on MAC treatment. Ethambutol 800 mg OD and Azithromycin 500 mg OD started. Patient restarted on ART treatment with Tenofovir, Lamivudine with Atazanavir/Ritonavir on 03/08/2017. Fever spikes subsided; Lymph node resolved. On 10/08/17, LFT showed AST – 22 U/L, ALT- 94 U/L and ALP- 642 U/L. Patient symptomatically better. Showed good clinical improvement and was discharged shortly. Patient showed good recovery and is now on regular follow ups.\n\n5 Discussion\nMycobacterium avium Complex (MAC) is a serologic complex of Mycobacterium avium and Mycobacterium intracellulare. Infection with MAC is extremely common in the late stages of HIV disease [1], [4]. The risk of infection increases linearly with decreasing CD4 counts below 50 cells/mm3 and with interruption of antiretroviral therapy [5], [6].\n\nAfter the entry of MAC organisms from the environment through inhalation or ingestion, the infection spreads via local lymphatics, disseminating haematogenously. The bacteria are taken up by mononuclear phagocytic cells throughout the body, and reticuloendothelial organs such as the liver, spleen, and bone marrow are the most frequently affected sites [7].\n\nFever can be seen in around 85% of patients with MAC infection. Some other clinical manifestations include weight loss, hepatosplenomegaly and intra-abdominal lymphadenopathy. Night sweats, diarrhoea, nausea and vomiting, and abdominal pain have also been reported [1], [4]. Laboratory tests may show anaemia and elevated levels of alkaline phosphatase and lactate dehydrogenase [1], [5].\n\nA rise in SGOT, SGPT was reported in this case, which could be part of granulomatous hepatitis due to disseminated MAC infection.\n\nA marked elevation in alkaline phosphatase is a special characteristic of disseminated MAC infection. The underlying pathology for increased alkaline phosphatase in HIV with disseminated MAC infection is due to the granulomatous infiltration and obstruction of the terminal branches of the biliary tree [6].\n\nAlthough, a single positive blood culture is considered evidence for disseminated MAC disease; intermittent bacteraemia in the presence of disease may delay positive identification of MAC by this method [8]. Fever in HIV patients should not be attributed to HIV infection itself. Diagnostic evaluation should be aggressive, and is most effectively guided by clinical symptoms, associated conditions, and stage of HIV disease [1]. Investigations with high diagnostic yield include blood, sputum cultures for mycobacteria, lymph node aspiration and biopsy, and bone marrow biopsy. FISH will help reduce delays in diagnosis and initiating treatment of patients in many tuberculosis-endemic countries. [9]\n\n5.1 Role of FISH in diagnosis\nFluorescent in situ hybridisation (FISH) is a molecular cytogenetic technique that utilizes short complementary fluorescent probes to localize and detect specific target DNA or RNA sequences. The presence of multiple copies of rRNA in the cytoplasm enables the reaction with specific probes to be visualized without PCR amplification of the target sequence [9].\n\nMTBC-MAC FISH assay was used in this case. Initially, the cervical lymph node aspirate was smeared on to a glass slide. The slide was then treated with green and orange fluorescent probes specific for Mycobacterium tuberculosis complex (MTBC) and Mycobacterium avium intracellulare complex respectively [9], [10].\n\nThe slide was observed under fluorescence microscope with dual filters (blue and green), since the bacilli fluoresced under green filter it was considered as Mycobacterium avium intracellulare complex as shown in Fig. 3, Fig. 4.Fig. 3 Absence of Mycobacterium tuberculosis complex hence no fluorescence is seen.\n\nFig. 4 Presence of Mycobacterium Avium Intracellulare complex as orange fluorescence by the bacilli is seen (white arrow).\n\n\n\nThis technique helps to detect and identify MTB and atypical mycobacteria, thus making it an important diagnostic tool [9].\n\n6 Conclusion\nIn late stages of HIV infection, in those with low CD4 counts, the risk of MAC infection is higher. In this case, even though the patient was on HAART for the last 15 years, due to non-compliance to ART, he developed MAC infection. Routine diagnostic methods such as blood culture and lymph node cultures were negative for MAC. MAC was however, finally detected and reported positive on FISH. A high index of clinical suspicion for MAC must be maintained in advanced HIV for its early identification and prompt initiation of treatment. FISH can therefore be a valuable and effective diagnostic tool in helping identify MAC.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nFunding\nThe authors received no financial support for the research, authorship, and/or publication of this article..\n\nCRediT authorship contribution statement\nVikas Prabhu: Investigation, Writing - original draft, Visualization. Steffi Coelho: Investigation, Writing - review & editing. Basavaprabhu Achappa: Conceptualization, Methodology, Supervision. Shrikala Baliga: Investigation, Resources. Leesha Sharon: Investigation, Resources. Jyotsna Shah: Resources.\n\nDeclaration of Competing Interest\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n1 Gregor L. Case report: mycobacterium avium complex infection as a cause of fever of unknown origin in HIV disease Dalhousie Med J 25 2 1997 10 13 \n2 Asmar S. Drancourt M. Rapid culture-based diagnosis of pulmonary tuberculosis in developed and developing countries Front Microbiol 6 2015 1184 26579092 \n3 DeLong E.F. Wickham G.S. Pace N.R. Phylogenetic stains: ribosomal RNA— based probes for the identification of single cells Science 1243 1989 1360 1363 \n4 Horsburgh C.R. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome N Engl J Med 324 19 1991 1332 1338 2017230 \n5 Karakousis P.C. Moore R.D. Chaisson R.E. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy Lancet Infect Dis 4 9 2004 557 565 15336223 \n6 El Chaer F. Harris N. El Sahly H. Hemmige V. Martinez Blanco E. Woc-Colburn L. Mycobacterium avium complex-associated cholecystitis in AIDS patient: a case description and review of literature Int J STD AIDS 27 13 2016 1218 1222 26023092 \n7 Horsburgh C.R. Jr. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS J Infect Dis 179 suppl 3 1999 S461 S465 10099120 \n8 Benson C.A. Ellner J.J. Mycobacterium avium complex infection and AIDS: advances in theory and practice Clin Infect Dis 17 1 1993 7 20 8353249 \n9 Shah J. Weltman H. Narciso P. Murphy C. Poruri A. Baliga S. Dual color fluorescence in situ hybridization (FISH) assays for detecting mycobacterium tuberculosis and mycobacterium avium complexes and related pathogens in cultures PLoS ONE 12 4 2017 1 14 \n10 Baliga S. Murphy C. Sharon L. Rapid method for detecting and differentiating Mycobacterium tuberculosis complex and non-tuberculous mycobacteria in sputum by fluorescence in situ hybridization with DNA probes Int J Infect Dis 75 2018 1 7 10.1016/j.ijid.2018.07.011 30048818\n\n",
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"issue": "21()",
"journal": "Journal of clinical tuberculosis and other mycobacterial diseases",
"keywords": "FISH; HAART; HIV; MAC; MTB; Tuberculosis",
"medline_ta": "J Clin Tuberc Other Mycobact Dis",
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"pages": "100188",
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"title": "Role of fluorescence in situ hybridization in detecting mycobacterium avium complex presenting as fever in treatment failure HIV.",
"title_normalized": "role of fluorescence in situ hybridization in detecting mycobacterium avium complex presenting as fever in treatment failure hiv"
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{
"abstract": "Diverse acute neurological injuries may cause acute cardiopulmonary events including neurogenic pulmonary edema (NPE) and neurogenic stunned myocardium (NSM). The mechanism is probably mediated by sympathetic nervous system activation. Focal central nervous system (CNS) lesions, such as demyelinating lesions in multiple sclerosis (MS), may also cause cardiopulmonary disturbances. We aim to review the acute cardiopulmonary events associated with MS relapses. We performed a literature search using PubMed, and selected case reports of acute cardiac and/or pulmonary events related to MS exacerbations. We grouped these events into three categories: 1) NPE with normal cardiac function; 2) NSM and Takotsubo cardiomyopathy (TTC); 3) coexisting myocardial dysfunction and pulmonary edema. In some cases, cardiac and pulmonary symptoms preceded the onset of neurological symptoms. The majority of cases were associated with acute demyelinating lesions located in the medulla. Acute brainstem MS relapses, with demyelinating lesions affecting the medulla, may cause acute cardiac and pulmonary events presumably secondary to sympathetic hyperstimulation. Specific regions in the medulla that regulate cardiac function, systemic blood pressure and pulmonary hydrostatic pressure seem to be responsible for these events.",
"affiliations": "Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA.;Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA.;Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA.;Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA.",
"authors": "Valencia-Sanchez|Cristina|C|;Goodman|Brent P|BP|;Carter|Jonathan L|JL|;Wingerchuk|Dean M|DM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1352458518823482",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "25(6)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Multiple sclerosis; Takotsubo cardiomyopathy; medulla oblongata; neurogenic pulmonary edema; neurogenic stunned myocardium",
"medline_ta": "Mult Scler",
"mesh_terms": "D006801:Humans; D008526:Medulla Oblongata; D009103:Multiple Sclerosis; D017682:Myocardial Stunning; D011654:Pulmonary Edema; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "758-765",
"pmc": null,
"pmid": "30657008",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "The spectrum of acute cardiopulmonary events associated with multiple sclerosis exacerbations.",
"title_normalized": "the spectrum of acute cardiopulmonary events associated with multiple sclerosis exacerbations"
} | [
{
"companynumb": "US-EMD SERONO-9001052",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INTERFERON BETA-1A"
},
"drugadditional": "3",
... |
{
"abstract": "Evidence on the effectiveness of first-line treatment for chronic Q fever, tetracyclines (TET) plus hydroxychloroquine (HCQ), and potential alternatives is scarce.\n\n\n\nWe performed a retrospective, observational cohort study to assess efficacy of treatment with TET plus quinolones (QNL), TET plus QNL plus HCQ, QNL monotherapy, or TET monotherapy compared to TET plus HCQ in chronic Q fever patients. We used a time-dependent Cox proportional hazards model to assess our primary (all-cause mortality) and secondary outcomes (first disease-related event and therapy failure).\n\n\n\nWe assessed 322 chronic Q fever patients; 276 (86%) received antibiotics. Compared to TET plus HCQ (n = 254; 92%), treatment with TET plus QNL (n = 49; 17%), TET plus QNL plus HCQ (n = 29, 10%), QNL monotherapy (n = 93; 34%), or TET monotherapy (n = 54; 20%) were not associated with primary or secondary outcomes. QNL and TET monotherapies were frequently discontinued due to insufficient clinical response (n = 27, 29% and n = 32, 59%). TET plus HCQ, TET plus QNL, and TET plus QNL plus HCQ were most frequently discontinued due to side effects (n = 110, 43%; n = 13, 27%; and n = 12, 41%).\n\n\n\nTreatment of chronic Q fever with TET plus QNL appears to be a safe alternative for TET plus HCQ, for example, if TET plus HCQ cannot be tolerated due to side effects. Treatment with TET plus QNL plus HCQ was not superior to treatment with TET plus HCQ, although this may be caused by confounding by indication. Treatment with TET or QNL monotherapy should be avoided; switches due to subjective, insufficient clinical response were frequently observed.",
"affiliations": "Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht.;Department of Internal Medicine, Division of Infectious Diseases and Radboud Expert Centre for Q Fever, Radboud University Medical Center, Nijmegen.;Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht.;Department of Internal Medicine and Infectious Diseases, Medical Centre Leeuwarden.;Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht.;Department of Medical Microbiology and Infection Control, Jeroen Bosch Hospital,'s-Hertogenbosch, the Netherlands.;Department of Internal Medicine and Infectious Diseases, University Medical Centre Utrecht.",
"authors": "van Roeden|Sonja E|SE|;Bleeker-Rovers|Chantal P|CP|;de Regt|Marieke J A|MJA|;Kampschreur|Linda M|LM|;Hoepelman|Andy I M|AIM|;Wever|Peter C|PC|;Oosterheert|Jan Jelrik|JJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015363:Quinolones; D013754:Tetracyclines; D006886:Hydroxychloroquine",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cix886",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "66(5)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002908:Chronic Disease; D016997:Coxiella burnetii; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D008875:Middle Aged; D057216:Propensity Score; D016016:Proportional Hazards Models; D011778:Q Fever; D015363:Quinolones; D012189:Retrospective Studies; D013754:Tetracyclines; D017211:Treatment Failure",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "719-726",
"pmc": null,
"pmid": "29040457",
"pubdate": "2018-02-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Treatment of Chronic Q Fever: Clinical Efficacy and Toxicity of Antibiotic Regimens.",
"title_normalized": "treatment of chronic q fever clinical efficacy and toxicity of antibiotic regimens"
} | [
{
"companynumb": "NL-CONCORDIA PHARMACEUTICALS INC.-GSH201807-002363",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare, potentially life-threatening complication of immunotherapy. We report a case of a 60-year-old female with a history of colorectal cancer treated with nivolumab immunotherapy who presented with new cardiomyopathy complicated by cardiogenic shock and ventricular arrhythmias. Treatment of ICI-associated myocarditis requires aggressive immunosuppression and supportive therapy. In this case, the patient required advanced mechanical circulatory support as a bridge to recovery. This case highlights the complexity of diagnosis, haemodynamic management, and treatment of fulminant ICI myocarditis.",
"affiliations": "Division of Cardiology, Department of Medicine, University of California, Los Angeles, MD 650 Charles E. Young Dr. South, A2-27 CHS, Los Angeles, CA, 90095, USA.;Division of Cardiology, Department of Medicine, University of California, Los Angeles, MD 650 Charles E. Young Dr. South, A2-27 CHS, Los Angeles, CA, 90095, USA.;Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Division of Cardiology, Department of Medicine, University of California, Los Angeles, MD 650 Charles E. Young Dr. South, A2-27 CHS, Los Angeles, CA, 90095, USA.;Division of Critical Care, Department of Emergency Medicine, University of California, Los Angeles, CA, USA.;Division of Hematology/Oncology, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA.;Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.;Division of Cardiology, Department of Medicine, University of California, Los Angeles, MD 650 Charles E. Young Dr. South, A2-27 CHS, Los Angeles, CA, 90095, USA.;Division of Cardiology, Department of Medicine, University of California, Los Angeles, MD 650 Charles E. Young Dr. South, A2-27 CHS, Los Angeles, CA, 90095, USA.;Division of Cardiology, Department of Medicine, University of California, Los Angeles, MD 650 Charles E. Young Dr. South, A2-27 CHS, Los Angeles, CA, 90095, USA.;Division of Cardiology, Department of Medicine, University of California, Los Angeles, MD 650 Charles E. Young Dr. South, A2-27 CHS, Los Angeles, CA, 90095, USA.",
"authors": "Stein-Merlob|Ashley F|AF|0000-0001-6261-6431;Hsu|Jeffrey J|JJ|;Colton|Bradley|B|;Berg|Christopher J|CJ|;Ferreira|Allison|A|;Price|Megan M|MM|;Wainberg|Zev|Z|;Baas|Arnold S|AS|;Deng|Mario C|MC|;Parikh|Rushi V|RV|;Yang|Eric H|EH|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1002/ehf2.13545",
"fulltext": "\n==== Front\nESC Heart Fail\nESC Heart Fail\n10.1002/(ISSN)2055-5822\nEHF2\nESC Heart Failure\n2055-5822\nJohn Wiley and Sons Inc. Hoboken\n\n34390221\n10.1002/ehf2.13545\nEHF213545\nESCHF-21-00102\nCase Report\nCase Reports\nKeeping immune checkpoint inhibitor myocarditis in check: advanced circulatory mechanical support as a bridge to recovery\nKeeping immune checkpoint inhibitor myocarditis in check\nA.F. Stein‐Merlob et al.\nStein‐Merlob Ashley F. https://orcid.org/0000-0001-6261-6431\n1 asteinmerlob@mednet.ucla.edu\n\nHsu Jeffrey J. 1 2\nColton Bradley 3\nBerg Christopher J. 1\nFerreira Allison 4\nPrice Megan M. 5\nWainberg Zev 3\nBaas Arnold S. 1 2\nDeng Mario C. 1 2\nParikh Rushi V. 1 2\nYang Eric H. 1 6\n1 Division of Cardiology, Department of Medicine University of California, Los Angeles MD 650 Charles E. Young Dr. South, A2‐27 CHS Los Angeles CA 90095 USA\n2 Ahmanson UCLA‐Cardiomyopathy Center, Division of Cardiology, Department of Medicine University of California, Los Angeles Los Angeles CA USA\n3 Division of Hematology/Oncology, Department of Medicine University of California, Los Angeles Los Angeles CA USA\n4 Division of Critical Care, Department of Emergency Medicine University of California Los Angeles CA USA\n5 Division of Hematology/Oncology Texas Oncology‐Baylor Charles A. Sammons Cancer Center Dallas TX USA\n6 UCLA‐Cardio‐Oncology Program, Division of Cardiology, Department of Medicine University of California, Los Angeles Los Angeles CA USA\n* Correspondence to: Ashley F. Stein‐Merlob, Division of Cardiology, Department of Medicine, University of California, MD 650 Charles E. Young Dr. South, A2‐27 CHS, Los Angeles, CA 90095, USA. Tel: 310‐206‐6286. Email: asteinmerlob@mednet.ucla.edu\n13 8 2021\n10 2021\n8 5 10.1002/ehf2.v8.5 43014306\n23 6 2021\n26 1 2021\n15 7 2021\n© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nImmune checkpoint inhibitor (ICI)‐associated myocarditis is a rare, potentially life‐threatening complication of immunotherapy. We report a case of a 60‐year‐old female with a history of colorectal cancer treated with nivolumab immunotherapy who presented with new cardiomyopathy complicated by cardiogenic shock and ventricular arrhythmias. Treatment of ICI‐associated myocarditis requires aggressive immunosuppression and supportive therapy. In this case, the patient required advanced mechanical circulatory support as a bridge to recovery. This case highlights the complexity of diagnosis, haemodynamic management, and treatment of fulminant ICI myocarditis.\n\nCardiomyopathy\nCardiac assist device\nAcute heart failure\nImmune checkpoint inhibitor myocarditis\nCardiooncology\nNational Institutes of Health Cardiovascular Scientist Training ProgramT32 HL007895 source-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:07.10.2021\nStein‐Merlob, A. F. , Hsu, J. J. , Colton, B. , Berg, C. J. , Ferreira, A. , Price, M. M. , Wainberg, Z. , Baas, A. S. , Deng, M. C. , Parikh, R. V. , and Yang, E. H. (2021) Keeping immune checkpoint inhibitor myocarditis in check: advanced circulatory mechanical support as a bridge to recovery. ESC Heart Failure, 8 : 4301–4306. 10.1002/ehf2.13545.\n==== Body\npmcIntroduction\n\nImmunotherapy has revolutionized cancer treatment by harnessing the native immune system for treatment of advanced malignancies. For immune regulation, T lymphocytes express receptors, including CTLA‐4 and PD‐1 receptors, which trigger coinhibitory signalling pathways to prevent T lymphocyte proliferation and migration. Tumour cells can express ligand receptors, like PD‐L1, to initiate this pathway and down‐regulate the local cellular immune response. Monoclonal antibodies, called immune checkpoint inhibitors (ICIs), block these receptors to reactivate the native antitumor response. 1 , 2 , 3 Since the first ICI was approved in 2011, seven approved agents are indicated for over 40 malignancies. 1 However, in 2014, the first series of cases of ICI‐associated myocarditis were reported with a high rate of fatality, from 27% to 50%. 4 , 5 Multiorgan toxicities, including cardiovascular, are due to off‐target activation of the immune response. Recognized cardiovascular immune‐mediated toxicities include myocarditis, vasculitis, pericarditis, arrhythmias, and Takotsubo cardiomyopathy. 1 , 4 Although ICI‐associated myocarditis is uncommon with an incidence of about 1%, 6 it is critical to recognize this potentially fatal complication. 7\n\nCase report\n\nA 60‐year‐old female with a history of colon cancer and Graves' disease was sent to the emergency department from clinic for an abnormal electrocardiogram (ECG). She had been referred for 3 weeks of palpitations and markedly reduced exercise tolerance. She denied chest pain, syncope, orthopnoea, paroxysmal nocturnal dyspnoea, or lower extremity oedema. She reported a single use of cocaine 7 days earlier.\n\nFrom an oncologic standpoint, the patient was diagnosed 9 months earlier with moderately differentiated T3N1 adenocarcinoma of the colon with a sporadic microsatellite instability mutation. She underwent hemicolectomy, three cycles of XELOX (capecitabine and oxaliplatin) chemotherapy and ongoing ICI therapy with nivolumab (first and last dose were 5 and 2 months prior).\n\nHer examination was remarkable for sinus tachycardia to 115 bpm, and cool extremities without evidence of volume overload. Initial ECG (Figure 1 A,B ) demonstrated a bidirectional fascicular ventricular tachycardia and diffuse ST segment elevation. Laboratory testing revealed significantly elevated troponin, brain natriuretic peptide and liver enzymes (Table 1 ). Influenza B IgG and IgM serologies were positive. Echocardiography demonstrated a newly reduced left ventricular ejection fraction (LVEF) of 30% with global hypokinesis. Coronary angiography revealed no significant epicardial coronary artery disease. Cardiac magnetic resonance imaging demonstrated normal left ventricular size with globally reduced systolic function (LVEF 38%) without delayed myocardial enhancement. Her initial diagnosis was presumed influenza‐associated myocarditis and unlikely ICI‐related, given the distant time from immunotherapy treatments and normal CMR. Metoprolol succinate, lisinopril, and spironolactone were initiated. Oral amiodarone was initiated for high‐risk arrhythmia, and she was discharged on hospital day (HD) 5 with a LifeVest (Zoll Medical Corporation, Chelmsford, MA) wearable defibrillator.\n\nFigure 1 (A) Baseline normal electrocardiogram (ECG) prior to initiation of chemotherapy and immunotherapy. (B) Initial presenting ECG with alternating fascicular ventricular tachycardia with 1:1 V‐A conduction and diffuse ST segment elevation. Ventricular morphologies correlate to outflow tract (left bundle branch morphology with superior axis) and apical (superior axis, negative precordial concordance) origins. (C) ECG on readmission to the emergency department unchanged from prior admission. (D) Repeat ECG prior to discharge showing normal sinus rhythm, normal QRS duration, new inferior Q waves, and poor R wave progression.\n\nTable 1 Laboratory values throughout clinical course\n\nLaboratory test (reference range)\tInitial presentation\tReadmission (HD 1)\tECMO cannulation (HD 3)\tDischarge (HD 19)\t\nBNP (<100 pg/mL)\t173\t1188\tN/A\t325\t\nTroponin I (<0.1 ng/mL)\t30.2\t18.2\t9.2\t0.09\t\nALT (8–64 U/L)\t361\t374\t205\t42\t\nAST (13–47 U/L)\t688\t431\t338\t24\t\nCreatinine (0.6–1.3 mg/dL)\t0.58\t1.69\t3.37\t1.79\t\nPotassium (3.6–5.3 mmol/L)\t4.4\t5.5\t3.4\t3.4\t\nLactate (5–25 mg/dL)\tN/A\t24\t45\t8\t\nLaboratory values taken throughout both hospitalizations. During readmission, all laboratory values decreased with immunosuppressive treatment and hemodynamic support. Although there may have been an element of hepatic congestive secondary to heart failure, liver enzymes (ALT & AST) were primarily thought to be elevated due to ICI‐associated hepatitis and similarly responded to immunosuppression.\n\nALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, B‐type natriuretic peptide; ECMO, extracorporeal membrane oxygenation; HD, hospital day; ICI, immune checkpoint inhibitor.\n\nNine days after discharge, she returned to the emergency department with worsening weakness and nausea. Her vitals were significant for tachycardia and hypotension. Exam revealed diminished distal pulses and cool extremities. Laboratory testing demonstrated worsening abnormalities from her prior admission (Table 1 ). ECG was unchanged (Figure 1 C ). Her presenting blood pressure was 60/40 mmHg with altered mental status. Bedside echocardiogram demonstrated LVEF < 10% and an intravenous dopamine infusion (2 mcg/kg/min) was initiated. Shortly thereafter, she experienced sustained ventricular tachycardia at 160 bpm with palpable pulses. Given concern for worsening cardiogenic shock, she was emergently transported to the cardiac catheterization laboratory for right heart catheterization and consideration of mechanical circulatory support.\n\nRight heart catheterization demonstrated a severely depressed cardiac index with mildly elevated right‐sided filling pressures (Table 2 ). A multidisciplinary discussion between oncology and cardiology highlighted the heterogeneity of onset, lack of CMR sensitivity in early disease, and importance of prompt treatment for ICI‐associated myocarditis. Immunosuppression was empirically started with high‐dose corticosteroids, antithymocyte globulin, and later plasmapheresis (Figure 2 B ). An endomyocardial biopsy (EMB) confirmed ICI‐associated myocarditis (Figure 2 A ). An Impella CP (Abiomed, Danvers, MA) was inserted for haemodynamic support. Nitroprusside and milrinone were added for vasodilator and inotropic support; however, the patient developed right heart failure (Table 2 ) and hypotension refractory to multiple vasopressors. Haemodynamic support was escalated to veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO). Notably, she was diagnosed with ICI‐associated ocular myasthenia, colitis, and hepatitis.\n\nTable 2 Serial right heart catheterization (RHC) data\n\nVariable\tPre‐Impella implantation (HD 1)\tPost‐Impella implantation (HD 1)\tImpella, inotropes, vasodilators (HD 2)\tPre‐ECMO cannulation (HD 3)\tImpella removal (HD 7)\tPre‐ECMO decannulation (HD 8)\tPost‐ECMO decannulation (HD 9)\t\nRAP (mmHg)\t11\t16\t9\t21\t9\t4\t1\t\nPAP (mmHg)\t24/16 (18)\t24/16 (18)\t19/10 (14)\t14/10 (12)\t20/12 (15)\t17/9 (12)\t14/5 (8)\t\nPCWP (mmHg)\t10\t18\tN/A\tN/A\tNA\tNA\tNA\t\nCardiac output (L/min) TD (Fick)\t1.30 (2.5)\t2.4 (3.6)\t3.9\t2.7\t4.0\t4.6\t3.6\t\nCardiac index (L/min/m2) TD (Fick)\t0.74 (1.46)\t1.36 (2.0)\t2.23\t1.54\t2.29\t2.628\t2.05\t\n(I) Prior to Impella CP placement, RHC shows mildly elevated right‐sided filling pressures with severely reduced cardiac output, which in conjunction with evidence of end organ damage indicated cardiogenic shock. (II) Post‐Impella CP implantation, there is improvement of cardiac output, but increased left and right‐sided filling pressures. (III) On Impella CP support (P8, flow rate 3.5 L/min) with inotropic support on milrinone (maximum dose 0.4 mcg/kg/min) and vasodilator therapy on nitroprusside (maximum dose 2 mcg/kg/min), haemodynamics improved significantly with normalization of left‐sided and right‐sided filling pressures and improvement of cardiac index > 2.2 L/min/m2. (IV) Patient then had haemodynamic decompensation with hypotension, significantly elevated right‐sided filling pressures, and low cardiac output indicating worsening right heart failure. Given the need for additional right‐sided support, patient was cannulated for ECMO. (V) At the time of Impella removal, haemodynamics had normalized off inotropic support. (VI) At the time of ECMO decannulation, haemodynamics continued to be stable off Impella and inotropic support. (VII) Post‐ECMO decannulation, stable haemodynamics continued.\n\nHD, hospital day; PCWP, pulmonary capillary wedge pressure; PAP, pulmonary arterial pressure; RAP, right atrial pressure; TD, thermodilution.\n\nFigure 2 (A) Endomyocardial biopsy with H&E stain at 20× magnification showing lymphocyte predominant infiltration of the myocardium with no eosinophils or giant cells. (B) Timeline showing troponin trend and timing of mechanical support and immunosuppression regimen. Antithymocyte globulin (ATG) dosage 0.75 or 1.5 mg/kg daily titrated to absolute lymphocyte count. Interruptions in plasmapheresis due to coagulopathy and bleeding requiring transfusion while on extracorporeal membrane oxygenation. (C) Cardiac magnetic resonance imaging (CMR) during second admission revealed patchy, predominantly mid myocardial delayed enhancement throughout the left ventricular myocardium suggestive of myocarditis (arrows indicate areas of late gadolinium enhancement). Not shown, CMR obtained on initial admission was negative for delayed gadolinium enhancement. ATG, antithymocyte globulin; ECMO, extracorporeal membrane oxygenation; LV, left ventricle; MRI, magnetic resonance imaging; RV, right ventricle.\n\nWith continued immunosuppression, haemodynamics and laboratory markers gradually improved (Figure 2 B ). Her Impella was removed on HD 7, and ECMO was decannulated on HD 8. Repeat CMR revealed new patchy mid myocardial delayed enhancement consistent with myocarditis (Figure 2 C ). Echocardiogram showed improved LVEF of 40%. She was discharged on a steroid taper with serial echocardiograms and serum troponins. ICI therapy was never reinitiated. At 2 years of follow up, she remains clinically stable with New York Heart Association Class II symptoms, LVEF mildly declined to 35% on medical therapy, and an implantable cardioverter defibrillator was placed for primary prevention. She currently has no evidence of recurrent malignancy or myocarditis.\n\nDiscussion\n\nThis case demonstrates the complexity of diagnosis and management of ICI‐associated myocarditis, an uncommon but potentially fatal complication. Clinical presentation varies from isolated biomarker abnormalities to heart failure, arrhythmia, and cardiogenic shock. Although 81% of cases occur within 3 months of initiating therapy, onset ranges from days to over 1 year indicating the importance of maintaining a high index of suspicion regardless of timing. 6 , 7 In this case, the delayed onset 5 months after therapy initiation led to a misdiagnosis.\n\nDiagnosis of ICI‐associated myocarditis includes biomarkers, ECG, and imaging evaluation. Troponin elevation is sensitive for ICI‐associated myocarditis and is abnormal in 94% of cases. 6 No specific troponin cut‐off has been identified, and in fact, troponin rise may be modest with peak Troponin T of 2.68 ng/mL (IQ 0.24–7.63) in patients with major adverse cardiac events (MACE). 6 ECG is abnormal in 89% of cases, and arrhythmias include conduction delays, atrial, and/or ventricular arrhythmias. Nearly half of patients with ICI‐associated myocarditis have a normal LVEF on presentation. 6 Abnormal global longitudinal strain on echocardiography is associated with an increased risk of MACE regardless of LVEF. 8 CMR detects delayed myocardial enhancement and oedema but lacks sensitivity especially early in the disease process (<4 days after presentation). 9 In this case, CMR findings only appeared on repeat imaging late in the clinical course. The current gold standard for diagnosis is EMB, characterized by extensive lymphocytic infiltration of the myocardium. In a proposed framework for diagnosis of ICI‐associated myocarditis, definite myocarditis like this case includes either (i) tissue pathological confirmation on EMB or autopsy or (ii) abnormal imaging on CMR or echocardiogram in the appropriate clinical scenario with abnormal biomarker and/or ECG findings. Diagnoses of ‘probable’ or ‘possible’ myocarditis include scenarios with isolated imaging, biomarker, or ECG findings. 10\n\nThe tenants of treatment of ICI‐associated myocarditis are immunosuppression, supportive care, and stopping ICI therapy. No randomized controlled trials have assessed ICI‐associated myocarditis treatments, but corticosteroids are the cornerstone of treatment. In uncomplicated ICI‐associated myocarditis, oral prednisone (1–2 mg/kg) is recommended; in severe or refractory cases, such as this patient, high‐dose IV methylprednisolone (500 mg to 1 g daily) is preferred. 11 An international, multicentre registry study showed that early administration (<24 h) and high doses (500–1000 mg per day) of corticosteroids were associated with decreased risk of MACE. 12 In severe or steroid‐resistant ICI‐associated myocarditis, additional agents target the cellular immune response including mycophenolate mofetil, antithymocyte globulin (antithymocyte globulin), and rituximab. 6 , 11 , 13 Dosing and use of these agents have been largely adapted from transplant rejection protocols.\n\nThe most novel aspect of this case was the use of advanced temporary MCS. ICI‐associated myocarditis can be fatal in up to half of those affected, and approximately, half of survivors will not have recovery of cardiac function. 6 , 7 Unlike other causes of myocarditis, these patients inherently have underlying malignancies and comorbidities that may lead to avoidance of aggressive interventions and ineligibility for advanced therapies such as heart transplants or durable ventricular assist devices. However, unlike most causes of myocarditis, particularly viral myocarditis, ICI‐associated myocarditis is effectively treated with immunosuppression, which may hasten cardiovascular recovery. It is therefore reasonable to pursue temporary MCS as a bridge to recovery. MCS options in this case of profound cardiogenic shock included intraaortic balloon pump, Impella, Tandem Heart (LivaNova PLC, London, UK), and VA‐ECMO. High‐quality randomized data for comparison of MCS devices is limited. Two prior cases in the literature report the use of VA‐ECMO in ICI‐associated myocarditis, but there are no reports of isolated or concomitant Impella use (‘ECPELLA’). 14 , 15 Due to primarily left heart failure, without need for maximal mechanical or respiratory support, the decision was made to proceed with Impella support. Despite this and maximal inotropic support, ongoing myocarditis led to worsening biventricular failure, requiring escalation to VA‐ECMO. With appropriate immunosuppression, patient was weaned off mechanical support.\n\nThe risks of restarting ICI therapy are unknown, but guidelines recommend always holding ICIs and permanently discontinuing for cardiotoxicity more than grade I (asymptomatic biomarker elevation). 11 Plasmapheresis removes ICI antibodies in severe cases given the long half‐life of ICIs (14.5 to 27.0 days). 16\n\nKnowledge of the presentation and treatment of ICI‐associated myocarditis is evolving, but it can be elusive to diagnose. Our case underscores the critical need for multidisciplinary approaches for rapid identification and treatment for this unique patient population, particularly in fulminant myocarditis complicated by cardiogenic shock. Further study is needed regarding which patients with ICI‐associated myocarditis will benefit from MCS given the unique dilemma of prognosis of their concomitant malignancy.\n\nConflict of interest\n\nNone declared.\n\nFunding\n\nRVP reports unrelated activities including research support from the American Heart Association and Janssen, and serving on the scientific advisory board (minor equity interest) of Stallion Cardio and HeartCloud. EHY reports unrelated activities including research support from CSL Behring. ASM is supported by the National Institutes of Health Cardiovascular Scientist Training Program (T32 HL007895).\n==== Refs\nReferences\n\n1 Hu J‐R , Florido R , Lipson EJ , Naidoo J , Ardehali R , Tocchetti CG , Lyon AR , Padera RF , Johnson DB , Moslehi J . Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 2019; 115 : 854–868.30715219\n2 Tajiri K , Ieda M . Cardiac Complications in Immune Checkpoint Inhibition Therapy. Front Cardiovasc Med. 2019; 6 : 3.30729114\n3 Lyon AR , Yousaf N , Battisti NML , Moslehi J , Larkin J . Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol 2018; 19 : e447–e458.30191849\n4 Escudier M , Cautela J , Malissen N , Ancedy Y , Orabona M , Pinto J , Monestier S , Grob JJ , Scemama U , Jacquier A , Lalevee N , Barraud J , Peyrol M , Laine M , Bonello L , Paganelli F , Cohen A , Barlesi F , Ederhy S , Thuny F . Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity. Circulation. 2017; 136 : 2085–2087.29158217\n5 Salem J‐E , Manouchehri A , Moey M , Lebrun‐Vignes B , Bastarache L , Pariente A , Gobert A , Spano JP , Balko JM , Bonaca MP , Roden DM . Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018; 19 : 1579–1589.30442497\n6 Mahmood SS , Fradley MG , Cohen JV , Nohria A , Reynolds KL , Heinzerling LM , Sullivan RJ , Damrongwatanasuk R , Chen CL , Gupta D , Kirchberger MC . Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018; 71 : 1755–1764.29567210\n7 Moslehi JJ , Salem J‐E , Sosman JA , Lebrun‐Vignes B , Johnson DB . Increased reporting of fatal immune checkpoint inhibitor‐associated myocarditis. The Lancet. 2018; 391 : 933.\n8 Awadalla M , Mahmood SS , Groarke JD , Hassan MZO , Nohria A , Rokicki A , Murphy SP , Mercaldo ND , Zhang L , Zlotoff DA , Reynolds KL . Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor‐Related Myocarditis. J Am Coll Cardiol. 2020; 75 : 467–478.32029128\n9 Zhang L , Awadalla M , Mahmood SS , Nohria A , Hassan MZO , Thuny F , Zlotoff DA , Murphy SP , Stone JR , Golden DLA , Alvi RM , Rokicki A , Jones‐O'Connor M , Cohen JV , Heinzerling LM , Mulligan C , Armanious M , Barac A , Forrestal BJ , Sullivan RJ , Kwong RY , Yang EH , Damrongwatanasuk R , Chen CL , Gupta D , Kirchberger MC , Moslehi JJ , Coelho‐Filho OR , Ganatra S , Rizvi MA , Sahni G , Tocchetti CG , Mercurio V , Mahmoudi M , Lawrence DP , Reynolds KL , Weinsaft JW , Baksi AJ , Ederhy S , Groarke JD , Lyon AR , Fradley MG , Thavendiranathan P , Neilan TG . Cardiovascular magnetic resonance in immune checkpoint inhibitor‐associated myocarditis. European Heart Journal. 2020; 41 : 1733–1743.32112560\n10 Bonaca MP , Olenchock BA , Salem J‐E , Wiviott SD , Ederhy S , Cohen A , Stewart GC , Choueiri TK , Di Carli M , Allenbach Y , Kumbhani DJ . Myocarditis in the Setting of Cancer Therapeutics. Circulation. 2019; 140 : 80–91.31390169\n11 Brahmer JR , Lacchetti C , Schneider BJ , Atkins MB , Brassil KJ , Caterino JM , Ginex P , Hallmeyer S , Holter Chakrabarty J , Leighl NB , Mammen JS , McDermott DF , Naing A , Nastoupil LJ , Phillips T , Porter LD , Puzanov I , Reichner CA , Santomasso BD , Seigel C , Spira A , Suarez‐Almazor ME , Wang Y , Weber JS , Wolchok JD , Thompson JA , National Comprehensive Cancer Network Management of Immune‐Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. JCO. 2018; 36 : 1714–1768.\n12 Zhang L , Zlotoff DA , Awadalla M , Mahmood SS , Nohria A , Hassan MZO , Thuny F , Zubiri L , Chen CL , Sullivan RJ , Alvi RM . Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor‐Associated Myocarditis. Circulation. 2020; 141 : 2031–2034.32539614\n13 Khunger A , Battel L , Wadhawan A , More A , Kapoor A , Agrawal N . New Insights into Mechanisms of Immune Checkpoint Inhibitor‐Induced Cardiovascular Toxicity. Curr Oncol Rep 2020; 22 : 1–11.31960161\n14 Frigeri M , Meyer P , Banfi C , Giraud R , Hachulla A‐L , Spoerl D , Friedlaender A , Pugliesi‐Rinaldi A , Dietrich PY . Immune Checkpoint Inhibitor‐Associated Myocarditis: A New Challenge for Cardiologists. Can J Cardiol. 2018; 34 : 92.e1–92.e3.\n15 Arangalage D , Delyon J , Lermuzeaux M , Ekpe K , Ederhy S , Pages C , Lebbé C . Survival After Fulminant Myocarditis Induced by Immune‐Checkpoint Inhibitors. Ann Intern Med. 2017; 167 : 683.28869988\n16 Herrmann J . Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat Rev Cardiol 2020; 17 : 474–502.32231332\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2055-5822",
"issue": "8(5)",
"journal": "ESC heart failure",
"keywords": "Acute heart failure; Cardiac assist device; Cardiomyopathy; Cardiooncology; Immune checkpoint inhibitor myocarditis",
"medline_ta": "ESC Heart Fail",
"mesh_terms": "D009202:Cardiomyopathies; D005260:Female; D006353:Heart-Assist Devices; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008875:Middle Aged; D009205:Myocarditis; D012770:Shock, Cardiogenic",
"nlm_unique_id": "101669191",
"other_id": null,
"pages": "4301-4306",
"pmc": null,
"pmid": "34390221",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D052061:Research Support, N.I.H., Extramural",
"references": "28869988;32231332;30191849;29442540;32029128;30729114;29158217;32539614;30442497;29536852;29567210;34390221;32514647;30715219;32112560;31390169;29275889",
"title": "Keeping immune checkpoint inhibitor myocarditis in check: advanced circulatory mechanical support as a bridge to recovery.",
"title_normalized": "keeping immune checkpoint inhibitor myocarditis in check advanced circulatory mechanical support as a bridge to recovery"
} | [
{
"companynumb": "US-009507513-2112USA001464",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": "4",
... |
{
"abstract": "Kaposi᾽s sarcoma (KS) can develop in 0.06% to 4.1% of kidney transplant recipients. Here we describe a case of 50-year-old man who developed KS a few months after kidney transplantation. After transplantation, he had delayed graft function and was managed by anti-thymocyte globulin (ATG) for five days. At the discharge, his immunosuppressive therapy was prednisolone 20 mg/day, tTacrolimus (Pprograf®) 4 mg/day, and mycophenolate mofetil (MMF) 2 gr/day, while he also took Vvalcyte and diltiazem. Once diagnosed with KS, the Prograf® (tacrolimus) was replaced by prednisolone (5 mg/day) and sirolimus (2 mg/day). Gradually the skin nodule on the patient arm disappeared, and the others nodule on the right his leg was decreased. It seems that the examination of skin should be a part of regular follow-up and dermatologist examination is recommended every 6 months.",
"affiliations": "Department of Internal Medicine, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.;Department of Dermatology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.;Mother and Newborn Health Research Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.",
"authors": "Najafi|Farzaneh|F|;Kafaie|Parichehr|P|;Neamatzadeh|Hossein|H|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D020123:Sirolimus",
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-6025",
"issue": "55(2)",
"journal": "Acta medica Iranica",
"keywords": "End stage renal disease; Kaposi’s sarcoma; Kidney; Transplantation",
"medline_ta": "Acta Med Iran",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012514:Sarcoma, Kaposi; D020123:Sirolimus; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "14540050R",
"other_id": null,
"pages": "139-141",
"pmc": null,
"pmid": "28282713",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of an Early Kaposi's Sarcoma Case Post Kidney Transplantation by Sirolimus: A Case Report.",
"title_normalized": "treatment of an early kaposi s sarcoma case post kidney transplantation by sirolimus a case report"
} | [
{
"companynumb": "IR-ACCORD-049342",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS\\TACROLIMUS ANHYDROUS"
},
"drugadditional":... |
{
"abstract": "HIV infection changed the scenario of infectious diseases. The pre-HAART (highly active antiretroviral therapy) era had resulted in new opportunistic infections. HIV and tuberculosis together had high mortality in countries with high prevalence of tuberculosis. Disseminated and extra pulmonary tuberculosis is common in PLHA (People Living with HIV and AIDS). IRIS (Immune Reconstitution Inflammatory Syndrome) after HAART is common (10% to 25%) in PLHA. Pott's spine is the most common presentation in PLHA of bone and skeletal system. IRIS tuberculosis, especially extra pulmonary tuberculosis, is the most common. In this case, we are presenting an IRIS disseminated tuberculosis in the form of acute osteomyelitis and mutilating dactylitis involving many joints of the fingers. Of 37 cases (9 from India) reported worldwide multiple dactylitis was never presented in the medical journals. This might be the first multiple dactylitis with extensive mutilation to the dactyls due to IRIS in a patient on ART.",
"affiliations": "1Center of Excellence for HIV and TB, Government Hospital of Thoracic Medicine, Tambaram, Chennai, Tamil Nadu, India.",
"authors": "Krishnaraj|Raja|R|;Chockalingam|Chandrasekar|C|;Krishnarajasekhar|O R|OR|;Ayyamperumal|Mahilmaran|M|;Narayanan|Ravichandran|R|;Satagopan|Kumar|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D002443:Ceftriaxone; D003023:Cloxacillin",
"country": "United States",
"delete": false,
"doi": "10.1177/1545109712449866",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-1097",
"issue": "11(5)",
"journal": "Journal of the International Association of Physicians in AIDS Care (Chicago, Ill. : 2002)",
"keywords": null,
"medline_ta": "J Int Assoc Physicians AIDS Care (Chic)",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D002443:Ceftriaxone; D003023:Cloxacillin; D005384:Finger Joint; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007711:Klebsiella pneumoniae; D008297:Male; D010019:Osteomyelitis; D011859:Radiography; D014033:Toe Joint; D014394:Tuberculosis, Osteoarticular",
"nlm_unique_id": "101185740",
"other_id": null,
"pages": "289-92",
"pmc": null,
"pmid": "22821806",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Immune Reconstitution Inflammatory Syndrome (IRIS) with acute tuberculous osteomyelitis and disseminated mutilating tuberculous dactylitis in a person living with HIV and AIDS (PLHA): a case report.",
"title_normalized": "immune reconstitution inflammatory syndrome iris with acute tuberculous osteomyelitis and disseminated mutilating tuberculous dactylitis in a person living with hiv and aids plha a case report"
} | [
{
"companynumb": "IN-MYLANLABS-2015M1009374",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "We present here the first published use of letermovir for the treatment of resistant cytomegalovirus (CMV) in a pediatric patient. A 14-year-old girl underwent a double unrelated umbilical cord blood transplantation to treat her sickle cell disease (hemoglobin SS) and developed ganciclovir-resistant CMV DNAemia with end-organ involvement that was treated successfully with a combination of foscarnet and letermovir. After she was transitioned to letermovir monotherapy for secondary prophylaxis, she developed recurrent DNAemia with laboratory-confirmed ganciclovir, foscarnet, and letermovir resistance.",
"affiliations": "Division of Pediatric Infectious Diseases, Duke University, Durham, North Carolina.;Division of Pediatric Infectious Diseases, Duke University, Durham, North Carolina.;Department of Epidemiology, Gillings School of Global Public Health and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.;Pediatric Bone Marrow Transplant Program, Duke University, Durham, North Carolina.;Pediatric Bone Marrow Transplant Program, Duke University, Durham, North Carolina.;Division of Pediatric Infectious Diseases, Duke University, Durham, North Carolina.;Division of Pediatric Infectious Diseases, Duke University, Durham, North Carolina.",
"authors": "Kilgore|Jacob T|JT|;Becken|Bradford|B|;Varga|Matthew G|MG|;Parikh|Suhag|S|;Prasad|Vinod|V|;Lugo|Debra|D|;Chang|Yeh-Chung|YC|",
"chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C000588473:letermovir",
"country": "England",
"delete": false,
"doi": "10.1093/jpids/piz050",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-7193",
"issue": "9(4)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": "antiviral resistance; cytomegalovirus (CMV); hematopoietic stem cell transplant; letermovir",
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": "D000085:Acetates; D000293:Adolescent; D000998:Antiviral Agents; D003586:Cytomegalovirus Infections; D024882:Drug Resistance, Viral; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D011799:Quinazolines; D016879:Salvage Therapy",
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "486-489",
"pmc": null,
"pmid": "31362308",
"pubdate": "2020-09-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30154125;25999800;11154213;21752907;24162611;29211658;27909435;22044356;2158278;26259791",
"title": "Use of Letermovir for Salvage Therapy for Resistant Cytomegalovirus in a Pediatric Hematopoietic Stem Cell Transplant Recipient.",
"title_normalized": "use of letermovir for salvage therapy for resistant cytomegalovirus in a pediatric hematopoietic stem cell transplant recipient"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP004757",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "In a previous trial, we found that combined 13-cis-retinoic acid, IFN-alpha, and alpha-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 (CD1) G/A870 single nucleotide polymorphism correlated with cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and protein expression, in association with cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cis-retinoic acid daily, alpha-IFN twice weekly, and alpha-tocopherol daily for 1 year; 14 nonprogressing patients then were randomized to maintenance fenretinide or placebo for 2 years. During induction, two patients had pathologic complete responses, six had partial responses (30% overall response rate), and five developed laryngeal cancer. There were no significant differences between maintenance fenretinide and placebo in response or cancer rates. Ten patients developed cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pretreatment and posttreatment CD1 protein expression. Consistent with our earlier report, shorter cancer-free survival was associated with the CD1 AA/AG genotype (P = 0.05). Extending our earlier work, high CD1 expression was associated with worse cancer-free survival overall (P = 0.04) and within each CD1 genotype group. These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.",
"affiliations": "Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030, USA. vpapadim@mdanderson.org",
"authors": "Papadimitrakopoulou|Vassiliki|V|;Izzo|Julie G|JG|;Liu|Diane D|DD|;Myers|Jeffrey|J|;Ceron|Tania L|TL|;Lewin|Jan|J|;William|William N|WN|;Atwell|Anthea|A|;Lee|J Jack|JJ|;Gillenwater|Ann|A|;El-Naggar|Adel|A|;Wu|Xifeng|X|;Lippman|Scott M|SM|;Hittelman|Walter N|WN|;Hong|Waun Ki|WK|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016898:Interferon-alpha; D019938:Cyclin D1; D017313:Fenretinide; D015474:Isotretinoin; D024502:alpha-Tocopherol",
"country": "United States",
"delete": false,
"doi": "10.1158/1940-6207.CAPR-08-0111",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1940-6215",
"issue": "2(1)",
"journal": "Cancer prevention research (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Cancer Prev Res (Phila)",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D019938:Cyclin D1; D005260:Female; D017313:Fenretinide; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha; D015474:Isotretinoin; D007818:Laryngeal Diseases; D007822:Laryngeal Neoplasms; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions; D024502:alpha-Tocopherol",
"nlm_unique_id": "101479409",
"other_id": null,
"pages": "14-21",
"pmc": null,
"pmid": "19139013",
"pubdate": "2009-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "2929313;10764424;16638786;11408495;3537787;17308274;15837897;6537892;9815768;9093712;14612495;12569141;15744163;5098108;7885166;1835622;18413827;3893773;9816241;7473809;2725166;8334674;9393879;17634526;1734084;10522499;9850093;8416267;7675441;8261419;8944297;10620636;2252043;3755977;19075276;9790547;1569455;1734085",
"title": "Cyclin D1 and cancer development in laryngeal premalignancy patients.",
"title_normalized": "cyclin d1 and cancer development in laryngeal premalignancy patients"
} | [
{
"companynumb": "US-ROCHE-623062",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INTERFERON ALFA-2A"
},
"drugadditional": "3",
... |
{
"abstract": "Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) has been popularized as an attractive alternative to redo surgical aortic valve replacement for bioprosthetic valve dysfunction. Acute valve thrombosis has been occasionally described after ViV-TAVR. Lack of anticoagulant therapy has been always considered a crucial risk factor. This report describes a rare case of early postoperative fatal ViV-TAVR thrombosis despite adequate anticoagulation in addition to dual antiplatelet therapy.",
"affiliations": "Division of Cardiac Surgery, University of Verona Medical School, Verona, Italy. Electronic address: alessandrafrancica@yahoo.it.;Division of Cardiac Surgery, University of Verona Medical School, Verona, Italy.;Division of Cardiac Surgery, University of Verona Medical School, Verona, Italy.;Division of Pathological Anatomy, University of Verona Medical School, Verona, Italy.;Division of Cardiology, University of Verona Medical School, Verona, Italy.;Division of Cardiology, University of Verona Medical School, Verona, Italy.;Division of Cardiac Surgery, University of Verona Medical School, Verona, Italy.;Division of Cardiac Surgery, University of Verona Medical School, Verona, Italy.",
"authors": "Francica|Alessandra|A|;Dodonov|Mikhail|M|;Tonelli|Filippo|F|;Paolino|Gaetano|G|;Pesarini|Gabriele|G|;Ribichini|Flavio|F|;Faggian|Giuseppe|G|;Onorati|Francesco|F|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2020.10.062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "112(1)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000369:Aged, 80 and over; D001021:Aortic Valve; D001024:Aortic Valve Stenosis; D001705:Bioprosthesis; D017809:Fatal Outcome; D005500:Follow-Up Studies; D006350:Heart Valve Prosthesis; D006801:Humans; D008297:Male; D011474:Prosthesis Design; D011475:Prosthesis Failure; D012307:Risk Factors; D013927:Thrombosis; D013997:Time Factors; D065467:Transcatheter Aortic Valve Replacement",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e21-e22",
"pmc": null,
"pmid": "33412136",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Early Postoperative Thrombosis of Transcatheter Aortic Valve-in-Valve Prosthesis.",
"title_normalized": "early postoperative thrombosis of transcatheter aortic valve in valve prosthesis"
} | [
{
"companynumb": "IT-AUROBINDO-AUR-APL-2021-039820",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditio... |
{
"abstract": "Itacitinib is a potent, selective JAK-1 inhibitor currently in phase 3 development for the treatment of acute and chronic graft-versus-host disease (GVHD) in combination with corticosteroids. Itacitinib is primarily eliminated via metabolism by cytochrome P-450 (CYP)3A4 with minimal renal elimination. A drug-drug interaction study was conducted to evaluate the impact of the strong CYP3A inhibitor itraconazole or the strong CYP3A4 inducer rifampin on the pharmacokinetics of itacitinib in healthy volunteers. In cohort 1, subjects received 200 mg sustained release (SR) tablets of itacitinib on days 1 and 6 and 200 mg itraconazole on days 2-7. In cohort 2, subjects received 200 mg SR itacitinib on days 1 and 9 and 600 mg rifampin on days 2-9. Thirty-six subjects were enrolled, 18 in each cohort with 17 completing itacitinib dosing in cohort 1 and 15 completing itacitinib dosing in cohort 2. Coadministration of itraconazole with itacitinib resulted in a nearly 5-fold increase in area under the concentration-time curve (AUC0-∞ ) (geometric mean ratio [GMR] 4.88, 90%Cl 4.17-5.72) and an ∼3-fold increase in peak concentration (Cmax ) (GMR 3.15, 90%Cl 2.58-3.54). Coadministration of rifampin with itacitinib resulted in a nearly 80% decrease in AUC0-∞ (GMR 0.208, 90%Cl 0.173, 0.249) and Cmax (GMR 0.231, 90%Cl 0.195, 0.274). Results of this study informed the study design of the phase 3 GVHD protocols with regard to coadministration of strong CYP3A inhibitors and CYP3A4 inducers. These data combined with phase 3 data will inform final dosing recommendations.",
"affiliations": "Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.;Incyte Corporation, Wilmington, DE, USA.",
"authors": "Barbour|April M|AM|;Punwani|Naresh|N|;Epstein|Noam|N|;Landman|Robert|R|;Cimino|Evan|E|;Yuska|Brad|B|;Wang|Phillip|P|;He|Kevin|K|;Chen|Xuejun|X|;Yeleswaram|Swamy|S|",
"chemical_list": "D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D047428:Protein Kinase Inhibitors; D017964:Itraconazole; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.1484",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2700",
"issue": "59(12)",
"journal": "Journal of clinical pharmacology",
"keywords": "CYP3A4; drug-drug interaction; itacitinib; itraconazole; pharmacokinetics; rifampin",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D012293:Rifampin; D055815:Young Adult",
"nlm_unique_id": "0366372",
"other_id": null,
"pages": "1641-1647",
"pmc": null,
"pmid": "31282592",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of Itraconazole or Rifampin on Itacitinib Pharmacokinetics When Administered Orally in Healthy Subjects.",
"title_normalized": "effect of itraconazole or rifampin on itacitinib pharmacokinetics when administered orally in healthy subjects"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-07143",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"dru... |
{
"abstract": "Guidelines recommend that patients with hepatitis C virus (HCV)-related liver disease be treated for HCV before liver transplant (LT) to eliminate the virus before surgery. However, the unpredictability of donor organ availability may limit treatment duration. Interruption of HCV treatment with resumption post-LT is 1 potential solution which has not been investigated widely.\n\n\n\nPatients from 5 clinical centers included in the large, national, noninterventional Hepa-C registry who started treatment with direct-acting antiviral agents while awaiting LT were identified retrospectively and followed up prospectively. Fifteen patients who had treatment interruptions around LT were identified.\n\n\n\nThe majority of patients (12/15) received interferon-free regimens, most commonly sofosbuvir + daclatasvir (8/12), for a total of 24 weeks (13/15). Treatment was discontinued temporarily for a median of 5 (range, 2-33) days. Fourteen patients completing 12 weeks of follow-up achieved a sustained virological response. One patient who died before week 12 posttreatment achieved a response at posttreatment week 4. Treatment was generally well tolerated. Serious adverse events were recorded in 2 of 15 patients (anaemia in 1 patient; pneumonia in 1 patient); all arose after LT.\n\n\n\nResumption of direct-acting antiviral agent therapy after a temporary interruption around LT was highly effective, achieving sustained virological response in all patients who completed 12 weeks of posttreatment follow-up. Treatment was generally well tolerated pretransplantation and posttransplantation, with a low rate of serious adverse events. Such a strategy may offer an important new approach to the treatment of patients awaiting LT which may be assessed in future studies.",
"affiliations": "1 Liver Unit, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHIM, CIBERehd, Majadahonda, Madrid, Spain. 2 Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. 3 Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebron, CIBERehd, Barcelona, Spain. 4 Hepatology and Liver Transplant Unit, Hospital Universitario Reina Sofía, IMIBIC, CIBERehd, Córdoba, Spain. 5 Gastroenterology and Hepatology Unit, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain. 6 Digestive Service, Hospital Universitario 12 de Octubre, Madrid, Spain. 7 Liver Unit, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid and CIBERehd, Madrid, Spain.",
"authors": "Fernández Carrillo|Carlos|C|;Crespo|Gonzalo|G|;de la Revilla|Juan|J|;Castells|Lluís|L|;Buti|Maria|M|;Montero|José Luis|JL|;Fábrega|Emilio|E|;Fernández|Inmaculada|I|;Serrano-Millán|Cristina|C|;Hernández|Victoria|V|;Calleja|José Luis|JL|;Londoño|María-Carlota|MC|",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0000000000001596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "101(5)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D058625:End Stage Liver Disease; D005260:Female; D005500:Follow-Up Studies; D019698:Hepatitis C, Chronic; D006801:Humans; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D019990:Perioperative Care; D011446:Prospective Studies; D012042:Registries; D012189:Retrospective Studies; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "1009-1012",
"pmc": null,
"pmid": "27906834",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful Continuation of HCV Treatment After Liver Transplantation.",
"title_normalized": "successful continuation of hcv treatment after liver transplantation"
} | [
{
"companynumb": "ES-TEVA-783683ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Fatal myocarditis is a rare complication in immunosuppressed children. Recent reports have linked human herpesvirus 6 (HHV-6) infection, typically a benign infection in childhood, with myocarditis. HHV-6 can reactivate during periods of immunosuppression. Here, we report 2 cases in which children were immunosuppressed, one for treatment of Evans syndrome and the other post hematopoietic stem cell transplantation, who developed rapid and fatal HHV-6-associated myocarditis. These cases suggest that HHV-6 infection should be considered as an etiology of myocarditis in immunosuppressed patients regardless of correlating blood levels. Early treatment of HHV-6 in patients with myocarditis could improve morbidity and mortality.",
"affiliations": "Divsion of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota; and.;Divsion of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota; and.;Divsion of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota; and.;Biocenter, Chair of Microbiology, University of Würzburg, Würzburg, Germany.;Divsion of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota; and.;Divsion of Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minnesota; and lundx072@umn.edu.",
"authors": "Stefanski|Heather E|HE|;Thibert|Kathryn A|KA|;Pritchett|Joshua|J|;Prusty|Bhupesh K|BK|;Wagner|John E|JE|;Lund|Troy C|TC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2015-1352",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "137(1)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000293:Adolescent; D002675:Child, Preschool; D017809:Fatal Outcome; D005260:Female; D006566:Herpesviridae Infections; D015654:Herpesvirus 6, Human; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009205:Myocarditis",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26681781",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17116768;17015795;25388833;21802354;15699250;23473961;21549850;24297820;24673253;16172268;20838386;24810656;15606551;11724892;22212513;23955460;15824982;21794043;19664576;21296175;23000642",
"title": "Fatal Myocarditis Associated With HHV-6 Following Immunosuppression in Two Children.",
"title_normalized": "fatal myocarditis associated with hhv 6 following immunosuppression in two children"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP000959",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"dru... |
{
"abstract": "We report four cases of glioblastoma in the pineal region. The patients presented a severe headache and vomiting. Brain imaging showed a heterogeneously enhanced tumor in the pineal region with obstructive hydrocephalus. Case 3 developed a subependymal dissemination. The patient went to ventricular-peritoneal shunt and subtotal or total resection and radiotherapy with/without chemotherapy. Cases 1 and 2 received radiation and died 8 and 11 later months. Cases 3 and 4 completed radiotherapy and chemotherapy, and survived 28 and 31 months after the initial diagnosis. Glioblastoma in the pineal region carry a poor prognosis and require neurooncology teams.",
"affiliations": "Department of Neurosurgery, Instituto Nacional de Enfermedades Neoplasicas, 15038 Lima, Peru.;Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, 15038 Lima, Peru.;Research Department, Instituto Nacional de Enfermedades Neoplasicas, 15038 Lima, Peru.;Department of Neurosurgery, Instituto Nacional de Enfermedades Neoplasicas, 15038 Lima, Peru.;Research Department, Instituto Nacional de Enfermedades Neoplasicas, 15038 Lima, Peru.;Research Department, Instituto Nacional de Enfermedades Neoplasicas, 15038 Lima, Peru.",
"authors": "Orrego|Enrique|E|;Casavilca|Sandro|S|;Garcia-Corrochano|Pamela|P|;Rojas-Meza|Sugey|S|;Castillo|Miluska|M|;Castaneda|Carlos A|CA|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/cns-2016-0047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2045-0907",
"issue": "6(4)",
"journal": "CNS oncology",
"keywords": "brain tumor; glioblastoma; pineal",
"medline_ta": "CNS Oncol",
"mesh_terms": "D000328:Adult; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D010870:Pineal Gland",
"nlm_unique_id": "101594668",
"other_id": null,
"pages": "251-259",
"pmc": null,
"pmid": "28990813",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "19269895;24807547;508133;16645719;9548342;8306360;24998223;4537183;3883555;6261912;17618441;18752674;12894287;16198924;26713151;26338394;26580928;4730334;11767290;1965444;24101287;2451717",
"title": "Glioblastoma of pineal region: report of four cases and literature review.",
"title_normalized": "glioblastoma of pineal region report of four cases and literature review"
} | [
{
"companynumb": "PE-MYLANLABS-2017M1082959",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo assess the immunomodulatory and clinical effects of lenalidomide with standard treatment of gemcitabine in patients with advanced pancreatic cancer.\n\n\nMETHODS\nPatients with advanced pancreatic cancer were treated in first line with lenalidomide orally for 21 days of a 28 days cycle and the standard regimen for gemcitabine. In Part I, which we previously have reported, the dose of lenalidomide was defined (n = 12). In Part II, every other consecutive patient was treated with either lenalidomide (Group A, n = 11) or gemcitabine (Group B, n = 10) during cycle 1. From cycle 2 on, all Part II patients received the combination.\n\n\nRESULTS\nA significant decrease in the proliferative response of peripheral blood mononuclear cells and the frequency of DCs were noted in patients at baseline compared to healthy control donors while the frequencies of CD4+ and CD8+ T cells, NK-cells and MDSCs were significantly higher in patients compared to controls. In Group A, a significant increase in the absolute numbers of activated (HLA-DR+) CD4 and CD8 T cells and CD8 effector memory T cells (p<0.01) was noted during treatment. A statistical increment in the absolute numbers of Tregs were seen after cycle 1 (p<0.05). The addition of gemcitabine, reduced most lymphocyte subsets (p<0.05). In Group B, the proportion of lymphocytes remained unchanged during the study period. There was no difference in overall survival, progression free survival and survival rate at one year comparing the two groups.\n\n\nCONCLUSIONS\nPatients with advanced pancreatic carcinoma had impaired immune functions. Lenalidomide augmented T cell reactivities, which were abrogated by gemcitabine. However, addition of lenalidomide to gemcitabine seemed to have no therapeutic impact compared to gemcitabine alone in this non-randomized study.\n\n\nBACKGROUND\nClinicalTrials.gov NCT01547260.",
"affiliations": "Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.;Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.;Department of Oncology, Danderyd University Hospital, Stockholm, Sweden.;Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.;Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.",
"authors": "Ullenhag|Gustav J|GJ|;Mozaffari|Fariba|F|;Broberg|Mats|M|;Mellstedt|Håkan|H|;Liljefors|Maria|M|",
"chemical_list": "D003841:Deoxycytidine; D013792:Thalidomide; C056507:gemcitabine; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0169736",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2809950210.1371/journal.pone.0169736PONE-D-16-38493Research ArticleBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsT CellsBiology and Life SciencesCell BiologyCellular TypesAnimal CellsImmune CellsWhite Blood CellsT CellsBiology and Life SciencesImmunologyImmune CellsWhite Blood CellsT CellsMedicine and Health SciencesImmunologyImmune CellsWhite Blood CellsT CellsMedicine and Health SciencesOncologyCancer TreatmentBiology and life sciencesCell biologyCellular typesAnimal cellsBlood cellsWhite blood cellsT cellsCytotoxic T cellsBiology and life sciencesCell biologyCellular typesAnimal cellsImmune cellsWhite blood cellsT cellsCytotoxic T cellsBiology and life sciencesImmunologyImmune cellsWhite blood cellsT cellsCytotoxic T cellsMedicine and health sciencesImmunologyImmune cellsWhite blood cellsT cellsCytotoxic T cellsMedicine and Health SciencesOncologyCancers and NeoplasmsGastrointestinal TumorsPancreatic CancerBiology and life sciencesCell biologyCellular typesAnimal cellsBlood cellsWhite blood cellsT cellsRegulatory T cellsBiology and life sciencesCell biologyCellular typesAnimal cellsImmune cellsWhite blood cellsT cellsRegulatory T cellsBiology and life sciencesImmunologyImmune cellsWhite blood cellsT cellsRegulatory T cellsMedicine and health sciencesImmunologyImmune cellsWhite blood cellsT cellsRegulatory T cellsBiology and Life SciencesToxicologyToxicityMedicine and Health SciencesPathology and Laboratory MedicineToxicologyToxicityBiology and life sciencesCell biologyCellular typesAnimal cellsBlood cellsWhite blood cellsNK cellsBiology and life sciencesCell biologyCellular typesAnimal cellsImmune cellsWhite blood cellsNK cellsBiology and life sciencesImmunologyImmune cellsWhite blood cellsNK cellsMedicine and health sciencesImmunologyImmune cellsWhite blood cellsNK cellsMedicine and Health SciencesSurgical and Invasive Medical ProceduresClinical and Immune Effects of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer Lenalidomide Combined with Gemcitabine in Advanced Pancreatic CancerUllenhag Gustav J. 12Mozaffari Fariba 3Broberg Mats 4Mellstedt Håkan 3Liljefors Maria 35*1 \nDepartment of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden2 \nDepartment of Oncology, Uppsala University Hospital, Entrance 78, Uppsala, Sweden3 \nDepartment of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden4 \nDepartment of Oncology, Danderyd University Hospital, Stockholm, Sweden5 \nDepartment of Oncology, Karolinska University Hospital Solna, Stockholm, SwedenRosell Rafael EditorCatalan Institute of Oncology, SPAINCompeting Interests: I have read the journal's policy and one author of this manuscript has the following competing interest. Maria Liljefors has declared one compensatory advisory role with Celgene Corporation. This does not alter the authors adherence to PLoS One policies on sharing data and materials. The other authors have declared that no competing interests exist.\n\nConceptualization: ML.\n\nFormal analysis: ML FM.\n\nFunding acquisition: ML HM GU.\n\nInvestigation: ML GU MB.\n\nMethodology: ML.\n\nResources: HM MB.\n\nSupervision: HM.\n\nVisualization: FM ML GU.\n\nWriting – original draft: ML GU.\n\nWriting – review & editing: HM ML GU.\n\n\n\n\n* E-mail: maria.gustafsson-liljefors@karolinska.se18 1 2017 2017 12 1 e016973628 9 2016 12 12 2016 © 2017 Ullenhag et al2017Ullenhag et alThis 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.Purpose\nTo assess the immunomodulatory and clinical effects of lenalidomide with standard treatment of gemcitabine in patients with advanced pancreatic cancer.\n\nPatients and Methods\nPatients with advanced pancreatic cancer were treated in first line with lenalidomide orally for 21 days of a 28 days cycle and the standard regimen for gemcitabine. In Part I, which we previously have reported, the dose of lenalidomide was defined (n = 12). In Part II, every other consecutive patient was treated with either lenalidomide (Group A, n = 11) or gemcitabine (Group B, n = 10) during cycle 1. From cycle 2 on, all Part II patients received the combination.\n\nResults\nA significant decrease in the proliferative response of peripheral blood mononuclear cells and the frequency of DCs were noted in patients at baseline compared to healthy control donors while the frequencies of CD4+ and CD8+ T cells, NK-cells and MDSCs were significantly higher in patients compared to controls. In Group A, a significant increase in the absolute numbers of activated (HLA-DR+) CD4 and CD8 T cells and CD8 effector memory T cells (p<0.01) was noted during treatment. A statistical increment in the absolute numbers of Tregs were seen after cycle 1 (p<0.05). The addition of gemcitabine, reduced most lymphocyte subsets (p<0.05). In Group B, the proportion of lymphocytes remained unchanged during the study period. There was no difference in overall survival, progression free survival and survival rate at one year comparing the two groups.\n\nDiscussion\nPatients with advanced pancreatic carcinoma had impaired immune functions. Lenalidomide augmented T cell reactivities, which were abrogated by gemcitabine. However, addition of lenalidomide to gemcitabine seemed to have no therapeutic impact compared to gemcitabine alone in this non-randomized study.\n\nTrial Registration\nClinicalTrials.gov NCT01547260\n\nThe Swedish Cancer Society110711Liljefors Maria The Karolinska Institute FoundationLiljefors Maria The Karolinska Institute FoundationMellstedt Håkan Stockholm County Council (ALF)20150070Liljefors Maria the Research Foundation Stiftelsen Onkologiska Klinikens i Uppsala ForskningsfondUllenhag Gustav J. Lion´s Cancer FundUllenhag Gustav J. Celgene Corporation, Summit, NJ, USALiljefors Maria Celgene Corporation, Summit, NJ, USAMellstedt Håkan This investigator-initiated study was supported by the Swedish Cancer Society (Grant no. 110711, URL: www.cancerfonden.se); The Karolinska Institute Foundation (URL: https://fonder.ki.se/) and the Stockholm County Council (ALF) (Grant nr. 20150070, URL: https://forskningsstod.vmi.se/Ansokan/start.asp); the Research Foundation Stiftelsen Onkologiska Klinikens i Uppsala Forskningsfond; Lion´s Cancer Fund and in part by a grant from Celgene Corporation, Summit, NJ, USA which provided the lenalidomide. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nPancreatic cancer is characterised by aggressive growth and treatment resistance [1]. The majority of patients presents with advanced disease and the five-year survival rate is less than 5% [2]. Even those twenty percent of patients who are eligible for radical surgery including adjuvant chemotherapy have a poor prognosis with only 20% alive at 5 years [3].\n\nFor patients with advanced disease, gemcitabine is the standard treatment resulting in a median survival time of 5.7 months [4]. Combining gemcitabine and capecitabine improved overall survival (OS) but with a more pronounced toxicity profile compared to gemcitabine alone [5]. Triple chemotherapy (FOLFIRINOX) also increased OS compared to gemcitabine, but again with added toxicity [6]. Blocking the epidermal growth factor receptor (EGFR) with erlotinib in combination with gemcitabine significantly improved OS but only with two months and hand-foot side effects were common [7]. Overall survival was also extended by two months adding nabpaclitaxel to gemcitabine [8]. Regardless of currently available treatments regimens, survival of pancreatic cancer patients remains dismal and new therapies are warranted.\n\nLenalidomide (Revlimid®), is a thalidomide analogue that was initially approved by the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA) for multiple myeloma (MM) [9,10]. The compound may exert anti-tumor effects through anti-angiogenic activities [11] and by the expansion of tumor antigen-specific T cells, augmenting natural killer (NK)—cell cytotoxicity [12]. Furthermore, lenalidomide stimulates T-cells inducing proliferation, cytokine production, and cytotoxic activity [12–14] and inhibits TNF-α and interleukin 12 production [15,16].\n\nClinical effects of lenalidomide alone have been observed in patients with various advanced solid tumors [17–20] or in combination with chemotherapy [21]. Combined treatment with gemcitabine and lenalidomide of pancreatic carcinoma cells in vitro induced a higher tumor cell killing than with either agent alone [22]. Treatment of patients with metastatic pancreatic carcinoma using immunomodulatory drugs, such as pomalidomide or lenalidome in combination with gemcitabine, showed no clinical effects [23,24](23, 24). However, our study was initiated before the results from those studies were published.\n\nGemcitabine exerts a direct cytotoxic effect on tumor cells [23], but also augments immune responses contributing to a therapeutic effect [24]. Gemcitabine may activate T cells [25], increase the number of dendritic cells (DCs) [26], augment loading of antigens onto antigen-presenting cells (APC) [27], down-regulate the frequency of T-regulatory (Treg) cells [28], as well as myeloid derived suppressor cells (MDSC) [29] and increase the production of T cell derived IL-6 [30]. Administration of gemcitabine may also render tumor cells more susceptible to T-cell mediated destruction by up-regulation of death receptors [31]. Furthermore, gemcitabine has been shown to enhance immune responses against cancer vaccines [25]. The data support that lenalidomide and gemcitabine in combination may be of interest to explore for the therapy of pancreatic carcinoma.\n\nWe have conducted a study in chemo-naive patients with advanced pancreatic cancer combining lenalidomide and gemcitabine. Part I of the trial, defining the lenalidomide dose has previously been reported [32]. In part II, patients were first treated with lenalidomide or gemcitabine alone respectively,followed by the combination of these two agents. In this report, immune responses and clinical effects of part II are presented as well as survival data for all patients.\n\nMaterials and Methods\nThe Protocol for this trial and supporting TREND Checklist are available as supporting information, see S1 File and S1 Fig. The CONSORT Flow Diagram is shown in Fig 1.\n\n10.1371/journal.pone.0169736.g001Fig 1 CONSORT Flow Diagram for the patients screened for and enrolled in part II.\nCorresponding data for patients enrolled in part I, has been published in Ullenhag GJ et al, PLOS ONE, 2015; 10(4).\n\nTo our knowledge, all ongoing and related trials for this drug/intervention are registered.\n\nThe study (ClinicalTrials.gov identifier, NCT01547260) (https://register.clinicaltrials.gov/) was approved by the Regional Ethical Review Boards for Stockholm and Uppsala on the 6th of October 2009 and by the Medical Products Agency Uppsala, Sweden. The study was registered at ClinicalTrials.gov only after inclusion began since registration was not a routine procedure in Sweden in 2009. Patients were treated according to the Declaration of Helsinki’s ethical principles for medical research involving human subjects. The trial was performed according to Good Clinical Practice guidelines. All patients provided an informed written consent prior to study entry.\n\nPatient population\nDetails regarding patients have been described elsewhere [32]. Briefly, eligible patients had histologically or cytologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the pancreas. No prior chemotherapy for metastatic or locally advanced disease was allowed. Other eligibility criteria included: age >18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, life expectancy > 12 weeks, adequate bone marrow, renal and hepatic functions as defined [32]. Patients enrolled in part I were recruited from the 14th January 2010 to the 20th May 2011, patients enrolled in part II were recruited from the 12th October 2011 to the 13th February 2013.All patients were followed up for survival every 3 month after discontinuation of the trial. The first follow up was on the 12th October 2010 and the last follow up was on the 11th November 2014.\n\nStudy design and treatment schedule\nThis dual-agent, three-centre, open-label phase I/II study was conducted at the Karolinska University Hospital, Departments of Oncology, Solna (parts I and II) and Danderyd (part II), respectively, and Department of Oncology, Uppsala University Hospital, Uppsala, Sweden (parts I and II).\n\nThirteen patients were recruited to part I and 21 patients to part II. Patients, who received at least two cycles of the treatment according to the study protocol, were considered to be evaluable. If therapy was discontinued before completion of two treatment cycles for other reasons than AEs as per protocol, the subject was replaced.\n\nThe primary study objectives of part I was to determine MTD (Maximum Tolerated Dose) and safety. In part II, the primary objective was to evaluate immunomodulatory effects. For both parts of the study, the secondary objective was to evaluate clinical efficacy.\n\nIn part I, lenalidomide was administered orally once daily for 21 days of a 28 day cycle. The dose-escalation procedure of lenalidomide in part I has previously been described [32]. Gemcitabine was administered at a dose of 1000 mg/m2 intravenously for 30 minutes, at days 1, 8 and 15 every 28 days. MTD of lenalidomide in combination with the standard dose of gemcitabine was established to 25 mg/day days 1–21 of 28 [32]. In part II, every other consecutively included patient was treated with either lenalidomide (Group A) or gemcitabine (Group B) as monotherapy, during treatment cycle number 1. From treatment cycle number 2, all patients (part II) were treated with lenalidomide in combination with gemcitabine. This design was chosen since we wanted to evaluate the immunomodulatory effects of either drug separately, in addition to the combined treatment. The patients received prophylactic low molecular weight heparin (LMWH) (dalteparin, Pfizer Inc. New York, USA) (5000 IU s.c. once daily) during lenalidomide treatment.\n\nPatient evaluation\nPatients were evaluated as previously described [32]. Progression-free survival (PFS) and OS were calculated from the time of start of study treatment until clinical and/or radiological signs of progression or until death, respectively. Survival rate at one year was calculated as the frequency of patients alive at week 52 after start of therapy. An electronic case report form (eCRF), PheedIt (SAS Institute) was used for recording.\n\nImmunoassays\nIn part II, peripheral blood samples were drawn for immune monitoring at three time-points; before treatment (baseline), at the end of treatment with lenalidomide or gemcitabine alone (after cycle 1) and after treatment with the combination of lenalidomide and gemcitabine (after cycle 2). Phenotyping of T cells (CD4, CD8), B cells and NK/NKT cells (CD16/CD56), Tregs and MDSCs was performed as described below.\n\nMonoclonal antibodies and other reagents\nAntibodies conjugated with FITC, PE, PerCP, APC, AF700 and Pacific blue against the surface on intracellular molecules CD3, CD4, CD8, CD16, CD25, CD56, CD69, CD95, CD123, CD178, CD197, CD45RA, HLA-DR, CD11c, CD11b, CD127, Foxp3, Perforin, Granzyme B, IFN-γ, IL-17 as well as the anti-human lineage cocktail, CD3,CD14,CD19,CD20, CD56 including isotype-matched controls were purchased from Biolegend (Nordic Biosite, Täby, Sweden) and eBioscience, (San Diego, CA, USA). PMA and ionomycin were purchased from Sigma (St Louis, MO, USA) and Brefeldin A was obtained from BD (Mountain view, CA, USA).\n\nCellular staining and flow cytometry\nPeripheral blood mononuclear cells (PBMC) were isolated from heparinized blood by separation on a Ficoll–Isopaque gradient (Amersham Pharmacia Biotech AB, Uppsala, Sweden). PBMC were used for cytokines secretion (IL-17/IFNγ) assay in T cells (CD4+/CD8+), NK cells (CD3-CD56+) and NKT cells (CD3+CD56+) as well as for T cell proliferation assays.\n\nLysed blood was used for detecting Tregs (CD4+CD25+CD123-/low Foxp3+), effector/memory CD4+/CD8+ cells (CD45RA+/-/CCR7+/-), DCs (Lin-HLA-DR+CD16+CD11c+CD123+), MDSCs (Lin-HLA-DR-CD16-CD11b+CD33+), lymphocyte subsets and Perforin/Granzyme B secretions by T, NK and NKT cells. Briefly, 1x106 cells per tube were incubated with the appropriate concentrations of antibodies or isotype controls for 30 min on ice. Intracellular staining of cells was done after surface staining, fixation, permeabilization, and incubation with specific antibodies. To assess the ability of T/NK/NKT cells to produce IL-17/IFNγ in response to stimuli, intracellular staining for cytokines was performed after treatment with PMA/Ionomycin for 3 hours. Treg staining was carried out according to the instruction of the manufacturer (eBioscience). Cells were analyzed using a LSRII (BD) and data analyzed by the Flowjo software (OR, USA) as described [33]. A positive staining was set at a fluorescence intensity displayed by<1% of the cells stained with the isotype control. Cell subsets are presented as absolute numbers (x 109/L).\n\nProliferation assay\nPBMC were stimulated with PHA (10 μg/ml) (Gibco BRL, Grand Island, NY, USA) in a 96-well culture plate. Cultures were incubated for 5 days. 1 mCi / well 3H-thymidine (Amersham Pharmacia Biotech, Uppsala, Sweden) was added for the final 16–18 h. Incorporated radioactivity was measured in a β-counter (Micro β1450, Wallace, Turku, Finland). Results are presented as stimulation index (SI) and calculated as the ratio of radioactivity of cells incubated with PHA compared to control cultures [34].\n\nHealthy controls\nBlood of healthy aged-match donors, recruited among health care and laboratory personnel, were used as controls.\n\nStatistical methods\nStatistical analyses were done using StatView® (SAS Institute Inc. Version 5.0.1., USA) and Prismversion 6.0 (Graphpad software, Ca, USA). Frequency and intensity of adverse events (AE) and serious adverse events (SAE) are subjects to descriptive analysis. PFS and OS time curves were plotted using the Kaplan-Meier method. Differences between survival curves were tested using the log-rank statistics. The chi-square and Fisher´s exact tests were applied for comparison of distribution between groups. The one way ANOVA for repeated measures was used to calculate statistical significance for cell markers. The Mann-Whitney test was used for comparison of patients at baseline with healthy controls. There was no adjustment for multiplicity. Results were considered to be statistically significant for p<0.05.\n\nResults\nPatient characteristics\nThirteen patients were included in the part I study. The patients characteristics has been described elsewhere [32]. Twenty-one were included in the part II study (Group A: n = 11, Group B: n = 10). Clinical characteristics of the patients included in part II are shown in Table 1. Median time from diagnosis to start of treatment with lenalidomide and gemcitabine was 7 weeks (range 2–11 weeks).\n\n10.1371/journal.pone.0169736.t001Table 1 Patients baseline characteristics and number of patients per treatment arm in phase II.\nPatient no.\tSex/age (years)\tECOG performance status\tSite of metastasis at inclusion\tPrevioustreatment\tTreatment Arm #\tNo. of treatment- cycles\tNo. of immune- samples\tPFS (weeks)\tOS (weeks)*\t\n201\tM/64\t0\tPeritoneum\tNone\tA\t4\t3\t10\t25\t\n202\tF/68\t1\tLiver\tNone\tB\t2\t3\t8\t32\t\n203\tF/61\t0\tLAPC w/o met*\tSurgery (P)**\tA\t2\t2\t8\t13\t\n204\tF/77\t0\tLiver\tNone\tB\t4\t3\t16\t76\t\n205\tM/78\t1\tLAPC w/o met\tNone\tA\t1\t1\tNE ##\t19\t\n206\tM/63\t1\tMultiple\tNone\tB\t1\t2\tNE\t7\t\n207\tF/66\t1\tPeritoneum\tSurgery (P)\tA\t5\t3\t19\t84\t\n208\tF/58\t0\tLAPC w/o met\tNone\tB\t4\t3\t16\t112\t\n209\tF/72\t1\tLAPC w/o met\tNone\tA\t6\t3\t23\t79\t\n210\tF/69\t0\tLiver\tNone\tB\t9\t3\t42\t48\t\n211\tF/73\t0\tNodes\tNone\tA\t10\t3\t39\t130\t\n212\tM/72\t1\tLAPC w/o met\tNone\tB\t4\t3\t17\t85\t\n213\tM/51\t0\tPeritoneum\tNone\tA\t2\t3\t8\t31\t\n214\tM/72\t1\tLAPC w/o met\tNone\tB\t2\t3\t8\t27\t\n215\tM/62\t1\tLungs\tSurgery (C)\tA\t2\t3\t8\t19\t\n216\tM/77\t1\tLAPC w/o met\tNone\tB\t2\t3\t8\t17\t\n217\tM/77\t1\tLiver\tNone\tA\t1\t1\tNE\t4\t\n218\tF/68\t0\tLiver\tNone\tB\t4\t3\t17\t26\t\n219\tF/66\t0\tLiver\tNone\tA\t2\t3\t7\t25\t\n220\tF/78\t0\tLAPC w/o met\tNone\tB\t15\t3\t66\t74\t\n221\tF/63\t1\tMultiple\tNone\tA\t3\t3\t15\t18\t\n* LAPC w/o met = locally advanced pancreatic cancer without metastasis.\n\n** Surgery (P) = surgery, palliative intention.\n\nSurgery (C) = surgery, curative intention (pancreaticoduodenectomy).\n\n# Arm A = lenalidomide monotherapy in cycle no. 1.\n\nArm B = gemcitabine monotherapy in cycle no. 1.\n\n## NE = not evaluable.\n\nTreatment scheduling performance\nDose reductions and treatment delays for patients in part I has been described previously [32]. In part II, a total number of 85 cycles were initiated (12 with lenalidomide as monotherapy; 9 with gemcitabine as monotherapy and 64 with the combination). Dose-reductions were frequently seen both for lenalidomide and gemcitabine. In Group A, 44.7% (17/38) of the treatment cycles were dose-reduced. The corresponding figure for Group B was 42.5% (20/47).\n\nIn twenty-four cycles, reduction was due to haematologic toxicities (in 23 cycles due to leucopenia/neutropenia and in one cycle thrombocytopenia). In eleven cycles, reduction was associated with non-haematologic toxicities (in three cycles nausea/vomiting, in two cycles muscle/skeletal pain, in two cycles fatigue, in one cycle abdominal pain, in one cycle elevated ALAT/ASAT value, in one cycle vein thrombosis and in one cycle pulmonary embolism). In two patients (no 205 and 217) lenalidomide was permanently withdrawn at day 14 during cycle 1 (see below).\n\nTreatment delays were uncommon. In four patients, four cycles were delayed due to nausea (n = 1) and viral infections (n = 3). In two patients, six cycles were delayed at the discretion of the patients. Median delay was 12 days (range 1–32 days).\n\nMedian number of treatment cycles was 2 (range 1–10) in Group A and 4 (range 1–15) in Group B. Median treatment duration time was 8 weeks (range 2–35 weeks) and 15 weeks (range 2–70 weeks) in Group A and B, respectively. For all patients, median treatment duration was 10 weeks (range 2–70 weeks).\n\nImmune responses\nPeripheral blood was drawn at baseline in 19 of the 21 enrolled patients. All nineteen patients completed immune testing after cycle 1 (Group A, n = 9, Group B, n = 10) and 17 patients also after cycle 2 (Group A, n = 8, Group B, n = 9).\n\nImmune responses before treatment\nA significant decrease in T-cell proliferation (PHA-stimulation) and the frequency of DCs was noted in patients at baseline as compared to healthy control donors. However, the frequencies of CD4+, CD8+ and NK-cells, producing perforin and granzyme B, as well as MDSCs were significantly higher in patients compared to controls (Table 2). No difference in other immune tests comparing patients at baseline and healthy controls were noted (data not shown). There was no significant difference in immune responses at baseline comparing patients in Group A and B (Figs 2–4).\n\n10.1371/journal.pone.0169736.g002Fig 2 Absolute numbers of subsets of T cells at baseline (BL), at the end of cycle 1 (End C1) and at the end of cycle 2 (End C2) in part II patients treated with either lenalidomide monotherapy during cycle 1 with the addition of gemcitabine from cycle 2 (Arm A) (Left column) (Fig 2 A, C, E and G) or gemcitabine monotherapy during cycle 1 with the addition of lenalidomide from cycle 2 (Arm B) (Right column) (Fig 2 B, D, F and H). Changes in the absolute numbers of CD4+ T cells (A, B), CD8+ T cells (C, D), HLA-DR positive CD+4 T cells (E, F) and HLA-DR positive CD8+ T cells (G, H) over the treatment course, n = number of patients analysed at each time-point. P-values refer to the comparison with BL, End C1 and End C2 by one way ANOVA with repeated measures. The box, with a line indicating median, represents the 25th and 75th percentiles. The top and bottom whiskers represent the 90th and 10th percentiles, respectively.\n\n10.1371/journal.pone.0169736.g003Fig 3 Absolute numbers of subsets of effector and effector memory T cells at baseline (BL), at the end of cycle 1 (End C1) and at the end of cycle 2 (End C2) in part II patients treated with either lenalidomide monotherapy during cycle 1 with the addition of gemcitabine from cycle 2 (Arm A) (Left column) (Fig 3 A, C, E and G) or gemcitabine monotherapy during cycle 1 with the addition of lenalidomide from cycle 2 (Arm B) (Right column) (Fig 3 B, D, F and H). Changes in the absolute numbers of CD8+ effector T cells (CD45RA+CCR7-CD8+) (C, D), CD8+ effector memory T cells (CD45RA-CCR7-CD8+) (G, H), CD4+ effector T cells (CD45RA+CCR7-CD4+) (A-B) and CD4+ effector memory T cells (CD45RA-CCR7-CD4+) (E, F) over the treatment course. n = number of patients analysed at each time-point. P-values refer to the comparison with BL, End C1 and End C2 by one way ANOVA with repeated measures. The box, with a line indicating median, represents the 25th and 75th percentiles. The top and bottom whiskers represent the 90th and 10th percentiles, respectively.\n\n10.1371/journal.pone.0169736.g004Fig 4 Absolute numbers of NKT-cells (CD3+CD56+CD16+) and regulatory T cells (Treg)(CD4+CD25+CD127-Foxp3+) at baseline (BL), at the end of cycle 1 (End C1) and at the end of cycle 2 (End C2) in part II patients treated with either lenalidomide monotherapy during cycle 1 with the addition of gemcitabine from cycle 2 (Arm A) (Left column) (Fig 4 A and C) or gemcitabine monotherapy during cycle 1 with the addition of lenalidomide from cycle 2 (Arm B) (Right column) (Fig 4 B and D). Changes in the absolute numbers of NKT-cells (A, B) and regulatory T cells (C, D) over the treatment course. n = number of patients analysed at each time-point. P-values refer to the comparison with BL, End C1 and End C2 by one way ANOVA with repeated measures. The box, with a line indicating median, represents the 25th and 75th percentiles. The top and bottom whiskers represent the 90th and 10th percentiles, respectively.\n\n10.1371/journal.pone.0169736.t002Table 2 Immune reactivity of patients with advanced pancreatic cancer before treatment compared to healthy donors.\nImmune function\tPatients Mean + SEM\t(n)\tControls Mean + SEM\t(n)\tp value\t\nPHA-stimulation of PBMC (SI)*\t38.8 ± 13\t(18)\t102.7 ± 17.6\t(19)\t<0.01\t\nLymphocyte subsets (%):\t\t\t\t\t\t\nCD3+CD8+perforin\t3.95 ± 1.1\t(19)\t0.7 ± 0.2\t(11)\t<0.01\t\nCD3+CD4+perforin\t2.2 ± 0.7\t(19)\t0.3 ± 0.05\t(11)\t<0.01\t\nNK + perforin\t12.3 ± 1.8\t(19)\t5.5 ± 1.0\t(11)\t<0.01\t\nCD3+CD8+granzyme B\t10.3 ± 2.0\t(19)\t5.2 ± 1.3\t(11)\t<0.05\t\nCD3+CD4+granzyme B\t3.0 ± 0.5\t(19)\t1.2 ± 0.3\t(11)\t<0.05\t\nNK+granzyme B\t12.0 ± 1.7\t(19)\t6.7 ± 0.6\t(11)\t<0.05\t\nDendritic cells (%)\t0.08 ± 0.02\t(19)\t0.5 ± 0.1\t(11)\t<001\t\nMyeloid derived suppressor cells (%)\t0.33 ± 0.07\t(19)\t0.06 ± 0.01\t(11)\t<0.01\t\n*Stimulation index.\n\nImmune responses during treatment\nIn Group A, a significant increase in the absolute numbers of activated CD4 and CD 8 T cells (HLA-DR+) (p < 0.01) was noted after cycle 1 (Fig 2E and 2G) but the addition of gemcitabine significantly reduced the total number of CD4 and CD8 T cells as well as the fraction of activated (HLA-DR+) T cells (Fig 2A, 2C, 2G and 2E).\n\nCD8+ effector memory T cells (CD45RA-CCR7-CD8+) increased significantly after cycle 1 compared to baseline (p<0.01) (Fig 3G) and after adding gemcitabine CD4 and CD8 effector (Fig 3A and 3C) as well as effector memory T cells decreased significantly (Fig 3E and 3G).\n\nA clear trend (p = 0.06) to an increase in absolute numbers of NK-T cells (CD3+CD16+CD56+) was observed after cycle 1 compared to baseline in Group A (Fig 4A) and after adding of gemcitabine, the numbers of NKT cells was reduced (p<0.05). No significant changes in NK cells were observed (data not shown). A statistically significant increment in the absolute numbers of regulatory T-cells (Treg) (CD4+CD25+CD127-FOXp3+) was also noted in Group A after cycle 1, compared to baseline (p<0.05) which was reduced to baseline after cycle 2 (Fig 4C).\n\nIn Group B, however, the proportion of absolute numbers of CD4+ and CD8+ T cells (Fig 2B and 2D), activated (HLR-DR+) CD4+ and CD8+ T cells (Fig 2F and 2H), CD4+ and CD8+ effector (Fig 3B and 3D) and effector memory T cells (Fig 3F and 3H), NK cells (data not shown), NK-T cells and Tregs (Fig 4B and 4D), did not change over time.\n\nIn both Group A and B, the frequencies of activated B cells (CD69+CD95+), CD4+ cells CD8 T cells and NK/NKT-cells producing perforin, granzyme B or IFNγ remained unchanged (data not shown)as well as the proportion of MDSCs and DCs (data not shown).\n\nSide-effects\nAdverse events (AEs) and serious adverse events (SAEs) in part I have recently been described [32]. Hematological and non-hematological toxicities in part II are summarized in Table 3. Hematological AEs (all grades) were the most common, gastrointestinal (GI) intolerance and fatigue.\n\n10.1371/journal.pone.0169736.t003Table 3 Summary of maximum grade for toxicity in Ph II (Arm A and Arm B) (aggregate for all treatment cycles) (NCI CTCAE.V3.0).\nToxicity\tArm A (n = 11)\tArm B (n = 10)\tTotal (n = 21)\t\n\tG* 1–4 No** (%)\tG 1–4 No (%)\tG 1–4 No (%)\tG 3–4 No (%)\t\nBlood/bone marrow\t\t\t\t\t\nAnemia\t2(18)\t3(30)\t5(24)\t0(0)\t\nLeukopenia\t7(64)\t7(70)\t14(67)\t0(0)\t\nNeutropenia\t6(55)\t6(60)\t12(57)\t6(28)\t\nThrombocytopenia\t5(45)\t6(60)\t11(53)\t0(0)\t\nCardiac general\t\t\t\t\t\nHypotension\t1(9)\t0(0)\t1(5)\t0(0)\t\nConstitutional symptoms\t\t\t\t\t\nFatigue\t11(100)\t9(90)\t20(95)\t3(14)\t\nFever, in the absence of neutropenia (ANC <1.0 x 109/L)\t2(18)\t4(40)\t6(28)\t0(0)\t\nDysgeusia\t2(18)\t2(20)\t4(19)\t0(0)\t\nDermatology/skin\t\t\t\t\t\nUrticaria/Rash\t1(9)\t2(20)\t3(14)\t0(0)\t\nDry skin\t0(0)\t1(10)\t1(5)\t0(0)\t\nPruritus/itching\t1(9)\t3(30)\t4(19)\t0(0)\t\nEndocrine\t\t\t\t\t\nHypothyroidism\t1(9)\t0(0)\t1(5)\t0(0)\t\nGastrointestinal\t\t\t\t\t\nConstipation\t2(18)\t0(0)\t2(9)\t0(0)\t\nDiarrhea\t4(36)\t5(50)\t9(43)\t0(0)\t\nDry mouth\t2(18)\t0(0)\t2(9)\t0(0)\t\nNausea\t6(55)\t5(50)\t11(53)\t0(0)\t\nVomiting\t1(9)\t2(20)\t3(14)\t1(5)\t\nAnorexia\t3(27)\t4(40)\t7(33)\t1(5)\t\nStomatitis\t0(0)\t2(20)\t2(9)\t0(0)\t\nColonic stenosis\t0(0)\t1(10)\t1(5)\t1(5)\t\nHepatobiliary/pancreas\t\t\t\t\t\nCholangitis\t1(9)\t0(0)\t1(5)\t1(5)\t\nInfection\t\t\t\t\t\nFebrile neutropenia (ANC<1.0x109/L, fever>38.5°C)\t1(9)\t0(0)\t1(5)\t1(5)\t\nSepticemia\t0(0)\t1(10)\t1(5)\t1(5)\t\nViral infection\t0(0)\t1(10)\t1(5)\t0(0)\t\nLymphatics\t\t\t\t\t\nEdema; limb\t0(0)\t3(30)\t3(14)\t0(0)\t\nMetabolic\t\t\t\t\t\nALAT elevated\t4(36)\t7(70)\t11(53)\t2(9)\t\nASAT elevated\t3(27)\t7(70)\t10(47)\t0(0)\t\nMusculoskeletal\t\t\t\t\t\nFracture\t1(9)\t0(0)\t1(5)\t1(5)\t\nNeurology\t\t\t\t\t\nDizziness\t5(45)\t1(10)\t6(28)\t2(9)\t\nNeuropathy–sensory/motor\t1(9)\t3(30)\t4(19)\t0(0)\t\nSomnolence\t1(9)\t0(0)\t1(5)\t1(5)\t\nPain\t\t\t\t\t\nMuscle\t3(27)\t1(10)\t4(19)\t0(0)\t\nAbdominal\t3(27)\t1(10)\t4(19)\t2(9)\t\nPulmonary/Upper respiratory\t\t\t\t\t\nDyspnea\t1(9)\t1(10)\t2(9)\t1(5)\t\nPneumonitis\t0(0)\t1(10)\t1(5)\t1(5)\t\nSecondary primary malignancy\t0(0)\t0(0)\t0(0)\t0(0)\t\nVascular\t\t\t\t\t\nThrombosis/thrombus/embolism\t2(18)\t1(10)\t3(14)\t2(9)\t\n* = Grade.\n\n** = Represents the number of subjects experiencing adverse events.\n\nThe incidence of neutropenia was 57% with 28% was of grade 3–4. There was one febrile neutropenia episode (5%) and one septicemia (5%). Thrombocytopenia and anemia (all grades) were noted in 53% and 24%, respectively, but only grade 1 or 2. No effects on lymphocyte, monocyte, eosinophil and basophil counts were noted (data not shown).\n\nFatigue was the most prominent non-hematological side-effect, noted in 95% of the patients, 14% was of grade 3. GI toxicities were common (diarrhea 53%, nausea 43% and anorexia 33%) and one episode of anorexia grade 3 as well as one of vomiting grade 3 were noted.\n\nElevation of ALAT or ASAT was reported in 53% and 47% (all grades), respectively, but only 9% were grade 3–4. There was one (5%) grade 2 hypothyroidism. No renal dysfunction was registered.\n\nDermatological toxicities (urticaria-rash/dry skin/pruritus-itching) were seen in 38%. Six patients (28%) had dizziness, 9% was of grade 3. Neuropathy, mainly neurosensory toxicity was noted in 19% (all grade 1–2). A grade 3 somnolence was seen in one patient.\n\nThere were three thromboembolic AEs, which occurred during or after cycle 2. Two were unilateral deep vein thrombosis (DVT) (one of grade 2 and one of grade 3). One patient had a grade 4 pulmonary embolism. Treatment with lenalidomide was hold during cycle 3 but restarted at a lower dose from cycle 4.\n\nTwelve SAEs were reported. Five were classified as probably not related to the trial drugs but underlying disease: grade 3 abdominal pain in pats no 201 and 203; progressive disease (in pats no 220 and 217); and a grade 3 fracture of the femoral neck in pat no 205; constipation related to disease progression in pat 220 which required surgical intervention but the patient died 18 days postoperatively; in pat 217 requiring hospitalization and the patient died after 8 days due to rapid disease progression. One patient (pat no 218) required hospital admission at three occasions due to diarrhea (grade 3), dyspnoea (grade 3) and septicemia (grade 4), respectively. One patient was treated for febrile neutropenia (grade 3) (no 209) and another for cholangitis (grade 3) (no 207). Two SAEs were grade 3 vomiting (no 212) and grade 3 DVT (no 219) respectively.\n\nClinical effects\nAll patients were evaluable for OS and survival rate at week 52. Twenty-nine patients completed at least two cycles of therapy and evaluable for PFS. In part I, one out of the twelve patients was withdrawn during cycle 1 due to vomiting related to underlying disease [32]. In part II, three out of the 21 patients were withdrawn before completion of two cycles: in two due serious adverse events (SAEs) (no 205 and 217, see above) and in another due to reduced performance status related to the underlying disease (pat no 206).\n\nMedian PFS in part I was 14 weeks (range; 8–66), in part II, Group A 10 weeks (7–39), and in Group B 16 weeks (range; 8–66) and in all patients together 15 weeks (range; 7–66). Median OS time in part I was 28.5 weeks (range; 12–204); in part II, Group A 25 weeks (range; 4–130), in part II Group B 40 weeks (range; 7–112) and in all patients together 27 weeks (range; 4–204). The OS and PFS curves for all patients in the study are shown in Fig 5. The survival rate at one year was 42% in part I, 27% in Group A (part II), 40% in Group B (part II) and 36% in all patients together. There was no statistical difference in OS, PFS or survival rate at one year comparing patients within the different groups or between patients in part I and part II.\n\n10.1371/journal.pone.0169736.g005Fig 5 Cumulative overall survival (OS) (solid black line) and progression-free survival (PFS) (solid grey line) from the start of study treatment until death (OS) and clinical and/or radiological signs of disease progression (PFS), respectively, for all patients in the study.\nNumber of evaluable patients for OS = 33 out of 33, for PFS = 29 out of 33.\n\nDiscussion\nIn this investigator-initiated phase I/II study, we examined the safety and therapeutic efficacy of a novel protocol using the immunomodulatory agent lenalidomide in combination with gemcitabine as first-line treatment of patients with advanced pancreatic cancer. The feasibility and tolerability of the combination regime in part I of the study, has recently been described [32].\n\nIn this report, the clinical effects for both part I and II are reported. This is the first study examining the immunomodulatory effects of lenalidomide as a single agent in patients with pancreatic cancer as compared to gemcitabine alone. Patients were shown to have impaired immune functions before entering the study. A significantly lower frequency of DCs and a significantly higher frequency of MDSCs compared to healthy controls were observed. These findings are in agreement with previous studies in patients with pancreatic cancer [35,36]. However, no difference in the total number of Tregs in patients compared to healthy volunteers could be noted in the present study while a significantly lower frequency was seen in patients compared to controls in a previous study [37]. Moreover, a significantly higher frequency of T-cells (CD4+, CD8+) and NK-cells producing perforin and granzyme B compared with healthy controls were noted, which might be related to the presence of tumor antigen-specific T cells as reported in pancreatic cancer patients [38]. Furthermore, the T cell proliferative capacity in response to mitogen was impaired, which is a common finding in cancer patients [39]. This might be due to increased immune suppression by MDSCs [40] and/or Tregs [41] as well as intrinsic T cell dysfunctions associated with eg. aberrant T cell signaling [42].\n\nIn cancer patients, lenalidomide treatment has been shown to augment the number of activated T cells [43] which was also noted in the present study. However, gemcitabine abrogated this effect. Our results are in contrast to a previous study showing that lenalidomide and gemcitabine in combination had clear immune-stimulatory effects [22]. The reasons for the contradictory results might be due to differences between artificial cancer cell lines and pancreatic cancer patients on treatment.\n\nIn preclinical and clinical studies, both gemcitabine [28,35] and lenalidomide [44,45] have been shown to inhibit the expansion and functional activity of Tregs.\n\nHowever, in another study an increased number was observed with lenalidomide treatment CLL patients (Palma M, personal communication) which was in line with the results of Group A. Furthermore, although the numbers of Tregs decreased after adding gemcitabine to lenalidomide treatment, there was no reduction in Tregs of gemcitabine monotherapy (Arm B).\n\nAlso the results of lenalidomide on NK cells are conflicting. A small but not significant increase of NK cells in lenalidomide treated patients was observed in the present study while others have noted an increase in NK cells as well as NK cell mediated cytotoxicity and still others observed no effects on NK cell functions [46].\n\nThe median number of treatment cycles in both part I and II [32] was similar to that of Infante et al [47]. Median PFS in the present study was comparable to that of gemcitabine alone [4] and the combination with lenalidomide [47], while overall survival seemed to be superior in our study. The good performance status (ECOG 0–1) in our study and different second line treatments might explain the difference.\n\nSide effects were mainly the same as to previous studies using lenalidomide or pomalidomide in combination with gemcitabine for advanced pancreatic cancer [47,48]. The overall side-effect profile was not more pronounced than expected. The frequency of grade 3–4 VTEs in this present trial was however lower than that noted when using aspirin as prophylactic anticoagulant [47]. No added toxicity was seen of the prophylactic LMWH schedule, as in concert with Maraveyas A et al [49].\n\nIn summary, patients with advanced pancreatic carcinoma had a suppressed immune system with reduced expansion of T and NK cells with a lytic capability. Lenalidomide seemed to expand activated T cells while addition of gemcitabine hampered those functions. Further studies are needed to explore the utility of immune-modulating agents in combination with gemcitabine in pancreatic carcinoma. Lenalidomide in combination with gemcitabine does not seem to be a rewarding treatment strategy. Other immunomodulatory approaches should be explored. Immune checkpoint antibodies might be an option to increase the therapeutic efficacy of gemcitabine.\n\nSupporting Information\nS1 Fig TREND Checklist.\n(PDF)\n\nClick here for additional data file.\n\n S1 File Study protocol.\n(PDF)\n\nClick here for additional data file.\n\n We are grateful to the staff at the Clinical trial units at Karolinska University Hospital Solna and Danderyd and Uppsala University Hospital, Uppsala, Sweden; Lena Bernrup, Maria Olsson, Annelie Billgren, Marja Metsämaa and datamanager Mats Hellström. We thank Ms. Leila Relander for excellent secretarial help. This investigator-initiated study was supported by the Swedish Cancer Society (Grant no. 110711, URL: www.cancerfonden.se); The Karolinska Institute Foundation (URL: https://fonder.ki.se/) and the Stockholm County Council (ALF) (Grant nr. 20150070, URL: https://forskningsstod.vmi.se/Ansokan/start.asp); the Research Foundation Stiftelsen Onkologiska Klinikens i Uppsala Forskningsfond; Lion´s Cancer Fund and in part by a grant from Celgene Corporation, Summit, NJ, USA which provided the lenalidomide. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nAbbreviations\nOSoverall survival\n\nPFSprogression-free survival\n\nNKnatural killer–cell\n\nDCdendritic cell\n\nTregT-regulatory cell\n\nMDSCmyeloid derived suppressor cell\n\nDVTdeep vein thrombosis\n\nLMWHlow molecular weight heparin\n\nPBMCperipheral blood mononuclear cell\n\nAEadverse event\n\nSAEserious adverse event\n==== Refs\nReferences\n1 Alexakis N , Halloran C , Raraty M , Ghaneh P , Sutton R , Neoptolemos JP . Current standards of surgery for pancreatic cancer . Br J Surg . 2004 ;91 (11 ):1410 –27 . 10.1002/bjs.4794 \n15499648 \n2 Freelove R , Walling AD . Pancreatic cancer: diagnosis and management . Am Fam Physician . 2006 ;73 (3 ):485 –92 . 16477897 \n3 Neoptolemos JP , Stocken DD , Bassi C , Ghaneh P , Cunningham D , Goldstein D , et al\nAdjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial . Jama . 2010 ;304 (10 ):1073 –81 . 10.1001/jama.2010.1275 \n20823433 \n4 Burris HA 3rd, Moore MJ , Andersen J , Green MR , Rothenberg ML , Modiano MR , et al\nImprovements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial . J Clin Oncol . 1997 ;15 (6 ):2403 –13 . 10.1200/jco.1997.15.6.2403 \n9196156 \n5 Cunningham D , Chau I , Stocken DD , Valle JW , Smith D , Steward W , et al\nPhase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer . J Clin Oncol . 2009 ;27 (33 ):5513 –8 . 10.1200/JCO.2009.24.2446 \n19858379 \n6 Conroy T , Desseigne F , Ychou M , Bouche O , Guimbaud R , Becouarn Y , et al\nFOLFIRINOX versus gemcitabine for metastatic pancreatic cancer . The New England journal of medicine . 2011 ;364 (19 ):1817 –25 . 10.1056/NEJMoa1011923 \n21561347 \n7 Moore MJ , Goldstein D , Hamm J , Figer A , Hecht JR , Gallinger S , et al\nErlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group . J Clin Oncol . 2007 ;25 (15 ):1960 –6 . 10.1200/JCO.2006.07.9525 \n17452677 \n8 Von Hoff DD , Ervin T , Arena FP , Chiorean EG , Infante J , Moore M , et al\nIncreased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine . The New England journal of medicine . 2013 ;369 (18 ):1691 –703 . PubMed Central PMCID: PMC4631139. 10.1056/NEJMoa1304369 \n24131140 \n9 FDA US Food and Drug Administration (FDA) 2013. Available from: www.fda.gov.\n10 European Medicine Agency (EMA) Science Medicine Health. SPC_Lenalidomide_PDF.REVLIMID—revised Feb 2013 2013. Available from: http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000717/WC500056018.pdf.\n11 Dredge K , Horsfall R , Robinson SP , Zhang LH , Lu L , Tang Y , et al\nOrally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro . Microvasc Res . 2005 ;69 (1–2 ):56 –63 . 10.1016/j.mvr.2005.01.002 \n15797261 \n12 Wu L , Parton A , Lu L , Adams M , Schafer P , Bartlett JB . Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers . Cancer immunology, immunotherapy: CII . 2011 ;60 (1 ):61 –73 . 10.1007/s00262-010-0919-9 \n20848094 \n13 LeBlanc R , Hideshima T , Catley LP , Shringarpure R , Burger R , Mitsiades N , et al\nImmunomodulatory drug costimulates T cells via the B7-CD28 pathway . Blood . 2004 ;103 (5 ):1787 –90 . 10.1182/blood-2003-02-0361 \n14512311 \n14 Teo SK . Properties of thalidomide and its analogues: implications for anticancer therapy . AAPS J . 2005 ;7 (1 ):E14 –9 . PubMed Central PMCID: PMC2751493. 10.1208/aapsj070103 \n16146335 \n15 Corral LG , Haslett PA , Muller GW , Chen R , Wong LM , Ocampo CJ , et al\nDifferential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha . J Immunol . 1999 ;163 (1 ):380 –6 . 10384139 \n16 Crane E , List A . Immunomodulatory drugs . Cancer Invest . 2005 ;23 (7 ):625 –34 . 10.1080/07357900500283101 \n16305990 \n17 Amato RJ , Hernandez-McClain J , Saxena S , Khan M . Lenalidomide therapy for metastatic renal cell carcinoma . Am J Clin Oncol . 2008 ;31 (3 ):244 –9 . 10.1097/COC.0b013e31815e451f \n18525302 \n18 Bartlett JB , Michael A , Clarke IA , Dredge K , Nicholson S , Kristeleit H , et al\nPhase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers . Br J Cancer . 2004 ;90 (5 ):955 –61 . PubMed Central PMCID: PMC2410215. 10.1038/sj.bjc.6601579 \n14997189 \n19 Miller AA , Case D , Harmon M , Savage P , Lesser G , Hurd D , et al\nPhase I study of lenalidomide in solid tumors . J Thorac Oncol . 2007 ;2 (5 ):445 –9 . 10.1097/01.JTO.0000268679.33238.67 \n17473661 \n20 Sharma RA , Steward WP , Daines CA , Knight RD , O'Byrne KJ , Dalgleish AG . Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide: phase I clinical trial of three dosing schedules in patients with solid malignancies . Eur J Cancer . 2006 ;42 (14 ):2318 –25 . 10.1016/j.ejca.2006.05.018 \n16899362 \n21 Sanborn SL , Gibbons J , Krishnamurthi S , Brell JM , Dowlati A , Bokar JA , et al\nPhase I trial of docetaxel given every 3 weeks and daily lenalidomide in patients with advanced solid tumors . Invest New Drugs . 2009 ;27 (5 ):453 –60 . 10.1007/s10637-008-9200-x \n19011760 \n22 Fryer RA , Barlett B , Galustian C , Dalgleish AG . Mechanisms underlying gemcitabine resistance in pancreatic cancer and sensitisation by the iMiD lenalidomide . Anticancer research . 2011 ;31 (11 ):3747 –56 . 22110196 \n23 Fritz S , Hackert T , Buchler MW . Pancreatic intraductal papillary mucinous neoplasm—where is the challenge? \nDigestive diseases . 2015 ;33 (1 ):99 –105 . 10.1159/000368448 \n25531503 \n24 Suzuki E , Sun J , Kapoor V , Jassar AS , Albelda SM . Gemcitabine has significant immunomodulatory activity in murine tumor models independent of its cytotoxic effects . Cancer biology & therapy . 2007 ;6 (6 ):880 –5 . 17582217 \n25 Plate JM , Plate AE , Shott S , Bograd S , Harris JE . Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer immunology, immunotherapy : CII . 2005 ;54 (9 ):915 –25 . 10.1007/s00262-004-0638-1 \n15782312 \n26 Soeda A , Morita-Hoshi Y , Makiyama H , Morizane C , Ueno H , Ikeda M , et al\nRegular dose of gemcitabine induces an increase in CD14+ monocytes and CD11c+ dendritic cells in patients with advanced pancreatic cancer . Japanese journal of clinical oncology . 2009 ;39 (12 ):797 –806 . 10.1093/jjco/hyp112 \n19797418 \n27 Nowak AK , Lake RA , Marzo AL , Scott B , Heath WR , Collins EJ , et al\nInduction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells . J Immunol . 2003 ;170 (10 ):4905 –13 . 12734333 \n28 Homma Y , Taniguchi K , Nakazawa M , Matsuyama R , Mori R , Takeda K , et al\nChanges in the immune cell population and cell proliferation in peripheral blood after gemcitabine-based chemotherapy for pancreatic cancer . Clinical & translational oncology: official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico . 2014 ;16 (3 ):330 –5 .\n29 Suzuki E , Kapoor V , Jassar AS , Kaiser LR , Albelda SM . Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity . Clinical cancer research: an official journal of the American Association for Cancer Research . 2005 ;11 (18 ):6713 –21 .16166452 \n30 Vizio B , Novarino A , Giacobino A , Cristiano C , Prati A , Ciuffreda L , et al\nPotential plasticity of T regulatory cells in pancreatic carcinoma in relation to disease progression and outcome . Experimental and therapeutic medicine . 2012 ;4 (1 ):70 –8 . PubMed Central PMCID: PMC3460315. 10.3892/etm.2012.553 \n23060925 \n31 Bergmann-Leitner ES , Abrams SI . Treatment of human colon carcinoma cell lines with anti-neoplastic agents enhances their lytic sensitivity to antigen-specific CD8+ cytotoxic T lymphocytes . Cancer immunology, immunotherapy: CII . 2001 ;50 (9 ):445 –55 . 11761438 \n32 Ullenhag GJ , Rossmann E , Liljefors M . A phase I dose-escalation study of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer . PloS one . 2015 ;10 (4 ):e0121197 PubMed Central PMCID: PMC4383423. 10.1371/journal.pone.0121197 \n25837499 \n33 Mozaffari F , Lindemalm C , Choudhury A , Granstam-Bjorneklett H , Lekander M , Nilsson B , et al\nSystemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer: a longitudinal study . Cancer immunology, immunotherapy: CII . 2009 ;58 (1 ):111 –20 . 10.1007/s00262-008-0530-5 \n18488220 \n34 Lindemalm C , Mozaffari F , Choudhury A , Granstam-Bjorneklett H , Lekander M , Nilsson B , et al\nImmune response, depression and fatigue in relation to support intervention in mammary cancer patients . Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer . 2008 ;16 (1 ):57 –65 .17562086 \n35 Bazhin AV , Shevchenko I , Umansky V , Werner J , Karakhanova S . Two immune faces of pancreatic adenocarcinoma: possible implication for immunotherapy . Cancer immunology, immunotherapy: CII . 2014 ;63 (1 ):59 –65 . 10.1007/s00262-013-1485-8 \n24129765 \n36 Yanagimoto H , Takai S , Satoi S , Toyokawa H , Takahashi K , Terakawa N , et al\nImpaired function of circulating dendritic cells in patients with pancreatic cancer . Clinical immunology . 2005 ;114 (1 ):52 –60 . 10.1016/j.clim.2004.09.007 \n15596409 \n37 Yamamoto T , Yanagimoto H , Satoi S , Toyokawa H , Hirooka S , Yamaki S , et al\nCirculating CD4+CD25+ regulatory T cells in patients with pancreatic cancer . Pancreas . 2012 ;41 (3 ):409 –15 . 10.1097/MPA.0b013e3182373a66 \n22158072 \n38 Schmitz-Winnenthal FH , Volk C , Z'Graggen K , Galindo L , Nummer D , Ziouta Y , et al\nHigh frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients . Cancer research . 2005 ;65 (21 ):10079 –87 . 10.1158/0008-5472.CAN-05-1098 \n16267034 \n39 Pituch-Noworolska A . The response of cancer patients' lymphocytes to mitogen. The effect of indomethacin on adherent and non-adherent cells activity . Archivum immunologiae et therapiae experimentalis . 1981 ;29 (2 ):161 –5 . 7305629 \n40 Srivastava MK , Sinha P , Clements VK , Rodriguez P , Ostrand-Rosenberg S . Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine . Cancer research . 2010 ;70 (1 ):68 –77 . PubMed Central PMCID: PMC2805057. 10.1158/0008-5472.CAN-09-2587 \n20028852 \n41 Wolf AM , Wolf D , Steurer M , Gastl G , Gunsilius E , Grubeck-Loebenstein B . Increase of regulatory T cells in the peripheral blood of cancer patients . Clinical cancer research: an official journal of the American Association for Cancer Research . 2003 ;9 (2 ):606 –12 .12576425 \n42 Iakoucheva LM , Brown CJ , Lawson JD , Obradovic Z , Dunker AK . Intrinsic disorder in cell-signaling and cancer-associated proteins . Journal of molecular biology . 2002 ;323 (3 ):573 –84 . 12381310 \n43 Lioznov M , El-Cheikh J Jr., Hoffmann F , Hildebrandt Y , Ayuk F , Wolschke C , et al\nLenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells . Bone marrow transplantation . 2010 ;45 (2 ):349 –53 . 10.1038/bmt.2009.155 \n19584825 \n44 Galustian C , Meyer B , Labarthe MC , Dredge K , Klaschka D , Henry J , et al\nThe anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells . Cancer immunology, immunotherapy: CII . 2009 ;58 (7 ):1033 –45 . 10.1007/s00262-008-0620-4 \n19009291 \n45 Lee BN , Gao H , Cohen EN , Badoux X , Wierda WG , Estrov Z , et al\nTreatment with lenalidomide modulates T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia . Cancer . 2011 ;117 (17 ):3999 –4008 . PubMed Central PMCID: PMC4349201. 10.1002/cncr.25983 \n21858802 \n46 Hayashi T , Hideshima T , Akiyama M , Podar K , Yasui H , Raje N , et al\nMolecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application . British journal of haematology . 2005 ;128 (2 ):192 –203 . 10.1111/j.1365-2141.2004.05286.x \n15638853 \n47 Infante JR , Arkenau HT , Bendell JC , Rubin MS , Waterhouse D , Jones GT , et al\nLenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas: a Sarah Cannon Research Institute phase II trial . Cancer biology & therapy . 2013 ;14 (4 ):340 –6 . PubMed Central PMCID: PMC3667874.23358470 \n48 Infante JR , Jones SF , Bendell JC , Spigel DR , Yardley DA , Weekes CD , et al\nA phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer . Eur J Cancer . 2011 ;47 (2 ):199 –205 . 10.1016/j.ejca.2010.09.002 \n21051221 \n49 Maraveyas A , Waters J , Roy R , Fyfe D , Propper D , Lofts F , et al\nGemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer . Eur J Cancer . 2012 ;48 (9 ):1283 –92 . 10.1016/j.ejca.2011.10.017 \n22100906\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "12(1)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D003841:Deoxycytidine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D013792:Thalidomide",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0169736",
"pmc": null,
"pmid": "28099502",
"pubdate": "2017",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "14997189;16146335;12734333;25837499;22110196;16267034;21561347;17582217;22100906;15499648;23358470;21051221;24131140;18488220;20848094;23860726;17473661;15638853;14512311;12381310;20823433;19011760;15797261;16899362;16305990;25531503;10384139;19009291;19858379;15596409;21858802;23060925;20028852;11761438;16477897;18525302;16166452;17562086;19584825;17452677;12576425;19797418;9196156;22158072;15782312;7305629;24129765",
"title": "Clinical and Immune Effects of Lenalidomide in Combination with Gemcitabine in Patients with Advanced Pancreatic Cancer.",
"title_normalized": "clinical and immune effects of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer"
} | [
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"companynumb": "SE-CELGENEUS-SWE-2015050826",
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"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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... |
{
"abstract": "BACKGROUND\nChemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma.\n\n\nMETHODS\nThis open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18-75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3.5 g/m(2) on day 1 (n=40) or methotrexate 3.5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice a day on days 2-3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00210314.\n\n\nRESULTS\nAll randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6-30) and 46% (31-61), respectively, (p=0.006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25-55) and 69% (55-83), respectively, (p=0.009). Grade 3-4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one).\n\n\nCONCLUSIONS\nIn patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone.\n\n\nBACKGROUND\nSwiss Cancer League.",
"affiliations": "Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy. andres.ferreri@hsr.it",
"authors": "Ferreri|Andrés J M|AJ|;Reni|Michele|M|;Foppoli|Marco|M|;Martelli|Maurizio|M|;Pangalis|Gerasimus A|GA|;Frezzato|Maurizio|M|;Cabras|Maria Giuseppina|MG|;Fabbri|Alberto|A|;Corazzelli|Gaetano|G|;Ilariucci|Fiorella|F|;Rossi|Giuseppe|G|;Soffietti|Riccardo|R|;Stelitano|Caterina|C|;Vallisa|Daniele|D|;Zaja|Francesco|F|;Zoppegno|Lucía|L|;Aondio|Gian Marco|GM|;Avvisati|Giuseppe|G|;Balzarotti|Monica|M|;Brandes|Alba A|AA|;Fajardo|José|J|;Gomez|Henry|H|;Guarini|Attilio|A|;Pinotti|Graziella|G|;Rigacci|Luigi|L|;Uhlmann|Catrina|C|;Picozzi|Piero|P|;Vezzulli|Paolo|P|;Ponzoni|Maurilio|M|;Zucca|Emanuele|E|;Caligaris-Cappio|Federico|F|;Cavalli|Franco|F|;|||",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(09)61416-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "374(9700)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D003561:Cytarabine; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008228:Lymphoma, Non-Hodgkin; D008727:Methotrexate; D008875:Middle Aged; D016016:Proportional Hazards Models; D012074:Remission Induction; D016896:Treatment Outcome",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1512-20",
"pmc": null,
"pmid": "19767089",
"pubdate": "2009-10-31",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial.",
"title_normalized": "high dose cytarabine plus high dose methotrexate versus high dose methotrexate alone in patients with primary cns lymphoma a randomised phase 2 trial"
} | [
{
"companynumb": "HK-PFIZER INC-2010035272",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
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"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThis randomized, double-blind study was conducted to evaluate the effect of gabapentin pretreatment on the hemodynamic response to laryngoscopy and endotracheal intubation (LETI) in treated hypertensive patients undergoing surgery.\n\n\nMETHODS\nA total of 100 controlled hypertensive patients aged 35-60 years, undergoing elective surgery under general anesthesia with endotracheal intubation, were randomly allocated into three groups. Group 1 patients received placebo at night and 2 hours prior to induction of anesthesia. Group 2 patients received placebo at night and 800 mg gabapentin 2 hours prior to induction of anesthesia. Group 3 patients received 800 mg gabapentin at night and 2 hours prior to induction of anesthesia. Anesthesia was induced with thiopentone, fentanyl, and vecuronium and maintained with isoflurane in oxygen and nitrous oxide. Patients' heart rate (HR), blood pressure (BP), and electrocardiography (ECG) changes were recorded prior to induction, after induction, and at 0 minutes, 1 minute, 3 minutes, 5 minutes, and 10 minutes after intubation. Any episodes of hypotension, bradycardia, tachycardia, hypertension, arrhythmia, and ST-T wave changes were recorded and treated accordingly.\n\n\nRESULTS\nThe HR was comparable among groups, with a transient rise just after intubation, followed by a gradual fall thereafter at 3 minutes, 5 minutes, and 10 minutes compared with baseline. A significant increase in BP after intubation was reported in Group 1 but not in Group 2 and Group 3. The mean arterial pressure (MAP) was significantly higher in Group 1 at 0 minute, 1 minute and 3 minutes postintubation as compared with Group 2 and Group 3 (p=0.014). Three patients in Group 1, four patients in Group 2, and 10 patients in Group 3 developed hypotension and were treated with ephedrine, whereas five patients in Group 1 and one patient in Group 2 had hypertension after tracheal intubation. There was no significant difference between the groups with respect to the number of patients who received ephedrine boluses and in whom isoflurane had to be increased due to hypertension. No episode of bradycardia, tachycardia, dysrhythmia, or ST-T wave changes was reported.\n\n\nCONCLUSIONS\nGabapentin 800 mg in a single or double dose was equally effective in attenuating the hypertensive response to laryngoscopy and tracheal intubation in treated hypertensive patients.",
"affiliations": "Department of Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;Department of Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. Electronic address: bhartineerja@yahoo.com.;Department of Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.",
"authors": "Bala|Indu|I|;Bharti|Neerja|N|;Ramesh|Nanjangud P|NP|",
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"keywords": "gabapentin; hemodynamic response; hypertensive patients; laryngoscopy; tracheal intubation",
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"title": "Effect of gabapentin pretreatment on the hemodynamic response to laryngoscopy and tracheal intubation in treated hypertensive patients.",
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"abstract": "OBJECTIVE\nSurvival outcome of locally advanced pancreatic cancer has been poor and little is known about prognostic factors of the disease, especially in locally advanced cases treated with concurrent chemoradiation. This study was to analyze overall survival and prognostic factors of patients treated with concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic cancer.\n\n\nMETHODS\nMedical records of 34 patients diagnosed with unresectable pancreatic cancer and treated with definitive CCRT, from December 2003 to December 2012, were reviewed. Median prescribed radiation dose was 50.4 Gy (range, 41.4 to 55.8 Gy), once daily, five times per week, 1.8 to 3 Gy per fraction.\n\n\nRESULTS\nWith a mean follow-up of 10 months (range, 0 to 49 months), median overall survival was 9 months. The 1- and 2-year survival rates were 40% and 10%, respectively. Median and mean time to progression were 5 and 7 months, respectively. Prognostic parameters related to overall survival were post-CCRT CA19-9 (p = 0.02), the Eastern Cooperative Oncology Group (ECOG) status (p < 0.01), and radiation dose (p = 0.04) according to univariate analysis. In multivariate analysis, post-CCRT CA19-9 value below 180 U/mL and ECOG status 0 or 1 were statistically significant independent prognostic factors associated with improved overall survival (p < 0.01 and p = 0.02, respectively).\n\n\nCONCLUSIONS\nOverall treatment results in locally advanced pancreatic cancer are relatively poor and few improvements have been accomplished in the past decades. Post-treatment CA19-9 below 180 U/mL and ECOG performance status 0 and 1 were significantly associated with an improved overall survival.",
"affiliations": "Department of Radiation Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Radiation Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Radiation Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.",
"authors": "Kwak|Yoo-Kang|YK|;Lee|Jong Hoon|JH|;Lee|Myung-Ah|MA|;Chun|Hoo-Geun|HG|;Kim|Dong-Goo|DG|;You|Young Kyoung|YK|;Hong|Tae-Ho|TH|;Jang|Hong Seok|HS|",
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"doi": "10.3857/roj.2014.32.2.49",
"fulltext": "\n==== Front\nRadiat Oncol JRadiat Oncol JROJRadiation Oncology Journal2234-19002234-3164The Korean Society for Radiation Oncology 10.3857/roj.2014.32.2.49Original ArticleClinical InvestigationDefinitive concurrent chemoradiotherapy in locally advanced pancreatic cancer Kwak Yoo-Kang MD1Lee Jong Hoon MD1Lee Myung-Ah MD2Chun Hoo-Geun MD2Kim Dong-Goo MD3You Young Kyoung MD3Hong Tae-Ho MD3Jang Hong Seok MD11 Department of Radiation Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.2 Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.3 Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.Correspondence: Hong Seok Jang, MD, Department of Radiation Oncology, Seoul St. Mary's Hospital, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Korea. Tel: +82-2-2258-1526, Fax: +82-2-592-1532, hsjang11@catholic.ac.kr6 2014 30 6 2014 32 2 49 56 31 3 2014 07 5 2014 21 5 2014 Copyright © 2014. The Korean Society for Radiation Oncology2014This 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.Purpose\nSurvival outcome of locally advanced pancreatic cancer has been poor and little is known about prognostic factors of the disease, especially in locally advanced cases treated with concurrent chemoradiation. This study was to analyze overall survival and prognostic factors of patients treated with concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic cancer.\n\nMaterials and Methods\nMedical records of 34 patients diagnosed with unresectable pancreatic cancer and treated with definitive CCRT, from December 2003 to December 2012, were reviewed. Median prescribed radiation dose was 50.4 Gy (range, 41.4 to 55.8 Gy), once daily, five times per week, 1.8 to 3 Gy per fraction.\n\nResults\nWith a mean follow-up of 10 months (range, 0 to 49 months), median overall survival was 9 months. The 1- and 2-year survival rates were 40% and 10%, respectively. Median and mean time to progression were 5 and 7 months, respectively. Prognostic parameters related to overall survival were post-CCRT CA19-9 (p = 0.02), the Eastern Cooperative Oncology Group (ECOG) status (p < 0.01), and radiation dose (p = 0.04) according to univariate analysis. In multivariate analysis, post-CCRT CA19-9 value below 180 U/mL and ECOG status 0 or 1 were statistically significant independent prognostic factors associated with improved overall survival (p < 0.01 and p = 0.02, respectively).\n\nConclusion\nOverall treatment results in locally advanced pancreatic cancer are relatively poor and few improvements have been accomplished in the past decades. Post-treatment CA19-9 below 180 U/mL and ECOG performance status 0 and 1 were significantly associated with an improved overall survival.\n\nPancreatic neoplasmsChemoradiotherapyCA19-9 antigen\n==== Body\nIntroduction\nAccording to the National Cancer Information Center of Korea, pancreatic cancer accounts for 2.3% of all cancer incidences and it is the 9th most common cancer in both men and women and 5th most common cause related to cancer death. Without clear early symptoms and with fast spread of the disease, more than 80% of pancreatic cancer is locally advanced at presentation [1]. Prognosis of locally advanced and unresectable pancreatic cancer is poor with a median survival of 6 to 10 months [2]. Treatment options for these cancers are chemotherapy, radiotherapy, chemoradiation, and palliative surgery. The Gastrointestinal Tumor Study Group reported prolonged survival using concurrent chemoradiation, with a median survival of 10 months, compared to radiotherapy alone [3]. Along with other trials, [4,5] the study established chemoradiation as standard for patients with locally advanced pancreatic cancer.\n\nMany studies in the past several decades have reported on different strategies concerning treatments of locally advanced pancreatic cancer. Most commonly used chemotherapeutic agents are 5-fluorouracil (5-FU) and gemcitabine. A number of other single agents and their combinations have been assessed [6,7,8]. Novel target agents are also under investigation [9]. From a radiotherapeutic point of view, radiation field modification, radiation dose escalation, and different treatment modalities have been attempted. Since pancreas is surrounded by the duodenum and small intestines, delivering radiation doses exceeding 50.4 Gy in conventional fractionation in traditional radiation fields were nearly impossible. With intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), dose escalation with more accurate targeting and normal tissue sparing are becoming feasible.\n\nHowever, even with all these attempts, treatment outcomes of locally advanced pancreatic cancer remain in the same range. Moreover, little is known about prognostic factors of the disease, especially in locally advanced cases treated with concurrent chemoradiotherapy (CCRT).\n\nIn this study, we retrospectively reviewed medical records of patients with locally advanced pancreatic cancer who were treated with definitive CCRT. Overall survival (OS) and progression-free survival (PFS) were analyzed and prognostic factors were assessed.\n\nMaterials and Methods\nMedical records of patients diagnosed with unresectable pancreatic cancer and treated with chemoradiation, from December 2003 to December 2012, were reviewed. Among 40 patients, 2 patients who received sequential chemoradiation, 3 patients treated below 40 Gy of radiation, and one patient with multiple hepatic metastases were excluded. Conclusively, 34 patients treated with CCRT were enrolled. Of the 34 patients, 25 patients were histologically confirmed whereas remaining 9 patients failed biopsy because of the difficulties in approaching due to abutment or invasion to major vessels. Twenty-six cases met the definition on unresectable disease, according to the National Comprehensive Cancer Network guidelines: 1) ≥180 degrees of superior mesentery artery encasement, any celiac abutment, or inferior vena cava abutment; 2) unreconstructible superior mesenteric vein and/or portal occlusion; 3) aortic invasion; and 4) distant metastasis [10]. Four pancreatic tail cancers, one T2 case, and one T3 case were included, which the surgeon considered inoperable because they had splenic vessel encasement, left renal artery encasement, or left adrenal invasion. One unresectable case with T-colon invasion and one T2 case which the patient refused surgery were also included. Exclusion criteria were co-existent malignancies, history of radiotherapy, and prior surgery, such as surgical resection or surgical bypass. Approval of our Institutional Review Board was achieved.\n\n1. Assessment\nChart review focused on patients' age, sex, the Eastern Cooperative Oncology Group (ECOG) performance status, tumor location (head, body, tail), jaundice (serum bilirubin levels), tumor histologic types, pre- and post-treatment CA19-9 levels (normal range was 0 to 37 IU/mL), and pre- and post-treatment esophagogastroduodenoscopy results. Abdomen and pelvis computed tomography (CT) scans were obtained and other radiologic studies like chest CT or FDG-positron emitting tomography scans to evaluate distant metastasis were done. Staging was done according to the American Joint Committee of Cancer (AJCC) 7th edition. If needed, endobiliary or percutaneous bile drainage was performed. After CCRT started, patients were interviewed once weekly during the whole course and routine complete blood counts and blood chemistry were examined for assessment. Patients were evaluated one month after completion of CCRT to examine the disease status and treatment outcomes. They were re-evaluated at every 3 to 6 months, thereafter.\n\n2. Radiotherapy\nRadiation was delivered at a median dose of 50.4 Gy (range, 41.4 to 55.8 Gy), once daily, 5 times per week, 1.8 to 3 Gy per fraction. Median time to complete CCRT was 5.5 weeks. Twenty-six patients were treated with conventional radiation therapy with 3-field or 4-box-field technique using high energy linear accelerator. The remaining eight patients were treated with IMRT using Tomotherapy.\n\nSimulation was done in supine position with both arms up together and Vac-Lok (CIVCO Medical Solutions, Coralville, IA, USA) was used for immobilization. For IMRT, compression with vacuum was done to minimize respiratory movements of the abdomen. Contrast enhanced CT simulation was done and 5-mm sliced CT was obtained at least one week before CCRT began.\n\nGross tumor and all visible lymph nodes were delineated slice by slice. Regional lymph nodes, such as anterior and posterior pancreaticoduodenal lymph nodes, supra- and infra-pancreatic head and body nodes, SMA nodes, celiac axis nodes, hepatoduodenal ligament nodes, para-aortic nodes, aortocaval nodes, and splenic artery nodes were included. For IMRT, clinical target volume (CTV) was the regional lymph nodes plus 0.5 cm margin around the gross tumors. With concern of set-up errors and organ movements, CTV with an additional 0.5 to 1 cm margin was defined as planning target volume (PTV).\n\nMost of the cases with conventional radiation therapy were treated with a total dose of 50.4 Gy/28 fx whereas median 50 Gy with daily 2.5 to 3 Gy/fx was delivered in cases with Tomotherapy. For patients treated with conventional radiation therapy, field size was reduced after 45 Gy to the gross tumor volumes. With Tomotherapy, simultaneous integrated boost was feasible with GTV receiving 50 to 60 Gy while PTV receiving 45 to 55 Gy in 20 to 25 fractions.\n\nWhen analyzing on radiation dose, equivalent dose in 1.8 Gy per fraction (EQD1.8) was calculated, using an estimated α/β ratio of 10.\n\n3. Chemotherapy\nChemotherapy regimen used for CCRT was 5-FU in most cases with one exception treated with FL (5-FU, leucovorin). Intravenous infusion of 5-FU was administered at a dose of 600 mg/m2, weekly, 4 to 5 times during radiotherapy or 1,000 mg/m2 for 3 days at the beginning and in the end of the radiotherapy. Gemcitabine, when given as neoadjuvant or adjuvant chemotherapy, was administered weekly at a dose of 200 mg/m2, intravenously.\n\nThirty-three patients received 5-FU chemotherapy and one patient received FL. Prior to CCRT, four patients (12%) received neoadjuvant chemotherapy with gemcitabine. Twenty-three patients (68%) were treated with adjuvant chemotherapy, most with gemcitabine.\n\n4. Statistical analyses\nPrimary endpoint of this retrospective study was OS and PFS rates. Secondary endpoints were prognostic factors, treatment response, and treatment toxicities. OS time was counted from the date of diagnosis to death or the last follow-up date in survivors. Progression free survival time was from the date of completion of CCRT to the date of progression. Survival curves and local control rates were achieved using the Kaplan-Meier method and the differences were evaluated by log-rank test. Univariate and multivariate analyses as well as Cox proportional hazards models were used to assess prognostic factors. Treatment response was assessed by comparing abdomen CTs taken before and after radiotherapy using Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 [11]. To identify the relationship between toxicities and radiation dose, Pearson correlation analysis was used. When interpreting the results, p-values less than 0.05 were considered significant. All data were computed and analyzed with SPSS ver. 12.0 for Windows (SPSS Inc., Chicago, IL, USA).\n\nResults\n1. Patients\nCharacteristics of all patients are shown in Table 1.\n\n2. Treatment response\nTreatment response was analyzable in 28 patients (82%); six patients had inadequate follow-up. Mean interval from the date of CCRT completion to treatment response evaluation was 26 days. Response evaluation was based on imaging studies taken within 3 months after completion of CCRT. None of the patients went through histologic confirmation. One patient achieved complete response and 10 patients (36%) achieved partial response. Fourteen patients (50%) had stable disease and the remaining three patients had progressive disease.\n\n3. Overall survival and progression-free survival\nWith a mean follow-up of 10 months (range, 0 to 49 months), median OS was 9 months. The 1- and 2-year survival rates were 40% and 10%, respectively. Median and mean time to progression were 5 and 7 months, respectively. Median time to local progression was 9 months and distant progression was 5 months. One-year local control rate was 8%. Failure pattern in 27 evaluable patients were as follows: 2 patients were free of local or distant progression at last follow-up. Five patients had local progression and 9 patients had distant progression. Both local and distant progression occurred in 12 patients. One patient was lost to follow-up. For those who developed distant metastasis, the most common site was peritoneum (26%), followed by liver (20%), lung, bone, and lymph node.\n\n4. Prognostic factors\nPrognostic parameters related to OS were post-CCRT CA19-9 (≥180 or <180 U/mL), ECOG status and radiation dose (≥53 or <53 Gy) according to univariate analysis (Table 2). In multivariate analysis, post-CCRT CA19-9 value below 180 U/mL and ECOG status 0 or 1 were statistically significant independent prognostic factors associated with improved OS (p < 0.01 and p = 0.02, respectively) (Figs. 1 and 2).\n\nPrognostic factors for PFS were also assessed. Only ECOG status showed statistical significance (p = 0.02) and post-CCRT CA19-9 value showed marginal significance (p = 0.06) in univariate analysis. In multivariate analysis, ECOG 0 or 1 had statistically better PFS than ECOG 2 or 3 (p = 0.02).\n\nOne-year local control rate in radiation dose below 53 Gy was 0% compared to 13% in radiation dose ≥53 Gy. However, there was no statistically significant relationship between local control rate and radiation dose ≥53 or <53 Gy (p = 0.47).\n\n5. Toxicities\nAcute toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0. All 34 patients were assessed for acute toxicities (Table 3). One patient suffered from grade 3 abdominal pain and thrombocytopenia with neutropenia. This patient was treated with neoadjuvant chemotherapy with 6 cycles of erlotinib and gemcitabine followed by CCRT with epirubicin, cisplatin, and oral UFT (ECU). One patient experienced grade 3 nausea. Three patients experienced duodenal or gastric ulcer bleeding within 2 months after CCRT completion and were managed by proton pump inhibitor. No treatment related life threatening events or death occurred. Late toxicities, which occurred 3 months after CCRT, were graded according to RTOG/EORTC Radiation Toxicity Grading [12]. Only 14 patients (40%) were evaluable for late complications because of follow-up loss and early deaths. One patient with duodenal 2nd portion obstruction required stent insertion. Correlation between toxicities and radiation dose or treatment modalities did not reach statistical significance.\n\nDiscussion and Conclusion\nPrognosis of unresectable, locally advanced pancreatic cancer is depressing and not many therapeutic advances have been forthcoming. In 1980, the Gastrointestinal Tumor Study Group (GITSG) reported better treatment outcomes of locally advanced pancreatic cancer with CCRT compared to radiotherapy alone with median survival times of 10 and 6 months, respectively [3]. Several other randomized trials comparing single modality therapy, either chemotherapy alone or radiotherapy alone, to CCRT was performed: a median survival of 8.3 to 11.4 months in combined-modality arms and 5.5 to 7.4 months in single-modality arms were reported [13,14]. In our study, the median OS was 9 months. Although our survival outcome is in the lower range of the reported data, grade 3 or higher late (7%) toxicities were acceptable and there were no fatal complications. In one prospective study, severe late toxicities (26%) occurred and there was 1 treatment related death although they showed improved OS with high dose radiotherapy [15].\n\nTo improve local control rates of unresectable pancreatic cancer, investigators are trying to find ways to deliver higher radiation doses. The GITSG in 1981 compared 40 Gy and 60 Gy plus 5-FU, but the results did not yield significant survival differences. The authors used anterior-posterior opposing radiation beams [3]. Murphy et al. [16] confirmed that radiation fields covering only the gross tumors and omitting prophylactic lymph nodes do not cause marginal failures. In their study, three-dimensional conformal radiotherapy technique was adopted and even with full-dose gemcitabine, they reported reduced toxicities. Chang et al. [15] reported on high-dose helical tomotherapy with concurrent chemotherapy and demonstrated significantly enhanced local control and long-term survival. Median radiation dose was 58.4 Gy. Golden et al. [17] demonstrated a superior OS in patients who received radiation dose exceeding 54 Gy. However, our study was incompetent in proving improved local control rate by delivering higher radiation dose. This was likely due to our targets in IMRT cases included regional lymph nodes, unlike other studies that included only gross tumors. Therefore, satisfying dose escalation could not be done. Perhaps with smaller targets confined to gross tumor volumes, we would be able to deliver higher doses and demonstrate an improved local control like the other two mentioned studies. Recent trials are improving on accurate targeting and dose escalation with IMRT, SBRT, or proton therapy, expecting on improvements in both local control rates and OS rates [18,19,20]. Although firm evidence with phase III trial is lacking, some of these studies suggest encouraging outcomes.\n\nIn this study, 44% had local and distant failure, 37% had distant metastasis, and 19% had local progression. High rates of distant failure imply that using more effective systemic chemotherapy in a CCRT regimen could improve treatment outcomes. FFCD-SFRO in 2001 reported improved survival rates by treating locally advanced pancreatic cancer with gemcitabine alone [21]. However, Crane et al. [22] compared the toxicity of CCRT with gemcitabine to 5-FU and demonstrated significantly higher severe toxicity in gemcitabine group. Several other groups analyzed on gemcitabine-based CCRT and reported superior or at least similar survival rates over 5-FU. Among these, some studies reduced toxicities by reducing radiation field size [16,23,24,25]. Upon these attempts, cautious anticipation can be made on reducing distant failures with a more effective systemic chemotherapy.\n\nSince the treatment outcome of unresectable pancreatic cancer is dismal, not much data are available to address prognostic factors of the disease. Several studies with different treatments and patient groups have shown a relationship between CA19-9 and treatment response [26,27,28]. Yoo et al. [29] reported pre-treatment and post-treatment CA19-9 levels were significantly related to OS in univariate analysis. In multivariate analysis, only pre-treatment CA19-9 was statistically significant. Their cut-off values for pre-treatment CA19-9 was 400 U/mL and for post-treatment CA19-9 was 200 U/mL. Micke et al. [30] also reported that CA19-9 was predictive for prognosis, response, and recurrence. Both pre- and post-treatment CA19-9 values were statistically significant. Their cut-off values were the median values; 420 U/mL for pre-treatment CA19-9 and 293 U/mL for post-treatment CA19-9. Montgomery et al. [31] published on post-resection CA19-9 values in adenocarcinoma of the pancreas and postoperative CA19-9 <180 U/mL had similar disease-free and median survival compared to the patients who reached normal values after resection. Our study also demonstrated improved OS with lower post-treatment CA19-9 values. Cut-off value used for analysis was the median of all measured post-treatment serum CA19-9 levels. Improved OS was observed in patients whose post-CCRT CA19-9 values were below 180 U/mL.\n\nThere are several limitations in this study. First, this is a retrospective study and selection bias is inevitable. Toxicities were recorded upon physicians' subjective judgments and this also could have contributed to inaccurate data collection. Moreover, our sample size is relatively small. To keep the cohort homogeneous, only a small number of patients were chosen. All of the patients were treated with radiation dose ≥40 Gy and treated with 5-FU, except for one case. In the current study, Lewis (Le) blood group antigen was not evaluated in the patients diagnosed with pancreatic cancer. In patients with Lea-b- phenotypes, CA19-9 elevation is not detected and this occurs in 5% of the population [32].\n\nDespite the limitations, treatment outcomes in our study are in the range of other published reports on the treatment of locally advanced pancreas cancer. Along with the results, we assume post-treatment serum CA19-9 levels and performance status have an impact on the prognosis of the disease.\n\nIn conclusion, this study shows comparable outcomes of locally advanced pancreatic cancer treated with CCRT as other studies with acceptable toxicities. The prognostic factors related to survival rates from this study were performance status and post-treatment serum CA19-9 levels. Since the results of CCRT with conventional fractionation and extant chemotherapy remains in a similar range for decades, the emerging and encouraging data on SBRT or proton therapy could be a treatment alternative in the future.\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Overall survival and post-treatment serum CA19-9 levels.\n\nFig. 2 Overall survival and Eastern Cooperative Oncology Group (ECOG) performance status.\n\nTable 1 Patient characteristics\n\nValues are presented as median (range) or number (%).\n\nECOG, Eastern Cooperative Oncology Group; CCRT, concurrent chemoradiotherapy; CA19-9, carbohydrate antigen 19-9; EQD1.8, equivalent dose in 1.8 Gy per fraction; RT, radiotherapy; IMRT, intensity-modulated radiation therapy.\n\nTable 2 Prognostic factors for overall survival\n\nCCRT, concurrent chemoradiotherapy; CA19-9, carbohydrate antigen 19-9; ECOG, Eastern Cooperative Oncology Group.\n\nTable 3 Acute and late toxicities\n\nCTCAT, Common Terminology Criteria for Adverse Events; RTOG/EORTC, Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer.\n==== Refs\n1 Royal RE Wolff RA Crane CH Cancer of pancreas DeVita VT Lawrence TS Rosenberg SA DeVita, Hellman, and Rosenberg's cancer: principles & practice of oncology 9th ed Philadelphia Lippincott Williams & Wilkins 2011 961 989 \n2 Park JK Yoon YB Kim YT Survival and prognostic factors of unresectable pancreatic cancer J Clin Gastroenterol 2008 42 86 91 18097296 \n3 Moertel CG Frytak S Hahn RG Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group Cancer 1981 48 1705 1710 7284971 \n4 Gastrointestinal Tumor Study Group Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone J Natl Cancer Inst 1988 80 751 755 2898536 \n5 Gastrointestinal Tumor Study Group A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma Ann Surg 1979 189 205 208 426553 \n6 Kornek GV Schratter-Sehn A Marczell A Treatment of unresectable, locally advanced pancreatic adenocarcinoma with combined radiochemotherapy with 5-fluorouracil, leucovorin and cisplatin Br J Cancer 2000 82 98 103 10638974 \n7 Safran H King TP Choy H Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study J Clin Oncol 1997 15 901 907 9060526 \n8 Hawes RH Xiong Q Waxman I Chang KJ Evans DB Abbruzzese JL A multispecialty approach to the diagnosis and management of pancreatic cancer Am J Gastroenterol 2000 95 17 31 10638554 \n9 Gorovets D Saif MW Huber K Novel treatment approaches for locally advanced pancreatic cancer JOP 2014 15 95 98 24618426 \n10 Kim HS Yi SY Jun HJ Definitive chemoradiation therapy with capecitabine in locally advanced pancreatic cancer Anticancer Drugs 2010 21 107 112 19829097 \n11 Eisenhauer EA Therasse P Bogaerts J New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 19097774 \n12 Cox JD Stetz J Pajak TF Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) Int J Radiat Oncol Biol Phys 1995 31 1341 1346 7713792 \n13 Cardenes HR Chiorean EG Dewitt J Schmidt M Loehrer P Locally advanced pancreatic cancer: current therapeutic approach Oncologist 2006 11 612 623 16794240 \n14 Earle CC Agboola O Maroun J Zuraw L Cancer Care Ontario Practice Guidelines Initiative's Gastrointestinal Cancer Disease Site Group The treatment of locally advanced pancreatic cancer: a practice guideline Can J Gastroenterol 2003 17 161 167 12677264 \n15 Chang JS Wang ML Koom WS High-dose helical tomotherapy with concurrent full-dose chemotherapy for locally advanced pancreatic cancer Int J Radiat Oncol Biol Phys 2012 83 1448 1454 22285669 \n16 Murphy JD Adusumilli S Griffith KA Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer Int J Radiat Oncol Biol Phys 2007 68 801 808 17379445 \n17 Golden DW Novak CJ Minsky BD Liauw SL Radiation dose ≥54 Gy and CA 19-9 response are associated with improved survival for unresectable, non-metastatic pancreatic cancer treated with chemoradiation Radiat Oncol 2012 7 156 22974515 \n18 Tozzi A Comito T Alongi F SBRT in unresectable advanced pancreatic cancer: preliminary results of a mono-institutional experience Radiat Oncol 2013 8 148 23799996 \n19 Trakul N Koong AC Chang DT Stereotactic body radiotherapy in the treatment of pancreatic cancer Semin Radiat Oncol 2014 24 140 147 24635871 \n20 Terashima K Demizu Y Hashimoto N A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis Radiother Oncol 2012 103 25 31 22300608 \n21 Barhoumi M Mornex F Bonnetain F Locally advanced unresectable pancreatic cancer: Induction chemoradiotherapy followed by maintenance gemcitabine versus gemcitabine alone: definitive results of the 2000-2001 FFCD/SFRO phase III trial Cancer Radiother 2011 15 182 191 21315644 \n22 Crane CH Abbruzzese JL Evans DB Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer? Int J Radiat Oncol Biol Phys 2002 52 1293 1302 11955742 \n23 Huang PI Chao Y Li CP Efficacy and factors affecting outcome of gemcitabine concurrent chemoradiotherapy in patients with locally advanced pancreatic cancer Int J Radiat Oncol Biol Phys 2009 73 159 165 18508203 \n24 Li CP Chao Y Chi KH Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study Int J Radiat Oncol Biol Phys 2003 57 98 104 12909221 \n25 Ogawa K Ito Y Hirokawa N Concurrent radiotherapy and gemcitabine for unresectable pancreatic adenocarcinoma: impact of adjuvant chemotherapy on survival Int J Radiat Oncol Biol Phys 2012 83 559 565 22019243 \n26 Abrams RA Grochow LB Chakravarthy A Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels Int J Radiat Oncol Biol Phys 1999 44 1039 1046 10421536 \n27 Heinemann V Schermuly MM Stieber P CA19-9: a pedictor of response in pancreatic cancer treated with gemcitabine and cisplatin Anticancer Res 1999 19 2433 2435 10470171 \n28 Ishii H Okada S Tokuuye K Protracted 5-fluorouracil infusion with concurrent radiotherapy as a treatment for locally advanced pancreatic carcinoma Cancer 1997 79 1516 1520 9118032 \n29 Yoo T Lee WJ Woo SM Pretreatment carbohydrate antigen 19-9 level indicates tumor response, early distant metastasis, overall survival, and therapeutic selection in localized and unresectable pancreatic cancer Int J Radiat Oncol Biol Phys 2011 81 e623 e630 21600705 \n30 Micke O Bruns F Kurowski R Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiochemotherapy Int J Radiat Oncol Biol Phys 2003 57 90 97 12909220 \n31 Montgomery RC Hoffman JP Riley LB Rogatko A Ridge JA Eisenberg BL Prediction of recurrence and survival by post-resection CA 19-9 values in patients with adenocarcinoma of the pancreas Ann Surg Oncol 1997 4 551 556 9367020 \n32 Magnani JL Steplewski Z Koprowski H Ginsburg V Identification of the gastrointestinal and pancreatic cancer-associated antigen detected by monoclonal antibody 19-9 in the sera of patients as a mucin Cancer Res 1983 43 5489 5492 6193872\n\n",
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"title": "Definitive concurrent chemoradiotherapy in locally advanced pancreatic cancer.",
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"abstract": "Aspergillus infection is more common among premature infants in neonatal intensive care units, who have decreased qualitative immune defenses and need various invasive treatment procedures. It is rare in normal full-term neonates, especially in newborn babies from the community. Moreover, the white blood cell (WBC) count and C-reactive protein (CRP) level may be normal or slightly changed in fungal infections, but the neonate reported in this study had significant increases in WBC and CRP. To the best of our knowledge, this is the first report on a full-term neonate from the community with aspergillus infection accompanied by significant increases in WBC and CRP levels.\n\n\n\nA 28-day-old infant, who received empirical antibiotic treatment for 10 days because of neonatal pneumonia, was referred to our neonatal department from the local hospital. The infant had persistent infection and multiple organ failure syndromes. Bronchoscopy and deep sputum smear were performed to identify the pathogen, which confirmed aspergillus infection in the sputum. Fluconazole was immediately administered, but the baby died after three days. Thereafter, an autopsy was performed with parental consent. There were multiple necrotic areas in the lungs and liver, and pathological examination revealed aspergillus.\n\n\n\nThe present case emphasized that community-sourced aspergillus infection can exist in full-term neonates, with significantly increased WBC count and CRP level. Advanced antibiotics were not effective in this case, and fungal infections should have been considered earlier.",
"affiliations": "Guangdong Women and Children Hospital, No. 13, Guangyuan West Road, Yuexiu District, 510000, Guangzhou, China.;Guangdong Women and Children Hospital, No. 13, Guangyuan West Road, Yuexiu District, 510000, Guangzhou, China.;Dongguan Children's Hospital, Guangdong Medical University, 523000, Dongguan, China.;Guangdong Women and Children Hospital, No. 13, Guangyuan West Road, Yuexiu District, 510000, Guangzhou, China.;Guangdong Women and Children Hospital, No. 13, Guangyuan West Road, Yuexiu District, 510000, Guangzhou, China.;Guangdong Women and Children Hospital, No. 13, Guangyuan West Road, Yuexiu District, 510000, Guangzhou, China. yxzh328@126.com.",
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"fulltext": "\n==== Front\nBMC Pediatr\nBMC Pediatr\nBMC Pediatrics\n1471-2431\nBioMed Central London\n\n2588\n10.1186/s12887-021-02588-1\nCase Report\nSevere extensive community acquired aspergillus infection in a full‐term infant accompanied with increases in white blood cell counts and C-reactive protein: a case report\nWang Yanli 1\nChen Wenjing 1\nWu Wenshen 2\nYu Dongling 1\nYan Huiheng 1\nYe Xiuzhen yxzh328@126.com\n\n1\n1 grid.459579.3 Guangdong Women and Children Hospital, No. 13, Guangyuan West Road, Yuexiu District 510000 Guangzhou, China\n2 grid.410560.6 0000 0004 1760 3078 Dongguan Children’s Hospital, Guangdong Medical University, 523000 Dongguan, China\n9 3 2021\n9 3 2021\n2021\n21 11814 8 2020\n2 3 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nAspergillus infection is more common among premature infants in neonatal intensive care units, who have decreased qualitative immune defenses and need various invasive treatment procedures. It is rare in normal full-term neonates, especially in newborn babies from the community. Moreover, the white blood cell (WBC) count and C-reactive protein (CRP) level may be normal or slightly changed in fungal infections, but the neonate reported in this study had significant increases in WBC and CRP. To the best of our knowledge, this is the first report on a full-term neonate from the community with aspergillus infection accompanied by significant increases in WBC and CRP levels.\n\nCase presentation\n\nA 28-day-old infant, who received empirical antibiotic treatment for 10 days because of neonatal pneumonia, was referred to our neonatal department from the local hospital. The infant had persistent infection and multiple organ failure syndromes. Bronchoscopy and deep sputum smear were performed to identify the pathogen, which confirmed aspergillus infection in the sputum. Fluconazole was immediately administered, but the baby died after three days. Thereafter, an autopsy was performed with parental consent. There were multiple necrotic areas in the lungs and liver, and pathological examination revealed aspergillus.\n\nConclusions\n\nThe present case emphasized that community-sourced aspergillus infection can exist in full-term neonates, with significantly increased WBC count and CRP level. Advanced antibiotics were not effective in this case, and fungal infections should have been considered earlier.\n\nKeywords\n\nAspergilloma\nFull‐term neonate\nCommunity infection\nAspergillus infection\nSignificant increases in WBC and CRP\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nAspergillus infection is more common in premature and extremely low birth weight infants in neonatal intensive care units, who have decreased qualitative immune defenses and need various invasive treatment procedures [1, 2]. It is typically rare in normal full-term neonates, especially those from the community. Additionally, the white blood cell (WBC) counts and C-reactive protein (CRP) levels are increased in fungal infections [3].\n\nCase presentation\n\nA male infant was transferred to our neonatal department from the local hospital on day 26 after birth with persistent infection and multiple organ failure syndromes. The baby was born on October 19, delivered by caesarean section at 39 weeks and two days. The infant’s birth weight was 3.15 kg. He had Apgar scores of 9 and 10 points at 5 and 10 min, respectively, and was vaccinated on day 1 after birth for hepatitis and BCG.\n\nThe 25-year-old mother did not have any specific medical history, and did not receive antibiotic treatment or antenatal steroids. The baby was healthy and fed with breast milk and formula after birth.\n\nOn day 16 after birth, the infant was taken to a level I hospital because of cough and fever. His body temperature was 38.6℃ and respiratory rate was 62 beats per minute. Antibiotic therapy with penicillin and cefotaxime was initiated due to suspected community-acquired bacterial infection at the local hospital. However, five days later, the baby developed dyspnea with persistent fever, so he was transferred to a level II hospital. On admission, the baby’s body temperature was 38.9℃ and respiratory rate was 72 beats per minute. Hence, nasal continuous positive airway pressure (nCPAP) treatment was given at that hospital, and meropenem and vancomycin were initiated for five days. However, the baby developed progressive dyspnea and low oxygen saturation, for which tracheal intubation and mechanical ventilation were needed. Thereafter, the baby was transferred to our neonatal department with fever and multiple organ failure syndromes.\n\nThe clinical examination of the infant on admission at our hospital showed the following: body temperature was 38.3℃, with intubation ,heart rate was 181 beats/min, body weight was 3.8 kg, blood pressure was 95/67 mmHg, pulse oxygen saturation (SpO2) was 86 % with 100 % FiO2.\n\nHe was presented with poor response, endotracheal intubation, flat and soft anterior fontanelle with 1.5 cm * 1.5 cm in size, and the bilateral pupils were circular and equal in size, reflecting light. The neck was soft with no resistance. The breath sounds of both lungs were symmetrical, but moist rales were detected in both lungs. The abdomen was flat and soft, with enlarged liver (40 mm below the ribs), not palpable under the spleen rib, with normal bowel sounds. The muscle tension of the limbs was increased. Hugging, holding, foraging and sucking reflexes were not elicited.\n\nBlood test results at the local hospital were as follows: WBC count was 28–45 × 109/L (normal range, < 20 × 109/L), C-reactive protein was 188.2 mg/L (normal range, < 10.0 mg/L), and procalcitonin (PCT) was 2.1 mg/L (normal range, < 0.1 mg/L). The remaining blood test markers were within normal limits: neutrophil granulocytes was 65 % (normal 50–70 %), platelet count (PLT) was 72 × 109/L (normal 100–350 × 109/L). The blood culture was negative.\n\nBlood test results on admission at our hospital were as follows: WBC count was 44 × 109/L and CRP was 548.98 mg/L, which were higher than before, but PLT was lower at 32 × 109/L, PCT was 4.8 mg/L, β-D glucan level was 210 ng/L (normal range, < 11.0). The remaining blood test markers were normal: neutrophil granulocytes was 61 %, IgA was 0.17 g/L, IgG was 2.2 g/L, and IgM was 0.27 g/L. Lymphocyte subset analysis showed: T% = 61.16 %, B% = 6.5 %, NK% = 12.03 %, CD4 + T = 33.33 %, CD8 + T = 29.33 %.\n\nThe X-ray results showed that the neonate presented with pneumonia, and with massive consolidation of right lung and atelectasis. Liver color ultrasound showed hyperechoic imaging, and ECG showed sinus tachycardia.\n\nBronchoscopy and deep sputum smear were immediately performed. The results revealed obvious endobronchitis, necrotic detritus, and pseudo-membrane in the trachea, right main bronchi and branches. The sputum was positive for Aspergillus fumigatus under microscopy. The subsequent blood culture also revealed the presence of Aspergillus fumigatus. Hence, we switched the antibiotics treatment with fluconazole, based on the results of drug sensitivity test. However, the baby died after three days due to clinical deterioration and multiple organ failure.\n\nWith the consent of his family, a biopsy was conducted on the infant to ascertain the cause of death. On gross examination, the lungs weighed 280 g, the left lung and right lung measured 90 × 70 × 30 mm and 11 × 8 × 5 mm, respectively. The cut surface of both lungs showed multiple areas with grey–white necrosis (Fig. 1A). The liver weighed 308 g and measured 170 × 80 × 50 mm. The cut surface of the liver showed multiple areas with grey–yellow necrosis (Fig. 1B). The brain weighed 520 g and the cut surface showed grey–yellow necrotic areas at the top of the brain, measuring 15 mm×15 mm. The skin also showed necrotic areas. The heart, kidneys and spleen were grossly unremarkable.\n\nFig. 1 Specimen of liver. a Gross specimen of the lung showing multiple friable grey–white necrotic areas. b Gross examination of the liver - Multiple nodular and cavitary lesions on the external surface\n\nThen the Olympus Camera (DP21) under the Olympus microscope BX51 with the software of camera was used to investigate pathology. Representative micro-sections from lungs, liver, brain and skin showed extensive multifocal areas of necrosis with acute and chronic inflammatory infiltrates (Figs. 2, 3 and 4), and the presence of fungal hyphae with a morphology similar to Aspergillus fumigatus. These fungal hyphae were also seen with Periodic acid-Schiff (PAS) staining (Fig. 5). Micro-sections examined from the heart, kidneys and spleen were unremarkable. The blood culture was positive for Aspergillus fumigatus. Thus, disseminated invasive aspergillosis was diagnosed.\n\nFig. 2 Photomicrophotographs of the lung, which reveal the destruction of intermingle with necrotic debris and fungal hyphae (H&E, 200X)\n\nFig. 3 Photomicrophotographs of the liver, which reveal hemorrhage and necrosis with hyphae (H&E, 400X)\n\nFig. 4 The fungal hyphae were septate with striated muscles, lymphocytes and eosinophils can be seen (H&E, 200X)\n\nFig. 5 PAS positive (arrows) in striated muscle revealing the presence of fungal hyphae (PAS, 200X)\n\nEpidemiological investigation\n\nAfter diagnosis of invasive aspergillosis, we performed an epidemiological investigation to identify the source of Aspergillus fumigatus. Detailed history recording revealed that the baby’s 73-year-old grandmother who lived with the family had a long-term chronic cough. The family lives on the first floor, the room is damp and has no sunshine. The grandmother could not see sunshine during confinement since the doors and windows were closed for a long time. The baby was nursed, cleaned and fed by the sick and coughing grandmother. The family habitually eats pickles and leftovers. Our request to test the grandmother was refused by the family. The family also refused tests for their immune system function. So whether immunological deficiency existed in the baby and the cause of aspergillosis remained unclear.\n\nDiscussion and conclusions\n\nNeonatal invasive fungal disease is mainly caused by Candida spp [4]. Aspergillosis is often localized to the skin and soft tissues [5]. Primary cutaneous aspergillosis (PCA) is common in premature infants because of defects in the skin barrier [6]. Neonatal aspergillosis is one of the most common causes of morbidity and mortality in premature neonates [7]. The clinical signs and symptoms of aspergillosis infection are often nonspecific. The patient in our report was a full-term baby from the community, without any risk factors. He had invasive Aspergillus fumigatus infection, which was an unusual case.\n\nThe major risk factor for invasive aspergillosis is the quantitative or qualitative deficiency of neutrophil granulocytes. Persistent febrile neutropenia is a high-risk factor in the early phase, but the neutrophil granulocytes were normal in this case. Initially, the infant presented with significantly increased WBC count and CRP level, which indicated bacterial infection or sepsis, and neutrophils and PCT were slightly increased. These findings led to confusion and misdiagnosis. However, some studies have reported Aspergillus fumigatus infection cases accompanied by high WBC and CRP along with low PCT [8–10]. So whether fungal infection should be considered if a baby has high WBC count and CRP level needs further study.\n\nIn summary, fungal infection should be considered if an empirical antibiotic treatment is not effective in an infant with high WBC and CRP, and low PCT. Also, more cultures are required from different samples or other means to achieve an early diagnosis.\n\nAcknowledgements\n\nWe thank all the pathologists of our hospital.\n\nAuthors’ contributions\n\nXY conceived of the correspondence. YW and WW contributed to the writing of the final version of the article. WCH contributed to the pathological section. DY and HY contributed to the data. All authors have read and approved the manuscript.\n\nFunding\n\nNo.\n\nAvailability of data and materials\n\nThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study was approved by the Ethics Committee of Guangdong Women and Children Hospital (No. 202101010) and complied with the Helsinki Declaration. Informed consent was obtained from the neonatal parents in this study.\n\nConsent for publication\n\nWritten informed consent was obtained from a parent of the study participant for publication of this care report, identifying images and accompanying clinical details. And the consent can be requested at any time.\n\nCompeting interests\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Wattier RL Dvorak CC Hoffman JA A prospective, international cohort study of invasive mold infections in children J Pediatric Infect Dis Soc 2015 4 313 22 10.1093/jpids/piu074 26582870\n2. Steinbach WJ Epidemiology of invasive fungal infections in neonates and children Clin Microbiol Infect 2010 16 1321e7 10.1111/j.1469-0691.2010.03288.x 20840541\n3. Li C Netea MG Teerenstra S Early proinflammatory cytokines and C-reactive protein trends as predictors of outcome in invasive Aspergillosis J Infect Dis 2010 202 9 1454 62 10.1086/656527 20879853\n4. Arsenault AB Bliss JM Neonatal candidiasis: new insights into an old problem at a unique host-pathogen interface Curr Fungal Infect Rep 2015 9 246 52 10.1007/s12281-015-0238-x 26779297\n5. Castagnola E Faraci M Fioredda F Invasive mould infections in newborns and children Early Hum Dev 2011 87 Suppl 1 67 9 10.1016/j.earlhumdev.2011.01.015 21123010\n6. Floriane Gallais J Denis O Koobar Simultaneous primary invasive cutaneous aspergillosis in two preterm twins: case report and review of the literature BMC Infect Dis 2017 17 535 10.1186/s12879-017-2646-8 28768499\n7. Ferreras-Antolin L Sharland, Warris A Management of invasive fungal disease in neonates and children Pediatr Infect Dis J 2019 38 6S Suppl 1 2 6 10.1097/INF.0000000000002317\n8. Beaune G Bienvenu F Pondarré C Serum procalcitonin rise is only slight in two cases of disseminated aspergillosis Infection 1998 26 3 168 9 10.1007/BF02771844 9646109\n9. Roques M Chretien ML Favennec C Evolution of procalcitonin, C-reactive protein and fibrinogen levels in neutropenic leukaemia patients with invasive pulmonary aspergillosis or mucormycosis Mycoses 2016 59 6 383 90 10.1111/myc.12487 26931315\n10. Ge YL, Zhang Q, Wang MH, et al. Negative (1,3)-β-D-glucan and elevated white blood cells combined procalcitonin masquerading as severe pneumonia eventually diagnosed as invasive pulmonary aspergillosis proven by bronchoalveolar lavage fluid culture in a diabetes patient: a case Q1 report and literature review. Clin Lab 2019;65(8):1551-4.\n\n",
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"abstract": "Multifocal cerebral venous sinus thrombosis (CVST) has a high mortality rate especially when patients present with stupor or coma. Medical treatment including anticoagulation raises concerns about the associated high risk of intracerebral hemorrhage. Treatment of multifocal CVST with mechanical thrombectomy devices and local tPA infusion have previously been reported. However, these devices may have technical limitations. Success of the new-generation aspiration thrombectomy device like the Penumbra system has been reported in few cases of isolated CVST without the use of chemical thrombolysis. We describe two cases in which mechanical thrombectomy were used in conjunction with intra-sinus tPA infusion. Both cases were complicated and failed initial anticoagulation. Penumbra 054 was used in both cases. The Penumbra 054 is a novel device that has a bigger lumen which provides compatibility with other microcatheters, if additional therapies are required. The larger internal diameter of this catheter also allows for stronger thrombo-aspiration, potentially effecting more rapid sinus recanalization. Both cases showed remarkable clinical recovery without any major complications. This is the first reported simultaneous use of the Penumbra system 054 along with tPA infusion. New devices such as the Penumbra system may offer additional therapeutic options in the treatment of multifocal CVST.",
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"references": "20016918;3339445;20205510;15858188;10835466;19877797;21293023;10319961;12646773;21990598",
"title": "Use of the Penumbra system 054 plus low dose thrombolytic infusion for multifocal venous sinus thrombosis. A report of two cases.",
"title_normalized": "use of the penumbra system 054 plus low dose thrombolytic infusion for multifocal venous sinus thrombosis a report of two cases"
} | [
{
"companynumb": "US-MYLANLABS-2022M1029500",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
... |
{
"abstract": "Actigraphy is a non-intrusive method of recording rest/activity cycles as well as a surrogate for sleep/wake activity. Standard actigraphy analysis is limited in ascribing discrete movement events to wake status during sleep. We applied a novel algorithm to overnight actigraphy data recorded simultaneously with video polysomnography-electroencephalography (video PSG-EEG) to determine its ability to define movement and sleep/wake patterns in children with autism spectrum disorder (ASD) and age-comparable typically developing (TD) controls.\n\n\n\nA previously published novel algorithm uses mathematical endpoints to analyze actigraphy data without assumptions about sleep/wake status, and smooths data using moving windows of increasing length. Nighttime activity level \"S\" events (S1-S5) determined by this algorithm (n = 273) were identified in 15 children ages 3-10 years (nine with ASD and six TD) who wore an AW2 Spectrum Actiwatch (Philips Respironics) while undergoing simultaneous video PSG-EEG. Data were analyzed to identify the time each activity level \"S\" event occurred, video movement events (movements captured by video and scored based on level of severity), and sleep/wake status defined by PSG-EEG. The relationships among activity level \"S\" events, video movement events, and sleep/wake status were analyzed statistically.\n\n\n\nActivity level \"S\" events, the presence and severity of video movement events, and sleep-wake status, were significantly associated. These associations were present in both participants with ASD and those who were typically developing.\n\n\n\nThis actigraphy algorithm shows promise for detecting nighttime movements and sleep/wake status and warrants further study in larger datasets of neurotypical children and those with neurodevelopmental disorders.",
"affiliations": "Sleep Disorders Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.;Sleep Disorders Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.;Sleep Disorders Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.;Philips Healthcare, Bend, OR, USA.;Sleep Disorders Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: beth.malow@vanderbilt.edu.",
"authors": "Alder|Megan L|ML|;Ye|Fei|F|;Run|Fan|F|;Bagai|Kanika|K|;Fawkes|Diane B|DB|;Peterson|Barry T|BT|;Malow|Beth A|BA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.sleep.2020.02.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1389-9457",
"issue": "71()",
"journal": "Sleep medicine",
"keywords": "Actigraphy; Activity; Algorithm; Autism spectrum disorder; Sleep",
"medline_ta": "Sleep Med",
"mesh_terms": "D056044:Actigraphy; D000465:Algorithms; D000067877:Autism Spectrum Disorder; D002648:Child; D002675:Child, Preschool; D006801:Humans; D017286:Polysomnography; D012890:Sleep",
"nlm_unique_id": "100898759",
"other_id": null,
"pages": "28-34",
"pmc": null,
"pmid": "32454300",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "14596726;16034284;19398354;18250091;14592388;21592392;18482108;30896090;20041592;22616853;28416048;23268697;11055457;23754339;27319572;16740591;25845697;28286917",
"title": "Application of a novel actigraphy algorithm to detect movement and sleep/wake patterns in children with autism spectrum disorder.",
"title_normalized": "application of a novel actigraphy algorithm to detect movement and sleep wake patterns in children with autism spectrum disorder"
} | [
{
"companynumb": "US-OTSUKA-2020_019771",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nStudies have shown that body composition, age, gender, changes in monocyte count and repeated dosing alter pharmacokinetic properties of PEGylated liposomal doxorubicin (PLD). However, limited information exists regarding the clinical risk factors of ovarian cancer patients who develop palmar plantar erythrodysesthesia (PPE) while receiving PLD for cancer recurrence.\n\n\nMETHODS\nWe conducted a retrospective cohort analysis of consecutive patients with recurrent ovarian and primary peritoneal cancer who were treated with PLD from 2005 to 2009. Clinical and pathologic data were abstracted from electronic medical records. Statistical analyses were performed using univariate and bivariate analyses, logistic regression, and log rank-tests.\n\n\nRESULTS\nTwenty-three percent (31/133) of patients developed PPE. Age, body mass index (BMI), race, stage, and histology did not significantly differ between PPE and non-PPE patients. There was a possible trend for decreasing PPE with increasing body mass index (BMI) (24.5% of normal weight, 27.5% of overweight; 23.8% of obese class I; 13.3% of obese class II; and 0% of obese class III), though not statistically significant. The number of chemotherapy regimens prior to PLD, and the mean cycles of PLD received did not differ between patients with and without PPE. 77.4% of PPE cases occurred within the first 3 infusion cycles. PPE was not associated with time to progression.\n\n\nCONCLUSIONS\nNearly one-quarter of ovarian cancer patients receiving PLD will develop PPE. Further investigation of factors such as BMI associated with PPE may aid in patient selection for PLD, and future development of other nanoparticle and liposomal agents.",
"affiliations": "Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA. Electronic address: Emily.ko@uphs.upenn.edu.",
"authors": "Ko|Emily M|EM|;Lippmann|Quinn|Q|;Caron|Whitney P|WP|;Zamboni|William|W|;Gehrig|Paola A|PA|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "131(3)",
"journal": "Gynecologic oncology",
"keywords": "Doxil; Ovarian cancer; PEGylated liposomal doxorubicin; PPE; Palmar plantar erythrodysesthesia",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic; D015331:Cohort Studies; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D060831:Hand-Foot Syndrome; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms; D011092:Polyethylene Glycols; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "683-8",
"pmc": null,
"pmid": "24096112",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical risk factors of PEGylated liposomal doxorubicin induced palmar plantar erythrodysesthesia in recurrent ovarian cancer patients.",
"title_normalized": "clinical risk factors of pegylated liposomal doxorubicin induced palmar plantar erythrodysesthesia in recurrent ovarian cancer patients"
} | [
{
"companynumb": "US-JNJFOC-20131202553",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Hepatitis infection has a high prevalence in patients with non-Hodgkin lymphoma. Our objective was to evaluate clinical characteristics and survival of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) who were hepatitis B and/or C (HBV/HCV) positive. We reviewed 224 patents diagnosed with DLBCL and found 21 to be HBV/HCV positive (9.3%). Significant differences were found in the number of nodal regions affected, four in HBV/HCV positive versus two in virus negative patients, and in liver involvement, which was greater in HBV/HCV positive patients (28.6% vs. 10%, p = 0.028). No significant differences were found in the two groups with respect to the number of relapses or the probability of overall or progression-free survival. Despite the finding of differences with respect to stage, total number of nodal regions affected and liver involvement, HBV/HCV positive and negative patients with DLBCL should receive the same treatment, and the disease responds and evolves equally.",
"affiliations": "Medical Oncology Service, Onco-Hematology Research Unit, Instituto de Investigación Sanitaria Puerta de Hierro, Hospital Universitario Puerta de Hierro-Majadahonda , Madrid , Spain.",
"authors": "Rubio|Judit|J|;Franco|Fernando|F|;Sánchez|Antonio|A|;Cantos|Blanca|B|;Méndez|Miriam|M|;Calvo|Virginia|V|;Maximiano|Constanza|C|;Perez|David|D|;Millán|Isabel|I|;Sánchez-Beato|Margarita|M|;Provencio|Mariano|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2014.963576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "56(6)",
"journal": "Leukemia & lymphoma",
"keywords": "Diffuse large B-cell lymphoma; HBV reactivation; HCV reactivation; hepatitis B; hepatitis C",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D016174:Hepacivirus; D006509:Hepatitis B; D006515:Hepatitis B virus; D006526:Hepatitis C; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate; D014775:Virus Activation; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1686-90",
"pmc": null,
"pmid": "25219591",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Does the presence of hepatitis virus B and C influence the evolution of diffuse large B-cell lymphoma?",
"title_normalized": "does the presence of hepatitis virus b and c influence the evolution of diffuse large b cell lymphoma"
} | [
{
"companynumb": "ES-ROCHE-1610606",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The case describes the successful percutaneous balloon mitral valvuloplasty under neuroprotection in a patient with severe symptomatic mitral stenosis and persistent left atrial appendage thrombus despite chronic warfarin therapy. Although the procedure was uneventful for any systemic embolism, the limitations of this approach are highlighted with authors still advocating that surgery remains the benchmark treatment for these patients. © 2014 Wiley Periodicals, Inc.",
"affiliations": "Department of Cardiology, Advanced Cardiac Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India.;Department of Cardiology, Advanced Cardiac Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India.;Department of Cardiology, Advanced Cardiac Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160 012, India.",
"authors": "Chakraborty|Saujatya|S|;Vadivelu|Ramalingam|R|;Bagga|Shiv|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ccd.25421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-1946",
"issue": "88(5)",
"journal": "Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions",
"keywords": "LAA; PBMV",
"medline_ta": "Catheter Cardiovasc Interv",
"mesh_terms": "D000368:Aged; D063126:Balloon Valvuloplasty; D006328:Cardiac Catheterization; D015150:Echocardiography, Doppler; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008943:Mitral Valve; D008946:Mitral Valve Stenosis; D000066829:Neuroprotection",
"nlm_unique_id": "100884139",
"other_id": null,
"pages": "E151-E154",
"pmc": null,
"pmid": "24482194",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Percutaneous balloon mitral valvuloplasty under neuroprotection: Too Early for Knighthood.",
"title_normalized": "percutaneous balloon mitral valvuloplasty under neuroprotection too early for knighthood"
} | [
{
"companynumb": "PHHY2017IN013815",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Kidney biopsies often show accumulation of lipids or lipidlike material. Evidence has been provided that lipids can directly initiate and contribute to the progression of glomerular and tubulointerstitial lesions. In this study we describe a renal lipidosis occurring in patients with a positive history of narcotic abuse who were enrolled in a methadone substitution program. All 3 patients presented with proteinuria (2.5-20 g/d) and impaired renal function. Renal biopsy revealed a pronounced extracellular and intracellular deposition of lipidlike material in the glomerular, interstitial, and tubular compartments. Known causes of lipid storage could be excluded clinically and morphologically. We consider this to be a distinct renal lipidosis associated with narcotic abuse, methadone intake, or intravenous abuse thereof.",
"affiliations": "From the Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (Drs Porubsky and Gröne); the Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany (Dr Porubsky); the Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany (Drs Kuppe, Moeller, and Floege); the Department of Internal Medicine, University Hospital Giessen and Marburg, Marburg, Germany (Dr Maier); the Department of Internal Medicine, University Hospital Giessen and Marburg, Giessen, Germany (Dr Birk); and the Medical Clinic and Policlinic, University Hospitals LMU, Munich, Germany (Dr Wörnle). Drs Porubsky and Kuppe contributed equally to the manuscript.",
"authors": "Porubsky|Stefan|S|;Kuppe|Christoph|C|;Maier|Tanja|T|;Birk|Horst-Walter|HW|;Wörnle|Markus|M|;Moeller|Marcus J|MJ|;Floege|Jürgen|J|;Gröne|Hermann-Josef|HJ|",
"chemical_list": "D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.5858/arpa.2013-0075-CR",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9985",
"issue": "138(5)",
"journal": "Archives of pathology & laboratory medicine",
"keywords": null,
"medline_ta": "Arch Pathol Lab Med",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D018450:Disease Progression; D005260:Female; D006801:Humans; D007668:Kidney; D007674:Kidney Diseases; D050356:Lipid Metabolism; D008064:Lipidoses; D008297:Male; D008691:Methadone; D008875:Middle Aged; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders",
"nlm_unique_id": "7607091",
"other_id": null,
"pages": "689-93",
"pmc": null,
"pmid": "24786128",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal lipidosis in patients enrolled in a methadone substitution program.",
"title_normalized": "renal lipidosis in patients enrolled in a methadone substitution program"
} | [
{
"companynumb": "DE-MYLANLABS-2014M1006840",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Immunoglobulin type gamma 4 (IgG4)-related disease is a relatively newly described clinical entity characterized by a distinctive histopathological appearance, increased numbers of IgG4 positive plasma cells and often, but not always, elevated serum IgG4 concentrations. The most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis marked with proteinuria, hematuria, decreased kidney function, hypocomplementemia, and radiologic abnormalities. Renal biopsy characteristics include dense lymphoplasmacytic tubulointerstitial nephritis that stains for IgG4, storiform fibrosis, and immune complex deposition in the interstitium and along tubule basement membranes. Treatment traditionally consists of prolonged glucocorticoids but cases refractory to glucocorticoids have been reported.We report a case of a 58-year-old Caucasian man who presented with fatigue, 50 pound weight loss, dyspnea, lymphadenopathy, and nephromegaly. The patient was first misdiagnosed as chronic interstitial nephritis secondary to renal sarcoid and was treated with repeated doses of prednisone. On his third relapse, he underwent a repeat renal biopsy and a diagnosis of IgG4-tubulointerstitial nephritis was confirmed. He was refractory to treatment with prednisone. The patient received Rituximab and had prompt sustained improvement in renal function. At 1 year post Rituximab treatment, his serum creatinine remains at baseline and imaging study revealed reduction in his kidney size.This is the first case report using Rituximab as a steroid sparing option for refractory IgG4-tubulointerstitial nephritis. More information is needed on the long-term effects of using of B-cell depleting agents for glucocorticoid resistant IgG4-tubulointerstitial nephritis.",
"affiliations": "From the Division of Nephrology (BAM, PJS, MGA); Osler Medical Residency Program (TN); and Division of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (SB).",
"authors": "McMahon|Blaithin A|BA|;Novick|Tessa|T|;Scheel|Paul J|PJ|;Bagnasco|Serena|S|;Atta|Mohamed G|MG|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D007074:Immunoglobulin G; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000001366",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2626639310.1097/MD.0000000000001366013665200Research ArticleClinical Case ReportRituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis Case Report and Review of the LiteratureMcMahon Blaithin A. MD, PhDNovick Tessa MDScheel Paul J. MDBagnasco Serena MDAtta Mohamed G. MD, MPHRaouf Hajji. From the Division of Nephrology (BAM, PJS, MGA); Osler Medical Residency Program (TN); and Division of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland (SB).Correspondence: Division of Nephrology, Johns Hopkins University School of Medicine, 1830 East Monument St, Suite 416, Baltimore, MD 21287 (e-mail: bmcmaho2@jhmi.edu).8 2015 14 8 2015 94 32 e136614 5 2015 18 7 2015 20 7 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nImmunoglobulin type gamma 4 (IgG4)-related disease is a relatively newly described clinical entity characterized by a distinctive histopathological appearance, increased numbers of IgG4 positive plasma cells and often, but not always, elevated serum IgG4 concentrations. The most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis marked with proteinuria, hematuria, decreased kidney function, hypocomplementemia, and radiologic abnormalities. Renal biopsy characteristics include dense lymphoplasmacytic tubulointerstitial nephritis that stains for IgG4, storiform fibrosis, and immune complex deposition in the interstitium and along tubule basement membranes. Treatment traditionally consists of prolonged glucocorticoids but cases refractory to glucocorticoids have been reported.\n\nWe report a case of a 58-year-old Caucasian man who presented with fatigue, 50 pound weight loss, dyspnea, lymphadenopathy, and nephromegaly. The patient was first misdiagnosed as chronic interstitial nephritis secondary to renal sarcoid and was treated with repeated doses of prednisone. On his third relapse, he underwent a repeat renal biopsy and a diagnosis of IgG4-tubulointerstitial nephritis was confirmed. He was refractory to treatment with prednisone. The patient received Rituximab and had prompt sustained improvement in renal function. At 1 year post Rituximab treatment, his serum creatinine remains at baseline and imaging study revealed reduction in his kidney size.\n\nThis is the first case report using Rituximab as a steroid sparing option for refractory IgG4-tubulointerstitial nephritis. More information is needed on the long-term effects of using of B-cell depleting agents for glucocorticoid resistant IgG4-tubulointerstitial nephritis.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nImmunoglobulin type gamma 4-related disease (IgG4-RD) is a newly described proinflammatory disorder defined by the combined presence of the characteristic histopathological appearance (lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis), increased numbers of IgG4-positive plasma cells, and often, but not always, elevated serum IgG4 concentrations.1 Renal involvement predominantly consists of tubulointerstitial nephritis (TIN), and ongoing tubulointerstitial inflammation and fibrosis are thought to cause progressive decline in renal function.2\n\nThe optimal treatment for IgG4-RD is unknown, and is largely based on retrospective case series.3 The mainstay of treatment is glucocorticoid therapy, which tends to induce rapid disease remission.4,5 Nevertheless, relapses are common, and necessitate prolonged glucocorticoid courses during which additional organ involvement often develops.3–5 Immunomodulatory agents have been used as treatment alternatives in cases of relapsing autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis.4,6 In particular, the B-cell depleting agent Rituximab has been documented as a successful glucocorticoid sparing option in several case series (Table 1) and in a recent prospective single-arm trial.3,4,6,7 There are limited data for Rituximab use in IgG4-TIN.\n\nTABLE 1 Profiles of IgG4-Related Disease Cases Treated With Rituximab\n\nTABLE 1 (Continued) Profiles of IgG4-Related Disease Cases Treated With Rituximab\n\nHerein, we report a patient with a classic clinical presentation for IgG4-TIN, who progressed despite prolonged treatment with glucocorticoids. We review the histopathological features of his kidney biopsy. We also describe the patient's dramatic clinical improvement 1 year after the administration of Rituximab despite the severe interstitial fibrosis and tubular atrophy seen on his renal biopsy. A brief summary of Rituximab use in nonrenal IgG4-related disease is provided.\n\nMETHODS\nInformed consent was obtained.\n\nCase Report\nA 58-year-old Caucasian man presented with fatigue, 50 pound weight loss, and dyspnea. Significant medical history included hypertension, diabetes, bipolar disorder, monoclonal gammopathy of undetermined significance, and remote stage 2 adenocarcinoma of the sigmoid colon treated surgically without chemotherapy or radiation (6 years prior). He initially presented with these symptoms to his oncologist during an annual follow-up. His physical examination was notable for stage 1 hypertension, BMI 30, relative euvolemia with no chest, cardiac, or abdominal abnormalities. His kidneys were not ballotable. He had no palpable lymphadenopathy and no skin lesions. Laboratory work revealed a creatinine of 2.1 mg/dL, up from 0.9 mg/dL 7 months prior, corresponding to a decline in his estimated glomerular filtration rate (eGFR) from 66 mL/min/1.73 m2 to 33 mL/min/1.73 m2. Urinalysis showed 1 + protein was negative for white and red blood cells, and without active sediment. He had a urinary protein to creatinine ratio of 373 mg/g. Initial work-up was notable for antinuclear antibody titers of 1:640 (homogeneous pattern), rheumatoid factor of 120, C3 of 105 mg/dL, C4 of <5 mg/dL, and erythrocyte sedimentation rate of 134 mm/hr. His complete blood count and complete metabolic panels were unremarkable. All further inflammatory and infectious studies were negative, including angiotensin-converting enzyme, antinuclear cytoplasmic antibodies, cryoglobulins, anti-RNP/Smith antibodies, serum and urine protein electrophoresis, hepatitis panel, and testing for human immunodeficiency virus.\n\nComputed tomography showed mediastinal lymphadenopathy, and calcified nodules in his lungs and spleen. Both kidneys were enlarged (right kidney measured 17.4 cm × 8.5 cm × 7.5 cm and left kidney measured 16.3 cm × 7.7 cm × 9.5 cm). There was persistent heterogeneity of the renal parenchyma and a soft tissue thickening was noted around the proximal renal collecting system bilaterally. His renal ultrasound also showed bilateral nephromegaly (right kidney 17.4 cm, left kidney 16.3 cm) without lesions or masses. He was referred to a nephrologist and kidney biopsy was performed, which showed chronic interstitial nephritis (not shown). Due to his biopsy findings, mediastinal lymphadenopathy and calcified nodules on imaging a diagnosis of sarcoidosis was suspected, and he was started on prednisone 60 mg with a 2-month taper to a maintenance dose of 10 mg. While consuming high-dose prednisone, the patient was hospitalized for an acute manic episode and elevated blood sugar levels resulting in a change in his oral hypoglycemic drug regimen. His creatinine initially fell to 1.0 mg/dL, but a further attempt to taper prednisone resulted in a rebound elevation in his creatinine again treated with high-dose prednisone that was tapered over 2 months. For 7 months he was maintained on prednisone 10 mg/day and despite this he suffered a third relapse in renal function (with peak creatinine values of 2.2 mg/dL) (Figure 1). As a result of glucocorticoid resistant disease and intolerable treatment side-effects, he was referred to our institution for a second opinion. A repeat kidney biopsy was performed; his eGFR at the time of biopsy was 35 mL/min per 1.73 m2. Light microscopy (Figure 2A) showed diffuse, variably dense inflammatory infiltrate in the interstitium. The inflammation did not show granulomatous features. There was extensive tubular loss, interstitial fibrosis, and atrophy (Figure 2B). The tubular atrophy was estimated to involve at least 90% of the cortical and medullary parenchyma. The fibrosis occasionally had a “storiform” pattern (Figure 2B). Immunofluorescence showed strong IgG peritubular granular staining and faint granular staining in the surrounding interstitium (Figure 2C). Immunofluorescence was also notable for fine granular staining of C3, C1q, kappa, and lambda light chains along tubule basement membranes and in the interstitium (not shown). Plasma cellular immunostaining for IgG4 demonstrated predominant IgG4-positive plasma cells (Figure 2D). Glomeruli showed mild expansion of the mesangial matrix, but there were no proliferative, microangiopathic, necrotizing, or cresentic lesions (Figure 2E). Electron microscopy showed normal glomerular ultrastructural features without electron dense deposits (Figure 2F), but electron dense deposits in the tubular basement membrane (Figure 2G).\n\nFIGURE 1 Patient's trend in estimated GFR over a 3-year period. Initially, his decline in renal function was treated with prednisone (60 mg/day). Attempts to taper prednisone resulted in rebound elevations in serum creatinine. After his third relapse in renal function, a repeat renal biopsy confirmed the diagnosis of IgG4-related renal disease. He was treated again with prednisone, but his renal function failed to improve and was subsequently treated with Rituximab (4 weekly doses of 375 mg/m2 (900 mg)). Corticosteroids were stopped 9 weeks after the 2nd renal biopsy. One year after treatment with Rituximab, estimated GFR was 50 mL/min/1.73 m2 and he was corticosteroid-free. CST = corticosteroids; GFR = glomerular filtration rate.\n\nFIGURE 2 Renal biopsy. A, Plasma cell rich interstitial infiltrate (H&E 600×); B, Storiform pattern of interstitial fibrosis (H&E, 400×); C, Immunofluorescence shows strong IgG peritubular granular staining and faint granular staining in the surrounding interstitium; D, IgG4-positive plasma cells in the interstitium, with faint peritubular and interstitial granular staining (400×); E, Unremarkable glomerulus (PAS-MS, 600×); F, Electron microscopy showing normal glomerular ultrastructural features and absence of electron dense deposits; G, Electron microscopy showing electron dense deposits in the tubular basement membrane.\n\nThe presence of plasmacytic-rich inflammatory infiltrate in the interstitium, storiform pattern of interstitial fibrosis, IgG4-positive plasma cells, and immune complex deposition along tubular basement membrane were diagnostic of IgG4-TIN and IgG4-RD.8,9,18 Post biopsy his serum IgG4 level was 139 mg/dL. He was treated with glucocorticoid monotherapy (prednisone 60 mg/day × 4 weeks). Despite this, the patient's creatinine continued to rise to 2.2 mg/dL. Given the patient's glucocorticoid resistance and intolerances, he was treated with Rituximab (4 weekly doses of 375 mg/m2 each equating to 900 mg). One year after treatment with Rituximab, his creatinine was 1.5 mg/dL [and has remained free from all immunosuppressive therapy over 1 year (Figure 1)]. Repeat renal imaging 1 year post Rituximab showed a reduction in nephromegaly (right kidney 14.5 cm and left kidney 15.5 cm). The patient's initial symptoms of dyspnea, fatigue, and weight loss had resolved and he had no further manic episodes. In addition, his blood glucose levels had stabilized on low-dose oral glyburide.\n\nDISCUSSION\nIgG4-RD, and in particular IgG4-TIN, typically responds rapidly to glucocorticoid therapy, although an exact treatment protocol has not been established.1,6,10 Recently, an international consensus guidance statement on the management and treatment of IgG4-related disease was published summarizing treatment strategies used in different parts of the world and involving 8 medical subspecialties.10 In this statement, glucocorticoids are postulated to be the first-line agent for induction of remission in all patients with active, untreated IgG4-RD unless contraindications to such treatment exist. Prednisone 30–40 mg/day was considered a common initial treatment dose. Even with the use of maintenance glucocorticoids, relapses in IgG4-RD patients are common.1,6,10 Following relapse disease, there is a consensus in North America and Europe that the combined introduction of glucocorticoid and glucocorticoid-sparing immunosuppressive agents from the start of treatment is appropriate in some patients.10 However, practice styles vary significantly across countries outside of North America and Europe with regard to use of a second immunosuppressive agent in addition to glucocorticoids from the start of treatment and may relate to lack of access to glucocorticoid-sparing agents.10\n\nOur patient initially achieved disease remission with glucocorticoids; however, the disease resistance seen after his third relapse may have been related to the dense interstitial fibrosis and atrophy seen on repeat renal biopsy. The degree of fibrosis on histopathology is thought to relate to treatment failure, with more fibrosis correlating to glucocorticoid-resistant disease.6,11 Steroid-sparing treatments with B-cell depleting agents such as Rituximab have been used successfully in isolated cases and case series of glucocorticoid-resistant extra-renal IgG4-RD (Table 1).4,6,11–17,19,20 In a prospective single-arm pilot trial using Rituximab as a single agent for IgG4-RD, 97% of patients (n = 30) achieved disease response that was maintained at 6 months.7 Rituximab can be effective in allowing discontinuation of all immunosuppressant's with durable remission in a number of cases of IgG4-RD (Table 1) with limited evidence for its use in IgG4-TIN. Despite the high degree of interstitial fibrosis and up to 90% tubular atrophy in this case, preservation of renal function was seen with Rituximab. This is in contrast to reports demonstrating partial or no efficacy of Rituximab when used with severely fibrosed organs such as the thyroid gland.4,13\n\nNephromegaly is not an unusual finding in IgG4-TIN, and potentially caused by cellular infiltration in the renal interstitium2,8,9 by plasma cells. In 1 study, 4 out of 23 patients with biopsy confirmed IgG4-TIN had nephromegaly (defined as >14.5 cm).8 Other radiographic abnormalities of IgG4-TIN include irregularly shaped hypoattenuated lesions and pseudotumor masses.2,8 In our case, Rituximab appeared to reduce his bilaterally enlarged kidneys to a relatively normal size (right kidney previously 17.4 cm was now 14.5 cm, left kidney previously 16.3 cm and now 15.5 cm). The patients estimated GFR normalized at his baseline GFR of 50 mL/min/1.73 m2.\n\nIn general, Rituximab is well tolerated with the most common side effects related to infusion reactions (fever, chills, hypotension, and headache). In a small prospective trial of Rituximab use in IgG4-RD, there was 1 report of Klebsiella urinary tract infection, and 1 report of cold agglutinin-mediated hemolytic anemia.7 In 1 systematic review, Rituximab was associated with increased leukopenia and cardiovascular morbidity.11 However, evidence from long-term large-scale data is lacking. Our patient tolerated Rituximab well and did not develop any immediate side-effects. More importantly, he was free from glucocorticoids 9 weeks after his initial diagnosis and more than 1 year after his first dose of Rituximab.\n\nIn summary, we describe the first case report of successful treatment of glucocorticoid refractory IgG4-TIN with Rituximab. Rituximab provided the opportunity for our patient to be free from glucocorticoids 9 weeks after his initial diagnosis. Our patient was a select case, he had an intolerance to glucocorticoids given his mania and hyperglycemia, but he also had lack of clinical effect with glucocorticoids after his third relapse with IgG4-renal disease. This provided the bases for use of an alternative immunosuppressive agent such as Rituximab, in the treatment of IgG4-TIN. Despite the significant degree of tubular atrophy and fibrosis seen on initial biopsy, our patient had preserved renal function and remained free of disease progression and dialysis over 1 year post Rituximab treatment. Rituximab afforded the opportunity to treat IgG4 disease without the toxicities observed by glucocorticoids. Despite the successful use of Rituximab in the treatment of refractory IgG4-TIN in this case, it should highlight glucocorticoids remain the first-line treatment for most patients with IgG4 disease and B-cell depleting agents may be considered in those patients with a major contraindication to glucocorticoid therapy or an incomplete response to glucocorticoids as observed in our patient.10 A randomized clinical trial is needed to define the optimal use and to determine the appropriate role of B cell depletion in IgG4-RD. More information is needed on the long-term effect of using of B-cell depleting agents for glucocorticoid-resistant IgG4-TIN, and the trajectory of disease in these patients.\n\nACKNOWLEDGMENT\nThe authors declare no acknowledgements.\n\nAbbreviations: AIP = autoimmune pancreatitis, IgG4 = immunoglobulin type gamma 4, IgG4-RD = immunoglobulin type gamma 4-related disease, TIN = tubulointerstitial nephritis.\n\nThe authors have no funding and no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Wallace ZS Stone JH \nAn update on IgG4-related disease . Curr Opin Rheumatol \n2015 ; 27 :83 –90 .25415530 \n2. Yamaguchi Y Kanetsuna Y Honda K \nCharacteristic tubulointerstitial nephritis in IgG4-related disease . Hum Pathol \n2012 ; 43 :536 –549 .21889187 \n3. Khosroshahi A Stone JH \nTreatment approaches to IgG4-related systemic disease . Curr Opin Rheumatol \n2011 ; 23 :67Y71 .21124087 \n4. Khosroshahi A Carruthers MN Deshpande V \nRituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients with IgG4-related disease . Medicine (Baltimore) \n2012 ; 91 :57 –66 .22210556 \n5. Kamisawa T Shimosegawa T Okazaki K \nStandard steroid treatment for autoimmune pancreatitis . Gut \n2009 ; 58 :1504 –1507 .19398440 \n6. Hart PA Topazian MD Witzig TE \nTreatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience . Gut \n2013 ; 62 :1607 –1615 .22936672 \n7. Carruthers MN Topazian MD Khosroshahi A \nRituximab for IgG4-related disease: a prospective, open-label trial . Ann Rheum Dis \n2015 ; 4 :1171 –1177 .25667206 \n8. Raissian Y Nasr SH Larsen CP \nDiagnosis of IgG4-related tubulointerstitial nephritis . J Am Soc Nephrol \n2011 ; 22 :1343 –1352 .21719792 \n9. Kawano M Saeki T Nakashima H \nProposal for diagnostic criteria for IgG4-related kidney disease . Clin Exp Nephrol \n2011 ; 22 :810 –819 .\n10. Khosroshahi A Wallace ZS Crowe JL \nInternational consensus guidance statement on the management and treatment of IgG4-related disease . Arthritis Rheumatol \n2015 ; 67 :1688 –1699 .25809420 \n11. Emery P Deodhar A Rigby WF \nEfficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)) . Ann Rheum Dis \n2010 ; 69 :1629 –1635 .20488885 \n12. Liao B Kamiya-Matsuoka C Fang X Smith RG \nRefractory IgG4-related intracranial hypertrophic pachymeningitis responded to rituximab . Neurol Neuroimmunol Neuroinflamm \n2014 ; 1 :e41 –e43 .25364775 \n13. Soh SB Pham A O’Hehir RE \nNovel use of rituximab in a case of Riedel's thyroiditis refractory to glucocorticoids and tamoxifen . J Clin Endocrinol Metab \n2013 ; 98 :3543 –3549 .23824414 \n14. Reder L Della-Torre E Stone JH \nClinical manifestations of IgG4-related disease in the pharynx: case series and review of the literature . Ann Otol Rhinol Laryngol \n2015 ; 124 :173 –178 .25204708 \n15. Chen TS Figueira E Lau OC \nSuccessful “medical” orbital decompression with adjunctive rituximab for severe visual loss in IgG4-related orbital inflammatory disease with orbital myositis . Ophthal Plast Reconstr Surg \n2014 ; 30 :e122 –e125 .\n16. Caso F Fiocco U Costa L \nSuccessful use of rituximab in a young patient with immunoglobulin G4-related disease and refractory scleritis . Joint Bone Spine \n2014 ; 81 :190 –192 .23932926 \n17. Carruthers M Khosroshahi A Augustin T \nThe diagnostic utility of serum IgG4 concentrations in IgG4-related disease . Ann Rheum Dis \n2014 ; 74 :14 –18 .24651618 \n18. Deshpande V Zen Y Chan JK \nConsensus statement on the pathology of IgG4-related disease . Mod Pathol \n2012 ; 25 :1181 –1192 .22596100 \n19. Jalilian C Prince HM McCormack C \nIgG4-related disease with cutaneous manifestations treated with rituximab: case report and literature review . Australas J Dermatol \n2014 ; 55 :132 –136 .24032760 \n20. Khosroshahi A Carruthers MD Deshpande V Leb L Reed JI Stone JH \nCutaneous immunoglobulin G4-related systemic disease . Am J Med \n2011 ; 124 :e7 –e8 .21722865 \n21. Wallace ZS Carruthers MN Khosroshahi A \nIgG4-related disease and hypertrophic pachymeningitis . Medicine (Baltimore) \n2013 ; 92 :206 –216 .23793110\n\n",
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"mesh_terms": "D058846:Antibodies, Monoclonal, Murine-Derived; D001327:Autoimmune Diseases; D001706:Biopsy; D006801:Humans; D007074:Immunoglobulin G; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D000069283:Rituximab",
"nlm_unique_id": "2985248R",
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"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis: Case Report and Review of the Literature.",
"title_normalized": "rituximab for the treatment of igg4 related tubulointerstitial nephritis case report and review of the literature"
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"abstract": "Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML.Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients.Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment.Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430-40. ©2017 AACR.",
"affiliations": "Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom. Charles.Craddock@uhb.nhs.uk paresh.vyas@imm.ox.ac.uk.;Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom.;MRC Molecular Haematology Unit and Centre for Haematology, Weatherall Institute of Molecular Medicine, University of Oxford and Oxford University Hospitals NHS Trust, Oxford, United Kingdom.;Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom.;Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom.;Centre for Statistics in Medicine, Oxford, United Kingdom.;MRC Molecular Haematology Unit and Centre for Haematology, Weatherall Institute of Molecular Medicine, University of Oxford and Oxford University Hospitals NHS Trust, Oxford, United Kingdom.;MRC Molecular Haematology Unit and Centre for Haematology, Weatherall Institute of Molecular Medicine, University of Oxford and Oxford University Hospitals NHS Trust, Oxford, United Kingdom.;MRC Molecular Haematology Unit and Centre for Haematology, Weatherall Institute of Molecular Medicine, University of Oxford and Oxford University Hospitals NHS Trust, Oxford, United Kingdom.;MRC Molecular Haematology Unit and Centre for Haematology, Weatherall Institute of Molecular Medicine, University of Oxford and Oxford University Hospitals NHS Trust, Oxford, United Kingdom.;Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom.;Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom.;Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom.;Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom.;Department of Haematology, Queen's University, Belfast, United Kingdom.;University Hospitals of North Midlands, Stoke on Trent, United Kingdom.;Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.;Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom.;The Christie NHS Foundation Trust, Manchester, United Kingdom.;Department of Haemato-Oncology, St Bartholomew's Hospital, Bart's Health NHS Trust, London, United Kingdom.;MRC Molecular Haematology Unit and Centre for Haematology, Weatherall Institute of Molecular Medicine, University of Oxford and Oxford University Hospitals NHS Trust, Oxford, United Kingdom. Charles.Craddock@uhb.nhs.uk paresh.vyas@imm.ox.ac.uk.",
"authors": "Craddock|Charles F|CF|;Houlton|Aimee E|AE|;Quek|Lynn Swun|LS|;Ferguson|Paul|P|;Gbandi|Emma|E|;Roberts|Corran|C|;Metzner|Marlen|M|;Garcia-Martin|Natalia|N|;Kennedy|Alison|A|;Hamblin|Angela|A|;Raghavan|Manoj|M|;Nagra|Sandeep|S|;Dudley|Louise|L|;Wheatley|Keith|K|;McMullin|Mary Frances|MF|;Pillai|Srinivas P|SP|;Kelly|Richard J|RJ|;Siddique|Shamyla|S|;Dennis|Michael|M|;Cavenagh|Jamie D|JD|;Vyas|Paresh|P|",
"chemical_list": "C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D001374:Azacitidine",
"country": "United States",
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"doi": "10.1158/1078-0432.CCR-17-1423",
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"issue": "23(21)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D003131:Combined Modality Therapy; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids; D007521:Isocitrate Dehydrogenase; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat",
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "6430-6440",
"pmc": null,
"pmid": "28765326",
"pubdate": "2017-11-01",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature.",
"title_normalized": "outcome of azacitidine therapy in acute myeloid leukemia is not improved by concurrent vorinostat therapy but is predicted by a diagnostic molecular signature"
} | [
{
"companynumb": "GB-CELGENEUS-GBR-2016117407",
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"abstract": "Pulmonary mycotic pseudoaneurysm is a rare complication of bacteremia with high associated mortality. We present a case of a large proximal pulmonary artery pseudoaneurysm as a result of methicillin-sensitive Staphylococcus aureus bacteremia, originating from a tunneled dialysis catheter infection. This case was ultimately managed conservatively with surveillance imaging and a prolonged intravenous antibiotic course, rather than with surgical or interventional management. To our knowledge, this is the first reported case of a mycotic pulmonary pseudoaneurysm due to septic embolization of an infected superior vena cava thrombus.",
"affiliations": "Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia, PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia, PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia, PA, USA.;Department of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia, PA, USA.",
"authors": "Torpey|Erin|E|https://orcid.org/0000-0002-2071-2094;Spears|Jenna|J|https://orcid.org/0000-0003-0182-7774;Al-Saiegh|Yousif|Y|https://orcid.org/0000-0003-4579-8610;Roeser|Mindi|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6456216",
"fulltext": "\n==== Front\nCase Rep Pulmonol\nCase Rep Pulmonol\nCRIPU\nCase Reports in Pulmonology\n2090-6846\n2090-6854\nHindawi\n\n10.1155/2021/6456216\nCase Report\nA Conservative Approach to a Large Mycotic Pulmonary Pseudoaneurysm\nhttps://orcid.org/0000-0002-2071-2094\nTorpey Erin e.l.torpey@gmail.com\n\nhttps://orcid.org/0000-0003-0182-7774\nSpears Jenna jenna.spears@pennmedicine.upenn.edu\n\nhttps://orcid.org/0000-0003-4579-8610\nAl-Saiegh Yousif\nRoeser Mindi\nDepartment of Medicine, Pennsylvania Hospital, University of Pennsylvania Health System (UPHS), Philadelphia, PA, USA\nAcademic Editor: Akif Turna\n\n2021\n18 11 2021\n2021 645621611 5 2021\n16 7 2021\nCopyright © 2021 Erin Torpey 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.\nPulmonary mycotic pseudoaneurysm is a rare complication of bacteremia with high associated mortality. We present a case of a large proximal pulmonary artery pseudoaneurysm as a result of methicillin-sensitive Staphylococcus aureus bacteremia, originating from a tunneled dialysis catheter infection. This case was ultimately managed conservatively with surveillance imaging and a prolonged intravenous antibiotic course, rather than with surgical or interventional management. To our knowledge, this is the first reported case of a mycotic pulmonary pseudoaneurysm due to septic embolization of an infected superior vena cava thrombus.\n==== Body\npmc1. Introduction\n\nA mycotic pulmonary pseudoaneurysm is a rare but deadly consequence of septic emboli in bacterial and fungal bloodstream infections. Timely diagnosis with appropriate imaging is crucial and requires a high index of suspicion. Early detection is important to instate prompt antimicrobial therapy and plan for potential management, as the mortality rate associated with pulmonary pseudoaneurysm rupture is greater than 50% [1].\n\n2. Methods\n\nCase report and review of the literature.\n\n3. Case\n\nA 49-year-old female on hemodialysis presented with fever and confusion and was found to have sepsis secondary to a tunneled dialysis catheter (TDC) line infection. The patient was febrile up to 103.1 degrees F, with a pulse of 116 bpm, SpO2 was 97% on room air, and blood pressure was 130/71 mmHg. On physical exam, the patient was orientated but slow to respond and globally weak. She was due to have her TDC removed, as she had a newly matured right upper extremity arteriovenous graft. She was empirically started on intravenous vancomycin, cefepime, and metronidazole. Her TDC was removed. She was found to be bacteremic with methicillin-sensitive Staphylococcus aureus (MSSA) and was narrowed to Cefazolin monotherapy. Interestingly, the patient's daily blood cultures remained persistently positive for MSSA for four further days, despite appropriate antibiotics and source removal. The patient was also persistently febrile for the majority of her hospitalization, despite targeted antibiotic therapy. Further investigation of other possible sources of infection ensued, including a computed tomography chest scan with intravenous contrast. This revealed 40-50 bilateral cavitating and noncavitating pulmonary nodules, and a large lower lobe consolidation felt to be secondary to septic emboli. She was also found to have an acute pulmonary embolism (PE) of the distal right segmental pulmonary artery. A filling defect was seen in the upper superior vena cava representing either a thrombus or fibrinous sheath from her previous TDC (Figure 1). Of note, the pulmonary arteries were of normal caliber on this scan. Transesophageal echocardiography was obtained and confirmed the presence of a mobile thrombus at the SVC and right atrial junction measuring 1.7 cm in the greatest dimension (Figures 2 and 3). The patient was subsequently started on a heparin infusion for her acute PE, and vascular surgery was consulted for further evaluation of the mobile thrombus. Vascular surgery felt neither lytic nor surgical intervention was warranted for the SVC thrombus and recommended follow-up imaging to monitor the SVC thrombus in one to two weeks. Ten days after the initial CT scan, a repeat CT chest with IV contrast revealed a new left lower lobe pulmonary artery pseudoaneurysm measuring 52 × 47 mm with irregular central contrast measuring 32 mm in dimension (Figure 4). This defect was felt to be mycotic in nature. Interventional radiology was consulted, who felt the patient was not a candidate for left pulmonary artery embolization due to the risk of left lung infarction. Thoracic surgery was consulted and discussed both conservative and surgical options with the patient. The conservative option included continuing intravenous antibiotics and completing weekly surveillance CT scans, with the hope of spontaneous involution and eventual resolution of the lesion. The second option was a left-sided pneumonectomy, which was deemed high-risk due to the proximity of the pseudoaneurysm to the main pulmonary artery. Ultimately, the patient opted to pursue conservative management and was followed closely by the thoracic surgery and infectious disease team. The patient completed eight weeks of IV Cefazolin. Despite her acute PE, anticoagulation was held in the setting of the large pseudoaneurysm and the associated significant bleeding risk. At a 2-month follow-up, her large pulmonary pseudoaneurysm had decreased in size to 38 × 42 × 40 mm. Notably, the patient had an interval decrease of peripheral thrombus within the pseudoaneurysm and resolution of her chronic right upper lobe pulmonary embolus. The nonocclusive SVC thrombus was found to be unchanged. The patient remained asymptomatic and clinically stable and is now off antibiotics. Given the stability of her pseudoaneurysm, her surveillance CT scans have been spaced out to every six months.\n\n4. Discussion\n\nInfection can cause focal aneurysmal degeneration of the arterial wall, leading to either a true or pseudoaneurysm [2]. When bacteremia or septic emboli are felt to be the source of the aneurysm, as was the case in this patient, the lesion is termed a mycotic aneurysm. Mycotic aneurysms are uncommon and most frequently involve the aorta and the cerebral, peripheral, and visceral arteries [2]. Mycotic aneurysms commonly present with symptoms such as fever, chills, back pain, and abdominal pain [3, 4]. There are only several reported cases of mycotic pulmonary artery aneurysms [2]. Although these cases are rare, they carry high associated mortalities of up to 50% [1]. The high mortality may be related to the architecture of the pulmonary arteries, as they lack an adventitial wall layer and are more likely to rupture than systemic aneurysms [1]. Mycotic aneurysms often arise as a result of septic embolization from infective endocarditis [2]. This patient had an atypical source of septic embolization as there was no evidence of endocarditis on transesophageal echocardiography; however, she did have a large thrombus in the distal SVC from an infected TDC, which was felt to be the source. The presentation of an infected aneurysm is dependent on its location [2]. While peripheral lesions may be pulsatile and painful, the involvement of deeper sites may only be associated with fever of unknown origin, as with this patient [2]. Patients with pulmonary artery aneurysms are often otherwise asymptomatic but can present with sepsis, life-threatening hemoptysis, and hypoxemia [2]. Clinical suspicion of an infected aneurysm should be confirmed with laboratory and imaging studies. Laboratory studies should include blood cultures, a complete blood count, and inflammatory markers. It is noted that blood cultures may have poor sensitivity and specificity in the diagnosis of mycotic aneurysm [5]. White cell counts and inflammatory markers are generally, but not always, elevated. Notably, blood cultures can be negative in 25-50 percent of patients and cannot be used to rule out the presence of an infected aneurysm. Initial imaging with a chest radiograph may reveal pulmonary nodules and focal consolidations near the pulmonary vasculature, however, definitive diagnosis, and procedural planning is accomplished with computed tomography angiography (CTA) [1]. CTA allows for timely and effective surgical or endovascular procedural planning [2]. The standard management of infected aneurysms includes antibiotic therapy with surgical debridement and revascularization as needed or endovascular management. Mycotic aneurysms are managed with a prolonged intravenous antibiotic course, similar to infective endocarditis [1]. Broad-spectrum coverage targeting both gram-positive and gram-negative pathogens should be initiated as soon as mycotic aneurysms are suspected and then narrowed pending culture results [1]. Management of pulmonary pseudoaneurysm can include endovascular therapies such as direct coil embolization, endovascular stenting, or embolization of the feeding vessel [1]. Coil embolization is preferred for larger lesions [1]. Surgical management carries a higher risk of morbidity and mortality and involves open thoracotomy, aneurysm resection, and lobectomy of the involved lobes [1]. A high degree of clinical suspicion is required to diagnose pulmonary pseudoaneurysm, given the indolent presentation and rarity of the condition. This is especially true in an atypical patient such as this case, without a history of intravenous drug use or endocarditis. Timely diagnosis is essential to institute appropriate treatment early and prevent nonemergent interventional management.\n\n5. Conclusion\n\nMycotic pulmonary pseudoaneurysm is a rare but life-threatening complication of bacteremia and septic emboli. This is an atypical case of septic embolization from an infected tunneled dialysis catheter. Mycotic pseudoaneurysm should be on the differential of a persistently febrile patient with a known potential source of septic embolization. Early detection is important to instate antibiotic therapy and plan for potential management. In cases with large proximal pulmonary pseudoaneurysms, both procedural and conservative managements carry a high risk of mortality. This case was managed conservatively with subsequent involution of the pulmonary artery pseudoaneurysm.\n\nData Availability\n\nThe data used to support the findings of this study are included within the article. The patient's information used to compile this case report is not disclosed and is protected under HIPAA.\n\nConflicts of Interest\n\nThe authors declare that there is no conflict of interest regarding the publication of this paper.\n\nFigure 1 Axial computed tomography angiography depicting a filling defect (arrow) in the upper superior vena cava at the junction of the left and right brachiocephalic veins.\n\nFigure 2 Transesophageal echocardiogram showing a mobile lesion at the junction of the SVC and right atrium. The lesion is irregular and measures about 1.7 cm in greatest dimension.\n\nFigure 3 Transesophageal echocardiogram with color Doppler showing mobile thrombus at the junction of the SVC and right atrium.\n\nFigure 4 Axial computed tomography angiography depicting a pseudoaneurysm measuring 52 × 47 mm with an irregular central contrast collection measuring 32 mm (marked above).\n==== Refs\n1 Koneru H. Biswas Roy S. Islam M. Pulmonary artery pseudoaneurysm: a rare cause of fatal massive hemoptysis Case Reports in Pulmonology 2018 2018 4 8251967 10.1155/2018/8251967\n2 Cajigas-Loyola S. C. Miller R. L. Spieler B. Carbonella G. Mycotic pulmonary artery aneurysm mimicking a Rasmussen aneurysm The Ochsner Journal 2018 18 1 104 107 29559882\n3 Pham O. H. McSorley S. J. Protective host immune responses to Salmonella infection Future Microbiology 2015 10 1 101 110 10.2217/fmb.14.98 2-s2.0-84921534384 25598340\n4 Wang J.-H. Liu Y.-C. L. Yen M.-Y. Mycotic aneurysm due to non-typhi Salmonella: report of 16 cases Clinical Infectious Diseases 1996 23 4 743 747 10.1093/clinids/23.4.743 2-s2.0-0029761034 8909837\n5 Sörelius K. di Summa P. G. On the diagnosis of mycotic aortic aneurysms Clinical Medicine Insights: Cardiology 2018 12 p. 117954681875967 10.1177/1179546818759678 2-s2.0-85055201100\n\n",
"fulltext_license": "CC BY",
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"title": "A Conservative Approach to a Large Mycotic Pulmonary Pseudoaneurysm.",
"title_normalized": "a conservative approach to a large mycotic pulmonary pseudoaneurysm"
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"abstract": "Patients with penicillin allergy labels often receive alternative antibiotics for perioperative prophylaxis, as opposed to first-line cephalosporins (cefazolin/cefuroxime). Provider misconceptions about the risk of cross-reactivity likely drive this prescribing behavior, which is problematic because of its association with increased risk of surgical-site infections.\n\n\n\nTo develop, implement, and assess the safety of a streamlined approach to perioperative antibiotic selection for surgical patients with a penicillin allergy label, to reduce the use of second-line antibiotics.\n\n\n\nA multidisciplinary task force developed an institutional algorithm for antibiotic selection in penicillin-allergic surgical patients. The percentage of patients receiving a first-line cephalosporin was compared before and after algorithm utilization. The safety of this approach was assessed via chart review of all patients who received epinephrine or diphenhydramine in the operating room, or diphenhydramine within 24 hours postoperatively, assessing for any adverse reactions to cephalosporin administration.\n\n\n\nBetween September 2016 and May 2019, 9.3% of surgical patients had documented penicillin allergy (n = 2296). At baseline, 22% of these patients received a cephalosporin, with an increase to more than 80% after algorithm implementation (P < .0001). Among 551 patients with penicillin allergy label who received a cephalosporin after algorithm implementation, no immediate allergic reactions requiring epinephrine were identified; 1 patient had a delayed rash that did not require cephalosporin discontinuation. Three patients received diphenhydramine for \"itching\" without rash in the setting of concomitant narcotic administration.\n\n\n\nUsing a streamlined algorithm, we were able to significantly reduce the use of second-line antibiotics in penicillin-allergic surgical patients without severe adverse reactions.",
"affiliations": "Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Atlanta, Ga. Electronic address: merin.kuruvilla@emoryhealthcare.org.;Division of Infectious Diseases, Atlanta, Ga.;Division of Infectious Diseases, Atlanta, Ga.;Department of Anesthesiology, Emory University School of Medicine, Atlanta, Ga.;Department of Anesthesiology, Emory University School of Medicine, Atlanta, Ga.;Department of Anesthesiology, Emory University School of Medicine, Atlanta, Ga.",
"authors": "Kuruvilla|Merin|M|;Sexton|Marybeth|M|;Wiley|Zanthia|Z|;Langfitt|Terry|T|;Lynde|Grant C|GC|;Wolf|Francis|F|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D010406:Penicillins",
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"doi": "10.1016/j.jaip.2019.12.016",
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"issue": "8(4)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Cross-reactivity; Penicillin allergy; Prophylactic antibiotics",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D002511:Cephalosporins; D004342:Drug Hypersensitivity; D006801:Humans; D010406:Penicillins",
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"title": "A Streamlined Approach to Optimize Perioperative Antibiotic Prophylaxis in the Setting of Penicillin Allergy Labels.",
"title_normalized": "a streamlined approach to optimize perioperative antibiotic prophylaxis in the setting of penicillin allergy labels"
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"abstract": "As critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose-toxicity relation.\n\n\n\nFrom six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject).\n\n\n\nAfter extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay.\n\n\n\nSurgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.",
"affiliations": "Division of Plastic and Reconstructive Surgery, Department of Surgery, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.;Division of Plastic and Reconstructive Surgery, Department of Surgery, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.;Department of Pathology, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.;Department of Obstetrics and Gynecology, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.;Division of Plastic and Reconstructive Surgery, Department of Surgery, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.;Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.;Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.;Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria. robert.mader@meduniwien.ac.at.",
"authors": "Nedomansky|Jakob|J|;Haslik|Werner|W|;Pluschnig|Ursula|U|;Kornauth|Christoph|C|;Deutschmann|Christine|C|;Hacker|Stefan|S|;Steger|Günther G|GG|;Bartsch|Rupert|R|;Mader|Robert M|RM|0000-0003-3017-8240",
"chemical_list": "D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D016207:Cytokines; D015251:Epirubicin; D004317:Doxorubicin",
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"fulltext": "\n==== Front\nCancer Chemother Pharmacol\nCancer Chemother Pharmacol\nCancer Chemotherapy and Pharmacology\n0344-5704\n1432-0843\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33907881\n4280\n10.1007/s00280-021-04280-8\nOriginal Article\nTissue distribution of epirubicin after severe extravasation in humans\nNedomansky Jakob 1\nHaslik Werner 1\nPluschnig Ursula 2\nKornauth Christoph 3\nDeutschmann Christine 4\nHacker Stefan 1\nSteger Günther G. 2\nBartsch Rupert 2\nhttp://orcid.org/0000-0003-3017-8240\nMader Robert M. robert.mader@meduniwien.ac.at\n\n2\n1 grid.22937.3d 0000 0000 9259 8492 Division of Plastic and Reconstructive Surgery, Department of Surgery, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria\n2 grid.22937.3d 0000 0000 9259 8492 Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria\n3 grid.22937.3d 0000 0000 9259 8492 Department of Pathology, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria\n4 grid.22937.3d 0000 0000 9259 8492 Department of Obstetrics and Gynecology, Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria\n27 4 2021\n27 4 2021\n2021\n88 2 203209\n4 1 2021\n14 4 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/.\nPurpose\n\nAs critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose–toxicity relation.\n\nMethods\n\nFrom six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject).\n\nResults\n\nAfter extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay.\n\nConclusion\n\nSurgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.\n\nKeywords\n\nExtravasation\nSurgery\nAnthracycline\nTissue concentration\nHPLC\nMedical University of ViennaOpen access funding provided by Medical University of Vienna.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nIn contrast to many predictions, cytotoxics are still the cornerstone of cancer treatment on a global scale. With patients benefitting from novel therapeutic combinations, they have more lines of treatment available, which in turn enhances the likelihood of an extravasation event in the long run. Extravasation, a dreaded complication of chemotherapy, is still an elusive field with little evidence and guidance for individual management due to the high number of influencing variables [1]. Although anthracyclines are potent vesicants, it is not known if there is a subcutaneous tissue dose–response relation with a threshold level to initiate irreversible cellular damage resulting in tissue necrosis [2]. Despite efforts to refine and to detail management guidelines by cancer organizations [3], educational efforts [4] and deep literature search with emphasis on clinical evidence for prevention and management in cancer nursing [5], this topic was not addressed so far due to its experimental character. Moreover, little is known about the distribution within the affected lesion and the tissue clearance to reduce the toxic pressure and enable wound healing [6]. In one of the rare reports, tissue concentrations of platinum have been analysed at the anatomical level exploiting the high sensitivity of laser-coupled mass spectrometry [7]. To this aim, we have analysed tissue specimen from patients with anthracycline extravasation scheduled for surgical management due to tissue necrosis. This class of compounds was considered particularly suitable for this approach due to the high persistence of doxorubicin in tissue over weeks upon DNA binding in target cells combined with high chemical stability [8, 9]. Surgically removed tissue was divided into several specimens for chromatographic analysis to draw a map of local anthracycline concentrations centred around the injection site. This picture was completed by the analysis of anthracyclines and cytokines in wound drains over time.\n\nMethods\n\nPatient characteristics\n\nSix patients, five women and one man, were enrolled in this study. Median patient age was 57 (45–78) years. In five of the six patients, the amount of the administered chemotherapeutic agent was documented (Table 1). The median amount of administered anthracycline was 133.8 mg (range 106.0–207.2 mg). Affected body sites were the forearm (3 cases), the cubital fossa (1 case), the dorsum of the hand (1 case) and the pectoral area (1 case). All patients were treated with surgical débridement followed by either split thickness skin grafting (3 cases) or local flaps (3 cases) for defect coverage.Table 1 Demographics\n\nSubject ID\tGender\tAge\tCancer type\tAdministered drug\tDose administered\t\nPatient 1\tF\t47\tBreast\tEpirubicin\t134.58 mg\t\nPatient 2\tF\t66\tBreast\tEpirubicin\t127 mg\t\nPatient 3\tF\t49\tBreast\tEpirubicin\t207.16 mg\t\nPatient 4\tF\t78\tBreast\tEpirubicin\t106 mg\t\nPatient 5\tF\t45\tBreast\tEpirubicin\t133.76 mg\t\nPatient 6\tM\t65\tB cell lymphoma\tDoxorubicin\tNot documented*\t\n* Patient 6 received the CHOP regimen with 50 mg doxorubicin/m2, but the exact dose could not be retrieved\n\nThe study was approved by the Institutional Review Board of the University Hospital Vienna and has, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.\n\nInitial conservative management\n\nAfter the extravasation was noticed, administration of the chemotherapeutic agent was stopped immediately and all patients except for one, who was primarily treated at an external hospital, received topical treatment with dimethyl sulfoxide (99% pure) every 8 h, allowed to air-dry and followed immediately by local cooling over a period of at least 7 days (up to 14 days maximum). This was done according to the standard protocol in our institution. Due to the late discovery of more than 40% of extravasation events [10], the indication for dexrazoxane could be frequently not met (not mentioning other factors such as hospitalization and the toxicity of the antidote itself). In parallel, the affected area was immobilized and treated with a polyurethane foam dressing containing silver ions to prevent a secondary infection (MepilexAg, Molnlycke Health Care, Goeteborg, Sweden). Regular controls were performed every 3–5 days depending on the condition and severity of the lesion. The decision for surgery was taken after demarcation of the irreversibly damaged area within the lesion (centrally visible as necrotic tissue) encompassed by erythema. The surgical intervention was then scheduled within a median number of 10 days (range 1–19).\n\nSurgical management after demarcation\n\nSurgeries were performed under general anaesthesia. The central skin necrosis and all of the encircling area showing erythema were resected including the deep fascia of the underlying muscle. The specimen was sent in for histological examination and high-performance liquid chromatography coupled to fluorometric detection. The tissue defects were covered either by split thickness skin grafts or tissue flaps (muscle or fascio-cutaneous). Split thickness skin grafts were covered with negative pressure wound therapy systems. Regular drains were used in tissue flaps. Postoperative drainage fluid was collected and analysed as well.\n\nAnalysis of anthracyclines by high-performance liquid chromatography (HPLC)\n\nAnthracyclines were analysed using an HPLC method coupled to fluorescence detection as described previously [11]. During surgical intervention, samples were collected from wound drains and from resected pathologic tissue specimen. Briefly, drain samples were centrifuged before injection into a HPLC system (Agilent series 1100, Germany), whereas tissue specimen were homogenised in 10% dimethyl sulfoxide in physiologic saline in a gentleMACS Dissociator (Miltenyi Biotec, Germany) according to the manufacturer’s instructions before injecting the centrifuged supernatant. HPLC conditions for the isocratic elution of epirubicin were 0.1% triethylamine in water (adjusted to pH 2 with trichloroacetic acid) and acetonitrile (68:32) at a flow rate of 1 ml/min on a LiChrospher 60 RP-select B column (5 mm particle size, from Merck, Germany) coupled to fluorescence detection (excitation: 478 nm; emission: 565 nm). The limit of detection was 1.03 ng epirubicin/100 mg tissue with a limit of quantification of 1.72 ng epirubicin/100 mg tissue defined as signal:noise ratio = 5:1. Samples were stored at −30 °C until analysis.\n\nResults\n\nIn this study, we investigated six subjects after extravasation of an anthracycline scheduled for surgical intervention. Based on this criterion, patients were heterogeneous in their demographics, although most of the patients had breast cancer (Table 1). Likewise, the anatomical location and dimension of the affected area differed among patients (Table 2). Surgery was performed with a median time frame of 32 days after extravasation (range 21–54 days) as surgery took place after demarcation of the affected area to identify necrotic tissue. The median hospital stay after surgery was 12.5 days (range 8–16 days). With the exception of subject 5, the necrotic area of enrolled patients prior to surgery was below 10% of the dimension of erythema. It was, however, much larger with 38% in the pectoral region in subject 5.Table 2 Extravasation characteristics\n\nSubject ID\tAffected site\tDays until surgery\tSize skin erythema (cm)\tSize skin necrosis (cm)\tDefect coverage\tHospital stay (days)\t\nPatient 1\tForearm\t38\t5 × 7\t0.8 × 0.7\tSkin graft\t8\t\nPatient 2\tCubital fossa\t54\t5 × 5\t1 × 1\tBrachioradialis flap\t11\t\nPatient 3\tForearm\t23\t13 × 7.5\t1.5 × 1.5\tSkin graft\t13\t\nPatient 4\tDorsum of the hand\t46\t4 × 4\t1 × 1\tRadial forearm flap\t12\t\nPatient 5\tPectoral region\t21\t14 × 6\t8 × 4\tLatissimus dorsi flap\t16\t\nPatient 6\tForearm\t26\t13.5 × 10\t5 × 2\tSkin graft\t16\t\n\nTissue concentrations differed substantially among patients ranging from a few nanograms up to 17 µg per 100 mg tissue (Table 3). Despite this high variability, some observations seem to apply in general. First, even in subjects with high tissue concentrations, there were regions without detectable anthracycline or only trace amounts of the drug. Second, the centre of the necrotic region was not necessarily the specimen with the highest drug concentration.Table 3 Individual anthracycline concentrations in tissue (ng anthracycline/100 mg tissue)\n\nSubject ID\tMinimum conc.\tMaximum conc.\tCentral conc.\t\nPatient 1\t0\t25\t25\t\nPatient 2\t0\t12\t0\t\nPatient 3\t0\t1402\t0\t\nPatient 4\t1\t3007\t244\t\nPatient 5\t3\t104\t25\t\nPatient 6\t0\t17,451\t11,819\t\nconc. concentration; central concentration refers to the specimen collected at the centre of the necrosis\n\nTo illustrate the tissue distribution within a lesion, two subjects have been chosen, the subject with the highest measured amounts of extravasated drug and an extensive extravasation as judged by the area of the affected lesion (Fig. 1) and one subject, where the drug has probably diffused away from its original position leaving the central part of the lesion with small amounts of epirubicin (Fig. 2).Fig. 1 Doxorubicin tissue distribution after extensive extravasation (subject 6). A 65-year-old male lymphoma patient suffered a doxorubicin extravasation on the right forearm (upper left picture). Surgery was performed 26 days after the incident (lower left picture). The defect was covered with a split-thickness skin graft (upper right picture). HPLC analysis showed a pyramid-shaped distribution pattern with the highest concentrations in the central area, where the extravasation originally happened (lower right picture)\n\nFig. 2 Epirubicin extravasation with substantial tissue distribution (subject 4). A 78-year-old female breast cancer patient suffered an epirubicin extravasation on the dorsum of her left hand. After demarcation, surgery was performed 46 days later. The defect was covered with a radial forearm flap. Indocyanine green video angiography immediately after the extravasation event (lower left picture) already predicted the central necrosis (dark area) and the hypervascularized erythema area (white area). HPLC analysis of the resected tissue showed the highest concentration of epirubicin in the most distal part, most likely due to the effects of gravitation affecting the distal extremities (lower right picture)\n\nThe patient shown in Fig. 2 was one out of three subjects with detectable amounts of drug at the resection border, whereas the other three patients followed the pattern shown in Fig. 1. Despite this, there were no complications in wound healing after surgery, which allowed resuming systemic treatment in all subjects. To emphasise these observations, wound drains were collected up to 5 days after surgical intervention to determine if residual drug was still washed out from the wound bed. In all six patients, wound drains were negative for anthracyclines throughout the whole observation period.\n\nIn parallel, wound drains were analysed for the presence of vascular growth factors and inflammatory cytokines. These profiles were compared with that monitored in patients undergoing routine surgery without cytotoxic treatment. In line with the absence of drug in wound drains, the time profiles of vascular growth factors (vascular endothelial growth factor, platelet-derived growth factor and angiopoietin) and the inflammatory cytokine interleukin-33 did not differ from the drain kinetics after routine surgery in healthy subjects.\n\nAs a consequence, one would expect to resume systemic treatment and to continue cancer chemotherapy within a reasonable time frame with minimal delay for the next therapeutic cycle. This corroborates the chosen management approach despite the limited number of observations.\n\nIn conclusion, extravasation was associated with a very high individual variability ranging from a few nanograms of anthracycline to micrograms in tissue, covering three orders of magnitude. Even very small amounts of the vesicant may be able to cause necrosis with the need for surgery. The surgical intervention after demarcation of the lesion was able to remove the drug as judged by the rapid wound healing, the absence of extravasated drug in wound drains resulting in the re-start of systemic treatment within a reasonable time frame.\n\nDiscussion\n\nThe patients investigated in this study showed a highly individual anthracycline distribution pattern after extravasation combined with a substantial difference in tissue sensitivity. Interestingly, the central part of the tissue removed during surgery, which was irreversibly damaged (full-thickness necrosis) in all subjects, was not always the area with the maximum anthracycline concentration. This pattern suggests that even small amounts of anthracyclines may act as a vesicant in subjects with high sensitivity to the cytotoxic in the subcutaneous tissue. This initial sensitivity may then be further aggravated by the impaired blood flow in the central part of the lesion as demonstrated by our group [12]. The hypoemic conditions within the lesion—observed in all three investigated patients of this cohort—result in hypoxic conditions thus fuelling tissue collapse. Moreover, anthracyclines are known to be stable in highly persistent in tissue as they are DNA intercalating agents and are released upon cell death. Subsequently, they may be incorporated in neighbouring cells, which drives a vicious cycle eventually leading to necrosis [8, 13]. As indocyanine green angiography was correctly predicting necrosis in all three examined patients, the central role of continuous blood flow as drug clearing mechanism from the affected lesion is emphasised with deleterious effects in combination with vesicants.\n\nIn previous studies with surgical management of extravasation injuries, the surgical approach and the timing of surgery were variable. Some authors resected only the necrotic tissue, whereas others resected the whole area which was macroscopically affected by the extravasation [14, 15]. Concerning the timing for the surgery, some authors recommend early debridement, whereas others preferred delayed debridement [16]. In previous studies with surgical management of extravasation injuries, the surgical approach and the timing of surgery were variable [11]. The surgical approach for the patients in this study was radical debridement of all tissue that was macroscopically affected by the extravasation after demarcation of the affected lesion. This approach did not only include areas with necrosis, but also areas with erythema. The goal was to eliminate the cytotoxic vesicant completely during one surgical intervention to create favourable conditions for successful defect coverage. In addition, minimising the risk for wound healing problems was supposed to reduce the delay for resumption of the next therapeutic cycle. Whenever suitable, surgeries were, therefore, scheduled shortly after a therapeutic cycle to provide the maximum time frame for complete wound healing before the next therapeutic cycle was scheduled. As surgery was performed with little variation approximately 3 to 6 weeks after extravasation in this study, a significant impact of timing on tissue levels of anthracyclines seems unlikely considering also the low tissue clearance of this class of compounds.\n\nFurther evidence for this approach came from the results of the HPLC analysis in the surgically removed tissue, which demonstrated the presence of the cytotoxic vesicant in areas with erythema. The absence of bacterial colonization but also that of inflammatory signals is of importance for successful graft take in skin transplantations ensuring defect coverage [17, 18]. Wound drains analysed in this study did not show elevated growth factor or interleukin-33 levels when compared with drains from conventional wound surgery. This fact in combination with the short postoperative healing times after skin grafting seems to support the chosen approach [10]. The absence of elevated inflammatory signals in the wound drains also questions the use of corticosteroids as intervention, which has been recommended in the past and is still is widely accepted despite discouraging results in animal studies and little evidence from histopathological studies, where migration of inflammatory cells in the affected lesions is a secondary event [19–21].\n\nLimitations of this investigation are the lack of information about the amount of extravasated drug, which would be helpful in the interpretation of a possible dose–toxicity relation. So far, there are no objective approaches to collect this valuable information as extravasation events are frequently detected only one or more days later [10]. Another limitation was that anthracyclines are converted to several known metabolites in the systemic circulation including the most relevant one doxorubicinol, whereas over time glucuronides are formed in blood to facilitate excretion. If present in tissue, however, we would have detected the main metabolite doxorubicinol in tissue samples and wound drains, which was, however, not the case. This at least suggests poor tissue metabolism of the drug, which is in line with high tissue persistence and low clearance of the drug from peripheral compartments.\n\nIn summary, anthracyclines initiate a vicious cycle upon extravasation with primary cellular damage, hypoemic conditions leading to hypoxic conditions with fast tissue necrosis. This effect may be caused already by very small amounts of extravasated anthracycline emphasising the role of prevention. Five of the six study patients experienced extravasation in body parts (hand, forearm, cubital fossa) of great importance for successfully managing daily life tasks. Skin grafts and local flaps, which were used for defect coverage after radical debridement, led in all cases to highly satisfying functional and aesthetic postoperative results with acceptable time delay for the next therapeutic treatment cycle. However, these investigations demonstrate that only strict intravasal application prevents tissue damage after application of anthracyclines, which may cause necrosis in the nanogram range. This study, therefore, provides experimental evidence why prevention is the most critical step when administering anthracyclines to avoid a dreaded complication.\n\nAcknowledgements\n\nThe authors would like to thank Zeljka Stojanovic for her valuable support during sample clean-up and HPLC analysis.\n\nAuthor contributions\n\nStudy concept and design: JN, WH, UP, CK, CD, GG, and RM; acquisition, analysis and interpretation of data: all authors; drafting of the manuscript: JN, WH, CK, CD, and RM; revision and final approval of the manuscript: all authors.\n\nFunding\n\nOpen access funding provided by Medical University of Vienna.\n\nData availability\n\nThe data sets generated in this study are sensitive data and subject to data protection. Therefore, they are available with some restrictions from the corresponding author on reasonable request in compliance with personal data regulation policies.\n\nDeclarations\n\nConflict of interest\n\nThe authors declare no conflicts of interest.\n\nEthics approval\n\nThe study was approved by the Institutional Review Board of the University Hospital Vienna and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.\n\nConsent to participate\n\nAll patients gave written informed consent according to the institutional guidelines in accordance with the ethical regulations of the Medical University of Vienna.\n\nConsent for publication\n\nAll authors have read the journal’s authorship statement, reviewed the submitted manuscript and agreed to this submission.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Mader I Furst-Weger P Mader RM Nogler-Semenitz E Wassertheurer S Extravasation of cytotoxic agents 2010 2 New York Springer\n2. Bhawan J Petry J Rybak ME Histologic changes induced in skin by extravasation of doxorubicin (adriamycin) J Cutan Pathol 1989 16 3 158 163 10.1111/j.1600-0560.1989.tb00032.x 2671070\n3. Perez Fidalgo JA Garcia Fabregat L Cervantes A Margulies A Vidall C Roila F Group EGW Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines Ann Oncol 2012 23 Suppl 7 vii167 vii173 10.1093/annonc/mds294 22997449\n4. Kim JT Park JY Lee HJ Cheon YJ Guidelines for the management of extravasation J Educ Eval Health Prof 2020 17 21 10.3352/jeehp.2020.17.21 32668826\n5. Melo JMA de Oliveira PP Souza RS da Fonseca DF Gonbtijo TF Rodrigues AB Prevention and conduct against the Extravasation of antineoplastic chemotherapy: a scoping review Rev Bras Enferm 2020 10.1590/0034-7167-2019-0008 33338167\n6. Linder RM Upton J Osteen R Management of extensive doxorubicin hydrochloride extravasation injuries J Hand Surg Am 1983 8 1 32 38 10.1016/S0363-5023(83)80048-3 6827049\n7. Egger AE Kornauth C Haslik W Hann S Theiner S Bayer G Hartinger CG Keppler BK Pluschnig U Mader RM Extravasation of Pt-based chemotherapeutics—bioimaging of their distribution in resectates using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) Metallomics 2015 7 3 508 515 10.1039/c4mt00308j 25659827\n8. Bowers DG Jr Lynch JB Adriamycin extravasation Plast Reconstr Surg 1978 61 1 86 92 10.1097/00006534-197801000-00015 339249\n9. Dorr RT Dordal MS Koenig LM Taylor CW McCloskey TM High levels of doxorubicin in the tissues of a patient experiencing extravasation during a 4-day infusion Cancer 1989 64 12 2462 2464 10.1002/1097-0142(19891215)64:12<2462::aid-cncr2820641211>3.0.co;2-9 2819656\n10. Pluschnig U Haslik W Bayer G Soleiman A Bartsch R Lamm W Steger GG Zielinski CC Mader RM Outcome of chemotherapy extravasation in a large patient series using a standardised management protocol Support Care Cancer 2015 23 6 1741 1748 10.1007/s00520-014-2535-2 25433440\n11. Haslik W Hacker S Felberbauer FX Thallinger C Bartsch R Kornauth C Deutschmann C Mader RM Port-a-Cath extravasation of vesicant cytotoxics: surgical options for a rare complication of cancer chemotherapy Eur J Surg Oncol 2015 41 3 378 385 10.1016/j.ejso.2014.11.042 25515823\n12. Haslik W Pluschnig U Steger GG Zielinski CC Schrogendorfer KF Nedomansky J Bartsch R Mader RM Indocyanine green video angiography predicts outcome of extravasation injuries PLoS ONE 2014 9 8 e103649 10.1371/journal.pone.0103649 25144707\n13. Wang JJ Cortes E Sinks LF Holland JF Therapeutic effect and toxicity of adriamycin in patients with neoplastic disease Cancer 1971 28 4 837 843 10.1002/1097-0142(1971)28:4<837::aid-cncr2820280406>3.0.co;2-4 4329505\n14. Onesti MG Carella S Fioramonti P Scuderi N Chemotherapy extravasation management: 21-year experience Ann Plast Surg 2017 79 5 450 457 10.1097/SAP.0000000000001248 28906302\n15. Shenaq SM Abbase EH Friedman JD Soft-tissue reconstruction following extravasation of chemotherapeutic agents Surg Oncol Clin N Am 1996 5 4 825 845 10.1016/S1055-3207(18)30355-7 8899947\n16. Scuderi N Onesti MG Antitumor agents: extravasation, management, and surgical treatment Ann Plast Surg 1994 32 1 39 44 10.1097/00000637-199401000-00008 8141535\n17. Gilliland EL Nathwani N Dore CJ Lewis JD Bacterial colonisation of leg ulcers and its effect on the success rate of skin grafting Ann R Coll Surg Engl 1988 70 2 105 108 3044237\n18. Hogsberg T Bjarnsholt T Thomsen JS Kirketerp-Moller K Success rate of split-thickness skin grafting of chronic venous leg ulcers depends on the presence of Pseudomonas aeruginosa: a retrospective study PLoS ONE 2011 6 5 e20492 10.1371/journal.pone.0020492 21655269\n19. Dorr RT Alberts DS Chen HS The limited role of corticosteroids in ameliorating experimental doxorubicin skin toxicity in the mouse Cancer Chemother Pharmacol 1980 5 1 17 20 10.1007/BF00578557 7460191\n20. Langstein HN Duman H Seelig D Butler CE Evans GR Retrospective study of the management of chemotherapeutic extravasation injury Ann Plast Surg 2002 49 4 369 374 10.1097/01.SAP.0000018030.28610.7A 12370641\n21. Luedke DW Kennedy PS Rietschel RL Histopathogenesis of skin and subcutaneous injury induced by adriamycin Plast Reconstr Surg 1979 63 4 463 465 10.1097/00006534-197904000-00003 424456\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0344-5704",
"issue": "88(2)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Anthracycline; Extravasation; HPLC; Surgery; Tissue concentration",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D016207:Cytokines; D004317:Doxorubicin; D015251:Epirubicin; D005260:Female; D006801:Humans; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D012871:Skin Diseases; D013524:Surgical Flaps; D014018:Tissue Distribution; D014945:Wound Healing",
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"pages": "203-209",
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"pubdate": "2021-08",
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"title": "Tissue distribution of epirubicin after severe extravasation in humans.",
"title_normalized": "tissue distribution of epirubicin after severe extravasation in humans"
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"abstract": "Heuristics and the application of fast-and-frugal trees may play a role in establishing a clinical decision-making framework for value-based oncology. We determined whether clinical decision-making in oncology can be structured heuristically based on the timeline of the patient's treatment, clinical intuition, and evidence-based medicine. A group of 20 patients with advanced non-small cell lung cancer (NSCLC) were enrolled into the study for extensive treatment analysis and sequential decision-making. The extensive clinical and genomic data allowed us to evaluate the methodology and efficacy of fast-and-frugal trees as a way to quantify clinical decision-making. The results of the small cohort will be used to further advance the heuristic framework as a way of evaluating a large number of patients within registries. Among the cohort whose data was analyzed, substitution and amplification mutations occurred most frequently. The top five most prevalent genomic alterations were TP53 (45%), ALK (40%), LRP1B (30%), CDKN2A (25%), and MYC (25%). These 20 cases were analyzed by this clinical decision-making process and separated into two distinctions: 10 straightforward cases that represented a clearer decision-making path and 10 complex cases that represented a more intricate treatment pathway. The myriad of information from each case and their distinct pathways was applied to create the foundation of a framework for lung cancer decision-making as an aid for oncologists. In late-stage lung cancer patients, the fast-and-frugal heuristics can be utilized as a strategy of quantifying proper decision-making with limited information.",
"affiliations": "Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA.;Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA.;Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA.;California Pacific Medical Center Research Institute, San Francisco, CA, USA.;Department of Clinical Supportive Care, City of Hope, Duarte, CA, USA.;Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, IL, USA.;Department of Medicine, University of Chicago, Chicago, IL, USA.;Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA.",
"authors": "Mambetsariev|Isa|I|;Pharaon|Rebecca|R|;Nam|Arin|A|;Knopf|Kevin|K|;Djulbegovic|Benjamin|B|;Villaflor|Victoria M|VM|;Vokes|Everett E|EE|;Salgia|Ravi|R|",
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"doi": "10.18632/oncotarget.25643",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 2564310.18632/oncotarget.25643Research PaperHeuristic value-based framework for lung cancer decision-making Mambetsariev Isa 1Pharaon Rebecca 1Nam Arin 1Knopf Kevin 2Djulbegovic Benjamin 3Villaflor Victoria M. 4Vokes Everett E. 5Salgia Ravi 11 Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA2 California Pacific Medical Center Research Institute, San Francisco, CA, USA3 Department of Clinical Supportive Care, City of Hope, Duarte, CA, USA4 Department of Medicine (Hematology and Oncology), Northwestern University, Chicago, IL, USA5 Department of Medicine, University of Chicago, Chicago, IL, USACorrespondence to:Ravi Salgia,rsalgia@coh.org6 7 2018 6 7 2018 9 52 29877 29891 18 1 2018 4 6 2018 Copyright: © 2018 Mambetsariev et al.2018This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.Heuristics and the application of fast-and-frugal trees may play a role in establishing a clinical decision-making framework for value-based oncology. We determined whether clinical decision-making in oncology can be structured heuristically based on the timeline of the patient's treatment, clinical intuition, and evidence-based medicine. A group of 20 patients with advanced non-small cell lung cancer (NSCLC) were enrolled into the study for extensive treatment analysis and sequential decision-making. The extensive clinical and genomic data allowed us to evaluate the methodology and efficacy of fast-and-frugal trees as a way to quantify clinical decision-making. The results of the small cohort will be used to further advance the heuristic framework as a way of evaluating a large number of patients within registries. Among the cohort whose data was analyzed, substitution and amplification mutations occurred most frequently. The top five most prevalent genomic alterations were TP53 (45%), ALK (40%), LRP1B (30%), CDKN2A (25%), and MYC (25%). These 20 cases were analyzed by this clinical decision-making process and separated into two distinctions: 10 straightforward cases that represented a clearer decision-making path and 10 complex cases that represented a more intricate treatment pathway. The myriad of information from each case and their distinct pathways was applied to create the foundation of a framework for lung cancer decision-making as an aid for oncologists. In late-stage lung cancer patients, the fast-and-frugal heuristics can be utilized as a strategy of quantifying proper decision-making with limited information.\n\nnon-small cell lung cancerheuristicsfast-and-frugal treesgenomicsframework\n==== Body\nINTRODUCTION\nLung cancer, the leading cause of cancer death among all ages, is expected to account for 234,030 newly diagnosed cases and 154,050 cancer related deaths in the United States in 2018 [1]. Lung cancer is histologically and molecularly heterogeneous with several subtypes and molecular alterations present. Non-small cell lung carcinoma (NSCLC) is one of the four major histologic types of lung cancer and represents approximately 85% of all lung cancer [2]. NSCLC is comprised of three main subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the most common subtype of NSCLC, comprising approximately 40% to 50% of all lung cancer [3, 4, 5].\n\nWhile years ago we relied solely on histopathology for information, the newer science of genomic-based classification of NSCLC has blurred the lines among histologic subtypes by demonstrating that lung cancer can be molecularly subclassified as either adenocarcinoma or neuroendocrine tumor based on its molecular markers [6]. This development of genomic-based characterization has shifted the focus of lung cancer treatment from merely general cytotoxic chemotherapy and radiation treatments to an integration of newer targeted therapeutics that can overcome the challenges of chemotherapeutic resistance and disease progression [7]. The discovery of various genetic driver mutations such as gain-of-function EGFR and KRAS mutations, ALK and ROS1 translocations, and MET amplifications/mutations has vastly improved the basic understanding of the biology of NSCLC [8]. This has also allowed for the development of targeted therapies for these mutations, such as EGFR tyrosine-kinase inhibitors which include erlotinib, gefitinib and afatinib, as well as newer third-generation TKIs such as osimertinib [9]. This new approach of genomic-based classification presents a challenge not only biologically but also clinically as more kinase inhibitors are developed and the biological understanding of driver mutations and NSCLC is further accentuated.\n\nThe clinical scenarios are more complex than just genomic heterogeneity. Although NSCLC is driven by multiple genetic pathways, no two cancers are alike, just as no two patients are alike in their treatments or philosophy of care. Integrating disparate information—clinical, biological, and psychological—remains the art of medicine. To improvise, one must have comfort with uncertainty and the basics of decision analysis in real time. A contemporary oncologist is tasked with constantly making tradeoffs in the clinic based on imprecise information, also known as improvising. We propose an idea of a heuristic framework for clinical decision-making, using key information from each patient's diagnosis, genomics, and cancer information that will allow physicians to make accurate decisions regarding the treatment plans of their patients. We describe below clinical scenarios from patients with NSCLC, arbitrarily divided into 10 “straightforward” cases and 10 “complex” cases by the degree of clinical intuition and complexity required to reach an optimal solution Supplementary Figures 1-20. The cases serve as a small template for a broader heuristic evaluation utilizing fast-and-frugal trees to understand the complexity of clinical care and accurate decision-making.\n\nRESULTS\nThere were ten types of mutations represented in this cohort and the majority of patients had more than one genetic mutation reported. After the genetic reports were compiled, the genes were sorted by frequency and correlated to the de-identified patient number as shown in a mutational tile plot (Figure 1). Mutational frequency is represented by the bar plot as well. Overall, the most common types of mutations found in this cohort were substitution and amplification. Genomic alterations were most frequently found in TP53 (9 out of 20 patients, 45%), ALK (8 out of 20, 40%), LRP1B (6 out of 20, 30%), CDKN2A (5 out of 20, 25%), and MYC (5 out of 20, 25%). Demographic information was also assessed as presented in the tile plot by gender, smoking history, and race. Among the cohort, majority of patients were male (12 patients, 60%) and had a history of smoking (13 patients, 65%). The most prevalent race was Caucasian (14 patients, 70%), with the rest identifying themselves as African American, Asian, or undisclosed. In Table 1 and Table 2 we evaluated the clinical decision-making process for 10 cases that were deemed straightforward and 10 cases that were deemed complex based on the number of steps taken during their treatment. Figure 2 shows a patient timeline of treatment for a straightforward and a complex case. Figure 3 and Figure 4 represent the initial steps towards creating a framework for lung cancer decision-making that would help guide physicians in patient treatment plans.\n\nFigure 1 Mutational profile of 20 patients represented by a heatmap (left)\nThe most frequent genomic alterations identified in this cohort are displayed on the left side of the heatmap. Overall, the most common types of mutations in this cohort were substitution and amplification shown by the mutational frequency bar plot above the heatmap. The heatmap on the right represents the gender, smoking history, and race of the cohort (Gender: Male = blue, Female = yellow; Smoking History: Nonsmoker = orange, Smoker = gray; Race: Caucasian = green, African American = red, Asian = dark blue, Undisclosed = white).\n\nTable 1 Straightforward cases\nStructure\tCase Summary\t\n\tA 68-year-old Caucasian male smoker with a history of 30 pack years was diagnosed with early stage non-small cell carcinoma, monitored with follow-up scans for five years. The patient then presented to the ER with chest pain and dyspnea. Workup showed metastatic disease with progression in the neck, chest, abdomen, liver, and pelvis. He was planned to start on palliative chemotherapy, which is not expected to prolong survival but improve quality of life. With this treatment the patient was expected to live two months. However, molecular testing by NGS showed a PRKARA1A-ALK fusion. The patient was then immediately started on a regimen of crizotinib at a dose of 250 mg per day and showed clinical and radiological response. Crizotinib is effective for patients with ALK-positive mutations and inhibits oncogenic activity of the kinase. He was expected to prolong progression-free survival for about seven months on this treatment regimen. The patient continued on crizotinib for six months before he was admitted to the ER due to loss of balance and passed away.\t\n\tA 70-year-old African American female non-smoker presented with a RUL mass, positive for adenocarcinoma. She underwent a RUL lobectomy and started on carboplatin and pemetrexed. Combination chemotherapy of Carboplatin and Pemetrexed is expected to prolong survival by four months compared to pemetrexed alone. However, results from a NGS test revealed an EGFR L858R exon 21 mutation of EGFR. Therefore, the decision was made to switch her treatment to erlotinib. Erlotinib is effective for patients with EGFR-positive mutations and inhibits its oncogenic activity. She continued on erlotinib for five months until a CT scan revealed an increase in nodules. She was switched to maintenance bevacizumab in addition to her erlotinib to inhibit angiogenesis via anti-VEGF activity. This addition to her regimen is expected to slow progression and she continues treatment.\t\n\tA 66-year-old African American male smoker was initially diagnosed with adenocarcinoma. A PET scan revealed a hypermetabolic tumor in the anterior mediastinum, right supraclavicular, and right axillary lymph node. The patient started treatment with Carboplatin and Paclitaxel, which was expected to improve his one-year survival by approximately 50 percent. Results from NGS reported an R1068* EGFR mutation, but no actionable mutations. He was then given 60 Gy of concurrent radiation therapy. Patient was tested for predictive prognostic response to erlotinib through a VeriStrat test and the results were VeriStrat Good. Therefore, the decision was made to start erlotinib treatment, which inhibits the mutated receptor. The patient continued on erlotinib with minimal symptoms and is expected to prolong survival by 19 percent.\t\n\tA 62-year-old Caucasian female smoker was symptomatic, but ignored her symptoms until a PET scan revealed LUL mass, positive for adenocarcinoma. A subsequent brain MRI was positive for metastasis. She started radiation therapy of 30 Gy to the LUL for two weeks to shrink the tumor. The patient then underwent NGS testing but it reported no actionable mutations. Therefore, chemotherapy was planned as the main course of treatment. However, the disease progressed rapidly and the patient was moved to hospice.\t\n\tA 72-year-old Caucasian male smoker was first evaluated for cough in 2012 and workup showed squamous cell carcinoma of the RUL. He started concurrent chemotherapy (carboplatin/paclitaxel) with radiation. Patients are expected to respond better to this combined-modality regimen than either treatment alone. Upon progression of disease, treatment was switched to carboplatin/nab-paclitaxel. NGS identified no actionable mutations and the patient started on a clinical trial.\t\n\tA 68-year-old Caucasian male smoker was diagnosed with metastatic adenocarcinoma. He started on carboplatin and pemetrexed. Combination chemotherapy of carboplatin and pemetrexed is expected to prolong survival by four months compared to pemetrexed alone. NGS testing reported a KRAS G12A alteration but no actionable mutations. Therefore, he continued on chemotherapy until a CT and PET scan showed progression. His treatment was switched to docetaxel and he stayed on treatment for two months. Second-line docetaxel for patients previously treated with platinum-based chemotherapy is expected to prolong survival by three months. However, docetaxel was held due to toxicity. The patient progressed rapidly and agreed to hospice care.\t\n\tA 72-year-old Caucasian male was first presented to a hospital with neck pain. Workup showed invasive adenocarcinoma of the lung with local metastasis. The patient started on carboplatin and pemetrexed and tissue was sent for molecular testing. Combination chemotherapy of carboplatin and pemetrexed is expected to prolong survival by four months compared to pemetrexed alone. NGS testing reported no actionable mutations. He tolerated five cycles and a CT scan showed stable disease. The patient was then switched to maintenance erlotinib (150 mg). Patients with stable disease after first-line chemotherapy are expected to respond to maintenance erlotinib with prolonged overall survival by more than two months than those with complete or partial response. He tolerated erlotinib well and continues with stable disease.\t\n\tA 79-year-old Caucasian female smoker was first diagnosed with Stage IV adenocarcinoma of the RUL. She was on a clinical trial for two months and continued to do well for seven years until a PET scan showed an enlarged hypermetabolic lymph node. She was off treatment for another two months with stable scans until one scan showed considerable suspicious growth. She underwent a right upper lobe wedge resection and continued off treatment with follow-up scans every six months.\t\n\tA 63-year-old Caucasian male smoker with NSCLC was initially presented with a right hilar mass. Further workup showed adenocarcinoma of RUL and metastasis in the brain and liver. NGS testing revealed no actionable mutations. Further scans revealed metastasis in the left adrenal gland. The recommended plan of care was a combination of carboplatin and pemetrexed. Combination chemotherapy of carboplatin and pemetrexed is expected to prolong survival by four months compared to pemetrexed alone. He tolerated this treatment regimen well, but further progression in the adrenal mass prompted a change of treatment and he was enrolled into a clinical trial.\t\n\tA 76-year-old Caucasian male smoker with a history of Stage IB lung adenocarcinoma. A routine CT scan showed a speculated mass in the RLL, but a PET scan revealed no FDG activity. The patient was diagnosed with polycythemia vera and testing came back positive for a V617F JAK2 mutation. UGT1A1 genotyping revealed a UGT1A1*28 promoter variant present, which supported the diagnosis of Gilbert syndrome. NGS testing revealed no actionable mutations and the patient continued off treatment with routine scans showing no evidence of disease.\t\nThe clinical structures of cases are read from left to right in chronological order.\n\nTable 2 Complex cases\nStructure\tCase Summary\t\n\tA 74 year-old Caucasian female never-smoker initially presented with invasive adenocarcinoma. She was treated with carboplatin, paclitaxel, and bevacizumab then maintenance bevacizumab with a good response. The addition of bevacizumab with the standard chemotherapy regimen is found to improve overall survival and progression-free survival in patients with advanced NSCLC. The patient was then switched to pemetrexed but stopped due to fatigue. NGS testing revealed an ALK-rearrangement and the patient started on crizotinib. Crizotinib is effective for patients with ALK-positive mutations and is expected to prolong progression-free survival for about seven months. She tolerated crizotinib with good response for sixteen months but was discontinued due to toxicities. The patient was switched to ceritinib, an ALK inhibitor targeted therapy effective for patients who progressed on crizotinib.\t\n\tA 32 year-old Caucasian female nonsmoker who initially presented with multiple RL nodules and metastatic disease in the spine. She underwent spine radiation and started on carboplatin and pemetrexed. Combination chemotherapy of carboplatin and pemetrexed is expected to prolong survival by four months compared to pemetrexed alone. NGS testing revealed an EML4-ALK rearrangement. She was immediately started on crizotinib, a targeted therapy effective for patients with ALK-positive mutations expected to prolong progression-free survival for about seven months. She restarted crizotinib despite secondary symptoms of nausea/diarrhea until progression of disease. She received palliative whole brain radiation to treat the brain metastases. Such therapy is not expected to prolong survival but to relieve symptoms. She was then placed on a clinical trial until her disease progressed. She was switched to ceritinib, an ALK inhibitor targeted therapy effective for patients who progressed on crizotinib, but showed poor response and high toxicity. She was then transferred to hospice.\t\n\tA 62 year-old Asian female nonsmoker with lung adenocarcinoma was EGFR L858R positive by NGS and started on erlotinib treatment. Erlotinib is effective for patients with EGFR-positive mutations and inhibits its oncogenic activity. A suspicious liver lesion was detected on a CT scan and a liquid biopsy was performed, but there was no T790M mutation. The appearance of an EGFR T790M mutation in liquid or tissue biopsies is a known mechanism of resistance to erlotinib. The patient then progressed by liver metastasis and was switched to carboplatin and paclitaxel. Combination chemotherapy of carboplatin and pemetrexed is expected to prolong survival by four months compared to pemetrexed alone. There was little to no response and the patient was transferred to hospice.\t\n\tA 53 year-old Caucasian female non-smoker was diagnosed with ALK positive adenocarcinoma metastatic to the liver and bones. She started treatment with carboplatin, pemetrexed, and bevacizumab. The addition of bevacizumab with the standard chemotherapy regimen is found prolong overall survival in patients with non-squamous NSCLC. She then went on to pemetrexed and bevacizumab maintenance, known to have a significant progression-free survival advantage, but was discontinued upon proteinuria and other complications. Patient had developed suspicious brain lesions and underwent whole brain radiation. She was then put on crizotinib. Patient progressed on crizotinib and underwent SRS to mitigate the tumor with greater precision than whole brain radiation therapy. Patient was put on clinical trial for a year but developed progression. The patient died four months later after being ineligible for another trial and unresponsive to further radiation.\t\n\tA 64 year-old Caucasian male who presented with NSCLC with an ALK rearrangement mutation. He had received one dose of palliative radiation before consultation, not mean to prolong survival but improve symptoms, and was then placed on a clinical trial. The patient continued on the trial despite progression of bone lesions due to good clinical response. However, after 12 months on treatment the patient developed further metastases in the bone. Palliative radiation therapy was done and NGS testing was done which revealed an EML4-ALK fusion. The patient began carboplatin and pemetrexed for six cycles. Combination chemotherapy of carboplatin and pemetrexed is expected to prolong survival by four months compared to pemetrexed alone. The patient started ceritinib, an ALK inhibitor, which he tolerated for 12 months until fluctuating LFTs. The patient was then put on a clinical trial. This was tolerated well until the patient developed progressive disease and was transferred to hospice.\t\n\tA 41 year-old Caucasian male nonsmoker who was initially diagnosed with metastatic adenocarcinoma. He started on carboplatin and pemetrexed, expected to prolong survival by four months compared to pemetrexed alone. He was offered a clinical trial but opted for continued chemotherapy with two cycles of pemetrexed maintenance, known to prolong overall survival and progression-free survival significantly. NGS revealed an ALK positive mutation and around the same time a CT confirmed progression of disease. Therefore, the patient immediately started on crizotinib, a targeted therapy effective for patients with ALK-positive mutations expected to prolong progression-free survival for about seven months. He remained on crizotinib for eight months but new lesions were detected. The patient underwent radiation therapy to the brain and spine and then was started on six cycles of carboplatin and pemetrexed. A NGS test from brain resection tissue reported EML4-ALK fusion. The patient was switched to crizotinib and pemetrexed combination maintenance, reported to have sustained clinical benefit in the CNS and minimal toxicities. This combination therapy was given for seven months until further progression. The patient was immediately switched to alectinib, an ALK inhibitor, but there was little to no response. The patient received palliative radiation therapy to the spine but it was solely to relieve symptoms and the patient died a month later.\t\n\tA 78 year-old Asian male smoker who was first diagnosed with a LUL mass positive for adenocarcinoma. A surgical resection was attempted but was deemed inoperable due to metastatic lymph nodes. NGS testing revealed an EGFR L858R mutation. Therefore, the patient was started on erlotinib, an EGFR inhibitor that increases progression-free survival in patients. He tolerated erlotinib for fifteen months until he was hospitalized for pleural effusion. The patient was immediately switched to afatinib, an EGFR inhibitor that has efficacy as a treatment after erlotinib progression, but showed toxicities and little to no response. The patient died in three months.\t\n\tA 53 year-old female smoker who was first diagnosed with extensive metastatic adenocarcinoma. The patient was started on aggressive chemotherapy of carboplatin, docetaxel, and bevacizumab, a regimen that yields good overall response rate and excellent overall survival and progression-free survival as a first-line treatment. The patient was then switched to second-line vinorelbine, gemcitabine, and bevacizumab combination for one month. During this time NGS testing reported ALK-positive mutation, and the patient progressed. Thus, the patient was switched to crizotinib, a targeted therapy effective for patients with ALK-positive mutations expected to prolong progression-free survival for about seven months, and during this time received whole brain radiation. She eventually progressed on crizotinib and eventually started on a clinical trial. She remained on the trial for twelve months until her death.\t\n\tA 67 year-old Caucasian male smoker with history of esophageal cancer was first diagnosed with squamous cell carcinoma of the lung. He underwent adjuvant 5-FU and carboplatin chemoradiation. He did well for eight years until follow up workup confirmed metabolic activity. NGS testing reported no actionable mutations and the patient started on carboplatin and gemcitabine, a regimen found to have significantly higher efficacy in overall survival versus gemcitabine alone. He tolerated it well until disease progression, at which point the patient was switched to carboplatin and docetaxel, shown to have significant clinical benefit in progression-free survival. Another NGS test showed no actionable mutations and instead VeriStrat testing, a predictive prognostic response to erlotinib, was done and was deemed beneficial. Therefore, the patient started on erlotinib. Once he progressed, the patient was switched to nab-paclitaxel, but continued to progress. PDT was issued instead of nab-paclitaxel but there was little disease response and the patient died within four months. Photodynamic therapy uses photosensitizing agent along with light to kill cancer cells for a palliative effect in advanced NSCLC.\t\n\tA 68 year-old African American male smoker who was first diagnosed with squamous cell carcinoma and was placed into a clinical trial. He had no progression for eleven months but then a biopsy showed metastatic disease and he was started on carboplatin and gemcitabine, a regimen found to have significantly higher efficacy in overall survival versus gemcitabine alone. Once he progressed, he was switched to docetaxel, a chemotherapy with significantly high 1-year survival rates as a second-line treatment, then dacomitinib but continued to progress. A NGS test revealed no actionable mutations. He was supposed to start on a clinical trial but was switched to SRS and chemotherapy due to progression of disease. Carboplatin and nab-paclitaxel was tolerated well but a follow up scan showed progressive disease. He started on a clinical trial but continued to be extremely symptomatic and even with whole brain radiation his condition worsened and there was little to no disease response. The patient died a month later.\t\nThe clinical structures of cases are read from left to right in chronological order.\n\nFigure 2 Representative timelines of patient treatment history\n(A) Timeline representation of straightforward case #1 with ALK positive NSCLC which did not undergo any adjuvant chemotherapy or radiation and eventually progressed with diffuse metastatic disease 5 years after diagnosis. (B) Timeline representation of complex case #4 with ALK positive adenocarcinoma that presented with extensive metastatic disease but was well managed and survived for an additional 5 years after diagnosis.\n\nFigure 3 Genomic FFT tree for actionable mutations in NSCLC\nFigure 4 Dendograms of clinical decision-making for actionable mutations in NSCLC\nDISCUSSION\nClinical heuristic framework\nThe genomic landscape of lung adenocarcinoma has not only advanced with the advent of next-generation sequencing, but also with the development of targetable therapeutics. The above 20 cases embody the overall multitude and complexity of cases an oncologist encounters throughout their career. The chemical structures of the patient treatment history were developed to understand the linear progression of each unique case as well as create a heuristic structure where the complexity of the structures indicated the complexity of decision-making. A heuristic, as defined by Gigerenzer and Gaissmaier, is a “strategy that ignores part of the information, with the goal of making decisions more quickly, frugally, and/or accurately than more complex methods” [10]. This methodology of thinking essentially describes the everyday rule-of-thumb that oncologists constantly use to leverage value-based medicine alongside evidence-based medicine to arrive at an optimal course of treatment for a patient. A physician relies on their own clinical expertise, intuition and past experience to quickly sift through a patient's clinical information and arrive at a decision that will be most beneficial to the patient. In most cases, the decisions made regarding treatment plans for patients are formulated from different sources: individual clinician insight, collaboration with other physicians, evidence-based clinical data, genomic testing, and more. The cases presented above show the divergence of clinical decision-making based on the initial conditions of each case. Though some cases may exhibit similar initial properties, such as the histology, metastatic disease, or an actionable mutation, each case diverges in functional outcomes based on the patient's progression and response.\n\nThe existence of a myriad of targets, both novel and traditional treatment options, has resulted in information overload with bewildering complexity in clinical decision-making. In addition, the advances in genomics and targeted therapies have not been accompanied with advances in the science of medical decision-making. A typical approach to improve practitioners’ decision-making is to develop evidence-based clinical practice guidelines (CPGs) by panels of experts who use their best clinical judgments to derive recommendations for practice. Increased explicitness and transparency in the process can be achieved by implementing CPGs as clinical pathways (CPs) (also known as clinical algorithms or flow-charts)[11]. There have been many frameworks, such as NCCN guidelines and pathways, that have attempted to streamline the process of clinical decision-making in oncology, but those methods have been limited by their inability to anticipate heterogeneity between individual patients. Expert decisions and situations in an uncertain world do not rely on estimating probabilities alone, but also on search rules, aspiration levels, lexicographic rules, and other heuristic principles [12]. However, we propose that it is possible to develop a platform of clinical decision-making that relies on categorical information to arrive at the most beneficial treatment option for the patient utilizing heuristics known as fast-and-frugal trees.\n\nFast-and-frugal trees can be best described as decision-making heuristics that can be analytically shown to provide the best possible solution to a problem with limited information [13]. They are typically presented as sequential “steps” taken with simple yes/no options that dictate a pathway in a decision tree tailored to the patient. Here we propose to establish a standardized template of fast-and-frugal trees for lung cancer decision-making that relies not only on established clinical expertise but also integrates value-based decision-making and published data into a heuristic platform. This would later be correlated and quantitated utilizing a large cohort of lung cancer patients in an effort to consolidate expertise in a quantitative manner (Figure 3). This “rule-of-thumb” decision-making to reach the best possible treatment would need to be verified and standardized in a quick manner to maximize benefit to patients. With the approach of more inhibitors, it will be essential to not only consider the genomic information but to correlate it with vital clinical information available with precision medicine. This is where heuristic strategies become significant by employing learned and evolved core capacities such as memory and recall to produce intuitive probabilities that are quick and rational [14]. Fast-and-frugal trees can be created and visualized utilizing the FFTrees package available in R [15]. The FFTrees function utilizes a training dataset as an argument, and generates several fast-and-frugal trees that attempt to classify patients into yes or no categories based on clinical information such as mutations and histology. The instructions for the package detail the step-by-step process for creating fast-and-frugal trees [15]. We believe this will be useful for decision-making, especially in the context of pathways that are being developed [16], so that all oncologists are able to arrive at these fast-and-frugal trees for clinical practice.\n\nAs an example, in straightforward case #2 we see a patient who was staged as pT3N1Mx, which is usually not considered for next-generation sequencing. However, a requested NGS test was able to identify an EGFR L858R mutation that then responded to erlotinib. The patient then progressed but was given combination therapy of erlotinib and afatinib to which she responded with stable disease. The benefit from NGS testing and combination treatment in this case outweighed the financial cost to the patient with a positive clinical outcome [17, 18]. This new work flow of ordering EGFR and ALK testing de novo radically transforms the treatment pathways a patient can undergo [19]. However, the detection of oncogenic mutations is not always clear cut as seen in complex case #1 where a patient who was ALK-negative by FISH but was determined to be ALK-positive by NGS [20]. The patient responded well to targeted ALK therapies, all because the second opinion testing by NGS transformed the treatment plan. This highlights both the negative and the positive value of genomic testing in that the FISH test had failed to determine an actionable mutation while the NGS test was able to detect it which offered the patient other treatment options. In this situation, heuristic of intuition was used to predict that the ALK FISH test may be inaccurate and an NGS test was ordered.\n\nIt is also important to note that though the list of targeted therapies for lung cancer continue to grow, there is still a gap between the mutational profile of all lung cancer patients and available therapeutics. For example, in straightforward case #3, we identified a patient whose genetic testing did not reveal any actionable mutations, but did reveal an R1068* mutation in EGFR. Heuristically from personal experience, it was predicted that a patient with a mutation in EGFR may benefit from TKI treatment, and so a VeriStrat™ test, a predictive prognostic response to erlotinib, was ordered to determine if the patient would be eligible for TKI treatment [21]. Due to the VeriStrat™ results, the patient was given and responded to erlotinib with minimal symptoms, highlighting the necessity of doubt and intuition when interpreting genomic mutations that do not at first appear to be actionable but can yield positive results when re-evaluated. However, while the VeriStrat™ test results have sound prognostic value, they are not infallible as seen in complex case #9. Although the patient was reported to be VeriStrat™ Good, erlotinib had little to no effect and ultimately resulted in progression of disease. On the other hand, there are more severe cases where the genetic testing does not offer the patient any options for treatment. For example, in straightforward case #4, the patient had no actionable genetic mutations and was offered chemotherapy but rapidly progressed before she could start treatment. In this case, the patient, who had a family history of lung cancer, was moved to hospice on the patient's wishes. This gives insight into the reality that rational decision-making in the clinic does not entirely rely on the highest expected utility, but must take into account the patient's values to avoid irrational overtreatment [22]. Unfortunately, cases with no actionable mutations are relatively frequent as seen in straightforward cases #6 and #9. Although both of thee patients were found to have a substitution mutation in KRAS, a driver mutation that comprises roughly 25% of all adenocarcinoma cases, it has no targetable therapy [23]. This reveals the level of uncertainty and intuitive thinking that is involved in oncology decision-making, especially considering there are currently no actionable treatments for a substantial portion of lung adenocarcinoma mutations.\n\nThough the use of targeted therapies has revolutionized lung cancer treatment options, it is vital to remember that they are not always guaranteed for success and resistance to therapies often develops in most cases [24]. In the example of complex case #6, it is shown that the patient had developed progression on crizotinib and was switched to six cycles of cisplatin and pemetrexed. There was noted to be a repeat sensitivity to pemetrexed after a treatment holiday and the patient continued for another seven months with crizotinib and pemetrexed combination maintenance [25, 26]. The equation for clinical decision-making becomes more complex when considering the mechanisms of resistance to targeted inhibitors. This is observed in complex case #5 where the patient was able to achieve prolonged survival on three different ALK inhibitors by switching between ALK inhibitors and cytotoxic chemotherapy to circumvent progression and tumor resistance [27]. This treatment plan of switching off between different tyrosine kinases inhibitors or between different TKIs and cytotoxic chemotherapy is noted in other cases as well [25, 28, 29]. These multiple cases reveal potential treatment pathways for patients who initially benefitted from crizotinib or erlotinib yet eventually progressed—but the majority of these treatment decisions were done based on intuition and quick re-evaluation of published evidence rather than definitive linear treatment pathways. This highlights the restrictions of evidence-based medicine where physicians are forced to follow guided paths with unsubstantiated linear outcomes rather than inference from patient value, tacit knowledge, and problem-solving frameworks [30]. The need for a physician-focused method of evaluating treatment options is essential as shown in Figure 4, especially as the landscape of targeted therapies continues to expand.\n\nIt is current NCCN guidelines to obtain molecular information on patients with adenocarcinoma variant of non-small cell lung cancer. To obtain this information, there are several vendors in this space including broad genomic panels (FoundationOne, Guardant 360) or single mutation analysis (e.g. BIOCEPT). However, sequencing of therapies has become more complex. Because the genomics of NSCLC can change over time and by site of metastatic disease, it is likely that the temporal integration of multiple liquid biopsy time points will be needed in the clinic to optimize treatment choice. As with any other test, the genomic testing can be noninformative or the interpretation can be challenging, as was illustrated in several cases described above. Temporal changes in genomics will be easier to interpret with longitudinal tracking software that can be accessed by the oncologist. However, we suggest that healthcare, oncology care especially, can be improved by the combination of a heuristic cognitive architecture, driven by human intuition and emotion, and a structured computational framework that may provide statistically viable approximations that can mimic everyday expertise in dealing with clinical uncertainty to arrive at a model of rationality that integrates patient values with treatment utility [22, 31]. Heuristic concepts are applied in certain branches of medicine, such as cardiovascular decision-making, specifically in the efficacy of fast-and-frugal trees in prescribing statins to prevent cardiovascular disease [32, 33]. This specialized FFT designed to assist in medical decision-making generated numerous permutations of pathways a physician could undergo depending on the patient criteria. This strategy was also applied in predicting the causes of community-acquired pneumonia in young children so that the appropriate antibiotic treatment is prescribed [34]. This study is a first analysis determining the decision-making value in the context of lung cancer and molecular analysis. It will be important to determine the value of other mutations besides EGFR and ALK through further analysis of other mutations such as ROS1, MET, HER2, BRAF, TRK, and others. We hope this forms a nidus for the future for further studies and robust dataset with large number of patients.\n\nThe field of genomics in NSCLC has exponentially grown within the last decade alone. The introduction of molecular testing and NGS have radically shifted the era of standardized healthcare in NSCLC to a more personalized and precise one as it continues to advance [35]. We witness the rapid changes regarding the value and efficacy of targeted therapies in different cases as seen by the recent FDA approval of immunotherapy pembrolizumab with carboplatin and pemetrexed as a first-line treatment in metastatic NSCLC [36, 37]. Even more recent, pembrolizumab was approved by the FDA as the first drug universally used based on a genetic biomarker of microsatellite instability-high or mismatch repair deficient instead of by cancer type [38]. This marks the first approval of a drug not manufactured for a particular type of cancer but instead by biomarkers expression in tumor cells regardless of its origin. This blurs the lines we initially placed between cancer types and introduces a new drug classification and potential research focuses based on tumor biomarkers. The value of genomic testing and personalized treatment plans is necessary as the landscape of NSCLC continues to evolve.\n\nIn much of oncology, the physician follows a well laid path, e.g. an NCCN guideline, or mimics a clinical trial that applies to the patient's clinical situation. However, as illustrated in these cases, many patients do not fall into a simple, uniform pathway on the NCCN guidelines so the oncologist must make decisions based on imprecise information through observing the results and discernment. Since there is no one “standard of care” in the new era of treating lung cancer, clinicians tend to find themselves on precarious grounds. The ability of the clinical oncologist to keep up with changes scientifically is being taxed as pathways are constantly evolving due to the introduction of newer medicine and treatment. Integrating disparate sources of knowledge becomes more complex and the physician lacks “point of care epidemiology” tools. Physicians in clinic must input multiple Bayesian priors—from history, physical examination, the medical literature, and our past successes and failures—to derive a treatment plan for each individual patient. The clinician is tasked with doing this in real time in a field such as NSCLC where the science is increasing at a rapid pace. We are at a crossroads where the complexity of managing patients with NSCLC is increasing at a rate that oncologists face time constraints [39]. This is the time when medical informatics, specifically heuristic decision-making and fast-and-frugal trees, can be judiciously applied to improve patient outcomes in NSCLC.\n\nMATERIALS AND METHODS\nPatients and subjects\nLung adenocarcinoma patients included in this analysis were evaluated at the University of Chicago Hospitals (UCH) from 2008 to 2015 and underwent genotype testing as requested by the primary clinical provider (n=20). Patients were consented to the Institutional Review Board (IRB) approved protocols 9571 and 13473, allowing our research team to obtain detailed clinical information such as course of treatment as well as the results of the clinical genetic testing to be analyzed. The testing was done through next-generation sequencing (NGS) and all data was reported in compliance with the Health Insurance Portability and Accountability Act (HIPAA) regulations.\n\nStudy design\nClinical patient data was collected, after consent, from both the UCH electronic medical records (EPIC) medical database and the Thoracic Oncology Research Program (TORP) Microsoft Access Databases. This allowed the research team to collect demographic data such as age, sex, race, histology, treatment course, and functional outcomes. In addition to the clinical data in the hospital database, tumor tissue testing results were obtained from a NGS provider.\n\nStatistical analysis\nNo formal statistical hypotheses were assessed and all statistical analyses were descriptive. The sample size was determined by examining ten straightforward and ten complex cases that each had unique clinical insight.\n\nMethods\nThe patient timelines and fast-and-frugal trees were created using Adobe Illustrator to display the unique features and differences of individual cases. The mutational tile plot was created by coding the type of mutation reported to a number in an excel spreadsheet. The spreadsheet was then uploaded into R programming and modified using the publicly available “pheatmap” module.\n\nSUPPLEMENTARY MATERIALS FIGURES\n We thank the clinical staff at the University of Chicago for their skill and dedication in helping the patients presented in this paper.\n\nCONFLICTS OF INTEREST\n\nAll authors in our study have no conflicts of interest.\n\nFUNDING\n\nThe authors received no funding for this project.\n\nAbbreviations\nNSCLCNon-small cell lung cancer\n\nNCCNNational Comprehensive Cancer Network\n\nALKAnaplastic lymphoma kinase\n\nEGFREpidermal growth factor receptor\n\nIRBInstitutional Review Board\n\nUCHUniversity of Chicago Hospital\n\nTORPThoracic Oncology Research Program\n\nFISHFluorescent in situ hybridization\n\nNGSNext-Generation Sequencing\n\nTKITyrosine kinase inhibitors\n\nFDAU.S. Food and Drug Administration\n==== Refs\nREFERENCES\n1 Siegel RL Miller KD Jemal A Cancer statistics, 2018 CA Cancer J Clin 2018 68 7 30 10.3322/caac.21442 29313949 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"title": "Heuristic value-based framework for lung cancer decision-making.",
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"abstract": "Linezolid is a synthetic antimicrobial agent of the oxazolidinone class with weak, nonspecific inhibitor of monoamine oxidase enzymes. Concomitant therapy with an adrenergic or serotonergic agent or consuming tyramine (>100 mg/day) may induce serotonin syndrome (SS). We present a case report of near-fatal adverse interaction between linezolid and escitalopram inducing SS in a 65-year-old woman with sepsis, under empirical antibiotic treatment. This report also summarizes the current relevant literature as identified via PubMed, EMBASE, and PsycINFO, supplemented with a manual search of cross references.",
"affiliations": "Department of Psychiatry, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, India.;Department of Forensic Medicine and Toxicology, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, India.",
"authors": "Kulkarni|Ranganath R|RR|;Kulkarni|Pratibha R|PR|",
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"doi": "10.4103/0253-7176.122245",
"fulltext": "\n==== Front\nIndian J Psychol MedIndian J Psychol MedIJPsyMIndian Journal of Psychological Medicine0253-71760975-1564Medknow Publications & Media Pvt Ltd India IJPsyM-35-41310.4103/0253-7176.122245Case ReportLinezolid-Induced Near-Fatal Serotonin Syndrome During Escitalopram Therapy: Case Report and Review of Literature Kulkarni Ranganath R. Kulkarni Pratibha R. 1Department of Psychiatry, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, India1 Department of Forensic Medicine and Toxicology, SDM College of Medical Sciences and Hospital, Dharwad, Karnataka, IndiaAddress for correspondence: Dr. Ranganath R. Kulkarni, Department of Psychiatry, SDM College of Medical Sciences and Hospital, Dharwad - 580 009, Karnataka, India. E-mail: dranant007@rediffmail.comOct-Dec 2013 35 4 413 416 Copyright: © Indian Journal of Psychological Medicine2013This 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.Linezolid is a synthetic antimicrobial agent of the oxazolidinone class with weak, nonspecific inhibitor of monoamine oxidase enzymes. Concomitant therapy with an adrenergic or serotonergic agent or consuming tyramine (>100 mg/day) may induce serotonin syndrome (SS). We present a case report of near-fatal adverse interaction between linezolid and escitalopram inducing SS in a 65-year-old woman with sepsis, under empirical antibiotic treatment. This report also summarizes the current relevant literature as identified via PubMed, EMBASE, and PsycINFO, supplemented with a manual search of cross references.\n\nAdverse eventescitalopramlinezolidserotonin syndrome\n==== Body\nINTRODUCTION\nMonoamine oxidases (MAO) are mitochondrial enzymes responsible for the metabolic breakdown of monoamines (serotonin, norepinephrine, and dopamine) in neuronal tissues causing depletion of monoamines and clinical depression; while MAO inhibitors (MAOIs) result in the clinical improvement of mood states. Interestingly, drugs that possess MAOI properties but are used for purposes unrelated to antidepressant activity are furazolidone (an antiinfective); procarbazine (drug used for Hodgkin's disease); and linezolid (an antibiotic used for serious infections).[1] We report a case of serious adverse drug interactions between escitalopram and linezolid precipitating near-fatal serotonin syndrome (SS) in an elderly female. Relevant literature was retrieved via PubMed, EMBASE, and PsycINFO using the keywords; “linezolid”, “escitalopram”, “serotonin syndrome” supplemented with a manual search of cross references.\n\nCASE REPORT\nA 65-year-old elderly female, from urban and middle socioeconomic background, presented with history suggestive of depressed mood, middle and late insomnia, anorexia, lethargy, reduced interest in pleasurable activities since 1 year. She was diagnosed as depressive disorder as per ICD-10 diagnostic criteria.[2] She had no prior medical history of hypertension, diabetes, or any drug intake. Escitalopram (5 mg/day) and clonazepam (0.25 mg/day) therapy showed partial improvement, fortnight later. Escitalopram was increased to 10 mg/day, while clonazepam was discontinued due to drowsiness, a month later. Patient had full remission of depressive symptoms with escitalopram (10 mg/day), 2 months later. Compliance with medications was ensured and supervised by her apprehensive spouse.\n\nPatient presented with acute onset high-grade fever, cough with greenish-yellow expectoration, breathlessness, and asthenia of a week's duration following recent travel. She had received antipyretics, mucolytics, expectorants, antibiotics (amoxicillin and clavulanate) for 5 days from medical practitioner but found no respite. Later, she was referred to physician and hospitalized. On admission, she had 101°F temperature, pulse rate of 126/min, and blood pressure (BP) of 136/88 mm Hg. Her general physical and systemic examination revealed no other abnormal findings, except for bilateral scattered fine crepitations and reduced bilateral air entry in lower respiratory areas. A complete blood count revealed leukocytosis (15640/cmm) and neutrophilia (80%). Her blood glucose (105 mg/dL), blood urea (25 mg/dL), and serum creatinine (1.0 mg/dL) were within normal limits. Electrocardiograph revealed no abnormalities. Her chest roentgenogram showed bilateral patchy consolidation suggestive of pneumonitis. Patient was treated with intravenous linezolid (600 mg twice daily), antipyretics, bronchodilators (etophylline), expectorants (guaiphenesin), mucolytics (ambroxol), and chest physiotherapy.\n\nWithin the first 24 hours of antibiotic treatment, the patient had a rapid clinical deterioration with restlessness, diaphoresis, tremor, shivering, myoclonus, diarrhoea, exaggerated deep tendon reflexes, hypoxia (SPO2-80% with 6-8 L of oxygen) and high fever (103°F), along with mental status changes such as disorientation, confusion, and hallucinatory behavior. However, in view of neurological symptoms, cranial computerized tomography and lumbar puncture for the exclusion of central nervous system (CNS) infection were performed but were unremarkable. The patient was intubated due to severe respiratory difficulties and transferred to the intensive care unit. Psychiatrist consultation was sought for delirium. Detailed history and sequence of emergence of events (including history of depression and escitalopram treatment from caregivers) were observed and SS was suspected. Linezolid and escitalopram were discontinued, and cyproheptadine (4 mg thrice daily) via the nasogastric tube was initiated. Pneumonitis was treated with intravenous cephalosporin (cefotaxime; 2 g twice daily) and aminoglycoside (amikacin; 500 mg twice daily) antibiotics. Patient showed the first signs of improvement few hours later. Withdrawal of sedation and ventilator weaning took place 48 hours later. Patient gradually regained consciousness and orientation to person, location, and time. At discharge, vital parameters were stable with pulse of 86 bpm and BP of 130/80 mm Hg. Patient was discharged with escitalopram 10 mg/day.\n\nDISCUSSION\nIn our case, addition of antibiotic linezolid (600 mg twice daily) for the treatment of acute onset pneumonia in a patient receiving serotonergic antidepressant, escitalopram (10 mg/day) for depressive disorder since 2 months, temporally led to the constellation of the neurological and mental state features in the absence of other CNS pathology led to the diagnosis of SS. We ruled out the possibility of other drug interactions, as none of them (paracetamol, etophylline, guaiphenesin, ambroxol) possess either adrenergic or serotonergic properties supplemented by literature search.\n\nLinezolid is a totally synthetic compound that was initially synthesized as a reversible MAOI class antidepressant.[3] Due to its weak, nonspecific MAO inhibition, concomitant therapy with an adrenergic or serotonergic agent or consuming tyramine (>100 mg/day) may increase the risk of SS.[1] It is believed to act through early inhibition of protein synthesis via binding to the 23S portion of the 50S ribosomal bacterial rRNA subunit inducing conformational structural changes and preventing tRNA to enter and functionally bind to the ribosome therefore inhibiting mRNA translation. Its oral bioavailability is nearly equal to intravenous administration, with plasma half-life of 4-6 h. Peak serum concentrations attain about 20 mcg/mL on 600 mg twice daily dosing in adults. Linezolid is 30% protein-bound and distributed widely to well-perfused tissues.[1] Linezolid is metabolized via oxidation procedure in a way independent of cytochrome P450 (CYP-450); consequently there is no possible pharmacokinetic mechanism of interaction between linezolid and other medication metabolized through CYP450 pathways. Although 80% of the dose of linezolid appears in the urine, dose modification has not been currently recommended in renal insufficiency as serum concentrations and half-life of the drug are not appreciably affected. However, linezolid and its breakdown products are eliminated by dialysis; the drug should be administered after hemodialysis.[1] Linezolid is generally well-tolerated, with some minor side-effects like gastrointestinal disturbances, headache, and rashes. Rarely, myelosuppression including anaemia, leukopenia, thrombocytopenia, and peripheral as well as optic neuropathy have been reported on prolonged use (>8 weeks).[1]\n\nEscitalopram is the S-enantiomer of racemic citalopram with antidepressant activity through selective serotonin reuptake inhibition (SSRI), a drug category that is believed to act through boosting of serotonin neurotransmission via blockade of serotonin reuptake pump, therefore theoretically more prone to be involved in the development of SS. It is 56% plasma protein bound with plasma half-life of 27-32 h and reaches steady state plasma levels in 7 days. It is metabolized to S-demethylcitalopram and S-didemethylcitalopram. The primary CYP isoenzymes involved in its metabolism are CYP 3A4, CYP 2D6, and CYP 2C19. Escitalopram displays linear and dose-proportional pharmacokinetics for single and multiple doses in the dose range of 10-30 mg/day. Its clearance in elderly subjects (>65 years) in single-dose and multiple-doses showed approximate increase of 50% in half-life. Its recommended daily dose in the geriatric population is 10 mg.[4]\n\nSS is a disorder typically caused by the combination of two or more medications with serotonergic properties due to increased serotonin release. It is characterized by restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, and mental status changes, such as confusion. It usually consists of a constellation of neurological and mental state symptoms and commonly diagnosed according to the widely accepted criteria,[5678] as summarized in Table 1. The pathophysiological mechanism of SS does not include idiosyncratic, neither idiopathic nor pharmacokinetic drug reactions, but is considered to be a predictable and preventable pharmacodynamic consequence of the excess of serotonergic agonism in CNS and peripheral serotonergic receptors.[7] Symptoms usually improve with the withdrawal of the predisposing drug agents plus supportive care, as there is no specific evidence-based treatment of the SS.[9] Cyproheptadine is a H1 histamine receptor antagonist as well as a nonspecific serotonin receptor antagonist,[10] may have a role in the management of SS (4 mg thrice daily).\n\nTable 1 Widely accepted diagnostic criteria for serotonin syndrome\n\nConcomitant use of MAOIs (including linezolid, furazolidone, and procarbazine) along with adrenergic/serotonergic antidepressants, St. John's wort, sibutramine, or opiate drugs that have SSRI-like properties (meperidine, tramadol, methadone, dextromethorphan, propoxyphene, and fentanyl) have been reported to precipitate dangerous SS.[1111213141516] Rarely, SS may also be precipitated by concomitant use of SSRIs with metoclopramide,[171819] sibutramine, fenfluramine or dexfenfluramine, lithium, dihydroergotamine, sumatriptan; but risk is severe when SSRIs and MAOIs are combined.[4] Linezolid has been reported to induce SS as an interaction with almost every category of antidepressant medications like imipramine,[20] amitriptyline,[2122] fluoxetine,[2324] citalopram,[32526] escitalopram,[25] paroxetine,[27] sertraline,[28] L-tryptophan (precursor of serotonin),[17] mirtazapine,[3] trazodone,[26] buspirone,[29] venlafaxine,[263031] and duloxetine.[32]\n\nPsychiatrists need to be aware that all SSRIs (except fluoxetine) should not be co-administered with MAOIs within 2 weeks of discontinuing either drug, lest may precipitate SS. Fluoxetine due to its long half-life is recommended to be stopped at least 5 weeks prior to initiation of MAOIs and conversely, MAOIs are to be discontinued at least 3 weeks prior to initiation of fluoxetine.[4] However, in patients receiving SSRIs who acutely require linezolid therapy for short-term (10-14 days) therapy, coadministration with careful monitoring is reasonable because SSRIs generally require tapering to avoid discontinuation symptoms.[1] Physicians utilizing these drugs (linezolid, furazolidone, procarbazine) need to be sensitized about potentially fatal SS when coadministered with antidepressant therapy. Clinicians need to exercise reasonable degree of care and skills to prevent such interactions primarily and also be competent to detect early and manage such adverse events, lest may amount to medical negligence.[33]\n\nSource of Support: Nil\n\nConflict of Interest: None.\n==== Refs\nREFERENCES\n1 MacDougall C Chambers HF Brunton LL Chabner BA Knollmann BC Protein synthesis inhibitors and miscellaneous antibacterial agents Goodman and Gilman's The Pharmacological Basis of Therapeutics 2011 12th ed New York McGraw Hill 1537 8 \n2 World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines 1992 10th ed Geneva World Health Organization \n3 DeBellis RJ Schaefer OP Liquori M Volturo GA Linezolid-associated serotonin syndrome after concomitant treatment with citalopram and mirtazapine in a critically ill bone marrow transplant recipient J Intensive Care Med 2005 20 351 3 16280409 \n4 Sussman N Sadock BJ Sadock VA Selective serotonin reuptake inhibitors Kaplan and Sadock's Comprehensive Textbook of Psychiatry 2009 9th ed Philadelphia Lippincott Williams and Wilkins 3191 205 \n5 Sternbach H The serotonin syndrome Am J Psychiatry 1991 148 705 13 2035713 \n6 Taylor JJ Wilson JW Estes LL Linezolid and serotonergic drug interactions: A retrospective survey Clin Infect Dis 2006 43 180 7 16779744 \n7 Boyer EW Shannon M The serotonin syndrome N Engl J Med 2005 352 1112 20 15784664 \n8 Dunkley EJ Isbister GK Sibbritt D Dawson AH Whyte IM The Hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules for serotonin toxicity QJM 2003 96 635 42 12925718 \n9 Perry PJ Wilborn CA Serotonin syndrome vs neuroleptic malignant syndrome: A contrast of causes, diagnoses, and management Ann Clin Psychiatry 2012 24 155 62 22563571 \n10 Graudins A Stearman A Chan B Treatment of the serotonin syndrome with cyproheptadine J Emerg Med 1998 16 615 9 9696181 \n11 Blumenfield M Gamboa MC Suojanen JK Sadock BJ Sadock VA Psychiatric care of the burned patient Kaplan and Sadock's Comprehensive Textbook of Psychiatry 2009 9th ed Philadelphia Lippincott Williams and Wilkins 2456 68 \n12 Ailawadhi S Sung KW Carlson LA Baer MR Serotonin syndrome caused by interaction between citalopram and fentanyl J Clin Pharm Ther 2007 32 199 202 17381671 \n13 Gollapudy S Kumar V Dhamee MS A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion J Clin Anesth 2012 24 251 2 22537574 \n14 Kirschner R Donovan JW Serotonin syndrome precipitated by fentanyl during procedural sedation J Emerg Med 2010 38 477 80 18757161 \n15 Reich M Lefebvre-Kuntz D Serotoninergic antidepressants and opiate analgesics: A sometimespainful association. A case report Encephale 2010 36 D119 23 20513454 \n16 Rastogi R Swarm RA Patel TA Case scenario: Opioid association with serotonin syndrome: Implications to the practitioners Anesthesiology 2011 115 1291 8 22037635 \n17 ColomarFerrá A VentayolBosch P Raurich JM Serotonin syndrome due to interaction between linezolid, tryptophan, and metoclopramide Med Intensiva 2009 33 360 1 19828401 \n18 Fisher AA Davis MW Serotonin syndrome caused by selective serotonin reuptake-inhibitors-metoclopramide interaction Ann Pharmacother 2002 36 67 71 11816261 \n19 Vandemergel X Beukinga I Neve P Serotonin syndrome secondary to the use of sertraline and metoclopramide Rev Med Brux 2000 21 161 3 10925598 \n20 Miller DG Lovell EO Antibiotic-induced serotonin syndrome J Emerg Med 2011 40 25 7 18455905 \n21 Nisijima K Shimizu M Abe T Ishiguro T A case of serotonin syndrome induced by concomitant treatment with low-dose trazodone and amitriptyline and lithium Int Clin Psychopharmacol 1996 11 289 90 9031998 \n22 Perry NK Venlafaxine-induced serotonin syndrome with relapse following amitriptyline Postgrad Med J 2000 76 254 6 10727586 \n23 Steinberg M Morin AK Mild serotonin syndrome associated with concurrent linezolid and fluoxetine Am J Health Syst Pharm 2007 64 59 62 17189581 \n24 Thomas CR Rosenberg M Blythe V Meyer WJ 3rd Serotonin syndrome and linezolid J Am Acad Child Adolesc Psychiatry 2004 43 790 15213578 \n25 Lorenz RA Vandenberg AM Canepa EA Serotonergic antidepressants and linezolid: A retrospective chart review and presentation of cases Int J Psychiatry Med 2008 38 81 90 18624020 \n26 Bergeron L Boulé M Perreault S Serotonin toxicity associated with concomitant use of linezolid Ann Pharmacother 2005 39 956 61 15827071 \n27 Wigen CL Goetz MB Serotonin syndrome and linezolid Clin Infect Dis 2002 34 1651 2 12032904 \n28 Clark DB Andrus MR Byrd DC Drug interactions between linezolid and selective serotonin reuptake inhibitors: Case report involving sertraline and review of the literature Pharmacotherapy 2006 26 269 76 16466332 \n29 Morrison EK Rowe AS Probable drug-drug interaction leading to serotonin syndrome in a patient treated with concomitant buspirone and linezolid in the setting of therapeutic hypothermia J Clin Pharm Ther 2012 37 610 3 22452676 \n30 Mason LW Randhawa KS Carpenter EC Serotonin toxicity as a consequence of linezolid use in revision hip arthroplasty Orthopedics 2008 31 1140 19226083 \n31 Packer S Berman SA Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid Am J Psychiatry 2007 164 346 7 17267801 \n32 Strouse TB Kerrihard TN Forscher CA Zakowski P Serotonin syndrome precipitated by linezolid in a medically ill patient on duloxetine J Clin Psychopharmacol 2006 26 681 3 17110838 \n33 Modi JP Kannan K Mathiharan K Medical negligence and consumer protection act Modi's A Textbook of Medical Jurisprudence and Toxicology 2012 24th ed Nagpur Lexis Nexis 119 68\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "35(4)",
"journal": "Indian journal of psychological medicine",
"keywords": "Adverse event; escitalopram; linezolid; serotonin syndrome",
"medline_ta": "Indian J Psychol Med",
"mesh_terms": null,
"nlm_unique_id": "7910727",
"other_id": null,
"pages": "413-6",
"pmc": null,
"pmid": "24379509",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports",
"references": "12925718;18624020;2035713;17381671;22563571;17189581;15827071;22037635;17267801;22452676;16779744;10925598;9031998;11816261;18757161;17110838;18455905;15784664;19828401;20513454;16466332;10727586;12032904;22537574;15213578;16280409;9696181;19226083",
"title": "Linezolid-induced near-fatal serotonin syndrome during escitalopram therapy: case report and review of literature.",
"title_normalized": "linezolid induced near fatal serotonin syndrome during escitalopram therapy case report and review of literature"
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"abstract": "OBJECTIVE\nThe efficacy of the all-oral administration of daclatasvir and asunaprevir for 24 weeks was compared with that of telaprevir for 12 weeks plus pegylated interferon and ribavirin (PEG-IFN/RBV) for 24 weeks, and that of simeprevir for 12 weeks plus PEG-IFN/RBV for 24 weeks, with a focus on the prevention of occurrence and recurrence of hepatocellular carcinoma (HCC). The levels of alanine aminotransferase (ALT) and α-fetoprotein (AFP) as suppressive markers of HCC were also measured.\n\n\nMETHODS\nPatients received daclatasvir and asunaprevir (n = 17), simeprevir plus PEG-IFN/RBV (n = 15) and telaprevir plus PEG-IFN/RBV (n = 25). Sustained virological response (SVR) and the mean change in the level of serum ALT, AFP and platelet (PLT) count were compared among the three groups.\n\n\nRESULTS\nNo difference in SVR was observed in patients given daclatasvir with asunaprevir (SVR4), telaprevir plus PEG-IFN/RBV or simeprevir plus PEG-IFN/RBV (SVR24). Also, no significant difference was observed in the mean change of serum ALT, AFP or PLT count among the three groups.\n\n\nCONCLUSIONS\nThe preventive effect of the IFN-free, all-oral regimen of daclatasvir and asunaprevir was observed with a focus on the occurrence and recurrence of HCC, as was IFN-based treatment with telaprevir or simeprevir plus PEG-IFN/RBV.",
"affiliations": "Division of Molecular Medicine and Medical Genetics, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Sugimoto|Kayo|K|;Kim|Soo Ryang|SR|;Kim|Soo Ki|SK|;Imoto|Susumu|S|;Tohyama|Madoka|M|;Kim|Ke Ih|KI|;Ohtani|Aya|A|;Hatae|Takashi|T|;Yano|Yoshihiko|Y|;Kudo|Masatoshi|M|;Hayashi|Yoshitake|Y|",
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"country": "Switzerland",
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"issue": "89 Suppl 2()",
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"references": null,
"title": "Comparison of Daclatasvir and Asunaprevir for Chronic HCV 1b Infection with Telaprevir and Simeprevir plus Peginterferon and Ribavirin, with a Focus on the Prevention of Occurrence and Recurrence of Hepatocellular Carcinoma.",
"title_normalized": "comparison of daclatasvir and asunaprevir for chronic hcv 1b infection with telaprevir and simeprevir plus peginterferon and ribavirin with a focus on the prevention of occurrence and recurrence of hepatocellular carcinoma"
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"abstract": "This case describes the prolonged treatment of a 38-year-old man with a transpelvic gunshot wound requiring a diverting ostomy and cystostomy for damage control procedures with a comminuted acetabular and femoral head fracture. The team used a ketamine drip for prolonged field care over 48 hours. The benefit of using a ketamine drip included low supply requirement, excellent analgesia, and ease of administration, but side-effects included somnolence and atelectasis necessitating oxygen supplementation before evacuation.",
"affiliations": null,
"authors": "Hall|Andrew B|AB|;Morrow|Lindsay|L|;Dixon|Michael|M|",
"chemical_list": "D000700:Analgesics; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1553-9768",
"issue": "20(3)",
"journal": "Journal of special operations medicine : a peer reviewed journal for SOF medical professionals",
"keywords": null,
"medline_ta": "J Spec Oper Med",
"mesh_terms": "D000328:Adult; D000698:Analgesia; D000700:Analgesics; D006801:Humans; D007649:Ketamine; D008297:Male; D010146:Pain; D059408:Pain Management; D014948:Wounds, Gunshot",
"nlm_unique_id": "101158402",
"other_id": null,
"pages": "120-121",
"pmc": null,
"pmid": "32969016",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ketamine Use for Prolonged Field Care Reduces Supply Use.",
"title_normalized": "ketamine use for prolonged field care reduces supply use"
} | [
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"companynumb": "US-PFIZER INC-2020385625",
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"activesubstancename": "KETAMINE HYDROCHLORIDE"
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{
"abstract": "Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder, and eculizumab and ravulizumab are its two approved therapies. Only few case series/reports have reported the outcomes of pregnancies in patients with PNH despite the increased risk of thrombosis. Similarly, there is limited knowledge regarding the effect of the approved treatments on conception and pregnancy outcomes. Here, we report the first series of pregnancies in PNH patients from the Middle Eastern region from our tertiary care hospital. Ten pregnancies in four females after diagnosis with PNH were identified. In terms of PNH management, only eculizumab was used, as the safety of ravulizumab use in pregnancies has not yet been established. In the antepartum period, the patients had variable symptoms that ranged from mild symptoms including epistaxis, tea-colored urine and vaginal bleeding to life-threatening vessel thrombosis. Further, red blood cell and platelet transfusions were required because of bleeding and hemolysis in four pregnancies. The pregnancy outcomes varied, but based on these, the safety of eculizumab use during pregnancy remained inconclusive. The postpartum period was complicated in one case by portal vein thrombosis and was managed accordingly. In conclusion, pregnant females with PNH are at an increased risk for complications due to PNH, and thus experienced hematologists and obstetricians should be involved jointly in their care.",
"affiliations": "Internal Medicine Department, Bahrain Defence Force Hospital and Royal Medical Services, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Adult Hematology/Bone Marrow Transplantation Section, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Adult Hematology, HSCT Section, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Adult Hematology/Bone Marrow Transplantation Section, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.",
"authors": "Al-Dosari|Yara Mohammad|YM|;Al-Zahrani|Hazza|H|;Al-Mohareb|Fahad|F|;Hashmi|Shahrukh|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/sjmms.sjmms_4_20",
"fulltext": "\n==== Front\nSaudi J Med Med Sci\nSaudi J Med Med Sci\nSJMMS\nSaudi Journal of Medicine & Medical Sciences\n1658-631X\n2321-4856\nWolters Kluwer - Medknow India\n\nSJMMS-9-178\n10.4103/sjmms.sjmms_4_20\nCase Series\nPregnancy with Paroxysmal Nocturnal Hemoglobinuria: A Case Series with Review of the Literature\nAl-Dosari Yara Mohammad 12\nAl-Zahrani Hazza 3\nAl-Mohareb Fahad 4\nHashmi Shahrukh 35\n1 Internal Medicine Department, Bahrain Defence Force Hospital and Royal Medical Services, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia\n2 King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia\n3 Adult Hematology/Bone Marrow Transplantation Section, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia\n4 Adult Hematology, HSCT Section, Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia\n5 Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA\nAddress for correspondence: Dr. Yara Mohammad AlDosari, King Faisal Specialist Hospital and Research Center, P.O. Box: 3354, Riyadh 11211, Saudi Arabia. E-mail: yara.m.aldosari@gmail.com\nMay-Aug 2021\n29 4 2021\n9 2 178189\n20 6 2020\n31 12 2020\n15 4 2020\nCopyright: © 2021 Saudi Journal of Medicine & Medical Sciences\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nParoxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder, and eculizumab and ravulizumab are its two approved therapies. Only few case series/reports have reported the outcomes of pregnancies in patients with PNH despite the increased risk of thrombosis. Similarly, there is limited knowledge regarding the effect of the approved treatments on conception and pregnancy outcomes. Here, we report the first series of pregnancies in PNH patients from the Middle Eastern region from our tertiary care hospital. Ten pregnancies in four females after diagnosis with PNH were identified. In terms of PNH management, only eculizumab was used, as the safety of ravulizumab use in pregnancies has not yet been established. In the antepartum period, the patients had variable symptoms that ranged from mild symptoms including epistaxis, tea-colored urine and vaginal bleeding to life-threatening vessel thrombosis. Further, red blood cell and platelet transfusions were required because of bleeding and hemolysis in four pregnancies. The pregnancy outcomes varied, but based on these, the safety of eculizumab use during pregnancy remained inconclusive. The postpartum period was complicated in one case by portal vein thrombosis and was managed accordingly. In conclusion, pregnant females with PNH are at an increased risk for complications due to PNH, and thus experienced hematologists and obstetricians should be involved jointly in their care.\n\nComplications\nparoxysmal nocturnal hemoglobinuria\npregnancy\n==== Body\nINTRODUCTION\n\nParoxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic stem cell disorder caused by somatic mutation in phosphatidylinositol glycan class A gene (PIGA gene), resulting in deficiency or absence of glycosylphosphatidylinositol (GPI)-anchored proteins.[1]\n\nClinical manifestation of PNH is characterized by intravascular hemolysis, bone marrow failure (BMF) and thrombosis. It can also mimic other hematological disorders such as aplastic anemia (AA) and myelodysplastic diseases (MDS), although PNH can have a combination of both AA and MDS.[23] According to Brando et al.,[4] classical signs and symptoms of PNH include hemoglobinuria or hemosiderinuria, unexplained direct antiglobulin tests, negative hemolysis, aplastic anemia, thrombosis at unusual sites and dystonic symptoms (abdominal pain or dysphagia). For confirmatory diagnosis, flow cytometry is used, as it can demonstrate the absence or deficiency in the expression of GPI-anchored protein in a sizable portion of peripheral blood, mainly in red blood cells (RBC), neutrophils and monocytes, called as 'PNH clones,' which are fundamentals in diagnosing PNH.[1567]\n\nPregnancy is a challenging period due to the physiological changes,[891011] and requires specific attention during interventions of chronic diseases, especially in hematological disorders. Further, pregnancy in patients with PNH increases maternal and fetal mortality and morbidity as a result of an exacerbation of intravascular hemolysis, thrombosis and bone marrow failure.[1213] In the management of PNH, eculizumab therapy has both been shown to be safe and effective as well as reported to potentially have teratogenic effects that may require dosage and frequency adjustments; the effect of ravulizumab on pregnancy outcomes has yet to be reported.[514151617]\n\nCurrently, there is no report from Saudi Arabia or the Middle East regarding the prevalence and incidence of pregnancy in PNH, in addition to limited data in general regarding PNH in pregnancy and the management approaches in such a high-risk group [Table 1].[181920] Therefore, this case series would add to existing literature.[11]\n\nTable 1 List of case series/case reports on pregnancy with paroxysmal nocturnal hemoglobinuria in the literature\n\nStudy\tYear\tRegion\tNumber of cases\t\nde Guibert et al.[19]\t2011\tFrance\t23\t\nAlashkar, et al.[21]\t2020\tGermany\t9\t\nKelly et al.[9]\t2015\tItaly\t6\t\nThe current case series\t2021\tRiyadh, Saudi Arabia\t4\t\nMiyasaka et al.[22]\t2016\tJapan\t3\t\nMorita et al.[13]\t2013\tJapan\t2\t\nRodríguez-Ferreras, et al.[23]\t2019\tSpain\t1\t\nBastos et al.[16]\t2018\tBrazil\t1\t\nDanilov et al.[24]\t2010\tBoston, USA\t1\t\nMarasca et al.[25]\t2010\tItaly\t1\t\nAndo et al.[26]\t2014\tJapan\t1\t\nSharma et al.[12]\t2015\tNew York, USA\t1\t\nPatriquin et al.[8]\t2015\tCanada\t1\t\nPatel et al.[27]\t2017\tFlorida, USA\t1\t\nVekemans et al.[28]\t2015\tBelgium\t1\t\nGessoni et al.[29]\t2015\tItaly\t1\t\nBjørge et al.[13]\t2003\tNorway\t1\t\nLauritsch-Hernandez et al.[11]\t2018\tSwitzerland\t1\t\nSingh et al.[10]\t2014\tIndia\t1\t\nBais et al.[30]\t1994\tAmsterdam\t1\t\nSasano et al.[31]\t2016\tJapan\t1\t\n\nDESCRIPTION OF CASES\n\nFor this case series, the data of all patients with PNH who presented to our Hematology, Stem Cell Transplantation & Cellular Therapy center between 2013 and 2021 were retrospectively analyzed. The study was approved by the Research Advisory Council (RAC)/Ethics Committee at King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.\n\nDuring the period, a total of 20 patients with PNH had been treated at our center. Of these eight were females: two were not within the reproductive age, two died following hematopoietic stem cell transplant complications, and the remaining four had 10 pregnancies after the diagnoses of PNH.\n\nThe diagnosis was initially based on clinical presentations, and then following the minimal essential criteria for PNH diagnosis including: (1) flow cytometry analysis of peripheral blood erythrocytes, granulocytes or both (PNH clone), (2) complete blood count (CBC), reticulocytes count, serum concentration of lactic dehydrogenase (LDH), bilirubin and haptoglobin, and (3) bone marrow biopsy for those with concomitant underlining bone marrow disease.[5] The eculizumab therapy protocol was as stated in the literature:[172032] initially a dose of 600 mg IV weekly for the first 4 weeks, followed by 900 mg IV for 1 week and then 900 mg every 2 weeks. Doses were modified or reduced based on the patient's tolerance to the regular dosing, in the presence of side effects, and per the availability of the medication in the pharmacy, given its cost.\n\nBelow is the summary of each patient's clinical course details regarding clinical features, relevant laboratory findings (e.g. hemograms, PNH clone, bilirubin and LDH), treatments, and the outcome are summarized in Tables 2 and 3.\n\nTable 2 Summary of cases and pregnancy outcomes with the use of eculizumab and anticoagulation therapy (the median values are stated for laboratory results)\n\nCase number\tPeriod\tLaboratory tests\t\n\t\nWBC (109/L)\tRBC (1012/L)\tHGB (g/L)\tPLT (109/L)\tTotal BILI (umol/L)\tLDH (U/L)\t\n1\tBaseline\t3.41\t3.26\t107\t134\t14\tNA\t\n\tIn pregnancy\t3.25\t2.33\t83\t33\t24.1\t545\t\n\tPostpartum\t3.82\t2.49\t90\t40\t-\t394\t\n2\tBaseline\t4\t2.90\t99.5\t29.5\t9\t281\t\n\tIn pregnancy 2.1\t8.37\t3.47\t105.5\t183\t6.55\t650\t\n\tPostpartum 2.1\tND\tND\tND\tND\tND\tND\t\n\tIn pregnancy 2.2\t7.88\t3.84\t111\t230\t7.5\t596\t\n\tPostpartum 2.2\t8.2\t3.77\t111\t212\t7.5\t596\t\n\tPostpartum 2.3\t-\t-\t130\t205\t4\t382\t\n3\tBaseline\t3.89\t3.33\t114.5\t131\t69.5\t921\t\n\tIn pregnancy 3.1\t5.06\t2.80\t87\t45\t15\t508\t\n\tPostpartum 3.1\tND\tND\tND\tND\tND\tND\t\n4\tBaseline\tNB\tNB\tNB\tNB\tNB\tNB\t\n\tIn pregnancy 4.1\t2.44\t2.52\t96.5\t52\t22.6\t1603.5\t\n\tPostpartum 4.1\t2.00\t2.46\t88\t61\t22\tND\t\n\tIn pregnancy 4.2\t2.15\t3.21\t91\t107\t14\t1133\t\n\tPostpartum 4.2\t2.01\t3.32\t90\t99\t12\tND\t\nWBC – White blood cells; RBC – Red blood cells; HGB – Hemoglobin; PLT – Platelets; BILI – Bilirubin; LDH – Lactic dehydrogenase; ND – Not done; NB – No baseline\n\nTable 3 Summary of cases and pregnancy outcomes with the use of eculizumab, anticoagulation therapy and documented complications (ante, intra, postpartum period)\n\nCase number\tMaternal age at PNH diagnosis (years)\tDiagnostic test PNH clone size (%)\tClinical presentation\tMaternal age at pregnancy (years)\tEculizumab\tAnticoagulants in pregnancy (mg)\tTransfusion\tComplications\tFollow up\t\n\t\t\t\nGranulocyte clone (%)\tMonocyte, clone (%)\tBefore pregnancy (mg)\tIn pregnancy (mg)\tAntepartum\tIntrapartum\tPostpartum\t\n1\t36\t67\t63\tFatigue, dizziness, heavy mensuration AA thrombocytopenia\t39\t900\t1200\tLMWH\tRBC, PLT\tPolyhydramnios, fetus LGA\tThrombocytopenia\tPVT, PLT Trans\tStable\t\n2.1\t25\t56.7\t48.2\tFatigue\t22\tNone\tNone\tLMWH\tRBC\tNone\tNone\tNone\tStable\t\n2.2\t\t\t\tAA\t23\tNone\tNone\tLMWH\tRBC\tEpistaxis, dark urine\tNone\tNone\tStable\t\n2.3\t\t\t\t\t29\tNone\tNone\tLMWH\tNone\tAbdominal pain, PV bleeding\tMissed Ab\tNone\t\t\n3.1\t32\t76.8\t80.6\tFatigue, abdominal pain, dizziness, skin thrombophlebitis\t37\tRefused\t600\tFondaparinux, HIT positive\tRBC, PLT\tPROM, PV, BMS exacerbation\tNone\tNone\tStable\t\n3.2\t\t\t\t\t38\t600\t600\tUnknown\tUnknown\tUnknown\tMissed Ab\tUnknown\t\t\n3.3\t\t\t\tAA\t38\t600\t600\tNot yet started (1st trimester)\tNone\tNone\tPregnant\tPregnant\t-\t\n4.1\t32\t43.2\t78.3\tBack pain\t35\t900\t600\tLMWH\tRBC, PLT\tIUFD\tNone\tNone\tStable\t\n4.2\t\t\t\tAA\t36\t900\t900\tLMWH\tNone\tIUFD followed by SCA\tNone\tNone\tStable\t\n4.3\t\t\t\tPancytopenia HepB\t37\t900\t900\tNone\tNone\tNone\tSp Ab\tNone\t-\t\nPNH – Paroxysmal nocturnal hemoglobinuria; AA – Aplastic anemia; PROM – Preterm rupture of membranes; LGA – Large for gestational age; PVT – Portal vein thrombosis; PV – Per vaginal; BMS – Bone marrow suppression; HepB – Hepatitis B; IUFD – Intrauterine fetal death; SCA – Spontaneous complete abortion. LMWH – Low-molecular-weight heparin; RBC – Red blood cells; PLT – Platelets; SP – Spontaneous; AB – Abortion; HIT – Heparin indiced thrombocytopenia\n\nCase 1\n\nA 43-year-old female diagnosed with PNH in 2013 (aged 38 years) manifesting with mild cytopenia and PNH clone of 63% on WBC–monocytes, was treated with 900 mg of eculizumab every 2 weeks (standard dose) and remained in a stable condition. In 2015, she became pregnant with a singleton; eculizumab was continued throughout the antepartum period, and the dose was increased to 1200 mg because of worsening clinical situation, especially anemia. In addition to prophylactic low-molecular-weight heparin (LMWH) (dose of 20 mg subcutaneous daily), ferrous sulfate and folic acid were also prescribed. At 33 weeks of gestation, the pregnancy was complicated with polyharmonies (amniotic fluid index, >24 cm) and large fetus for gestational age that required hospitalization for observation and monitoring.\n\nAt 38 weeks of gestation, after the failure of induction of labor, a caesarian section was performed. In addition, RBC and platelet transfusions were given intrapartum. The product was a full-term infant with a birth weight of 4000 grams (larger than the average childbirth weight in Saudi Arabia) with an Apgar score of 9, who was admitted in the neonatal intensive care unit (NICU) with a stable course. The infant had dysmorphic features, macrocephaly, hypotonia, right undescended testes and Hirschsprung disease, which is most likely because the family had a strong history of multiple congenital anomalies. In the immediate postpartum period, the patient complained of acute abdominal pain, and ultrasound (US) doppler confirmed portal and superior mesenteric vein thrombosis, following which dose of LMWH was increase to 40 mg subcutaneous daily and dose was adjusted according to the platelet count, which ranged at that time between 17 to 33 × 109/L.\n\nThe transient thrombocytopenia required platelet transfusion and the patient stabilized without any complications and was maintained on subhepatic LMWH. Six weeks post-delivery, she was shifted to rivaroxaban for long-term anticoagulation. On the last follow up in October 2020, she continued to have no acute events on maintenance eculizumab (900 mg) every 2 weeks and rivaroxaban.\n\nCase 2.1\n\nA 31-year-old lady was diagnosed with PNH in 2015 (aged 25 years). The patient had a history of bone marrow failure, received antithymocyte globulin therapy followed by cyclosporine and achieved complete remission. Five years later, patient presented with iron deficiency symptoms and hemolysis manifesting as tea-colored urine with rise of PNH clone size to WBC was 48.2%. She had not been on eculizumab therapy; the reason for the same was not clearly stated in our registry but could be because the patient had a stable disease course.\n\nIn 2017, she became pregnant, and was treated with 40 mg of enoxaparin for high risk of thrombosis. The antepartum period was stable with no complication, except for mild epistaxis. Fetal US was normal with no intrauterine growth restriction (IUGR). Spontaneous vaginal delivery occurred at 39 weeks of gestation after induction of labor with no complications. The product infant was stable, birth weight of 3020 g, Apgar score was 9, with no NICU admissions. Postpartum period was uncomplicated and LMWH prophylaxis (40 mg) was given for 6 weeks post-delivery.\n\nThe patient was followed-up every 3 months at the hematology clinic for assessment of disease control and iron replacement compliance, as needed (for any drop in hemoglobin). The assessment was based on clinical symptoms and laboratory parameters including hemoglobin, LDH, bilirubin, haptoglobin, reticulocytes and renal function to observe any signs of hemolysis.[16]\n\nCase 2.2\n\nThe patient had her second pregnancy in 2018, following which folic acid and prophylactic LMWH was started. During her follow up, she developed tea-colored urine and epistaxis at 27 weeks of gestation. Thus, signs of hemolysis were confirmed with hemoglobin: 114 g/L, reticulocyte auto 86.8 109/L, haptoglobin <0.1/L and LDH 596 U/L. The prophylactic dose of LMWH was maintained on 40 mg and she was advised for good hydration. Fetal US showed normal interval growth with no IUGR and normal blood flow.\n\nEmergency C-section at 39 weeks of gestation was performed due to hyperstimulation and fetal distress with no complications. The product infant was stable with a birth weight of 3000-gram, Apgar score of 9 and with no NICU admission. The postpartum period was uneventful and LMWH prophylaxis was initiated post-delivery and continued for 6 weeks.\n\nCase 2.3\n\nThe patient had her third pregnancy in November 2020 and was started on prophylactic LMWH of 40 mg. During the regular follow up, she complained of mild discomfort in the left leg (calf region), and accordingly deep vein thrombosis ruled out by US doppler. In her 8th week of gestation, the patient complained of lower abdominal pain and vaginal bleeding. A transvaginal US confirmed non-viable pregnancy and missed abortion, and thus she underwent emergency evacuation and curettage. Laboratory parameters was reassuring and did not show any signs of hemolysis. Postpartum period was uneventful, and she was discharged in a stable condition after 2 days and with advice to continue on prophylactic LMWH until her next follow up.\n\nCASE 3.1\n\nA 39-year-old female was diagnosed with PNH in 2013 (aged 32 years), manifesting with fatigability, skin thrombophlebitis and PNH on WBC clone size was 80.6%. The patient refused treatment with eculizumab at that time. However, she had a history of severe aplastic anemia for couple of years controlled on cyclosporine and aspirin (81 mg) because of worsening of her cytopenia. She had a history of four abortions, three intrauterine fetal deaths (IUFD) and one stillbirth due to brain atrophy.\n\nIn 2017, the patient became pregnant, and enoxaparin 40 mg and folic acid supplement were added to aspirin; however, cyclosporine was discontinued to avoid its teratogenicity. The antepartum period was complicated with bone marrow suppression, mild vaginal bleeding, frequent hemolysis and dropping of platelets level, and thus she required frequent RBC and platelet transfusion, glucocorticoid and intravenous immunoglobulin therapy. At 31-week of gestation, 600 mg eculizumab was started as she presented with low platelets and low hemoglobin. Enoxaparin was switched to prophylactic fondaparinux (2.5 mg) because the patient developed heparin-induced thrombocytopenia (HIT). However, fetal US showed normal interval growth and normal blood flow.\n\nPreterm rupture of membranes occurred at 36 weeks of gestation, then induction of labor started and eventually progressed with spontaneous vaginal delivery. The infant was full term and stable, weighted 2320 grams, the Apgar score was 9, and had no complications that required NICU admissions. Postpartum period was completed with no complications and she was continued on eculizumab and fondaparinux for 6 weeks.\n\nCase 3.2\n\nDuring regular follow ups, the patient had a missed abortion in January 2019 despite being on eculizumab. The details are not known, as the diagnosis was in a local hospital; however, laboratory parameters were within normal range and no hemolysis or drop in hemoglobin was detected.\n\nCase 3.3\n\nIn the last follow up at the time of reporting this case, patient was pregnant and advised to continue with eculizumab (600 mg every 4 weeks), but fondaparinux was not started, as the patient was in her first trimester.[33] In addition, an expert obstetrician was consulted for following the patient.\n\nCase 4.1\n\nA 38-year-old female diagnosed with PNH in 2014 (aged 32 years) manifested with back pain, pancytopenia, hepatitis B infection (on Tenofovir therapy), PNH clone size on WBC of 78.3%, and bone marrow biopsy showing hypocellularity but no features of myelodysplasia. Initially, the patient remained on cyclosporine 100 mg and planned for stem cell transplantation, but patient refused treatment.\n\nIn 2016, the patient agreed for treatment and was started on eculizumab 900 mg. She had frequent RBC and platelet transfusions. In 2017, she became pregnant with a singleton; however, the gestation did not progress. The pregnancy was complicated by IUFD at 25 weeks of gestation, despite treatment with eculizumab, enoxaparin and folic acid. Platelet transfusion was given during the termination of pregnancy. The postpartum period was uncomplicated and LMWH was continued postpartum for 3 weeks\n\nCase 4.2\n\nIn 2018, while on treatment with 900 mg eculizumab, the patient again became pregnant. At 28 weeks of gestation, she presented to the emergency department (ED) with vaginal bleeding and abdominal pain, and after a few hours, she delivered dead fetus and placenta spontaneously. The patient was admitted for 1 day for monitoring, and then discharged on 40 mg prophylactic enoxaparin for 6 weeks.\n\nCase 4.3\n\nOn November 2020, during the telephonic follow up due to the COVID-19 pandemic, the patient reported that she became pregnant, but the pregnancy terminated spontaneously while on eculizumab therapy. In the last follow up in hematology clinic in January 2021, patient was in a stable condition clinically and laboratory, and advised to continue eculizumab regimen.\n\nDISCUSSION\n\nPNH often occurs in females during the reproductive age. Conception is discouraged in patients with PNH because of increased risk of thrombosis.[22] The high possibility of thrombosis is likely related to pregnancy physiological changes such as increase in complement activity and hypercoagulability state and also with the pathophysiology of PNH that might augment the risk of emergency delivery.[18222934] Thrombosis is associated with serious complications for the mother and the fetus, and thus obstetrician experts are involved in care of pregnant patients with PNH.[417]\n\nIn this case series, we present the course of 10 pregnancies in four patients after PNH diagnosis and add to the limited data available in the literature.[41517] To the best of the authors knowledge, only 62 cases have been published in 20 articles discussing pregnancy with PNH, with the current paper being one of few series and the first from the Middle East region [Tables 1 and 4].\n\nTable 4 Review of literature for pregnancy with paroxysmal nocturnal hemoglobinuria\n\nCase number\tReference\tNumber of cases\tMaternal age at pregnancy\tAnticoagulation therapy\tEculizumab therapy\t\n\t\t\nBefore pregnancy\tDuring pregnancy\tDuring pregnancy (duration of dose if stated)\tPostpartum (mg)\t\n1\tAlashkar, et al.\t9\tNS\tNS\tNS\t900 mg\t900\t\n2\tAlashkar, et al.\t9\t\tNS\tNS\t900–1800 mg\t900\t\n3\tAlashkar, et al.\t9\t\t\tNS\t1200–1800 mg\t1200\t\n4\tAlashkar, et al.\t9\tNS\tNS\tNS\t900–1200 mg\t900\t\n5\tAlashkar, et al.\t9\tNS\tNS\tNS\t900–1200 mg\t900\t\n6\tAlashkar, et al.\t9\tNS\tNS\tNS\t900–1200 mg\t900\t\n7\tAlashkar, et al.\t9\tNS\tNS\tNS\t900–1200 mg\t900\t\n8\tAlashkar, et al.\t9\tNS\tNS\tNS\tNone\t900\t\n9\tAlashkar, et al.\t9\t\tNS\tNS\t900 mg\t900\t\n10\tAlashkar, et al.\t9\t\tNS\tNS\t900 mg\t900\t\n11\tAlashkar, et al.\t9\t\tNS\tNS\t900–1200 mg\t900\t\n12\tAlashkar, et al.\t9\tNS\tNS\tNS\tNone\tNone\t\n13\tAlashkar, et al.\t9\t\tNS\tNS\t900 mg\t900\t\n14\tAlashkar, et al.\t9\t\tNS\tNS\t900 mg\t900\t\n15\tAlashkar, et al.\t9\tNS\tNS\tNS\tNone\tNone\t\n16\tAlashkar, et al.\t9\tNS\tNS\tNS\t900 mg\t900 mg\t\n17\tRodríguez-Ferreras, et al.\t1\t39\tNone\tNone\t600 mg for 4 weeks then 900 mg every 2 weeks\tYes\t\n18\tBastos et al.\t1\t38\tNone\tProphylactic LMWH\t900–1200 mg (forced reduction due unavailability)\t1200\t\n19\tDanilov et al.\t1\t34\tTherapeutic heparin\tTherapeutic heparin\tFrom 30 weeks\tYes\t\n20\tKelly et al.\t6\t25\tWarfarin\tTherapeutic heparin\tUp to 5 weeks\tNo\t\n21\tKelly et al.\t6\t22\tNot known\tNot known\tUp to 14 weeks\tNo\t\n22\tKelly et al.\t6\t26\tNot known\tTherapeutic heparin\tUp to 4 weeks\tNo\t\n23\tKelly et al.\t6\t27\tNo\tProphylactic heparin\tEntire pregnancy (increased from 28 weeks)\tYes\t\n24\tKelly et al.\t6\t35\tNo\tTherapeutic heparin\tFrom 27 weeks (weekly)\tYes\t\n25\tKelly et al.\t6\t28\tWarfarin\tTherapeutic heparin\tEntire pregnancy\tYes\t\n26\tMarasca et al.\t1\t34\tNo\tProphylactic heparin\tEntire pregnancy\tYes\t\n27\tAndo et al.\t1\t37\tNo\tNo\tEntire pregnancy\tYes\t\n28\tSharma et al.\t1\t32\tNo\tProphylactic heparin\tEntire pregnancy (increased from 30 weeks)\tYes\t\n29\tPatriquin et al.\t1\t30\tNo\tProphylactic heparin\tEntire pregnancy (increased from 2nd trimester)\tYes\t\n30\tMiyasaka et al.\t3\t34\tNo\tProphylactic heparin\tEntire pregnancy\tYes\t\n31\tMiyasaka et al.\t3\t30\tNo\tProphylactic heparin\tFrom 27 weeks\tYes\t\n32\tMiyasaka et al.\t3\t29\tNo\tProphylactic heparin\tFrom 18 weeks\tYes\t\n33\tPatel et al.\t1\t24\tNo\tProphylactic heparin\tFrom 10 weeks\tYes\t\n34\tVekemans et al.\t1\t41\tNo\tProphylactic LMWH\tEntire pregnancy\tYes\t\n35\tGessoni et al.\t1\tNS\tNo\tProphylactic LMWH\tEntire pregnancy\tYes\t\n36\tBjørge et al.\t1\t35\tWarfarin\tTherapeutic heparin\tNS\tNS\t\n37\tLauritsch-Hernandez et al.\t1\t27\tOral anticoagulation, Vitamin K antagonist\tTherapeutic heparin\tEntire pregnancy\tYes\t\n38\tSingh et al.\t1\t23\tNo\tNo\tNo\tNo\t\n39\tMorita et al.\t2\t30\tNo\tProphylactic heparin\tNS\tNS\t\n40\tMorita et al.\t2\t41\tNS\tTherapeutic heparin\tNS\tNS\t\n41\tBais et al.\t1\t30\tNo\tNo\tNo\tNo\t\n42\tGuibert et al.\t23\t27\tNo\tNo\tNS\tNS\t\n43\tGuibert et al.\t23\t26\tNo\tNo\tNS\tNS\t\n44\tGuibert et al.\t23\t27\tNo\tLMWH\tNS\tNS\t\n45\tGuibert et al.\t23\t27\tTherapeutic LMWH\tLMWH\tNS\tNS\t\n46\tGuibert et al.\t23\t21\tLMWH\tLMWH\tNS\tNS\t\n47\tGuibert et al.\t23\t38\tDanaparoid\tDanaparoid\tNS\tNS\t\n48\tGuibert et al.\t23\t21\tDanaparoid\tDanaparoid\tNS\tNS\t\n49\tGuibert et al.\t23\t32\tNo\tLMWH\tNS\tNS\t\n50\tGuibert et al.\t23\t29\tDanaparoid\tDanaparoid\tNS\tNS\t\n51\tGuibert et al.\t23\t32\tDanaparoid\tDanaparoid\tNS\tNS\t\n52\tGuibert et al.\t23\t31\tLMWH\tLMWH\tNS\tNS\t\n53\tGuibert et al.\t23\t24\tLMWH\tLMWH\tNS\tNS\t\n54\tGuibert et al.\t23\t30\tNo\tNo\tNS\tNS\t\n55\tGuibert et al.\t23\t24\tDanaparoid\tDanaparoid\tNS\tNS\t\n56\tGuibert et al.\t23\t22\tLMWH\tLMWH\tNS\tNS\t\n57\tGuibert et al.\t23\t26\tLMWH\tLMWH\tNS\tNS\t\n58\tGuibert et al.\t23\t28\tNo\tNo\tNS\tNS\t\n59\tGuibert et al.\t23\t27\tDanaparoid\tDanaparoid\tNS\tNS\t\n60\tGuibert et al.\t23\t27\tNS\tNS\tNS\tNS\t\n63\tGuibert et al.\t23\t26\tLMWH\tLMWH\tNS\tNS\t\n64\tGuibert et al.\t23\t27\tNo\tNo\tNS\tNS\t\n65\tGuibert et al.\t23\t28\tNo\tNo\tNS\tNS\t\n66\tGuibert et al.\t23\tNA\tLMWH\tLMWH\tNS\tNS\t\n67\tSasano et al.\t1 (1.2)\t29\tNo\tProphylactic heparin\tNo\tNo\t\n68\tSasano et al.\t1 (2.2)\t33\tNo\tTherapeutic UFH\tNo\tNo\t\n69\tOur case 1\t4\t42\tNo\tProphylactic LMWH\t1200\t900\t\n70\tOur case 2.1\t4\t29\tNo\tProphylactic enoxaparin\tNo\tNo\t\n71\tOur case 2.2\t4\t29\tNo\tProphylactic enoxaparin\tNo\tNo\t\n72\tOur case 2.3\t4\t29\tNo\tProphylactic enoxaparin\tNo\tNo\t\n73\tOur case 3.1\t4\t38\tNo\tFondaparinux (due to HIT)\t600 (started 31 weeks)\t600\t\n74\tOur case 3.2\t4\t38\tNo\tNo\t600\t600\t\n75\tOur case 3.3\t4\t38\tNo\tNot yet started (patient in 1st trimester)\t600\t600\t\n76\tOur case 4.1\t4\t37\tNo\tEnoxaparin\t900\t900\t\n77\tOur case 4.2\t4\t37\tNo\tProphylactic enoxaparin\t900\t900\t\n78\tOur case 4.3\t4\t37\tNo\tNo\t900\t900\t\n\t\nCase number\tComplications\tMode of delivery (indication)\tNewborn status\t\n\t\nIntrapartum\tPostpartum\t\n\t\n1\tHemolysis, RBC trans\tNS\tVaginal\tHealthy\t\n2\tBH, RBC trans\tNS\tVaginal\tHealthy\t\n3\tBH, RBC trans\tNS\tVaginal\tHealthy\t\n4\tBH, BCS, RBC/PLT trans, cholecystitis\tNS\tCS\tHealthy\t\n5\tBCS, cholecystitis RBC/PLT trans\tNS\tCS\tHealthy\t\n6\tBH\tNS\tCS\tHealthy\t\n7\tBH\tNS\tVaginal\tHealthy\t\n8\tSp Ab, RBC trans\tNS\tVaginal\tDead\t\n9\tSp Ab\tNS\tVaginal\tDead\t\n10\tSp Ab\tNS\tVaginal\tDead\t\n11\tBH\tNS\tCS\tHealthy\t\n12\tSp Ab, RBC trans\tNS\tVaginal\tDead\t\n13\tStillbirth\tNS\tVaginal\tDead\t\n14\tMedical Ab\tNS\t-\tDead\t\n15\tSp Ab\tNS\tVaginal\tDead\t\n16\tRBC Trans, precplampsia\tNS\tCS\tStillbirth\t\n17\tHeavy vaginal bleeding, abdominal pain\tNone\tVaginal\tSp Ab (1st trimester)\t\n18\tAKF, hemolytic anemia, RBC trans\tHospitalized\tEmergency CS\tHealthy\t\n19\tThrombocytopenia RBC/PLT trans\tNone\tCS (twin-breech)\tHealthy\t\n20\tNone\tNone\tNS\tHealthy\t\n21\tNone\tFUO\tNS\tHealthy\t\n22\tNone\tNone\tNS\tHealthy\t\n23\tBH, RBC trans\tNone\tSVD\tHealthy\t\n24\tNone\tPPH\tCS (twin)\tHealthy\t\n25\tPreeclampsia\tNone\tCS (preeclampsia)\tHealthy\t\n26\tNone\tNone\tSVD\tHealthy\t\n27\tNone\tNone\tCS (breech)\tHealthy\t\n28\tBH, RBC trans\tNone\tCS (elective)\tHealthy\t\n29\tBH, RBC trans\tNone\tCS (placenta previa)\tHealthy\t\n30\tBH, RBC trans\tNone\tSVD\tHealthy\t\n31\tPreeclampsia\tNone\tCS (preeclampsia)\tHealthy\t\n32\tNone\tPPH\tSVD\tHealthy\t\n33\tNone\tNone\tSVD\tHealthy\t\n34\tRBC trans\tRBC tans\tSVD\tHealthy\t\n35\tPE, BULT\tPPE, PE, BULT, abdominal angina with TPI\tCS (fetal distress)\tHealthy\t\n36\tChorioamnionitis secondry to IOL\tPPH, LVT (liver failure, BCS, BMF)\tCS (failed IOL)\tHealthy\t\n37\tNone\tNone\tCS (transverse presentation)\tHealthy\t\n38\tPROM\tSepsis, ARF, PRES\tSVD\tNS\t\n39\tNone\tNone\tEmergency CS (reduction fetal heartbeat)\tNS\t\n40\tNone\tNone\tCS (breech)\tNS\t\n41\tPLT trans\tHemolytic crisis, PMVT, IC\tSVD\tHealthy\t\n42\tNone\tNone\tNA\tHealthy\t\n43\tHELLP, PLT trans\tNone\tCS (failed IOL)\tHealthy\t\n44\tNone\tNone\tSVD\tHealthy\t\n45\tNone\tBCS\tCS (failed IOL)\tHealthy\t\n46\tNone\tNone\tCS (NS)\tHealthy\t\n47\tAnemia, RBC trans\tNone\tCS (failed IOL)\tHealthy\t\n48\tNone\tNone\tSVD\tHealthy\t\n49\tNone\tNET infections\tNA\tHealthy\t\n50\tNone\tFebrile neutropenia\tSVD\tHealthy\t\n51\tNone\tCerebral infarction\tSVD\tHealthy\t\n52\tNone\tNone\tCS (failed IOL)\tHealthy\t\n53\tNone\tHepatic and splenic VTE\tSVD\tHealthy\t\n54\tNone\tNone\tSVD\tHealthy\t\n55\tHemorrhagic delivery\tNone\tSVD\tHealthy\t\n56\tNone\tNone\tCS (failed IOL)\tHealthy\t\n57\tNone\tNone\tCS (failed IOL)\tHealthy\t\n58\tNone\tThrombocytopenia, PLT trans, PPH, mesenteric VTE\tSVD\tHealthy\t\n59\tNone\tUterine hematoma, RBC trans\tSVD\tHealthy\t\n60\tNS\tNS\tNS\tTherapeutic abortion\t\n63\tNone\tNone\tCS (NS)\tHealthy\t\n64\tNone\tNone\tSVD\tFetal death\t\n65\tNone\tNone\tCS (failed IOL)\tAFD\t\n66\tNone\tCerebral VTE\tNA\tHealthy\t\n67\tRBC trans, mild preeclampsia\tNone\tSVD\tHealthy\t\n68\tRBC trans\tNone\tSVD\tHealthy\t\n69\tRBC, PLT trans\tPSMVT, thrombocytopenia, PLT Trans\tCS (IOL)\tNICU, dysmorphic features\t\n70\tNone\tNone\tSVD\tHealthy\t\n71\tNone\tNone\tEmergency CS (fetal distress)\tHealthy\t\n72\tLower abdominal pain, PV bleeding\tNone\tEmergency evacuation/curettage\tMissed Ab\t\n73\tPV bleeding, thrombocytopenia, hemolysis, RBC/PLT trans (before introducing eculizumab)\tNone\tSVD\tHealthy\t\n74\tUnknown\tUnknown\tSVD\tMissed Ab\t\n75\tNone\tPregnant\tPregnant\t-\t\n76\tIUFD, PLT trans\tNone\tSVD\tIUFD\t\n77\tPV bleeding\tNone\tSVD\tSp Ab\t\n78\tNone\tNone\tSVD\tSp Ab\t\nTrans – Transfusion; NS – Not stated; PLT – Platelets; RBC – Red blood cells; BH – Breakthrough hemolysis; BCS – Budd-chiari syndrome; SP – Spontaneous; AB – Abortion; PVT – Portal vein thrombosis; CS – Caesarean section; FUO – Fever of unknown origin; SVD – Spontaneous vaginal delivery; PPH – Postpartum hemorrhage; PPE – Pleural peritoneal effusion; PE – Pulmonary embolism; BULT – Bilateral upper limb thrombophlebitis; TPI – Transient paralytic ileus; LVT – Liver vein thrombosis; IOL – Induction of labor; BMF – Bone marrow failure; ARF – Acute renal failure; PRES – Posterior reversible encephalopathy syndrome; PMVT – Portal mesenteric vein thrombosis; IC – Ischemic colitis; NA – Not available; NET – Nose-ear-throat; VTE – Venous thromboembolism; PSMVT – Portal and superior mesenteric vein thrombosis; ICU – Intensive care unit; HIT – Heparin indiced thrombocytopenia; IUFD – Intrauterine fetal death; IUFD – Intrauterine fetal deaths; PV – Per vaginal; LMWH – Low-molecular-weight heparin; UFH – Unfractionated heparin; PROM – Preterm rupture of membranes; AKF – Acute kidney failure; HELLP – Hemolysis elevated liver enzymes and low platelets\n\nClinical presentation of our patients varied from mild symptoms such as back pain and thrombophlebitis to severe potential symptoms such as bone marrow failure and life-threatening vessel thrombosis. However, three of the four patients had complete hypoplastic bone marrow features and hemolysis [Tables 2 and 3]. Antepartum maternal complications included thrombocytopenia and hemolysis manifesting as epistaxis and dark urine, in addition to poor significant outcome such as termination of pregnancy because of IUFD or spontaneous abortion. During the antepartum period, platelet and RBC transfusions were on demand for all our patients when platelets counts were >20 or <50 or hemoglobin was <80 mg/L and at the time of delivery. During the delivery phase, three cases were planned for induction of labor for spontaneous vaginal delivery, and three cases had spontaneous abortion. In addition, two cases underwent cesarean section delivery due to failed induction of labor and fetal distress and one case had a missed abortion and underwent emergency evacuation and curettage. According to the existing literature and our case series, the mode of delivery (i.e., cesarean sections and spontaneous) were almost equal, suggesting that PNH might not have a significant impact on the mode of delivery.\n\nThe postpartum period was controlled clinically and with follow up parameters for hemolysis (CBC, LDH, haptoglobin, reticulocytes and bilirubin)[17] and thrombosis complications. All patients were maintained on prophylactic LMWH for 6 weeks after delivery. The postpartum period was uncomplicated in three cases except for Case 1, wherein portal vein thrombosis was reported and managed conservatively with no further complications.\n\nFetal outcomes for our patients were significant for two cases. In Case 1, the infant was large for the gestational age, with congenital anomaly, and was admitted to the NICU. In Case 4, the patient had IUFD and four abortions. Interestingly, Case 2, who was not on eculizumab, delivered a healthy fetus, whereas the other three patients who were on eculizumab had the above-mentioned fetal complications. From the literature, 86% of the newborns have been found to be healthy, 6% had fetal deaths, and in 8%, the outcomes were not stated with variable usage of eculizumab. Therefore, eculizumab might have a rule in the relatively safe conclusion discussed in the evidence.\n\nWe found that in the literature, the use of anticoagulants during pregnancy varied: 60% used prophylactic heparin, 18% had therapeutic doses of heparin, 16% did not receive any anticoagulants and in 4% its usage was not stated. Therefore, the preferable use of prophylactic or therapeutic strategy in pregnancy with PNH could not be determined.[9] It should be noted that unless contraindicated, prophylactic LMWH is prescribed to pregnant women during the third trimester and continued for 6–12 weeks postpartum, as the risk of thrombosis is high.[3134] Many studies recommend it when the clone size is >50%. In our cases, all our patients received anticoagulants (enoxaparin/fondaparinux) during both antepartum and postpartum periods.\n\nAccording to Parker et al.,[5] thrombophilia is the leading cause of mortality in PNH, with thromboembolic events being directly related to the PNH clone size. The study by Hall et al.[20] supports this hypothesis, as they found that in patients with PNH clone >50% GPI-AP–deficient granulocytes, the 10-year risk of thrombosis in PNH patient was 44% and it was 5.8% in patients with <50% GPI-AP–deficient granulocyte. In another study, it was shown that compared with patients with PNH clone of 20%, those with >70% GPI-AP–deficient granulocytes had an 11.8-fold increased risk of thrombosis. Therefore, observing clone size can assist in the management plan, in addition to the hypercoagulable state of pregnancy, which tremendously increases the risk of thrombosis.[24]\n\nThe efficacy of anticoagulants in pregnancy with PNH have been supported strongly by Morita et al.[33] and Patel et al.[27] whereas de Guibert et al.[19] reported some cases with thrombosis even after the use of anticoagulants. Therefore, there is need for further studies that provide stronger evidence for use of antithrombotic medications in pregnancy with PNH.\n\nEculizumab and ravulizumab are the approved medication for management of PNH. There is contrasting evidence regarding the safety of eculizumab use in pregnancy, as it has been reported to not cross the cord blood/placental barrier or be excreted in the breast milk, but it has also been reported that some proportion does cross cord blood/placental barrier.[11] In the study by Kelly et al.,[9] eculizumab was detected in low levels in 7 of 20 cord blood samples. Eculizumab was also found in the placental blood of two patients with PNH after delivery, but with normal complement activity. Therefore, evidence suggests that in cases of suggests that if eculizumab does cross the placenta, the levels are very low to activate the complement system and cause any adverse effects to the fetus.[9] In PNH generally, a multinational longitudinal study found that eculizumab effectively stops intravascular hemolysis, thereby reducing risk of thrombosis and improving the quality of life.[16] However, specifically during pregnancy, its safety remains unclear as reported by Rodríguez-Ferreras and Velasco-Roces[23] that the Drug's Technical Data Sheet and studies have warned regarding its potential teratogenic risk and discourage its use. This contrasts with the observations of other case series and recent reviews about its safety during pregnancy.[891826283435]\n\nIn the cases reported by Guibert et al. (which account for 52% of all reported cases in the literature), eculizumab was not prescribed during either antepartum or postpartum periods. Overall, its use varied [Table 4], with 22% of all cases receiving it during the entire pregnancy, 18% in different trimesters and 8% did not receive it. During postpartum, 30% of the reported cases received eculizumab, and 14% did not. However, in our cases, three patients received eculizumab during antepartum and postpartum, but Case 2 did not and the reason for not initiating this therapy was not documented. In Case 3, the patient initially refused the therapy, but it was initiated at 31 weeks of gestation and postpartum; notably, both cases remained stable. The eculizumab dosage and frequency usually increased during pregnancy due to the physiological and pathophysiological factors of pregnancy and PNH, respectively, an approach supported by the existing literature.[16]\n\nOverall, the findings in our cases and existing literature outcomes are similar. Management of pregnancy with PNH is based on observational data and preexisting published experience; therefore, there is need for an established protocol to standardize management plans for such a high-risk group.\n\nCONCLUSION\n\nBased on our experience from the reported cases, it can be stated that pregnancy is not recommended in patients with PNH due to the high risk of complications, and in cases of pregnancies, both hematological and obstetrician experts should be involved in patient care. All PNH pregnancies should be monitored clinically and through laboratory parameters for any symptoms/signs of hemolysis or thrombosis and to determine use prophylactic anticoagulants for thrombosis prevention and for use of eculizumab therapy. The safety of eculizumab use during pregnancy remain inconclusive, and thus there is need for prospectively studies with long-term follow-up to determine the effectiveness of eculizumab as well as determine the outcome of pregnancy with PNH.\n\nEthical considerations\n\nThis case series was approved by the Research Advisory Council /Ethics Committee at King Faisal Specialist Hospital (Ref no.: RAC#2131-049), and adhered to the guidelines of the Declaration of Helsinki, 2013.\n\nPeer review\n\nThis article was peer-reviewed by two independent and anonymous reviewers.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n\n1 Brodsky RA Paroxysmal nocturnal hemoglobinuria Blood 2014 124 2804 11 25237200\n2 Yu F Du Y Han B A comparative analysis of clinical characteristics of patients with paroxysmal nocturnal hemoglobinuria between Asia and Europe/America Int J Hematol 2016 103 649 54 27059871\n3 Patel SJ Ajebo G Kota V Guddati AK Analysis of outcomes in hospitalized pregnant patients with acute myeloid leukemia Am J Blood Res 2020 10 68 75 32923085\n4 Brando B Gatti A Preijers F Flow cytometric diagnosis of paroxysmal nocturnal hemoglobinuria: Pearls and pitfalls – A critical review article EJIFCC 2019 30 355 70 31814811\n5 Parker C Omine M Richards S Nishimura JI Bessler M Ware R Diagnosis and management of paroxysmal nocturnal hemoglobinuria Blood 2005 106 3699 709 16051736\n6 Mercuri A Farruggia P Timeus F Lombardi L Onofrillo D Putti MC A retrospective study of paroxysmal nocturnal hemoglobinuria in pediatric and adolescent patients Blood Cells Mol Dis 2017 64 45 50 28380398\n7 Muñoz-Linares C Ojeda E Forés R Pastrana M Cabero M Morillo D Paroxysmal nocturnal hemoglobinuria: A single Spanish center's experience over the last 40 yr Eur J Haematol 2014 93 309 19 24758317\n8 Patriquin C Leber B Increased eculizumab requirements during pregnancy in a patient with paroxysmal nocturnal hemoglobinuria: Case report and review of the literature Clin Case Rep 2015 3 88 91 25767703\n9 Kelly RJ Höchsmann B Szer J Kulasekararaj A de Guibert S Röth A Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria N Engl J Med 2015 373 1032 9 26352814\n10 Singh A Sikka P Suri V Agrawal N Chopra S Kumar B Pregnancy in a patient with paroxysmal nocturnal hemoglobinuria Int J Reprod Contracept Obstet Gynecol 2014 3 285 7\n11 Lauritsch-Hernandez LS Kraehenmann F Balabanov S Kimmich N Eculizumab application during pregnancy in a patient with paroxysmal nocturnal hemoglobinuria: A case report with review of the literature Clin Case Rep 2018 6 1582 7 30147909\n12 Sharma R Keyzner A Liu J Bradley T Allen SL Successful pregnancy outcome in paroxysmal nocturnal hemoglobinuria (PNH) following escalated eculizumab dosing to control breakthrough hemolysis Leuk Res Rep 2015 4 36 8 26052501\n13 Bjørge L Ernst P Haram KO Paroxysmal nocturnal hemoglobinuria in pregnancy Acta Obstet Gynecol Scand 2003 82 1067 71 10 14616248\n14 Sahu KK Dhibar DP Varma S Malhotra P CML with pregnancy: Real challenges in developing nations Leuk Lymphoma 2017 58 1518 9 27852145\n15 Lee SE Lee JW Safety of current treatments for paroxysmal nocturnal hemoglobinuria Expert Opin Drug Saf 2021 20 171 9 33249943\n16 Bastos JM Pinheiro PL Rocha LC Bicalho EC Cazeli AB Marcondes SS Therapeutic challenges in pregnant women with paroxysmal nocturnal hemoglobinuria: A case report Medicine (Baltimore) 2018 97 e12155 30200112\n17 Füreder W Sperr WR Heibl S Zebisch A Pfeilstöcker M Stefanzl G Prognostic factors and follow-up parameters in patients with paroxysmal nocturnal hemoglobinuria (PNH): Experience of the Austrian PNH network Ann Hematol 2020 99 2303 13 32856141\n18 Miyasaka N Kanakura K Konoshita T Nishmura J Pregnancy in Paroxysmal Nocturnal Hemoglobinuria 2017 Japan Springer, Tokyo 347 58\n19 de Guibert S Peffault de Latour R Varoqueaux N Labussière H Rio B Jaulmes D Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: The French experience Haematologica 2011 96 1276 83 21606169\n20 Hall C Richards S Hillmen P Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) Blood 2003 102 3587 91 12893760\n21 Alashkar F Saner FH Vance C Schmücker U Herich-Terhürne D Dührsen U Köninger A Röth A Pregnancy in classical paroxysmal nocturnal hemoglobinuria and aplastic anemia–paroxysmal nocturnal hemoglobinuria: a high-risk constellation Front Med 2020 7 543372\n22 Miyasaka N Miura O Kawaguchi T Arima N Morishita E Usuki K Pregnancy outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: A Japanese experience and updated review Int J Hematol 2016 103 703 12 26857155\n23 Rodríguez-Ferreras A Velasco-Roces L Eculizumab-related abortion in a woman with paroxysmal nocturnal hemoglobinuria: A case report J Reprod Infertil 2019 20 252 5 31897393\n24 Danilov AV Brodsky RA Craigo S Smith H Miller KB Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab Leuk Res 2010 34 566 71 19954846\n25 Marasca R Coluccio V Santachiara R Leonardi G Torelli G Notaro R Pregnancy in PNH: Another eculizumab baby Br J Haematol 2010 150 707 8 20553271\n26 Ando Y Kida M Saika M Chizuka A Hangaishi A Urabe A Pregnancy and delivery in a PNH patient treated with eculizumab Rinsho Ketsueki 2014 55 2288 93 25501409\n27 Patel A Unnikrishnan A Murphy M Egerman R Wheeler S Richards A Paroxysmal nocturnal hemoglobinuria in pregnancy: A dilemma in treatment and thromboprophylaxis Case Rep Hematol 2017 2017 7289126 29147590\n28 Vekemans MC Lambert C Ferrant A Saussoy P Havelange V Debiève F Management of pregnancy in paroxysmal nocturnal hemoglobinuria on long-term eculizumab Blood Coagul Fibrinolysis 2015 26 464 6 25688464\n29 Gessoni G Canistro R Bergamini L Valverde S Gessoni F Nani G Postpartum thrombotic complication in a patient with paroxysmal nocturnal hemoglobinuria Blood Coagul Fibrinolysis 2015 26 458 63 25688459\n30 Bais J Pel M von dem Borne A van der Lelie H Pregnancy and paroxysmal nocturnal hemoglobinuria Eur J Obstet Gynecol Reprod Biol 1994 53 211 4 8200469\n31 Sasano T Tomimatsu T Nishimura J Matsumura I Kanakura Y Kimura T Two consecutive pregnancies in a patient with paroxysmal nocturnal haemoglobinuria treated with anticoagulant therapy at different doses Blood Coagul Fibrinolysis 2016 27 109 12 26258669\n32 Moyo VM Mukhina GL Garrett ES Brodsky RA Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays Br J Haematol 2004 126 133 8 15198744\n33 Morita Y Nishimura J Shimada T Tanaka H Serizawa K Taniguchi Y Successful anticoagulant therapy for two pregnant PNH patients, and prospects for the eculizumab era Int J Hematol 2013 97 491 7 23456264\n34 Kelly R Arnold L Richards S Hill A Bomken C Hanley J The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab Br J Haematol 2010 149 446 50 20151973\n35 Sarno L Tufano A Maruotti GM Martinelli P Balletta MM Russo D Eculizumab in pregnancy: A narrative overview J Nephrol 2019 32 17 25 30159857\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2321-4856",
"issue": "9(2)",
"journal": "Saudi journal of medicine & medical sciences",
"keywords": "Complications; paroxysmal nocturnal hemoglobinuria; pregnancy",
"medline_ta": "Saudi J Med Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101675905",
"other_id": null,
"pages": "178-189",
"pmc": null,
"pmid": "34084110",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "26052501;26352814;30159857;27059871;30200112;32923085;23456264;25688464;25237200;29147590;31897393;26258669;8200469;30147909;24758317;25688459;16051736;14616248;33102497;20553271;19954846;20151973;28380398;26857155;25767703;21606169;15198744;12893760;25501409;33249943;27852145;32856141;31814811",
"title": "Pregnancy with Paroxysmal Nocturnal Hemoglobinuria: A Case Series with Review of the Literature.",
"title_normalized": "pregnancy with paroxysmal nocturnal hemoglobinuria a case series with review of the literature"
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{
"abstract": "Influenza is a cause of significant morbidity and mortality worldwide. Myocarditis is a rare complication of the virus and can vary widely in severity. The published cases of influenza B myocarditis in children tend to be severe with a high mortality rate. Current standard treatment of viral myocarditis is supportive care, although immunomodulatory therapies, such as steroids and intravenous immunoglobulin, are often used. T cells have been implicated in causing significant myocyte damage in myocarditis by leading to the downstream production of antibodies against viral and myocyte antigens; this has created a theoretical basis for the use of antithymocyte globulin to target T cells in these patients. We present a case of acute fulminant influenza B myocarditis in a pediatric patient that required mechanical circulatory support and improved only after treatment with antithymocyte globulin.",
"affiliations": "Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York-Presbyterian, Columbia University Medical Center, New York, New York jep9124@nyp.org.;Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York-Presbyterian, Columbia University Medical Center, New York, New York.;Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York-Presbyterian, Columbia University Medical Center, New York, New York.;Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York-Presbyterian, Columbia University Medical Center, New York, New York.;Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York-Presbyterian, Columbia University Medical Center, New York, New York.;Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York-Presbyterian, Columbia University Medical Center, New York, New York.;Division of Pediatric Cardiology, Morgan Stanley Children's Hospital of New York-Presbyterian, Columbia University Medical Center, New York, New York.",
"authors": "Piccininni|Jenna A|JA|;Richmond|Marc E|ME|;Cheung|Eva W|EW|;Lee|Teresa M|TM|;Law|Sabrina P|SP|;Addonizio|Linda J|LJ|;Zuckerman|Warren A|WA|",
"chemical_list": "D000961:Antilymphocyte Serum",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2018-0884",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "142(5)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000293:Adolescent; D000961:Antilymphocyte Serum; D004452:Echocardiography; D004562:Electrocardiography; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D009981:Influenza B virus; D007251:Influenza, Human; D009205:Myocarditis",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30352793",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Influenza Myocarditis Treated With Antithymocyte Globulin.",
"title_normalized": "influenza myocarditis treated with antithymocyte globulin"
} | [
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP010327",
"fulfillexpeditecriteria": "2",
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"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
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"abstract": "Chronic myeloid leukemia (CML) is an uncommon entity in pediatric patients. CML in chronic phase (CML-CP) has a relatively favorable outcome. Leukostasis occurs in 9.7% of patients with CML. One of the most serious leukostasis-related complications is intracranial hemorrhage (ICH). However, this is very rare in patients with CML-CP, and few early mortalities have been reported in CML patients with leukostasis. We report the case of a 14-year-old female patient with CML-CP who developed ICH 8 days after admission. A 14-year-old girl developed symptoms of fatigue and slight fever and was diagnosed with CML-CP. She was treated with imatinib and received low-molecular-weight heparin owing to coagulation abnormalities. However, 6 days later, she developed sensorineural hearing loss, which is a symptom of leukostasis. She received hydroxyurea to reduce her white blood cell (WBC) count, and her treatment was changed from imatinib to nilotinib. The WBC and platelet counts remained unchanged, blast counts did not increase, and mild coagulation abnormality persisted. Eight days after admission, she suddenly lost consciousness and experienced respiratory arrest. Cranial computed tomography revealed multiple ICH lesions and brain hernia. She received intensive care but was diagnosed with brain death by electroencephalography and died 14 days after hospitalization. ICH is very rare in patients with CML-CP; however, patients with leukostasis and coagulation abnormalities can develop severe hemorrhage, even in the chronic phase. Thus, it is necessary to accurately estimate the cause and provide appropriate treatment for these patients.",
"affiliations": "Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan.;Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan.;Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan.;Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan.;Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan.;Department of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan.",
"authors": "Takahashi|Nobuhisa|N|;Sano|Hideki|H|;Mochizuki|Kazuhiro|K|;Kobayashi|Shogo|S|;Ohara|Yoshihiro|Y|;Kikuta|Atsushi|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000515011",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\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\n10.1159/000515011\ncro-0014-0525\nCase Report\nIntracranial Hemorrhage in a Pediatric Patient with Chronic Myeloid Leukemia in Chronic Phase: A Case Report\nTakahashi Nobuhisa *\nSano Hideki\nMochizuki Kazuhiro\nKobayashi Shogo\nOhara Yoshihiro\nKikuta Atsushi\nDepartment of Pediatric Oncology, Fukushima Medical University, Fukushima, Japan\n*Nobuhisa Takahashi, Department of Pediatric Oncology, Fukushima Medical University, 1 Hikariga-oka, Fukushima 960-1295 (Japan), a429323@fmu.ac.jp\nJan-Apr 2021\n22 3 2021\n22 3 2021\n14 1 525530\n3 2 2021\n3 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.\nChronic myeloid leukemia (CML) is an uncommon entity in pediatric patients. CML in chronic phase (CML-CP) has a relatively favorable outcome. Leukostasis occurs in 9.7% of patients with CML. One of the most serious leukostasis-related complications is intracranial hemorrhage (ICH). However, this is very rare in patients with CML-CP, and few early mortalities have been reported in CML patients with leukostasis. We report the case of a 14-year-old female patient with CML-CP who developed ICH 8 days after admission. A 14-year-old girl developed symptoms of fatigue and slight fever and was diagnosed with CML-CP. She was treated with imatinib and received low-molecular-weight heparin owing to coagulation abnormalities. However, 6 days later, she developed sensorineural hearing loss, which is a symptom of leukostasis. She received hydroxyurea to reduce her white blood cell (WBC) count, and her treatment was changed from imatinib to nilotinib. The WBC and platelet counts remained unchanged, blast counts did not increase, and mild coagulation abnormality persisted. Eight days after admission, she suddenly lost consciousness and experienced respiratory arrest. Cranial computed tomography revealed multiple ICH lesions and brain hernia. She received intensive care but was diagnosed with brain death by electroencephalography and died 14 days after hospitalization. ICH is very rare in patients with CML-CP; however, patients with leukostasis and coagulation abnormalities can develop severe hemorrhage, even in the chronic phase. Thus, it is necessary to accurately estimate the cause and provide appropriate treatment for these patients.\n\nKeywords\n\nChild\nIntracranial hemorrhage\nChronic myeloid leukemia in chronic phase\n==== Body\nIntroduction\n\nChronic myeloid leukemia (CML) is an uncommon entity in children and accounts for 2–3% of all cases of pediatric leukemias [1]. CML in chronic phase (CML-CP) has a relatively favorable outcome. Suttorp et al. [2] reported an event-free survival rate of 97% by 18 months in the CML-PAED-II phase III trial. Leukostasis is a pathologic condition caused by hypoxemia due to vascular occlusion in leukemic patients with hyperleukocytosis. Leukostasis occurs in 9.7% of patients with CML [3]. One of the most serious leukostasis-related complications is intracranial hemorrhage (ICH) [4]. However, this is very rare in patients with CML-CP, and few early mortalities have been reported in CML patients with leukostasis [5]. We report the case of a 14-year-old patient with CML-CP who developed ICH 8 days after admission.\n\nCase Report\n\nA 14-year-old girl with initial symptoms of fatigue and slight fever was admitted to our hospital. No symptoms of the central nervous system or respiratory system were noted. Physical examination showed that her liver and spleen were palpable at 8 and 10 cm below their respective costal margins. Her white blood cell (WBC) count was 75.4 × 104/μL (blasts, 2%; myelocytes, 50%; metamyelocytes, 8%; neutrophils, 29%; monocytes, 2%; lymphocytes, 1%; basophils, 2%), her hemoglobin level was 8.5 g/dL, and her platelet count was 17.2 × 104/μL.\n\nBiochemical examination results revealed an elevated lactate dehydrogenase level of 1,579 IU/L and a soluble interleukin-2 receptor level of 969 IU/mL. No liver dysfunction, renal dysfunction, or electrolyte abnormalities were noted. Coagulation test results were as follows: prothrombin time-international normalized ratio (PT-INR), 1.42 (range, 0.8–1.2); activated partial thromboplastin time (APTT), 43.0 s (range, 23.0–38.0 s); fibrinogen level, 163 mg/dL (range, 181–398 mg/dL); D-dimer, 9.4 μg/mL (range, <1.0 μg/mL); fibrin/fibrinogen degradation products (FDP), 26.7 μg/mL (range, <5.0 μg/mL); and antithrombin III (AT III) level, 107% (range, 80–130%).\n\nNo ICH or lung infiltration was observed on contrast-enhanced computed tomography (CT). Bone marrow aspiration showed hypercellularity (nucleated cell count 81.6 × 104/μL) but no increased blasts. The chromosomal karyotype was 46XX, t(9:22)(q34:q11.1). In chimeric gene analysis using the novel real-time quantitative polymerase chain reaction method, a high level of BCR-ABL protein was detected. The BCR-ABL T315I mutation, which indicates imatinib resistance, was not detected. Thus, the patient fulfilled all the 2017 World Health Organization diagnostic criteria for CML-CP.\n\nThe patient received hydration, allopurinol, and low-molecular-weight heparin (dalteparin sodium 75 IU/kg) after admission to our hospital because we were concerned that her condition would progress to tumor lysis syndrome [6] and disseminated intravascular coagulation (DIC) [7] with the treatment. Her condition was diagnosed as CML-CP 3 days after admission, and imatinib was administered. However, 6 days later, the patient developed sensorineural hearing loss (Fig. 1). We judged this sensorineural hearing loss as a symptom caused by leukostasis, and the patient received hydroxyurea to reduce her WBC count. Her treatment also changed from imatinib to nilotinib. The WBC and platelet counts remained unchanged, blast counts did not increase, and the mild coagulation abnormality persisted.\n\nEight days after admission, the patient suddenly lost consciousness and experienced respiratory arrest. Cranial CT revealed multiple ICH lesions and brain hernia (Fig. 2). Her WBC count was 73.3 × 104/μL (blasts, 2%), and platelet count was 20.2 × 104/μL. Coagulation test results were as follows: PT-INR, 1.28; APTT, 46.5 s; fibrinogen level, 184 mg/dL; D-dimer, 4.6 μg/mL; FDP, 9.2 μg/mL; and AT III level, 116%. The patient received intensive care but was diagnosed with brain death by electroencephalography and died 14 days after hospitalization. An autopsy was not performed because permission could not be obtained from her family (Fig. 3).\n\nDiscussion\n\nLeukostasis is a pathologic condition that is caused by hypoxemia due to vascular occlusion in leukemic patients with hyperleukocytosis. Patients with CML are at risk of developing leukostasis when their WBC count is >30.0 × 104/μL and spleen size >10 cm [3]; thus, it is surmised that our patient was at high risk of developing leukostasis. The main symptoms of leukostasis include respiratory symptoms, such as dyspnea, and central nervous system symptoms, such as headache, visual impairment, sensorineural hearing loss, and tinnitus. Other symptoms include myocardial ischemia and erectile dysfunction [8]. In patients with CML, the main symptoms of leukostasis are ocular symptoms (13.4%) and priapism (6.6%) [3]. In this patient, the initial symptom of leukostasis was sensorineural hearing loss.\n\nThe Japanese Pediatric Leukemia/Lymphoma Study Group's CML Committee reviewed records of 256 Japanese CML pediatric patients aged <20 years between 1996 and 2011 at 93 institutes and reported that although 21 of 214 CML-CP patients complained of symptoms caused by leukostasis, there were few early mortalities in CML patients with leukostasis [3]. However, other reports have described that CML-CP patients experience ICH due to leukostasis [5]. Leukostasis symptoms usually occur because of occlusion of the cerebral microvasculature, leading to ICH [9]. In this patient, the main cause of ICH was microvascular occlusion caused by leukostasis. Other reports suggested that coagulation abnormalities such as DIC associated with hyperleukocytosis [10] and acquired von Willebrand disease [11] were the causes of ICH; however, in our patient, the DIC score defined using the diagnostic criteria for DIC of the Japanese Society on Thrombosis and Hemostasis (2017 edition) was 3, and there was no exacerbation of a coagulation abnormality. However, few patients with CML-CP develop fatal bleeding. Nonetheless, some CML cases with severe bleeding caused by multiple factors, including platelet dysfunction [12], fibrinolytic activation [13], and side effects of tyrosine kinase inhibitors [14], have been reported. We used low-molecular-weight heparin because we were worried that her condition would progress to DIC with the treatment [7]. However, the use of low-molecular-weight heparin may have affected the coagulation function of this patient. The use of anticoagulants in such patients should be considered thoroughly.\n\nOur patient received hydration, allopurinol, low-molecular-weight heparin, and tyrosine kinase inhibitor after admission to our hospital because her condition was diagnosed as CML-CP, and the severity of her leukostasis was moderate (Novotny grading system grade 2 [15]). However, she developed severe ICH and died. It is possible that the reason for her severe cerebral hemorrhage was not only leukostasis but also the complicated coagulopathy in CML. Thus, further investigations for coagulopathy should have been performed. However, her condition progressed so rapidly that complicated coagulopathy could not be scrutinized.\n\nConclusion\n\nICH is very rare in patients with CML-CP. However, in the case of CML with leukostasis and coagulopathy, abnormal coagulation is caused by various pathologic conditions. Thus, it is necessary to accurately estimate the cause and provide appropriate treatment for these patients.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the patient's parents for publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nThere were no funding sources.\n\nAuthor Contributions\n\nN. Takahashi drafted the initial manuscript. K. Mochizuki, S. Kobayashi, and Y. Ohara were involved in the care of the patient. A. Kikuta reviewed and revised the manuscript and approved the final manuscript as submitted. H. Sano supervised each step of the writing of the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.\n\nFig. 1 Cranial computed tomography at the onset of the loss of consciousness and respiratory arrest showing multiple intracranial hemorrhagic legions.\n\nFig. 2 Pure-tone audiometry. Both air conduction and bone conduction thresholds worsened, and there were no significant differences between air and bone conduction thresholds. This patient developed bilateral sensorineural hearing loss.\n\nFig. 3 The patient was treated with imatinib but developed sensorineural hearing loss. She received hydroxyurea, and her treatment was changed from imatinib to nilotinib. However, she suddenly lost consciousness and experienced respiratory arrest. She received intensive care but died 14 days after hospitalization.\n==== Refs\nReferences\n\n1 Hijiya N Schultz KR Metzler M Millot F Suttorp M Pediatric chronic myeloid leukemia is a unique disease that requires a different approach Blood 2016 127 (4) 392 9 26511135\n2 Suttorp M Schulze P Glauche I Göhring G von Neuhoff N Metzler M Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia: results from a phase III trial Leukemia 2018 32 1657 69 29925908\n3 Kurosawa H Tanizawa A Tono C Watanabe A Shima H Ito M Leukostasis in children and adolescents with chronic myeloid leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group Pediatr Blood Cancer 2016 63 (3) 406 11 26485422\n4 Kouzuki K Umeda K Saida S Kato I Hiramatsu H Funaki T Sudden intracranial hemorrhage in a patient with atypical chronic myeloid leukemia in chronic phase J Pediatr Hematol Oncol 2018 40 (8) e553 6 29227326\n5 Wang H Cao F Li J Sun K Jin J Wang M Intracerebral hemorrhage as the initial presentation of chronic myeloid leukemia: a case report and review of the literature Front Neurol 2020 11 571576 33193017\n6 Hua J Iwaki Y Inoue M Hagihara M Tumor lysis syndrome soon after treatment with hydroxyurea followed by nilotinib in two patients with chronic-phase chronic myelogenous leukemia Int J Hematol 2013 98 (2) 243 6 23649869\n7 Martí-Carvajal AJ Anand V Solà I Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia Cochrane Database Syst Rev 2015 2015 (6) CD008562\n8 Rollig C Ehninger G How I treat hyperleukocytosis in acute myeloid leukemia Blood 2015 125 (21) 3246 52 25778528\n9 Lichtman MA Rowe JM Hyperleukocytic leukemias: rheological, clinical, and therapeutic considerations Blood 1982 60 (2) 279 83 7046844\n10 Giammarco S Chiusolo P Piccirillo N Di Giovanni A Metafuni E Laurenti L Hyperleukocytosis and leukostasis: management of a medical emergency Expert Rev Hematol 2017 10 (2) 147 54 27967252\n11 Assem MM Aly MAM Salam IA Shaheen MH Zuhair MN Saleh M Acquired von Willebrand disease in hematologic malignancies at the National Cancer Institute (NCI) Egypt J Egypt Natl Cancer Inst 2000 12 117 23\n12 Akay OM Mutlu F Gülbaş Z Platelet dysfunction in patients with chronic myeloid leukemia: does imatinib mesylate improve it? Turk J Haematol 2016 33 (2) 127 30 26377244\n13 Rość D Kremplewska-Nalezyta E Gadomska G Bielis L [Hemostatic disturbances in chronic myeloid leukemia] Wiad Lek 2007 60 (3–4) 138 42 17726865\n14 Kim MS Lee DH Lee YR Kim DK Bae SH Hwang JY A case of subdural hematoma in patient with chronic myeloid leukemia treated with high-dose imatinib mesylate Korean J Hematol 2010 45 (1) 73 5 21120168\n15 Novotny JR Müller-Beissenhirtz H Herget-Rosenthal S Kribben A Dührsen U Grading of symptoms in hyperleukocytic leukaemia: a clinical model for the role of different blast types and promyelocytes in the development of leukostasis syndrome Eur J Haematol 2005 74 (6) 501 10 15876254\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(1)",
"journal": "Case reports in oncology",
"keywords": "Child; Chronic myeloid leukemia in chronic phase; Intracranial hemorrhage",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "525-530",
"pmc": null,
"pmid": "33976629",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "15876254;26511135;7046844;29227326;21120168;23649869;26107113;17726865;27967252;26485422;26377244;25778528;29925908;33193017",
"title": "Intracranial Hemorrhage in a Pediatric Patient with Chronic Myeloid Leukemia in Chronic Phase: A Case Report.",
"title_normalized": "intracranial hemorrhage in a pediatric patient with chronic myeloid leukemia in chronic phase a case report"
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"activesubstancename": "IMATINIB MESYLATE"
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{
"abstract": "Prostate cancer is the second most common cancer in men. Diagnosis of early disease is based on prostate biopsy which is carried out because of symptoms of prostatism or asymptomatic rise in PSA. On the other side, advanced disease can locally invade and metastasise to lymph nodes, bones, lungs, etc. Initial presentation of prostate cancer in form of brain metastasis is extremely seldom. Similarly, prostate cancer, which metastasised to the breast, is very rare too. Here, we discuss two unique cases of prostate cancer, one of them had an initial presentation of brain metastasis from prostate adenocarcinoma and the other case had an established diagnosis of prostate cancer metastasised to the breast. In theory, cancer can cause metastatic spread to any part of the body; however diversity into such presentation or progression from prostate cancer has not been frequently noticed.",
"affiliations": "Tamworth Rural Referral Hospital, Tamworth Rural Referral Hospital, Tamworth, N.S.W., Australia.;University of New England, Tamworth Rural Referral Hospital, Tamworth, N.S.W., Australia.;University of Newcastle, Tamworth Rural Referral Hospital, Tamworth, N.S.W., Australia.;Tamworth Rural Referral Hospital, Tamworth Rural Referral Hospital, Tamworth, N.S.W., Australia.;Medical Oncology, Tamworth Rural Referral Hospital, Tamworth, N.S.W., Australia.",
"authors": "Mandaliya|Hiren|H|;Sung|Joshua|J|;Hill|Joanna|J|;Samali|Ramin|R|;George|Mathew|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000442045",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000442045cro-0008-0526Published online: November, 2015Prostate Cancer: Cases of Rare Presentation and Rare Metastasis Mandaliya Hiren a*Sung Joshua bHill Joanna cSamali Ramin aGeorge Mathew daTamworth Rural Referral Hospital, Tamworth Rural Referral Hospital, Tamworth, N.S.W., AustraliabUniversity of New England, Tamworth Rural Referral Hospital, Tamworth, N.S.W., AustraliacUniversity of Newcastle, Tamworth Rural Referral Hospital, Tamworth, N.S.W., AustraliadMedical Oncology, Tamworth Rural Referral Hospital, Tamworth, N.S.W., Australia*Hiren Mandaliya, Tamworth Rural Referral Hospital, Tamworth, NSW 2340 (Australia), E-Mail hammandalia@gmail.comSep-Dec 2015 26 11 2015 26 11 2015 8 3 526 529 Copyright © 2015 by S. Karger AG, Basel2015This 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.Prostate cancer is the second most common cancer in men. Diagnosis of early disease is based on prostate biopsy which is carried out because of symptoms of prostatism or asymptomatic rise in PSA. On the other side, advanced disease can locally invade and metastasise to lymph nodes, bones, lungs, etc. Initial presentation of prostate cancer in form of brain metastasis is extremely seldom. Similarly, prostate cancer, which metastasised to the breast, is very rare too. Here, we discuss two unique cases of prostate cancer, one of them had an initial presentation of brain metastasis from prostate adenocarcinoma and the other case had an established diagnosis of prostate cancer metastasised to the breast. In theory, cancer can cause metastatic spread to any part of the body; however diversity into such presentation or progression from prostate cancer has not been frequently noticed.\n\nKey Words\nProstate cancerRare presentationMetastasis\n==== Body\nIntroduction\nBrain metastasis from prostate cancer is a rare and late manifestation. This develops in patients with prolonged survival. In addition, only few cases with brain metastasis preceding the diagnosis of prostate cancer have been reported in literature [1]. Unlike melanoma and carcinomas of the lung, breast, kidney and colon, it is rare for prostate cancer to metastasise to the central nervous system and even rarer to have diagnostic manifestation as a brain metastasis, making it the topic of this case report.\n\nMetastasis to the breast from a primary prostate adenocarcinoma is a rare occurrence, as the breast is an uncommon site of metastases in general, and even less frequent in prostate cancer. There is evidence that suggests that hormone manipulation in treatment of prostate cancer could predispose to breast metastasis. Oestrogen therapy, which was previously the mainstay in the treatment of prostate cancer, has been linked to the development of breast metastasis [2].\n\nCase Presentation\nCase 1\nThe case of a 61-year-old male with a gradual onset right-sided facial palsy, dysarthria and hemiparesis for a few weeks is presented. His past medical history was not significant and did not have a history of smoking or alcohol intake. He was generally well otherwise. His initial CT scan of the brain was suggestive of a left temporal lobe mass, which was confirmed on brain MRI as a large irregularly enhancing mass lesion in the left temporal lobe with solid and cystic components, possible were a primary or metastatic carcinomatous process. His initial blood tests including full blood counts, liver functions, renal functions, electrolytes were normal. However, is tumour markers particularly PSA (prostate specific antigen) was 1,152 mg/l (normal value less than 5 mg/l). He underwent stereotactic craniotomy for excision of the mass. Histopathology showed metastatic adenocarcinoma with immunohistochemistry (CK7 negative, CK20 negative and PSA positive) which favoured metastatic prostatic adenocarcinoma. Post-operatively his PSA dropped to 23 mg/l. CT scan of the chest/abdomen/pelvis did not show any metastatic lesions or prostatic enlargement. However, his bone scan showed increased uptake in multiple ribs and anterior superior iliac spine. He improved remarkably following surgery on neurological aspects. With a diagnosis of metastatic prostatic adenocarcinoma, he underwent palliative whole brain radiotherapy after surgery. He was also commenced on goserelin acetate as an androgen deprivation therapy. His PSA normalised to 3.7 mg/l within 7 weeks. He has been doing exceptionally well since then and having ongoing clinical biochemical and radiological response without any evidence of disease recurrence nearly 36 months following the initial event.\n\nCase 2\nAn 80-year-old male was diagnosed with prostate cancer in 2011. It was an adenocarcinoma with Gleeson score of 4 + 3 = 7. His initial PSA was 6.7 mg/l. He was started on leuprorelin and bicalutamide. He has shown ongoing response to dual androgen blockade for nearly 4 years. Early in the same year, he presented with a painless swelling in his right breast. It was a 5 × 4 cm sized, hard, non-tender swelling at right breast, without any underlying bone tenderness or lymphadenopathy. Given his long-standing androgen deprivation therapy, the initial diagnosis was gynaecomastia. Ultrasound of the right breast revealed a lobulated retro-areolar lesion of the breast measuring 18 × 20 × 46 mm in diameter with well-defined margins, more in favour of atypical gynaecomastia. There was no abnormality on the right breast and no evidence of ipsilateral axillary or supraclavicular or neck lymphadenopathy. Core biopsy showed a malignant infiltrate with positive staining for PSA. The stains for CK7/CK20, oestrogen receptor, progesterone receptor, CD31, CD34, design and smooth muscle actin were negative. Surprisingly, these results were consistent with metastatic adenocarcinoma of the prostate involving the right breast.\n\nDiscussion\nMetastasis to breast is most commonly seen with contralateral breast cancer and only 2% of all breast tumours are originating from non-mammary cancers [3]. The most common non-mammary cancers which metastasise to the breast are leukaemia, melanoma, lymphoma, ovarian cancer, lung cancer and gastric cancer [3]. Prostate cancer on the other hand metastasises more commonly to the bones, lung, liver, pleura and adrenal glands [4]. The rare occurrence of metastasis to breast is suggested to be due to the breast having large areas of fibrous tissue with a relatively poor blood supply [5]. Metastasis to the breast is even more unlikely in males, 5–6 times less frequent than in females [6]. There is evidence that suggests that hormonal manipulation in prostate cancer treatment could predispose to breast metastasis. Oestrogen therapy, which was previously the mainstay in the treatment of prostate cancer, has been linked to the development of breast metastasis [2, 7]. Although our patient was not treated with oestrogen therapy, non-steroidal anti-androgen therapy (bicalutamide) is known to increase circulating levels of oestrogen due to competitive inhibition of central androgen receptors which blocks the negative feedback loop therapy increasing luteinizing hormone secreation which leads to increased production of testosterone which becomes aromatised to oestrogen. Despite this, there is no clear predisposing factors found correlating with the development of breast metastasis, and there have been few recorded cases of prostate cancer which metastasised to the breast without any prior hormonal therapy [8]. Other differentials for breast enlargement are gynaecomastia, primary breast cancer or metastasis to the breast from cancer which is rare too. Histopathology from a breast lump including immunohistochemistry is a useful tool to derive a final diagnosis [9]. PSA and PAP (prostatic acid phosphatase) stains on IHC (immunohistochemistry) would certainly help to differentiate the nature of the pathology [10]. Although PSA shows some activity in gynaecomastia, PAP is more specific for metastasis from prostate cancer [11]. Metastatic disease of non-mammary neoplasms involving infiltration of the breast carries a grave prognosis and indicates widely disseminated disease [6].\n\nBrain metastasis is common in cancer, but prostate cancer rarely metastasises to the brain [12]. Approximately 1.6% of prostate cancer patients have brain metastasis in a large retrospective analysis of 16,280 patients with prostate cancer [13]. Cerebral metastasis from prostate cancer as an initial presentation is extremely rare [14]. The predominant clinical presentation of brain metastasis from prostate carcinoma was confusion and related to intracranial hypertension or diffuse cortical dysfunction such as delirium (50%), headache (34%), short-term memory deficits (17%) and hemiparesis (5%) [13]. Treatments available for intracranial metastasis include neurosurgery, radiation therapy and hormonal manipulation [15]. Our case presented with predominantly right-sided weakness and underwent neurosurgical resection and radiotherapy followed by androgen deprivation therapy. His disease state is still under control.\n\nConclusion\nBrian metastasis from prostate cancer is a rare event, and neurological symptoms as a first clinical manifestation are reported in limited cases only. Brain metastasis in prostate cancer should be treated similarly like any other brain metastasis. Similarly, breast metastasis from prostate cancer is a very uncommon entity. To differentiate it from gynaecomastia and metastasis from other source is very much essential, as treatment and prognosis widely varies.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 Catane R Kaufman J West C Brain metastasis from prostatic carcinoma Cancer 1976 38 2583 2587 1000485 \n2 Hesdorffer C Bezwoda WR Metastases of prostate cancer to breast. A case report S Afr Med J 1987 72 504 505 3660162 \n3 Njiaju UO Truica CI Metastatic prostatic adenocarcinoma mimicking inflammatory breast carcinoma: a case report Clin Breast Cancer 2010 10 E3 E5 20133250 \n4 Bubendorf L Schopfer A Wagner U Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients Hum Pathol 2000 31 578 583 10836297 \n5 Mun SH Ko EY Han BK Breast metastases from extramammary malignancies: typical and atypical ultrasound features Korean J Radiol 2014 15 20 28 24497788 \n6 Smymiotis V Theodosopoulos T Marinis A Metastatic disease in the breast from nonmammary neoplasms Eur J Gynaecol Oncol 2005 26 547 550 16285577 \n7 Moldwin RM Orihuela E Breast masses associated with adenocarcinoma of the prostate Cancer 1989 63 2229 2233 2720573 \n8 Mostofi FK Grading of prostatic carcinoma Cancer Chemother Rep 1975 59 111 117 48413 \n9 Sahoo S Smith RE Potz JL Rosen PP Metastatic prostatic adenocarcinoma within a primary solid papillary carcinoma of the male breast Arch Pathol Lab Med 2001 125 1101 1103 11473469 \n10 Green LK Klima M The use of immunohistochemistry in metastatic prostatic adenocarcinoma to the breast Hum Pathol 1991 22 242 246 1706305 \n11 Kidwai N Gong Y Sun X Expression of androgen receptor and prostate-specific antigen in male breast carcinoma Breast Cancer Res 2004 6 R18 R23 14680496 \n12 Fervenza FC Wolanskyj AP Eklund HE Richardson RL Brain metastasis: an unusual complication from prostatic adenocarcinoma Mayo Clin Proc 2000 75 79 82 10630761 \n13 Tremont-Lukats IW Bobustuc G Lagos GK Brain metastasis from prostate carcinoma: The M D Anderson Cancer Center experience Cancer 2003 98 363 368 12872358 \n14 Kasabian NG Previte SR Kaloustian HD Ganem EJ Adenocarcinoma of the prostate presenting initially as an intracerebral tumor Cancer 1992 70 2149 2151 1394044 \n15 Kunkler RB Cooksey G Millac P Carcinoma of the prostate presenting with a cerebral metastasis Br J Urol 1993 71 103 104 8435719\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "8(3)",
"journal": "Case reports in oncology",
"keywords": "Metastasis; Prostate cancer; Rare presentation",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "526-9",
"pmc": null,
"pmid": "26668576",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "2720573;24497788;16285577;8435719;1000485;14680496;3660162;1706305;11473469;1394044;10836297;48413;12872358;10630761;20133250",
"title": "Prostate Cancer: Cases of Rare Presentation and Rare Metastasis.",
"title_normalized": "prostate cancer cases of rare presentation and rare metastasis"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-178797",
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{
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"activesubstancename": "BICALUTAMIDE"
},
"dr... |
{
"abstract": "A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.",
"affiliations": "Department of Pediatrics, Division of Pediatric Endocrinology, University of North Carolina, Chapel Hill, NC 27599-7236, USA.",
"authors": "Coulter|Don W|DW|;Walko|Christine|C|;Patel|Jai|J|;Moats-Staats|Billie M|BM|;McFadden|Andrew|A|;Smith|Scott V|SV|;Khan|Wasiuddin A|WA|;Bridges|Arlene S|AS|;Deal|Allison M|AM|;Oesterheld|Javier|J|;Davis|Ian J|IJ|;Blatt|Julie|J|",
"chemical_list": "D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; C401859:temsirolimus; D004155:Diphenhydramine; D020123:Sirolimus",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0b013e32835dc7c5",
"fulltext": null,
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"issn_linking": "0959-4973",
"issue": "24(4)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D004155:Diphenhydramine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D003875:Drug Eruptions; D057239:Early Termination of Clinical Trials; D005221:Fatigue; D005260:Female; D006402:Hematologic Diseases; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D052016:Mucositis; D009369:Neoplasms; D010146:Pain; D020123:Sirolimus; D014635:Valproic Acid",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "415-21",
"pmc": null,
"pmid": "23328074",
"pubdate": "2013-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21287536;19097774;15983389;16899619;17913896;17579623;20332142;21452015;21301319;17538086;15557548;14990647;21629704;18630505;17230517;14710364;20978924;21115653;15955899;21690471;15136596;22033322;19261329;21827982;11742974",
"title": "Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors.",
"title_normalized": "valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors"
} | [
{
"companynumb": "US-PFIZER INC-2013245411",
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
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... |
{
"abstract": "About 15% of myopathies present with distal weakness. Lack of sensory deficit, and preservation of sensory responses and deep tendon reflexes, favors a myopathic cause for distal weakness. Electromyogram confirms this diagnosis. Profuse spontaneous discharges are common in inflammatory, metabolic, and myofibrillar myopathy (MFM). If the clinical picture indicates a specific disease such as facioscapulohumeral muscular dystrophy (FSHD), genetic testing provides the quickest diagnosis. Otherwise, muscle biopsy can distinguish specific features. The common causes of myopathic distal weakness are FSHD, myotonic dystrophy, and inclusion body myositis. Other causes include MFM, distal muscular dystrophies, metabolic myopathies, and congenital myopathies.",
"affiliations": "Department of Medicine, Nerve and Muscle Center of Texas, Baylor College of Medicine, 6624 Fannin # 1670, Houston, TX 77030, USA. Electronic address: shaibani@bcm.edu.",
"authors": "Shaibani|Aziz|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-8619",
"issue": "34(3)",
"journal": "Neurologic clinics",
"keywords": "Distal; Myofibrillar; Myopathy; Weakness",
"medline_ta": "Neurol Clin",
"mesh_terms": "D000328:Adult; D000368:Aged; D049310:Distal Myopathies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8219232",
"other_id": null,
"pages": "547-64",
"pmc": null,
"pmid": "27445241",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Distal Myopathies: Case Studies.",
"title_normalized": "distal myopathies case studies"
} | [
{
"companynumb": "US-APOPHARMA INC-2016AP016231",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN CALCIUM"
},
"drugadditional"... |
{
"abstract": "Clinical Cases in Hepatitis 2018 was an interactive educational program for Australian physicians (gastroenterologists, hepatologists, and infectious disease specialists) actively involved in the treatment of liver diseases including hepatitis C virus, hepatitis B virus, and non-alcoholic steatohepatitis. This educational program sponsored by Gilead Sciences took place on October 12-13, 2018, and provided timely, informative case-based, and practical education to Australian physicians. This report summarizes keynote lectures from international leaders in the field of hepatitis C virus, hepatitis B virus, and non-alcoholic steatohepatitis and practical clinical case studies designed to inform and educate Australian physicians on managing challenging patients.",
"affiliations": "Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia.;St Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia.;Alfred Hospital, Monash University Melbourne, Melbourne, Victoria, Australia.;Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.",
"authors": "Strasser|Simone I|SI|;Thompson|Alexander J|AJ|;Roberts|Stuart K|SK|;George|Jacob|J|;|||",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jgh.14720",
"fulltext": null,
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"issn_linking": "0815-9319",
"issue": "34 Suppl 1()",
"journal": "Journal of gastroenterology and hepatology",
"keywords": "hepatitis B virus; hepatitis C virus; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis",
"medline_ta": "J Gastroenterol Hepatol",
"mesh_terms": "D001315:Australia; D019468:Disease Management; D004493:Education; D004502:Education, Medical, Continuing; D005260:Female; D006509:Hepatitis B; D006526:Hepatitis C; D006801:Humans; D008107:Liver Diseases; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease",
"nlm_unique_id": "8607909",
"other_id": null,
"pages": "5-15",
"pmc": null,
"pmid": "31282011",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Cases in Hepatitis: Towards improving liver disease management in Australia.",
"title_normalized": "clinical cases in hepatitis towards improving liver disease management in australia"
} | [
{
"companynumb": "AU-MYLANLABS-2019M1071920",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Despite progress in treating lupus nephritis, the incidence of end-stage chronic kidney disease has increased. Renal transplantation is the treatment of choice for these patients and has been successfully performed on systemic lupus erythematosus (SLE) since 1959. The main concern in these patients is post-transplant lupus nephritis recurrence. Several questions remain for SLE patients following transplantation, including fear of lupus nephritis recurrence, choice of immunosuppressive therapy, and how to manage the disease and associated complications to reduce morbidity and risk of death.",
"affiliations": "Division of Nephrology and Kidney Transplantation, Onofre Lopes University Hospital, Natal, Rio Grande do Norte (RN), Brazil. Electronic address: nefrologiahuol@gmail.com.;Division of Nephrology and Kidney Transplantation, Onofre Lopes University Hospital, Natal, Rio Grande do Norte (RN), Brazil.;Division of Nephrology and Kidney Transplantation, Onofre Lopes University Hospital, Natal, Rio Grande do Norte (RN), Brazil.;Division of Nephrology and Kidney Transplantation, Onofre Lopes University Hospital, Natal, Rio Grande do Norte (RN), Brazil.;Nephropathology Institute, Minas Gerais Federal University School of Medicine, Belo Horizonte, Minas Gerais, Brazil.;Division of Nephrology and Kidney Transplantation, Onofre Lopes University Hospital, Natal, Rio Grande do Norte (RN), Brazil.;Division of Internal Medicine, Onofre Lopes University Hospital, Natal (RN), Brazil.",
"authors": "Vale|Pedro|P|;Quinino|Raquel|R|;Costa|Kellen|K|;Júnior|Tomás|T|;Araújo|Stanley|S|;Fechine|Laíse|L|;Cunha|Rinadja|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2019.05.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008181:Lupus Nephritis; D008875:Middle Aged; D012008:Recurrence",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1614-1617",
"pmc": null,
"pmid": "31155203",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Post-transplant Lupus Nephritis Recurrence: A Case Report and Review of the Literature.",
"title_normalized": "post transplant lupus nephritis recurrence a case report and review of the literature"
} | [
{
"companynumb": "BR-PFIZER INC-2019265490",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": nu... |
{
"abstract": "Traditional laboratory markers are insensitive in distinguishing between patients with acute liver failure (ALF) who will require urgent liver transplantation (LT) from those who will recover spontaneously, particularly within 24 h of presentation. Coagulation factor-V (FV) may improve the accuracy of outcome prediction in ALF due to its predominant synthesis in the liver and short half-life in plasma.\n\n\n\nPatients enrolled in the ALF Study Group Registry from a single site had FV determined within 24 h of presentation (Derivation-Cohort). Area under the receiver operating characteristic curves (AUROC) dichotomized by ALF etiology [acetaminophen (APAP) or non-APAP] were constructed to evaluate the diagnostic performance of FV for transplant-free-survival (TFS). Multivariate logistic regression modeling was performed using FV and other clinical variables to predict TFS. Accuracy of FV and multivariable model were performed in a Validation-Cohort from a different site.\n\n\n\n90-patients (56% with APAP) were included in the Derivation-Cohort. Median FV was significantly higher in TFS versus those who died/LT (31% vs. 15%, respectively; p = 0.001). When dichotomized by etiology, AUROC for FV was 0.77 for APAP (cutoff, sensitivity, specificity 10.5%, 79%, 69%, respectively) and 0.77 for non-APAP (22%, 85%, 67%, respectively). When the optimal cutoffs for FV in the Derivation-Cohort were applied to the Validation-Cohort (N = 51; 59% with APAP), AUROC for FV was 0.75 for APAP (sensitivity/specificity 81/44) and 0.95 for non-APAP (sensitivity/specificity 90/73). In multivariate analyses, AUROC for FV model was 0.86 in the Derivation-Cohort and 0.90 in the Validation-Cohort.\n\n\n\nAdmission FV may improve selection of patients who are likely to improve without LT.",
"affiliations": "Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, USA. kpatidar@iu.edu.;Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.;Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.;Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, USA.;Division of Transplant Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.;Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, USA.;Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.",
"authors": "Patidar|Kavish R|KR|;Davis|Brian C|BC|;Slaven|James E|JE|;Ghabril|Marwan S|MS|;Kubal|Chandrashekhar A|CA|;Lee|William M|WM|;Stravitz|Richard T|RT|",
"chemical_list": "D015415:Biomarkers; D005165:Factor V",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-020-06197-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "66(2)",
"journal": "Digestive diseases and sciences",
"keywords": "Acetaminophen overdose; Fulminant liver failure; Intensive care unit; Kings College Criteria; Liver transplantation; MELD",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000328:Adult; D015415:Biomarkers; D015331:Cohort Studies; D005165:Factor V; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010343:Patient Admission; D011379:Prognosis; D015203:Reproducibility of Results; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "619-627",
"pmc": null,
"pmid": "32185661",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "4908702",
"title": "Admission Factor V Predicts Transplant-Free Survival in Acute Liver Failure.",
"title_normalized": "admission factor v predicts transplant free survival in acute liver failure"
} | [
{
"companynumb": "US-JNJFOC-20210223735",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Four patients had diarrhea due to Clostridium difficile after receiving chemotherapy for cancer. None of the patients had received antibiotics for at least 4 weeks before the onset of diarrhea. At the time of admission of any of these four patients no outbreak of diarrhea was noted on the ward. Each patient was admitted with the acute onset of diarrhea after receiving chemotherapy, at different times of the year. Diarrhea was clinically important and was associated with dehydration, toxemia, and blood in the stool in all cases. Diagnosis of C difficile was confirmed by endoscopic examination, positive biopsy specimen, and positive test for toxin in the stool. All patients recovered after undergoing specific treatment. Drugs not believed to carry serious risk to the bowel mucosa may facilitate proliferation of C difficile. Patients with severe diarrhea after receiving chemotherapy, particularly those with blood in the stool, should be promptly tested for C difficile even in the absence of a history of antibiotic administration. Early and specific treatment can prevent additional morbidity and reduce cost of care.",
"affiliations": "Department of Neoplastic Diseases, Mount Sinai Hospital, New York, NY 10029-6574.",
"authors": "Kamthan|A G|AG|;Bruckner|H W|HW|;Hirschman|S Z|SZ|;Agus|S G|SG|",
"chemical_list": "D004768:Enterotoxins",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9926",
"issue": "152(8)",
"journal": "Archives of internal medicine",
"keywords": null,
"medline_ta": "Arch Intern Med",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016360:Clostridioides difficile; D003131:Combined Modality Therapy; D003967:Diarrhea; D004761:Enterocolitis, Pseudomembranous; D004768:Enterotoxins; D005243:Feces; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "0372440",
"other_id": null,
"pages": "1715-7",
"pmc": null,
"pmid": "1497405",
"pubdate": "1992-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clostridium difficile diarrhea induced by cancer chemotherapy.",
"title_normalized": "clostridium difficile diarrhea induced by cancer chemotherapy"
} | [
{
"companynumb": "US-PFIZER INC-2020472643",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to evaluate the feasibility and toxicity of CHOP-14, with rituximab (R-CHOP-14), supported by pegfilgrastim, in untreated diffuse large B-cell lymphoma (DLBCL).\n\n\nMETHODS\nThis study included 50 patients with DLBCL with a median age of 55 years (range: 22-70). Sixty-two percent had an International Prognostic Index score >1, 40% had bulky disease and 52% had stage IV disease. CHOP was administered every 14 days, preceded on day 1 by rituximab (375 mg/m2) and followed on day 3 by pegfilgrastim (6 mg per cycle). Toxicity was calculated over 277 cycles administered; feasibility was calculated over 227, since the first cycle in each patient was not susceptible to delay or dose-reduction.\n\n\nRESULTS\nTherapy was delivered on time in 92% of cycles, with the relative dose intensity being 95% for doxorubicin and cyclophosphamide. Grade 4 neutropenia developed in 19% of cycles and neutropenic fever in 4% of cycles (16% of patients), with a median duration of 3 days (range: 2-10). The program was completed in 40 of 50 patients (80%); reasons for withdrawal included progression in three patients, interstitial pneumonia in four, prolonged severe neutropenia in two and septic shock in one patient. Severe adverse events occurred on 12 occasions (4% of cycles), involving 11 patients (22% of total); the most frequent severe adverse event was interstitial pneumonia which occurred in seven patients (14% of total). In three cases, Pneumocystis carinii pneumonia was documented; no cotrimoxazole prophylaxis had been given and a correlation with hypogammaglobulinemia was observed. The complete remission rate was 74%; the 2-year event-free and overall survival rates were 72% and 68%, respectively.\n\n\nCONCLUSIONS\nA single dose of pegfilgrastim per cycle of R-CHOP allowed on-time delivery of this chemotherapy in DLBCL, with a low incidence of febrile neutropenia; the risk of P. carinii pneumonia makes cotrimoxazole prophylaxis essential in this setting.",
"affiliations": "Division of Hematology, IRCCS Policlinico San Matteo, University of Pavia, Italy. ebrusa@smatteo.pv.it",
"authors": "Brusamolino|Ercole|E|;Rusconi|Chiara|C|;Montalbetti|Luigi|L|;Gargantini|Livio|L|;Uziel|Lilj|L|;Pinotti|Graziella|G|;Fava|Sergio|S|;Rigacci|Luigi|L|;Pagnucco|Guido|G|;Pascutto|Cristiana|C|;Morra|Enrica|E|;Lazzarino|Mario|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000069585:Filgrastim; D011241:Prednisone",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "91(4)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D016393:Lymphoma, B-Cell; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D011092:Polyethylene Glycols; D011241:Prednisone; D011994:Recombinant Proteins; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "496-502",
"pmc": null,
"pmid": "16537117",
"pubdate": "2006-04",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity.",
"title_normalized": "dose dense r chop 14 supported by pegfilgrastim in patients with diffuse large b cell lymphoma a phase ii study of feasibility and toxicity"
} | [
{
"companynumb": "IT-AMGEN-UK162932",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nTo raise awareness of a rare but serious adverse effect of a commonly used medication.\n\n\nMETHODS\nReport of a case.\n\n\nRESULTS\nA previously healthy 42-year-old woman presented with acute-onset delirium with psychotic features as a consequence of levofloxacin therapy. Withdrawal of the medication was associated with return of the patient's normal mental status.\n\n\nCONCLUSIONS\nThe new quinolone derivatives (levofloxacin, sparfloxacin, grepafloxacin, trovafloxacin, gatifloxacin and moxifloxacin), also called gyrase inhibitors, are known for their potential to cause central nervous system-related adverse effects, including headache, dizziness and insomnia. Risk factors for neurotoxicity include renal insufficiency, underlying central nervous system (CNS) disease and increased CNS penetration of drug. Acute delirium resulting from levofloxacin therapy is an exceedingly rare complication that has been thought to occur more commonly in elderly patients. Here, we describe levofloxacin-induced delirium with psychotic features in a relatively young, otherwise healthy female.",
"affiliations": "Department of Internal Medicine, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.",
"authors": "Kiangkitiwan|Boonsong|B|;Doppalapudi|Avanthi|A|;Fonder|Margaret|M|;Solberg|Kim|K|;Bohner|Brian|B|",
"chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D015242:Ofloxacin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.genhosppsych.2007.11.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "30(4)",
"journal": "General hospital psychiatry",
"keywords": null,
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000900:Anti-Bacterial Agents; D003693:Delirium; D005260:Female; D006304:Health Status; D006801:Humans; D064704:Levofloxacin; D015242:Ofloxacin; D011605:Psychoses, Substance-Induced; D012852:Sinusitis; D014717:Vertigo",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "381-3",
"pmc": null,
"pmid": "18585545",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Levofloxacin-induced delirium with psychotic features.",
"title_normalized": "levofloxacin induced delirium with psychotic features"
} | [
{
"companynumb": "US-Glenmark Generics Europe Ltd.-GGEL20110800764",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drug... |
{
"abstract": "Zoledronic acid (ZA), a highly potent intravenous bisphosphonate (BP), has been increasingly used in children with primary and secondary osteoporosis due to its convenience of shorter infusion time and less frequent dosing compared to pamidronate. Many studies have also demonstrated beneficial effects of ZA in other conditions such as hypercalcemia of malignancy, fibrous dysplasia (FD), chemotherapy-related osteonecrosis (ON) and metastatic bone disease. This review summarizes pharmacologic properties, mechanism of action, dosing regimen, and therapeutic outcomes of ZA in a variety of metabolic bone disorders in children. Several potential novel uses of ZA are also discussed. Safety concerns and adverse effects are also highlighted.",
"affiliations": "Division of Endocrinology, Department of Pediatrics, Nationwide Children's Hospital/the Ohio State University College of Medicine, Columbus, Ohio, USA.;Division of Nephrology, Department of Pediatrics, Nationwide Children's Hospital/the Ohio State University College of Medicine, Columbus, Ohio, USA.",
"authors": "Bowden|Sasigarn A|SA|;Mahan|John D|JD|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/tp.2017.09.10",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-4336",
"issue": "6(4)",
"journal": "Translational pediatrics",
"keywords": "Zoledronic acid (ZA); acute phase reaction (APR); bone mineral density (BMD); fragility fractures; hypercalcemia; metabolic bone disease; osteonecrosis (ON); osteoporosis",
"medline_ta": "Transl Pediatr",
"mesh_terms": null,
"nlm_unique_id": "101649179",
"other_id": null,
"pages": "256-268",
"pmc": null,
"pmid": "29184807",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "20524999;21542743;26811713;28529724;18775204;27864686;12686715;23712442;21894214;26090982;28233020;28117876;12093986;20131072;15877730;26124831;19648791;20514467;14729043;28585373;24356182;27492436;14651779;26171800;26845496;26892041;22297733;17574945;16904014;21820091;27462588;27778394;12549750;11208851;18718815;26494410;21254232;26615086;23835890;27638613;15520785;28516132;25193159;17566815;27049615;24680381;27235668;26082799;16046206;15756228;27725317;21298747;11283917;21242224;19614941;11960203;26308295;21947829;16434452;12733732;23934636;15792214;26792372;22437628;27747122;15706555;22876543;21293106;24631254;14998220;26330244;22870429;28608802",
"title": "Zoledronic acid in pediatric metabolic bone disorders.",
"title_normalized": "zoledronic acid in pediatric metabolic bone disorders"
} | [
{
"companynumb": "FI-CIPLA LTD.-2017US20602",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "The literature contains few reports of patients with four more or more synchronous primary malignancies. We report the case of a 74-year-old woman who presented with synchronous primary malignant neoplasms of the breast (metaplastic carcinoma), lung (squamous cell carcinoma), esophagus (adenocarcinoma), and colon (adenocarcinoma). She was treated with multimodality therapy and demonstrated a favorable response at early follow-up. To our knowledge, this combination of synchronous primary malignancies has not been previously reported. The management of patients with multiple synchronous primary malignancies introduces a number of unique challenges which necessitate highly individualized treatment plans that may not strictly adhere to standard practices in the setting of a single malignancy.",
"affiliations": "Department of General Surgery; Rush University Medical Center, Chicago, IL, U.S.A.;Department of General Surgery; Rush University Medical Center, Chicago, IL, U.S.A.;Department of General Surgery; Rush University Medical Center, Chicago, IL, U.S.A.;Department of Medicine; Rush University Medical Center, Chicago, IL, U.S.A.;Department of Medicine; Rush University Medical Center, Chicago, IL, U.S.A.;Department of Pathology; Rush University Medical Center, Chicago, IL, U.S.A.;Department of Cardiovascular and Thoracic Surgery; Rush University Medical Center, Chicago, IL, U.S.A.",
"authors": "Klairmont|Matthew|M|;Kopkash|Katherine|K|;Favuzza|Joanne|J|;Hill|Marisa|M|;Rao|Ruta|R|;Mahon|Brett|B|;Seder|Christopher W|CW|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "35(11)",
"journal": "Anticancer research",
"keywords": "Synchronous primary malignant neoplasms; individualized treatment; multiple primary malignant neoplasms",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D001943:Breast Neoplasms; D002294:Carcinoma, Squamous Cell; D003110:Colonic Neoplasms; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009367:Neoplasm Staging; D009378:Neoplasms, Multiple Primary; D011379:Prognosis",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6159-62",
"pmc": null,
"pmid": "26504043",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Four Synchronous Primary Malignancies of the Breast, Lung, Colon and Esophagus.",
"title_normalized": "four synchronous primary malignancies of the breast lung colon and esophagus"
} | [
{
"companynumb": "US-ACTAVIS-2016-11526",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "40 patients seen in general practice and psychiatric outpatient clinics who had taken lorazepam or diazepam alone in regular dosage for a mean period of 3.6 years had their benzodiazepine replaced by propranolol (60--120 mg/day) or placebo for two weeks under double-blind conditions. Depending on the criteria for the definition of an abstinence syndrome, 27--45% of the patients had withdrawal symptoms during the study. Propranolol did not affect the drop-out rate or the incidence of withdrawal symptoms but significantly reduced their severity in patients completing the study. The percentage fall in serum levels of desmethyldiazepam in patients who experienced withdrawal symptoms after stopping diazepam was significantly greater in patients with no withdrawal symptoms.",
"affiliations": null,
"authors": "Tyrer|P|P|;Rutherford|D|D|;Huggett|T|T|",
"chemical_list": "D014151:Anti-Anxiety Agents; D010919:Placebos; D011433:Propranolol; D008140:Lorazepam; D003975:Diazepam",
"country": "England",
"delete": false,
"doi": "10.1016/s0140-6736(81)92861-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "1(8219)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D014151:Anti-Anxiety Agents; D003975:Diazepam; D006801:Humans; D008140:Lorazepam; D010919:Placebos; D011433:Propranolol; D013375:Substance Withdrawal Syndrome; D013997:Time Factors",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "520-2",
"pmc": null,
"pmid": "6111632",
"pubdate": "1981-03-07",
"publication_types": "D016430:Clinical Trial; D018848:Controlled Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Benzodiazepine withdrawal symptoms and propranolol.",
"title_normalized": "benzodiazepine withdrawal symptoms and propranolol"
} | [
{
"companynumb": "GB-ROCHE-2501791",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
"drugad... |
{
"abstract": "We describe the case of a 50-year-old woman presenting to our acute medicine department with generalised non-specific symptoms on a background of HIV managed on triple therapy (tenofovir, lamivudine and zidovudine). On admission, she was noted to be acidotic with proteinuria, glycosuria, hypophosphataemia and generalised body pain, and was diagnosed with Fanconi's renotubular syndrome secondary to tenofovir. It was also noted that she had elevated liver dysfunction markers, and an MRI of the liver revealed a focal stricture near the ampulla of Vater, resulting in a diagnosis of AIDS cholangiopathy. These two diagnoses are rare complications of HIV, and the presence of both these pathologies in a single patient has never been reported in the literature before, and we therefore believe that this case is the first of its kind.",
"affiliations": "Acute Medical Unit, Croydon University Hospital, London, UK.;Acute Medical Unit, Croydon University Hospital, London, UK.;Acute Medicine, National University Hospital, Singapore, Singapore.;Acute Medical Unit, Croydon University Hospital, London, UK.",
"authors": "Maweni|Robert|R|;Kallampallil|Jins|J|;Leong|Szewai|S|;Akunuri|Srikanth|S|",
"chemical_list": "D019380:Anti-HIV Agents; D019259:Lamivudine; D015215:Zidovudine; D000068698:Tenofovir",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222333",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "hiv / aids; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D019380:Anti-HIV Agents; D002761:Cholangitis; D005198:Fanconi Syndrome; D005260:Female; D015658:HIV Infections; D006801:Humans; D019259:Lamivudine; D008875:Middle Aged; D000068698:Tenofovir; D015215:Zidovudine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29167218",
"pubdate": "2017-11-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21994858;21799568;12460055;7503081;27742226;9755224;27465879;27029778;14572564;20880175;12037153;17026723;11563082;8810689;24368854;8666325;23020883;26032649;17496056;21671843;21435764;27128332;23465971",
"title": "Concomitant AIDS cholangiopathy and Fanconi syndrome as complications of HIV in a single patient.",
"title_normalized": "concomitant aids cholangiopathy and fanconi syndrome as complications of hiv in a single patient"
} | [
{
"companynumb": "GB-GLAXOSMITHKLINE-GB2017191717",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": "1",
... |
{
"abstract": "Long-term albendazole treatment should be given to all patients with unresectable hepatic alveolar echinococcosis as dramatic regression is possible in 15%-20%. It may be prudent to prepare a living donor for possible salvage transplant in case of a severe complication. Preemptive transplantation in mildly symptomatic patients should be discouraged.",
"affiliations": "Department of General Surgery İstanbul Faculty of Medicine İstanbul University İstanbul Turkey.;Department of Radiology İstanbul Faculty of Medicine İstanbul University İstanbul Turkey.;Department of Pathology İstanbul Faculty of Medicine İstanbul University İstanbul Turkey.;Department of General Surgery İstanbul Faculty of Medicine İstanbul University İstanbul Turkey.;Department of General Surgery İstanbul Faculty of Medicine İstanbul University İstanbul Turkey.;Department of General Surgery İstanbul Faculty of Medicine İstanbul University İstanbul Turkey.",
"authors": "Ocak|Sönmez|S|;Poyanlı|Arzu|A|;Güllüoğu|Mine|M|;İbiş|Cem|C|;Tekant|Yaman|Y|;Özden|İlgin|İ|https://orcid.org/0000-0001-7360-628X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4666",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4666\nCCR34666\nCase Report\nCase Reports\nDramatic response to albendazole in transplantation candidates with unresectable hepatic alveolar hydatid disease\nOCAK et al.\nOcak Sönmez 1 2 sonmezdr@gmail.com\nsonmezdr@gmail.com\n\nPoyanlı Arzu 3\nGüllüoğu Mine 4\nİbiş Cem 1\nTekant Yaman 1\nÖzden İlgin https://orcid.org/0000-0001-7360-628X\n1\n1 Department of General Surgery İstanbul Faculty of Medicine İstanbul University İstanbul Turkey\n2 Samsun Education and Research Hospital Samsun Turkey\n3 Department of Radiology İstanbul Faculty of Medicine İstanbul University İstanbul Turkey\n4 Department of Pathology İstanbul Faculty of Medicine İstanbul University İstanbul Turkey\n* Correspondence\nSönmez Ocak, Barış Bulvarı, Kadıköy Mahallesi No:199 PK:55090, İlkadım/Samsun, Turkey.\nEmails: sonmezdr@gmail.com; sonmezdr@gmail.com\n\n21 8 2021\n8 2021\n9 8 10.1002/ccr3.v9.8 e0466621 6 2021\n06 2 2021\n06 7 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nLong‐term albendazole treatment should be given to all patients with unresectable hepatic alveolar echinococcosis as dramatic regression is possible in 15%–20%. It may be prudent to prepare a living donor for possible salvage transplant in case of a severe complication. Preemptive transplantation in mildly symptomatic patients should be discouraged.\n\nLong‐term albendazole treatment should be given to all patients with unresectable hepatic alveolar echinococcosis as dramatic regression is possible in 15%–20%. It may be prudent to prepare a living donor for possible salvage transplant in case of a severe complication. Preemptive transplantation in mildly symptomatic patients should be discouraged.\n\nAlbendazole\nalveolar hydatid\ndramatic regression\nEchinococcus multilocularis\nliver transplantation\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.5 mode:remove_FC converted:21.08.2021\nOcakS, PoyanlıA, GüllüoğuM, İbişC, TekantY, Özdenİ. Dramatic response to albendazole in transplantation candidates with unresectable hepatic alveolar hydatid disease. Clin Case Rep. 2021;9 :e4666. 10.1002/ccr3.4666\n\nFunding information\n\nNot applicable\n==== Body\n1 INTRODUCTION\n\nHepatic alveolar echinococcosis (AE) lesions caused by Echinococcus multilocularis, behave like malignant tumors: they invade the surrounding liver parenchyma, metastasize to the regional lymph nodes and also disseminate to the lungs, and the brain via the hematogenous route.1 The prognosis of untreated AE is very poor: 15‐year survival is practically 0%.2 Radical surgery followed by two years of chemotherapy with benzimidazole derivatives is the only curative option but approximately 25%–70% of the patients are suitable for this treatment.1, 3, 4, 5, 6, 7, 8, 9, 10 Mass screening in endemic regions increases the probability of resection.11\n\nThe remaining patients receive life‐long benzimidazole treatment because interruption may result in exacerbation, except in highly selected cases.3, 12, 13, 14, 15 Albendazole is used more often than mebendazole as it is effective at lower doses and has better intestinal absorption.3 Benzimidazole treatment is believed to be parasitostatic rather than parasiticidal in the high majority of the cases.3, 16 In a review of 19 studies including 5 or more patients, success rate varied between 55% and 100%; “treatment was classed as successful if the disease had not progressed for >1 year and if there were no side‐effects necessitating a change of treatment.”17 Death due to progressive disease occurs in approximately 20–25% of the cases in 10 years.3, 18 In other words, a patient who receives albendazole as a primary treatment is, in principle, considered to be a candidate for life‐long palliation or transplantation (in highly selected cases with liver‐only disease).10, 19, 20, 21, 22, 23\n\nIn this case series, we present 4 patients who were possible candidates for liver transplant due to giant (>15 cm) unresectable AE lesions and in whom dramatic regression under albendazole treatment was observed.\n\n2 CASE SERIES\n\nForty‐two patients with AE were treated between 2002 and 2016. Partial hepatectomy was performed in 12 patients; long‐term albendazole was started in the remaining 30. Eventually, liver transplantation was required in two patients (for recurrent cholangitis and albendazole hepatotoxicity precluding treatment in one patient each).\n\nOf the remaining 28 patients, two died early due to septic complications and six were lost to follow‐up. Two patients had slow progression. Thirteen patients have had stable disease. One patient had mild regression. The data of the four patients with dramatic regression were presented in this report. Lesion volume was estimated by multiplying the three largest perpendicular dimensions of the lesion and π/6 and % decrease of the lesion was calculated for all cases.\n\n2.1 Case 1\n\nA previously healthy 45‐year‐old woman attended the outpatient clinic for abdominal pain and discomfort. The results of the liver biochemistry tests were as follows: AST: 23 U/L ALT: 19 U/L, GGT: 85 U/L (<85), ALP: 171 U/L (35–105), total bilirubin: 0.4 mg/dL, INR: 0.93. Abdominal magnetic resonance imaging (MRI) revealed a heterogeneous, 19‐cm liver mass filling the left lobe and extending to the right lobe (Figure 1A). The left hepatic and the middle hepatic veins and the left branch of the portal vein were thrombosed. Also, the right anterior portal vein branch was compressed by the mass. Ultrasonography‐guided core‐needle biopsy confirmed the radiologic diagnosis of AE. The MELD score of the patient was 6, that is, she was not eligible for the cadaveric waiting list. Because there was a high risk of portal vein thrombosis, a living donor was prepared. Simultaneously, albendazole at 10 mg /kg/day (3 weeks of treatment with 1‐week intervals) was started. At 4 months, the lesion size and appearance were unchanged. At 8 months, liquefaction of some of the previously solid areas was detected (Figure 1B); albendazole dose was increased to 15mg/kg/day. Subsequent films showed progressive liquefaction of the lesion; for example, the MRI image at 21 months (Figure 1C). Lesion size had decreased to 5.3 cm at 38 months (Figure 1D). Although the results of the biochemical tests were within normal limits (AST: 16 U/L, ALT: 11 U/L, ALP: 46 U/L, GGT: 16 U/L, total bilirubin: 0.4 mg/dL), the magnetic resonance cholangiopancreatography (MRCP) showed a persistent complex hilar stricture not suitable for surgical reconstruction. She is receiving albendazole treatment and will be re‐evaluated for liver transplantation if the mass regrows or she experiences cholangitis attacks.\n\nFIGURE 1 A: The 19‐cm AE mass filling the left lobe and extending to the right lobe. Estimated lesion volume was 1704 cm3. B, Eight months after proper albendazole treatment, liquefaction of some of the previously solid areas were detected. C, Progressive liquefaction of the lesion was shown on the MRI image at 21 months. D, The lesion size was dramatically decreased at the 38 months. The final lesion volume was 8 cm3 (99% decrease)\n\n2.2 Case 2\n\nA 52‐year‐old woman was examined for a 17‐cm liver mass in segments 4–5–6 (Figure 2A). Ultrasonography‐guided core‐needle biopsy confirmed the radiologic diagnosis of AE. Right portal vein branch embolization was performed as a preparation for extended right hepatectomy. However, adequate hypertrophy of the future remnant liver could not be achieved. The patient was considered for liver transplantation but was excluded because of her severe bipolar disorder. After a few months of albendazole treatment, the patient was lost to follow‐up. She returned 4 years later. She had continued albendazole regularly except for the last 5 months. The computed tomography (CT) scan showed dramatic regression of the mass to 8 cm as well as liquefaction of its content (Figure 2B). In the fifth year of treatment, she developed febrile neutropenia (neutrophil count: 66 /mm3). An expert hematologist identified albendazole as the sole likely cause. Albendazole was stopped and neutropenia responded to the granulocyte colony‐stimulating factor. The mass has been stable for 6 years without treatment (Figure 2C).\n\nFIGURE 2 A, A 17‐cm AE mass extending from the right lobe and segment 4 of liver. Estimated lesion volume was 1127 cm3. B, Liquefaction and dramatic regression were detected after 4 years of albendazole treatment. The final lesion volume was 240 cm3 (79% decrease). C, The mass has been stable for six years after cessation of albendazole treatment\n\n2.3 Case 3\n\nA 55‐year‐old woman was referred for possible liver transplantation for unresectable AE refractory to albendazole. The lesion (longest dimension: 28 cm) had remained stable for 6 years of treatment. A very encouraging aspect was that the content had been extensively liquefied (Figure 3A). Her relevant laboratory test results were as follows: AST: 36 U/L, ALT: 37 U/L, ALP: 302 U/L (35–105), GGT: 110 U/L (< 85), total bilirubin: 0.8 mg/dL, INR: 1.2. The results of the whole blood count were within normal limits. A percutaneous catheter was placed from the left side. Initially, 2500 mL of bile‐colored fluid was drained; the volume decreased to 30 mL on day 6. The patient was discharged on the 7th day with albendazole treatment. Follow‐up CT after 15 months later showed dramatic regression of the lesion (Figure 3B). All intrahepatic branches of portal vein except that of the right anterior were thrombosed; grade 1–2 esophageal varices were observed on esophagogastroduodenoscopy. Her MELD score was 8. Although the presence of the catheter had a negative effect on her quality of life, the result of our risk‐benefit analysis did not favor living‐donor liver transplantation. The catheter was eventually removed but had to be reinserted only to be removed again. She has been under albendazole treatment for a total of 14 years and catheter free for the last 6 months. The final lesion size is 5 cm (Figure 3C).\n\nFIGURE 3 A, Initial MRI image of the lesion measuring 28 cm. Estimated lesion volume was 2749 cm3. B, After percutaneous drainage, the lesion volume was reduced dramatically. C, The patient was has been catheter free for six months and final lesion size was 5 cm. The final lesion volume was 18 cm3 (99% decrease)\n\n2.4 Case 4\n\nA 31‐year‐old man with hepatic AE diagnosed two years ago had been referred to our department for liver transplant. He admitted that he did not use albendazole regularly. CT demonstrated a 16‐cm mass filling the entire right lobe of the liver and containing a central necrotic area in the center. The trajectories of the right and middle hepatic veins were completely occupied by the mass which abutted the left hepatic vein in the parenchyma. Additionally, there was another mass measuring 6 cm at the tip of the left lobe; the hypertrophy of left lobe was not evident. (Figure 4A). Therefore, the case was considered inoperable. No metastases were detected in the brain or the lungs. The patient was considered for liver transplantation because of the risk of Budd‐Chiari syndrome that could be developed after thrombosis of the only remaining hepatic vein. On one hand, his wife was prepared for possible liver donation. On the other hand, proper albendazole treatment was instituted. After 3 months, the patient was hospitalized for abscess in the right AE cavity. A percutaneous catheter was placed and about 1500 ml of pus was drained. After resolution of acute infection, the patient was discharged with the catheter; albendazole at 10mg/kg/day was continued. Follow‐up CT taken one month later (Figure 4B) demonstrated that almost all the liquid component of the cyst had disappeared and the lesion was dramatically smaller. The catheter could be removed three months later. He took albendazole regularly for 5 months after drainage but then discontinued the therapy. Abdominal CT obtained 10 months after drainage revealed that the mass had regressed to 6 cm. Albendazole was started again but he did not take the drug and attend the outpatient clinic regularly. The remnant mass remained practically stable for 6 years (Figure 4C); the patient was urged to take his condition seriously. Partial compliance could be achieved.\n\nFIGURE 4 A, A 31‐year‐old man with bilobar (right lobe 16 cm, left lobe 6 cm) hepatic AE. Estimated lesion volume was 1845 cm3. B, A percutaneous catheter was replaced into the liquefied‐infected right lobe lesion. C, The shrunken mass has been practically stable for 6 years despite partial patient compliance. The final lesion volume was 42 cm3 (98% decrease)\n\n3 DISCUSSION\n\nLiver transplantation—the most extensive liver resection—has been proposed as an alternative approach for unresectable hepatic alveolar hydatid disease.24 To date, approximately 100 liver transplantations have been reported by various authors.10, 19, 20, 21, 22, 23 The published indications for these mostly cadaveric liver transplantations were end‐stage liver failure, bilobar disease with hilar involvement, recurrent cholangitis, and chronic Budd‐Chiari syndrome.19 The perioperative mortality was higher than experienced in patients with other causes of end‐stage liver disease; however, 5‐year survival rates (70–85%) were encouraging.19, 23Bresson‐Hadni et al suggested that “The early deaths could certainly be avoided in the future by selecting patients before the terminal stage of the disease.”19 This proposal is logical but difficult to implement in the Na‐MELD era because most patients with AE are not cirrhotic; in other words, they would not be eligible for a cadaveric liver in the absence of severe complications.\n\nOn the other hand, living‐donor liver transplantation may provide flexibility because the decision to transplant can be made at an earlier stage. The points to consider are as follows: There is a risk of recurrence and distant organ metastasis due to immunosuppressive treatment especially in cases which the AE mass cannot be removed with wide negative margins.25 This risk is a much more disturbing concern in “early” transplantations than in operations for end‐stage liver disease.\n\nThere are morbidity and mortality risks for the living donor.26\n\nThere is a risk of premature or unnecessary transplantations. It has been stated that\n\n“In the other situations, represented by chronic parasitic Budd‐Chiari syndrome and/or huge pseudo‐tumoral AE, the decision to perform LT is far more difficult to make. In fact, such patients, even with very impressive radiological imagings, may be asymptomatic or pauci‐symptomatic, due to the very slow progression of the parasitic larvae. ………….. The natural history of these “tumoral” and/or “vascular” AE was unknown. That explains the initial tendency for early indication for LT in such cases, due to the fear of acute Budd‐Chiari syn‐ drome occurrence or extra‐hepatic progression via the inferior vena cava….However, to our knowledge, acute parasitic Budd‐Chiari syndrome has never been reported in AE.”.19\n\nAt the crux of the issue is the definition of treatment failure under proper albendazole administration. Although the desired goal of the treatment is the regression of the tumor, lack of disease progression is considered as a success because the enlarging mass may cause severe problems such as biliary obstruction, cholangitis, abscess, cirrhosis, and portal hypertension.1, 2 To complicate the issue further, it has been reported that “Despite successful long‐term chemotherapy, late complications such as esophageal variceal bleeding or cholestatic complications‐probably due to postchemotherapy fibrosis with involvement of hilar structures‐ may occur.”27 Although long‐term benzimidazole treatment stabilizes the disease in 55–100% of the patients, disappearance of the lesions was reported in two patients only (a total of 3 small lesions measuring 2, 3, and 4 cm).17, 18, 28, 29 Marked regression has been noted in 3 patient series.18, 27, 28 Amman et al reported regression in 48.6% of their patients (n: 18); of these 18 patients had lesions measuring 12 cm or larger; the degree of regression in this subgroup was 40–70%.27 Ishizu et al reported volume reductions between 70 and 100% in 5 out 9 patients with measurable lesions.28 Unfortunately, the largest dimensions and the actual volumes were not reported except for a single case.28 Liu et al reported regression in 7 out of 20 patients; the stated dimensions are incompatible with regression in one patient; in the remaining 6 patients, the largest dimensions of the lesions measuring initially median (range) 10.5 cm (5–14) decreased by 10–40%.18 A very important original finding in the present report is that marked regression of giant lesions (> 15 cm) is possible in 15–20% of the patients with unresectable AE (4/28 of all patients, 4/22, excluding 6 patients lost to follow‐up).\n\nThe data summarized above show that proper albendazole treatment is indicated before a decision to transplant is made, except in patients with end‐stage liver disease. However, only 60–70% of the patients in two reviews received pretransplant benzimidazole treatment.19, 23 In a single‐center report by Özdemir et al, six of ten patients received albendazole, albeit irregularly, and adjuvant treatment was given only if a residual mass was left.21 Similarly, Aydinli et al stated that all of their 27 patients were given albendazole since the time of diagnosis but response of the mass (regression, stable, or progression) was not reported.20 In the report on 20 patients by Patkowski et al, albendazole was given for only 6 weeks before transplantation.22 All 4 patients presented in this report had giant AE masses. Three of them had been referred to our institution for liver transplantation. The patient with bipolar disorder was considered for transplant after failure of portal vein embolization to render extended right hepatectomy safe but finally excluded. The common finding of all 4 patients was that the lesions were liquefied. Azizi et al reported that Kodama type 5 lesions (large cyst without a solid component) showed negligible FDG uptake on PET/CT whereas most of the calcified lesions were metabolically active.30, 31 The radiological evolution in our cases is in accordance with these findings. AE may present as a large hepatic abscess,32 presumably as a result of bacterial infection of the liquefied mass as was observed in Case 4. Percutaneous drainage is the recommended treatment.33 A case reported by Köroğlu et al showed a very striking course: a 9‐cm lesion AE lesion that was solid on ultrasonography(US) became partially liquefied on US and CT after two years of albendazole treatment; 4 months later, he presented with a hepatic abscess: the liquefied component had enlarged and became infected. Percutaneous drainage resulted in complete resolution of the lesion.34 The right lobe lesion Case 4 in the present report showed a similar course; had the patient been more compliant with albendazole treatment, complete resolution might have been achieved.\n\nAn intriguing question is—which factors account for the discordant courses (regression‐stable disease‐progression) of the patients receiving the same treatment? The two likely candidates are plasma drug levels and sensitivity of the parasite to albendazole. Plasma drug levels exhibit a very wide variation and do not seem to explain the differences between patients.27 More data are required to translate the favorable experience in a small subset of patients (marked regression) to all inoperable patients.\n\nHepatotoxicity and myelotoxicity are the most serious adverse effects of albendazole; discontinuation of treatment may be required in up to 4% of the cases.3 Among the 30 patients who were candidates for long‐term albendazole treatment in the present series, severe hepatotoxicity (one of the two patients who underwent liver transplantation), and aplastic anemia (Case 2) developed in one patient each.\n\nIn conclusion, long‐term albendazole treatment should be given to all patients with unresectable hepatic AE. It may be prudent to prepare a living donor for possible salvage transplantation in case of a severe complication such as recurrent cholangitis, acute portal vein thrombosis, or albendazole hepatotoxicity. Liquefaction may be a sign of response to albendazole. Percutaneous drainage of the liquefied mass may be beneficial for reducing the risk of bacterial infection and relieving symptoms due to large masses. Dramatic regression with proper albendazole treatment is possible in 15–20% of the patients with unresectable hepatic AE masses. Preemptive liver transplantation in asymptomatic/mildly symptomatic patients should be discouraged.\n\nCONFLICT OF INTEREST\n\nThe authors report no conflict of interest.\n\nAUTHOR CONTRIBUTIONS\n\nSO and İÖ: Conceptualization, design, and draft manuscript. AP (radiology), MG (pathology), Cİ (clinical), YT (clinical), and İÖ (attending physician of the patients): Data acquisition. İÖ: Administrative, technical and material support, and supervision. All authors: Critical revision.\n\nETHICS APPROVAL AND CONSENT TO PARTICIPATE\n\nThis is a retrospective study on the clinical data of patients treated at our institution; our Institutional review board (IRB) does not require ethical approval for such studies.\n\nPATIENT CONSENT FOR PUBLICATION\n\nAt the time of hospitalization at our institution, all patients give written consent for anonymous use of their clinical data for teaching and scientific purposes.\n\nACKNOWLEDGMENTS\n\nPublished with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nData available on request from the authors.\n==== Refs\nREFERENCES\n\n1 KernP. Clinical features and treatment of alveolar echinococcosis. Curr Opin Infect Dis. 2010;23 (5 ):505‐512.20683265\n2 AmmannRW, EckertJ. Cestodes. Echinococcus. Gastroenterol Clin North Am. 1996;25 (3 ):655‐689.8863045\n3 BrunettiE, KernP, VuittonDA. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop. 2010;114 (1 ):1‐16.19931502\n4 PolatKY, BalikAA, CelebiF. Hepatic alveolar echinococcosis: clinical report from an endemic region. Can J Sur. 2002;45 (6 ):415.\n5 EmreA, OzdenI, BilgeO, et al. Alveolar echinococcosis in Turkey. Experience from an endemic region. Dig Surg. 2003;20 (4 ):301‐305.12789026\n6 KadryZ, RennerEC, BachmannLM, et al. Evaluation of treatment and long‐term follow‐up in patients with hepatic alveolar echinococcosis. Br J Surg. 2005;92 (9 ):1110‐1116.16044412\n7 ButtenschoenK, ButtenschoenDC, GruenerB, et al. Long‐term experience on surgical treatment of alveolar echinococcosis. Langenbecks Arch Surg. 2009;394 (4 ):689.18651165\n8 KawamuraN, KamiyamaT, SatoN, et al. Long‐term results of hepatectomy for patients with alveolar echinococcosis: a single‐center experience. J Am Coll Surg. 2011;212 (5 ):804‐812.21398158\n9 DuC, LiuZ, YangX. Hepatectomy for patients with alveolar echinococcosis: Long‐term follow‐up observations of 144 cases. Int J Surg. 2016;1 (35 ):147‐152.\n10 ChenKF, TangYY, WangR, et al. The choose of different surgical therapies of hepatic alveolar echinococcosis: A single‐center retrospective case‐control study. Medicine. 2018;97 (8 ):e0033.29465544\n11 SatoN, NamienoT, FuruyaK, et al. Contribution of mass screening system to resectability of hepatic lesions involving Echinococcus multilocularis. J Gastroenterol. 1997;32 (3 ):351‐354.9213249\n12 HemphillA, MüllerJ. Alveolar and cystic echinococcosis: towards novel chemotherapeutical treatment options. J Helminthol. 2009;83 (2 ):99‐111.19296876\n13 ReuterS, BuckA, ManfrasB, et al. Structured treatment interruption in patients with alveolar echinococcosis. Hepatology. 2004;39 :509‐517.14768005\n14 CrouzetJ, GrenouilletF, DelabrousseE, et al. Personalized management of patients with inoperable alveolar echinococcosis undergoing treatment with albendazole: usefulness of positron‐emission‐tomography combined with serological and computed tomography follow‐up. Clin Microbiol Infect. 2010;16 (6 ):788‐791.19912267\n15 AmmannRW, StumpeKD, GrimmF, et al. Outcome after discontinuing long‐term benzimidazole treatment in 11 patients with non‐resectable alveolar echinococcosis with negative FDG‐PET/CT and anti‐EmII/3‐10 serology. PLoS Negl Trop Dis. 2015;9 (9 ):e0003964.26389799\n16 WilsonJF, RauschRL, McMahonBJ, SchantzPM. Parasiticidal effect of chemotherapy in alveolar hydatid disease: review of experience with mebendazole and albendazole in Alaskan Eskimos. Clin Infect Dis. 1992;15 (2 ):234‐249.1520758\n17 ReuterS, JensenB, ButtenschoenK, KratzerW, KernP. Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature. J Antimicrob Chemother. 2000;46 (3 ):451‐456.10980173\n18 LiuYH, WangXG, GaoJS, QingYaoY, HortonJ. Continuous albendazole therapy in alveolar echinococcosis: long‐term follow‐up observation of 20 cases. Trans R Soc Trop Med Hyg. 2009;103 (8 ):768‐778.19457528\n19 Bresson‐HadniS, KochS, MiguetJP, et al. Indications and results of liver transplantation for Echinococcus alveolar infection: an overview. Langenbecks Arch Surg. 2003;388 (4 ):231‐238.12905036\n20 AydinliB, OzturkG, ArslanS, et al. Liver transplantation for alveolar echinococcosis in an endemic region. Liver Transpl. 2015;21 (8 ):1096‐1102.26074280\n21 ÖzdemirF, InceV, BarutB, OnurA, KayaalpC, YilmazS. Living donor liver transplantation for Echinococcus alveolaris: single‐center experience. Liver Transpl. 2015;21 (8 ):1091‐1095.25981332\n22 PatkowskiW, KotulskiM, RemiszewskiP, et al. Alveococcosis of the liver – strategy of surgical treatment with special focus on liver transplantation. Transpl Infect Dis. 2016;18 (5 ):661‐666.27416884\n23 AliakbarianM, TohidinezhadF, EslamiS, Akhavan‐RezayatK. Liver transplantation for hepatic alveolar echinococcosis: literature review and three new cases. Infect Dis (Lond). 2018;50 (6 ):452‐459.29363377\n24 Bresson‐HadniS, FranzaA, MiguetJP, et al. Orthotopic liver transplantation for incurable alveolar echinococcosis of the liver: report of 17 cases. Hepatology. 1991;13 (6 ):1061‐1070.2050323\n25 Bresson‐HadniS, KochS, BeurtonI, et al. Primary disease recurrence after liver transplantation for alveolar echinococcosis: Long‐term evaluation in 15 patients. Hepatology. 1999;30 (4 ):857‐864.10498634\n26 NydamTL, ReddyMS, PomfretEA, RelaM. Progression of living liver donation worldwide. Curr Opin Organ Transplant. 2018;23 (2 ):162‐168.29432257\n27 AmmannRW, IlitschN, MarincekB, FreiburghausAU. Effect of chemotherapy on the larval mass and the long‐term course of alveolar echinococcosis. Hepatology. 1994;19 (3 ):735‐742. 10.1002/hep.1840190328 8119701\n28 IshizuH, UchinoJ, SatoN, AokiS, SuzukiK, KuribayashiH. Effect of albendazole on recurrent and residual alveolar echinococcosis of the liver after surgery. Hepatology. 1997;25 (3 ):528–531. 10.1002/hep.510250305 9049192\n29 Bresson‐HadniS, BeurtonI, BartholomotB, et al. Alveolar echinococcosis. Hepatology. 1998;27 (5 ):1453‐1456.9581710\n30 AziziA, BlagosklonovO, LounisA, et al. Alveolar echinococcosis: correlation between hepatic MRI findings and FDG‐PET/CT metabolic activity. Abdom Imaging. 2015;40 (1 ):56‐63.24970734\n31 KodamaY, FujitaN, ShimizuT, et al. Alveolar echinococcosis: MR findings in the liver. Radiology. 2003;228 (1 ):172‐177.12750459\n32 ButtenschoenK, Carli ButtenschoenD, GruenerB, et al. Long‐term experience on surgical treatment of alveolar echinococcosis. Langenbecks Arch Surg. 2009;394 (4 ):689‐698.18651165\n33 Bresson‐HadniS, VuittonDA, BartholomotB, et al. A twenty‐year history ofalveolar echinococcosis: analysis of a series of 117 patients from eastern France. Eur J Gastroenterol Hepatol. 2000;12 (3 ):327‐336.10750654\n34 KorogluM, AkhanO, GelenMT, et al. Complete resolution of an alveolar echinococcosis liver lesion following percutaneous treatment. Cardiovasc Intervent Radiol. 2006;29 (3 ):473‐478.16228851\n\n",
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"title": "Dramatic response to albendazole in transplantation candidates with unresectable hepatic alveolar hydatid disease.",
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"abstract": "Marizomib, a natural marine product, is an irreversible proteasome inhibitor currently under investigation in relapsed-refractory multiple myeloma (RRMM) and malignant glioma. Central nervous system-multiple myeloma (CNS-MM) is a rare manifestation of extra-medullary disease with few therapeutic options, highlighting the unmet clinical need in these patients. Marizomib demonstrated encouraging activity in RRMM and has emerging clinical activity in glioma, making it a potential CNS-MM therapeutic intervention. Herein, we present two patients with RRMM and CNS involvement who benefited from marizomib-based therapy. These cases provide the first proof of principle for further exploring marizomib in CNS-MM patients.",
"affiliations": "M&S Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA.;M&S Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA.;Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.;M&S Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA.;Triphase Accelerator, San Diego, CA, USA.;Dana-Farber Cancer Institute, Boston, MA, USA.;Triphase Accelerator, San Diego, CA, USA.;Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.",
"authors": "Badros|Ashraf|A|;Singh|Zeba|Z|;Dhakal|Binod|B|;Kwok|Young|Y|;MacLaren|Ann|A|;Richardson|Paul|P|;Trikha|Mohit|M|;Hari|Parameswaran|P|",
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"journal": "British journal of haematology",
"keywords": "central nervous system relapse; clinical studies; marizomib; multiple myeloma",
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"mesh_terms": "D000328:Adult; D016543:Central Nervous System Neoplasms; D006801:Humans; D007783:Lactones; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011758:Pyrroles",
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"title": "Marizomib for central nervous system-multiple myeloma.",
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"abstract": "BACKGROUND\nAutoimmune pancreatitis (AIP) is a subset of inflammatory pancreatic disease, responsive to corticosteroid therapy. It is prone to being affected by diabetes mellitus, but the effectiveness of steroid therapy on pancreatic endocrine function is still controversial. We present a case of AIP, focusing on pancreatic endocrine function after steroid therapy.\n\n\nMETHODS\nThe patient was referred to our hospital with exacerbation of diabetic control and pancreatic swelling. By admission, the insulin secretory capacity was severely impaired. The patient was diagnosed with AIP and treated with prednisolone, resulting in marked improvement of the pancreatic swelling. Glycemic control worsened transiently after initiation of steroid therapy, but insulin requirements decreased along with tapering prednisolone dosage. Pancreatic cytology showed that the acinar structure had been destroyed, and the islets had disappeared. Insulin and glucagon immunostaining revealed slightly scattered alpha and beta cells within the fibrotic stroma. The patient notably showed improved pancreatic alpha cell function predominantly after steroid therapy, despite partial improvement of beta cell function.\n\n\nCONCLUSIONS\nAn imbalance between alpha and beta cell function may contribute to insufficient diabetic control in some patients with AIP. The pancreatic endocrine function test in combination with pancreatic cytology could be helpful when considering the treatment strategy for diabetic control in patients with AIP.",
"affiliations": "First Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.;First Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan. ariyasu@wakayama-med.ac.jp.;First Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.;First Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.;First Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.;First Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.;Department of Laboratory Medicine, Wakayama Medical University, Wakayama, Japan.;Department of Human Pathology, Wakayama Medical University, Wakayama, Japan.;Department of Human Pathology, Wakayama Medical University, Wakayama, Japan.;First Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.",
"authors": "Takeshima|Ken|K|;Ariyasu|Hiroyuki|H|http://orcid.org/0000-0002-9307-1275;Iwakura|Hiroshi|H|;Kawai|Shintaro|S|;Uraki|Shinsuke|S|;Inaba|Hidefumi|H|;Furuta|Machi|M|;Warigaya|Kenji|K|;Murata|Shin-Ichi|SI|;Akamizu|Takashi|T|",
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"doi": "10.1007/s13300-018-0434-0",
"fulltext": "\n==== Front\nDiabetes Ther\nDiabetes Ther\nDiabetes Therapy\n1869-6953\n1869-6961\nSpringer Healthcare Cheshire\n\n29725970\n434\n10.1007/s13300-018-0434-0\nCase Report\nPredominant Improvement of Alpha Cell Function after Steroid Therapy in a Patient with Autoimmune Pancreatitis: Case Report\nTakeshima Ken 1\nhttp://orcid.org/0000-0002-9307-1275\nAriyasu Hiroyuki ariyasu@wakayama-med.ac.jp\n\n1\nIwakura Hiroshi 1\nKawai Shintaro 1\nUraki Shinsuke 1\nInaba Hidefumi 1\nFuruta Machi 2\nWarigaya Kenji 3\nMurata Shin-ichi 3\nAkamizu Takashi 1\n1 0000 0004 1763 1087 grid.412857.d First Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan\n2 0000 0004 1763 1087 grid.412857.d Department of Laboratory Medicine, Wakayama Medical University, Wakayama, Japan\n3 0000 0004 1763 1087 grid.412857.d Department of Human Pathology, Wakayama Medical University, Wakayama, Japan\n3 5 2018\n3 5 2018\n6 2018\n9 3 13851395\n25 3 2018\n© The Author(s) 2018\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nIntroduction\n\nAutoimmune pancreatitis (AIP) is a subset of inflammatory pancreatic disease, responsive to corticosteroid therapy. It is prone to being affected by diabetes mellitus, but the effectiveness of steroid therapy on pancreatic endocrine function is still controversial. We present a case of AIP, focusing on pancreatic endocrine function after steroid therapy.\n\nCase Report\n\nThe patient was referred to our hospital with exacerbation of diabetic control and pancreatic swelling. By admission, the insulin secretory capacity was severely impaired. The patient was diagnosed with AIP and treated with prednisolone, resulting in marked improvement of the pancreatic swelling. Glycemic control worsened transiently after initiation of steroid therapy, but insulin requirements decreased along with tapering prednisolone dosage. Pancreatic cytology showed that the acinar structure had been destroyed, and the islets had disappeared. Insulin and glucagon immunostaining revealed slightly scattered alpha and beta cells within the fibrotic stroma. The patient notably showed improved pancreatic alpha cell function predominantly after steroid therapy, despite partial improvement of beta cell function.\n\nConclusion\n\nAn imbalance between alpha and beta cell function may contribute to insufficient diabetic control in some patients with AIP. The pancreatic endocrine function test in combination with pancreatic cytology could be helpful when considering the treatment strategy for diabetic control in patients with AIP.\n\nKeywords\n\nAlpha cell\nAutoimmune pancreatitis (AIP)\nDiabetes mellitus (DM)\nGlucagon\nIgG4-related disease (IgG4-RD)\nissue-copyright-statement© Springer Healthcare Ltd., part of Springer Nature 2018\n==== Body\nIntroduction\n\nAIP is a subset of inflammatory pancreatic disease, characterized by diffuse or focal pancreatic swelling responsive to corticosteroid therapy [1]. There are two types of AIP depending on pathologic features: lymphoplasmacytic sclerosing pancreatitis (type 1) and granulocytic epithelial lesions (type 2).\n\nImmunoglobulin G4-related disease (IgG4-RD) is a recently proposed clinical entity [2]. The condition is characterized by elevated serum IgG4 levels, IgG4-positive plasmacytes, and lymphocyte infiltration into multiple organs, resulting in tissue fibrosis and organ dysfunction. In addition to the pancreas, the lacrimal gland, salivary gland, thyroid gland, biliary duct, and retroperitoneal tissue can also be involved in this disease [3, 4]. Type 1 AIP is considered a pancreatic manifestation of IgG4-RD [5].\n\nApproximately 40–80% of AIP is reported to be associated with diabetes mellitus [6–9]. Although improvement of insulin secretion has been reported [10–12], contrarily, worsening of insulin resistance after steroid therapy has also been reported [6]. Thus, the effectiveness of corticosteroids in pancreatic endocrine function remains controversial. The function of beta cells has been examined, but alpha cell function has never been evaluated before and after steroid therapy in AIP.\n\nTo the best of our knowledge, this is the first report of AIP with predominant improvement of alpha cell function after steroid therapy; it suggests that an imbalance between alpha and beta cell functions contributes to insufficient diabetic control in some patients with AIP. Pancreatic endocrine function tests in combination with pancreatic cytology could be helpful for the treatment of diabetes mellitus in AIP.\n\nCase Report\n\nA 73-year-old male was referred to our hospital with worsening diabetes mellitus and pancreatic swelling. He had a history of hypertension, brain infarction, and atrial fibrillation. His son also has diabetes mellitus. He had been diagnosed with type 2 diabetes mellitus 30 years previously and treated with oral hypoglycemic agents. His diabetes has been well controlled with HbA1c levels between 6 and 7%. The patient has non-proliferative diabetic retinopathy, but no diabetic nephropathy or neuropathy. He had lost his appetite 7 months before referral and lost 10 kg bodyweight over 6 months. Diabetic control had worsened 3 months prior with HbA1c levels of 12.6%, and insulin therapy was started by his family physician. To control for malignancy, computed tomography (CT) was performed, showing diffuse swelling of the pancreas.\n\nOn admission, the patient’s general condition was fair, and he had no abdominal or back pain. The body mass index (BMI) was 19.6 kg/m2 and blood pressure was 121/80 mmHg. He was hospitalized in our department, and basal-bolus insulin therapy was initiated under a 1700-kcal/day diet calculated by BMI (28.7 kcal/kg). Pre-prandial blood glucose levels fluctuated severely between 50 and 300 mg/dl, and 12 units/day of human insulin was needed to maintain blood glucose. Blood tests showed insufficient insulin secretion: fasting plasma blood glucose, 141 mg/dl; plasma C-peptide (CPR), 0.14 ng/ml; CPR index (CPI), 0.14; urinary CPR, 4.1 μg/day (Table 1).Table 1 Laboratory data on admission\n\nUrinalysis\t\n Protein\t(–)\t\t\t\n Glucose\t(–)\t\t\t\n Occult blood\t(–)\t\t\t\n Ketone\t(–)\t\t\t\n\t\t\tReference range\t\nHematology\t\n White blood cells\t6070\t/ml\t(3500–9800)\t\n Red blood cells\t448 × 104\t/ml\t(420–550)\t\n Hemoglobin\t13.2\tg/dl\t(13.5–17.5)\t\n Platelets\t17.9 × 104\t/ml\t(13–37)\t\nBlood chemistry\t\n Total protein\t6.5\tg/dl\t(6.7–8.1)\t\n Albumin\t3.5\tg/dl\t(3.9–4.9)\t\n Immunoglobulin G\t1704\tmg/dl\t(870–1700)\t\n Immunoglobulin G4\t539\tmg/dl\t(5–117)\t\n Aspartate aminotransferase\t20\tIU/l\t(7–38)\t\n Alanine aminotransferase\t21\tIU/l\t(4–44)\t\n Lactate dehydrogenase\t192\tIU/l\t(124–222)\t\n Alkaline phosphatase\t131\tIU/l\t(106–322)\t\n γ-Glutamyltranspeptidase\t15\tIU/l\t(13–64)\t\n Amylase\t105\tIU/l\t(44–132)\t\n Pancreatic amylase\t9\tIU/l\t(18–53)\t\n Lipase\t31\tIU/l\t(13–49)\t\n Elastase-1\t< 80\tIU/l\t(0–300)\t\n Cholinesterase\t193\tIU/l\t(240–496)\t\n Creatine kinase\t62\tIU/l\t(60–290)\t\n Blood urea nitrogen\t20.0\tmg/dl\t(8–20)\t\n Creatinine\t0.99\tmg/dl\t(0.53–1.02)\t\n Sodium\t142\tmEq/l\t(135–145)\t\n Potassium\t3.8\tmEq/l\t(3.5–5)\t\n Chloride\t108\tmEq/l\t(98–107)\t\n Total cholesterol\t131\tmg/dl\t(130–219)\t\n Triglyceride\t44\tmg/dl\t(30–150)\t\n Fasting plasma glucose\t141\tmg/dl\t(70–109)\t\n HbA1c (NGSP)\t10.0\t%\t(4.9–6.0)\t\n C-peptide reactivity\t0.20\tng/ml\t(1.1–3.3)\t\n GADAb\t< 5.0\tU/ml\t(< 5.0)\t\n CA19-9\t71.5\tU/ml\t(≤ 37)\t\n Span-1\t41.2\tU/ml\t(0–30)\t\n DUPAN-2\t109\tU/ml\t(0–150)\t\nUrinary chemistry\t\n Creatine\t723\tmg/day\t(500–1500)\t\n Sodium\t58\tmEq/day\t(70–250)\t\n Potassium\t29\tmEq/day\t(25–100)\t\n Chloride\t64\tmEq/day\t(70–250)\t\n Urinary C-peptide reactivity\t4.1\tμg/day\t(50–1300)\t\nNGSP National Glycohemoglobin Standardization Program, GADAb anti-GAD antibody\n\nAbdominal ultrasonography and contrast-enhanced CT imaging showed diffuse swelling of the pancreas and a capsule-like rim around the pancreas, both imaging features typical of AIP (Fig. 1a, b). Magnetic resonance cholangiopancreatography (MRCP) revealed diffuse irregular narrowing of the main pancreatic duct (Fig. 1c, d). 18F-FDG PET/CT showed diffuse tracer uptake (SUVmax, 3.22) in the pancreas (Fig. 1e, f). No FDG uptake in extra-pancreatic organs, such as the salivary glands or retroperitoneum, was confirmed.Fig. 1 Imaging findings on admission. Abdominal ultrasonography and the contrast-enhanced CT scan showed diffuse swelling of the pancreas with effacement of the lobular contour (a, b). MRI revealed diffuse irregular narrowing of the main pancreatic duct and intra-pancreatic bile duct (c, d). 18F-FDG PET/CT showed diffuse tracer uptake in the pancreas with SUVmax of 3.22 (e, f)\n\nEndoscopic-ultrasound-guided fine-needle aspiration (EUS-FNA) was performed to differentiate the pancreatic cancer. Pancreatic cytology revealed remarkable lymphoplasmacytic infiltration and fibrosis, a severely destroyed acinar structure, and absence of islets; however, there was no evidence of malignancy (Fig. 2a). IgG4 immunostaining revealed the presence of IgG4-positive plasma cells (Fig. 2b). The total number of IgG4-positive plasma cells was 33/HPF, and the IgG4/CD138 ratio was 82.5%. The anti-CD138 antibody was used to count plasma cells instead of the anti-IgG antibody [13].Fig. 2 Endoscopic-ultrasound-guided fine-needle aspiration (EUS-FNA) cytology features of the pancreas. Hematoxylin and eosin staining of the pancreas showed remarkable lymphoplasmacytic infiltration and fibrosis (a). The pancreatic acinar structure had been destroyed, and islets were absent. IgG4 immunostaining revealed the presence of IgG4-positive plasma cells (b). The total number of IgG4-positive plasma cells was 33/HPF, and the IgG4/CD138 ratio was 82.5%. Insulin (c) and glucagon (d) immunostaining revealed slightly scattered β- and α-cells within the fibrotic stroma. Filled downward triangles indicate positive cells for each immunostaining\n\nThus, we diagnosed our patient with type 1 AIP [3, 14]. He was initially treated with prednisolone 35 mg/day (0.6 mg/kg), which was tapered by 5 mg/day every 2 weeks according to the international consensus for the treatment of AIP (Fig. 3) [15]. Pancreatic morphology was reevaluated with abdominal ultrasonography and CT scan after 12 weeks of prednisolone treatment, which showed marked improvement of the pancreatic swelling and capsule-like rim around the pancreas (Fig. 3). Prednisolone was tapered to 15 mg/day over 12 weeks without recurrence.Fig. 3 Diabetic control and clinical course of AIP during steroid therapy. Mean daily pre-prandial blood glucose (closed circle), serum IgG4 levels (closed square), and HbA1c levels (red bar) were measured during treatment with prednisolone. Glycemic control worsened transiently after initiation of steroid therapy; however, it improved as prednisolone was tapered. After 12 weeks of steroid therapy, CT imaging showed marked improvement of the pancreatic swelling. Serum IgG4 levels also decreased without a relapse of AIP\n\nPancreatic endocrine and exocrine function was evaluated before and after 4 weeks of steroid therapy under adequate glycemic control. Considering the daily variance of blood glucose, we measured fasting plasma glucose (FPG) and C-peptide immunoreactivity (CPR) for several days, shown in the scatterplot; the gradient of the regression line increased after 4 weeks of steroid therapy (Fig. 4a). The CPR index also increased significantly (Fig. 4b; p = 0.016, Student's t test, Excel statistics), and the meal tolerance test showed improvement of the change in CPR (ΔCPR) (Fig. 4c). No recovery of the CPR secretory response was shown by 75 g OGTT, but the area under the curve (AUC)-CPR increased (Fig. 4d, e). These results suggested partial recovery of beta cell function due to steroid therapy.Fig. 4 Pancreatic endocrine function compared before and after steroid therapy. The gradient of the regression line between FPG and CPR (a), the CPR index (b), and ΔCPR in the meal tolerance test (c) improved after 4 weeks of steroid therapy. Recovery of the CPR secretory response was not shown by 75 g OGTT, but the area under the curve (AUC)-CPR improved after steroid therapy (d, e). ATT showed remarkable improvement of glucagon secretion, which was measured using both conventional radioimmunoassay (f) and the sandwich ELISA kit (g)\n\nAn arginine tolerance test (ATT) was also performed to evaluate alpha cell function. Over 30 min, 30 g l-arginine hydrochloride was administered, and plasma glucagon levels were measured at 0, 10, 20, 30, 45, 60, and 90 min. Plasma glucagon levels were analyzed using both the conventional Glucagon RIA Kit (R-M; Millipore, Billerica, MA) and E-M sandwich ELISA kit (E-M; Mercodia Glucagon ELISA, Uppsala, Sweden). The plasma glucagon response was low and delayed before treatment; it improved remarkably, however, after 4 weeks of steroid therapy (Fig. 4f, g).\n\nFor further assessment of pancreatic islet damage, immunostaining of insulin and glucagon in pancreatic cytology specimens was added; a few beta and alpha cells were scattered within the fibrotic stroma without intact islet structures (Fig. 2c, d).\n\nRegarding pancreatic exocrine function, pancreatic enzyme levels were low on admission (Table 1). In addition, an N-benzoyl-l-tyrosyl-P-aminobenzoic acid (BT-PABA) test was performed before and again 4 weeks after steroid therapy; the excretion rate of p-aminobenzoic acid (PABA) was 23.1% and 22.4%, respectively (reference value: 73.4–90.4%). Suggesting no improvement of pancreatic exocrine insufficiency, the patient was administered pancrelipase 1350 mg/day to treat malabsorption.\n\nThe patient needed a maximum insulin dose of 32 units/day after initiating steroid therapy, but the dose was decreased to 21 units/day after prednisolone had been tapered to 15 mg/day with an HbA1c level of 6.7%. Insulin requirements are expected to decline along with prednisolone tapering.\n\nAll procedures reported here were in accordance with the ethical standards of the Wakayama Medical University Hospital Ethics Committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all subjects in the case report included in the study.\n\nDiscussion\n\nOur patient was being treated for diabetes mellitus and newly diagnosed with AIP when diabetic control worsened. In previous reports, approximately 30–40% of AIP patients with diabetes mellitus had a history of diabetic treatment before AIP onset [6, 16]. Importantly, the worsening of diabetic control can lead to an AIP diagnosis.\n\nTanaka et al. first reported recovery of pancreatic endocrine function in AIP [10]. They assessed beta cell function before and after steroid therapy using 75 g OGTT and reported that the insulin response improved after steroid therapy. Approximately 13% of AIP patients had improved glucose tolerance after steroid therapy [12]. In this report, patients with a low insulin secretory capacity before treatment could not be freed from insulin after steroid therapy.\n\nOur patient showed severe destruction of the insulin secretory capacity on admission. Although endocrine function tests revealed partial recovery of beta cell function after 4 weeks of steroid therapy, it was not enough to stop insulin therapy. This outcome is consistent with a previous report [12].\n\nATT is one of the tests to assess alpha cell function via measurement of the glucagon secretory capacity [17]. In diabetic patients, glucagon hypersecretion after arginine administration has been reported [18]. Our patient had had long-standing diabetes before the occurrence of AIP, so some of the changes in alpha and beta cell function and pancreatic cytology could be attributed to that. Alpha cell function, however, had been destroyed at the onset of AIP, which is more characteristic of AIP than diabetes mellitus [19].\n\nThe patient notably showed remarkable improvement in the glucagon response to arginine just 4 weeks after starting steroid therapy, so the changes in pancreatic endocrine conditions could be mainly attributed to AIP. As far as we know, the recovery of alpha cell function has never been reported in AIP.\n\nThis implies that alpha cell function is more likely to improve than beta cell function. An imbalance between alpha and beta cell function could therefore occur, which may contribute to insufficient diabetic control. Glucagon inhibitory agents could be a potential treatment option in some patients with AIP; however, studies of more patients are needed to confirm these findings.\n\nIn our patient, blood glucose had fluctuated severely with insulin therapy before admission; he had hypoglycemic episodes and needed to take glucose tablets. After starting treatment with PSL, the number of hypoglycemic events decreased, which contributed to the improvement of glycemic control. Recovery of alpha cell function could help avoid hypoglycemic events. Also, partial recovery of insulin secretion might contribute to stabilization of blood glucose.\n\nIn Japan, radioimmunoassay kits have been used to measure glucagon. This conventional kit uses a polyclonal antibody recognizing the C-terminal region of glucagon, which could cross-react with the glucagon-like peptides secreted by the intestine. Recently, a more pancreatic glucagon-specific sandwich ELISA kit (Mercodia Glucagon ELISA) became available in our country, so we used it to reanalyze the plasma glucagon levels [18]. Both kits showed marked improvement of glucagon secretion after steroid therapy (Fig. 4f, g).\n\nPancreatic pathology of type 1 AIP is characterized by remarkable fibrosis and inflammatory cell infiltration surrounding acinar and ductal cells [20]. Although some islets are infiltrated with mononuclear cells with disruption, the majority of islets are reportedly preserved [10]. In addition, beta cell volume decreases in AIP compared with diabetic patients, but the alpha cell volume is the same as that of diabetic patients [21].\n\nIn our patient, the pancreatic cytology features as well as endocrine function tests suggested severe destruction of the islets. This result can explain why our patient is still in an insulin-dependent state after treatment with steroid therapy. We judged that the pancreatic cytology specimen had sufficient volume to evaluate the islet structure in our patient, but the limitations of the EUS-FNA specimen, such as sample quality and technical errors, should be considered.\n\nAnother possible factor affecting pancreatic endocrine function is cytokines. In patients with IgG4-RD, inflammatory cells infiltrate organs, resulting in enlargement of the organs and fibrosis. The cytokine profile is type 2 helper T (Th2)-predominate, which activates eosinophilia, IgG4 and IgE production, and fibrosis [2]. Regarding the association of cytokines and insulin secretion, focal or systemic inflammatory cytokines cause beta cell dysfunction [22]. Although the association between cytokines and pancreatic endocrine dysfunction in AIP is reported, further evaluation is needed [10]. Unfortunately, in our patient, cytokine levels were not assessed.\n\nGlucose intolerance in AIP is complicated by multiple factors, including the degree of pancreatic islet damage, cytokines, the balance between alpha and beta cell function, and corticosteroid-induced insulin resistance. Prediction of the recovery of pancreatic endocrine function before steroid therapy in patients with AIP is an issue for future study.\n\nConclusion\n\nWe report AIP with predominant improvement of alpha cell function after steroid therapy. This result suggests an imbalance between alpha and beta cell function contributing to insufficient diabetic control in AIP after steroid therapy. Pancreatic endocrine function tests in combination with pancreatic cytology could be helpful in determining an adequate treatment strategy for diabetes mellitus associated with AIP.\n\nAcknowledgements\n\nThe authors are grateful to the patient for his kind contribution to this report.\n\nFunding\n\nNo funding or sponsorship was received for this study or publication of this article. The article processing charges were funded by the authors.\n\nEditorial Assistance\n\nWe also thank Dr. Yuta Ishiyama and Yuina Akagi for helping with our clinical practice and Benjamin Phillis from Wakayama Medical University for assistance with the English language editing.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nDisclosures\n\nKen Takeshima, Hiroyuki Ariyasu, Hiroshi Iwakura, Shintaro Kawai, Shinsuke Uraki, Hidefumi Inaba, Machi Furuta, Kenji Warigaya, Shin-ichi Murata, and Takashi Akamizu have nothing to declare.\n\nCompliance with Ethics Guidelines\n\nAll procedures reported here were in accordance with the ethical standards of the Wakayama Medical University Hospital Ethics Committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all the subject of the case report included in the study.\n\nData Availability\n\nData sharing is not applicable to this article, as no data sets were generated or analyzed during the current study.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced digital features\n\nTo view enhanced digital features for this article go to 10.6084/m9.figshare.6148916.\n==== Refs\nReferences\n\n1. Shimosegawa T Chari ST Frulloni L International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association Pancreatology Pancreas 2011 40 352 358 10.1097/MPA.0b013e3182142fd2 21412117\n2. Stone JH Zen Y Deshpande V IgG4-related disease N Engl J Med 2012 366 539 551 10.1056/NEJMra1104650 22316447\n3. Umehara H Okazaki K Masaki Y Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011 Mod Rheumatol 2012 22 21 30 10.3109/s10165-011-0571-z 22218969\n4. Takeshima K Inaba H Ariyasu H Clinicopathological features of Riedel’s thyroiditis associated with IgG4-related disease in Japan Endocr J 2015 62 725 731 10.1507/endocrj.EJ15-0175 26052139\n5. Hamano H Kawa S Horiuchi A High serum IgG4 concentrations in patients with sclerosing pancreatitis N Engl J Med 2001 344 732 738 10.1056/NEJM200103083441005 11236777\n6. Nishimori I Tamakoshi A Kawa S Influence of steroid therapy on the course of diabetes mellitus in patients with autoimmune pancreatitis: findings from a nationwide survey in Japan. Research Committee on Intractable Pancreatic Diseases, the Ministry of Health and Welfare of Japan Pancreas 2006 32 244 248 10.1097/01.mpa.0000202950.02988.07 16628078\n7. Nishino T Toki F Oyama H Shimizu K Shiratori K Long-term outcome of autoimmune pancreatitis after oral prednisolone therapy Intern Med 2006 45 497 501 10.2169/internalmedicine.45.1565 16702740\n8. Maire F Le Baleur Y Rebours V Outcome of patients with type 1 or 2 autoimmune pancreatitis Am J Gastroenterol 2011 106 151 156 10.1038/ajg.2010.314 20736934\n9. Miyamoto Y Kamisawa T Tabata T Short and long-term outcomes of diabetes mellitus in patients with autoimmune pancreatitis after steroid therapy Gut Liver 2012 6 4 501 504 10.5009/gnl.2012.6.4.501 23170157\n10. Tanaka S Kobayashi T Nakanishi K Corticosteroid-responsive diabetes mellitus associated with autoimmune pancreatitis Lancet 2000 356 910 911 10.1016/S0140-6736(00)02684-2 11036899\n11. Ketikoglou IG Elefsiniotis IS Vezali EV Moulakakis AM Diabetes mellitus responsive to corticosteroids in autoimmune pancreatitis J Clin Gastroenterol 2004 38 910 10.1097/00004836-200411000-00016\n12. Hirano K Isogawa A Tada M Long-term prognosis of autoimmune pancreatitis in terms of glucose tolerance Pancreas 2012 41 691 695 10.1097/MPA.0b013e31823b67b1 22249131\n13. Mizushima I Yamada K Harada K Diagnostic sensitivity of cutoff values of IgG4-positive plasma cell number and IgG4-positive/CD138-positive cell ratio in typical multiple lesions of patients with IgG4-related disease Mod Rheumatol 2017 10.1080/14397595.2017.1332540 28880691\n14. Okazaki K Kawa S Kamisawa T Japanese clinical guidelines for autoimmune pancreatitis Pancreas 2009 38 849 866 10.1097/MPA.0b013e3181b9ee1c 19745774\n15. Okazaki K Chari ST Frulloni L International consensus for the treatment of autoimmune pancreatitis Pancreatology 2017 17 1 6 10.1016/j.pan.2016.12.003 28027896\n16. Miyazawa M Takatori H Shimakami T Prognosis of type 1 autoimmune pancreatitis after corticosteroid therapy-induced remission in terms of relapse and diabetes mellitus PLoS One 2017 10.1371/journal.pone.0188549 29166415\n17. Unger RH Aguilar-Parada E Müller WA Eisentraut AM Studies of pancreatic alpha cell function in normal and diabetic subjects J Clin Invest 1970 49 837 848 10.1172/JCI106297 4986215\n18. Matsuo T Miyagawa J Kusunoki Y Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzyme-linked immunosorbent assay J Diabetes Investig 2016 7 324 331 10.1111/jdi.12400\n19. Ito T Kawabe K Arita Y Hisano T Evaluation of pancreatic endocrine and exocrine function in patients with autoimmune pancreatitis Pancreas 2007 34 254 259 10.1097/01.mpa.0000250127.18908.38 17312466\n20. Farris AB 3rd Lauwers GY Deshpande V Autoimmune pancreatitis-related diabetes: quantitative analysis of endocrine islet cells and inflammatory infiltrate Virchows Arch 2010 457 329 336 10.1007/s00428-010-0948-y 20632032\n21. Tanaka S Kobayashi T Nakanishi K Evidence of primary beta-cell destruction by T-cells and beta-cell differentiation from pancreatic ductal cells in diabetes associated with active autoimmune chronic pancreatitis Diabetes Care 2001 24 1661 1667 10.2337/diacare.24.9.1661 11522716\n22. Rabinovitch A An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus Diabetes Metab Rev 1998 14 129 151 10.1002/(SICI)1099-0895(199806)14:2<129::AID-DMR208>3.0.CO;2-V 9679667\n\n",
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"journal": "Diabetes therapy : research, treatment and education of diabetes and related disorders",
"keywords": "Alpha cell; Autoimmune pancreatitis (AIP); Diabetes mellitus (DM); Glucagon; IgG4-related disease (IgG4-RD)",
"medline_ta": "Diabetes Ther",
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"title": "Predominant Improvement of Alpha Cell Function after Steroid Therapy in a Patient with Autoimmune Pancreatitis: Case Report.",
"title_normalized": "predominant improvement of alpha cell function after steroid therapy in a patient with autoimmune pancreatitis case report"
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"abstract": "Leclercia adecarboxylata, a ubiquitous Gram-negative bacillus, is generally viewed as an opportunistic pathogen because it is rarely cultured from clinical samples. Although rare, bacteremia due to L. adecarboxylata tends to occur in immunocompromised hosts and patients with systemic comorbidities. Only one case of bacteremia due to L. adecarboxylata has been reported in a previously healthy patient. We describe a male patient with an active peptic ulcer who developed L. adecarboxylata bacteremia after a long-term use of nonsteroidal anti-inflammatory drugs. The abdomen is believed to have been the most probable portal of entry. After appropriate medical management, the patient recovered without sequela.",
"affiliations": "Department of Emergency Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.;Division of Infectious Diseases, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.;Department of Pulmonary and Critical Care Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.;Department of Emergency Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.;Department of Emergency and Critical Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.;Departments of Emergency and Critical Care Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.;Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: hsporen@ntu.edu.tw.",
"authors": "Jean|Shio-Shin|SS|;Lee|Wen-Sen|WS|;Bai|Kuan-Jen|KJ|;Lam|Carlos|C|;Hsu|Chin-Wang|CW|;Chen|Ray-Jade|RJ|;Hsueh|Po-Ren|PR|",
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"issue": "49(3)",
"journal": "Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi",
"keywords": "Bacteremia; Immunocompetent; Leclercia adecarboxylata; Nonsteroidal anti-inflammatory drugs; Peptic ulcer",
"medline_ta": "J Microbiol Immunol Infect",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016470:Bacteremia; D004755:Enterobacteriaceae; D004756:Enterobacteriaceae Infections; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D010437:Peptic Ulcer",
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"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Leclercia adecarboxylata bacteremia in a patient with long-term use of nonsteroidal anti-inflammatory drugs.",
"title_normalized": "leclercia adecarboxylata bacteremia in a patient with long term use of nonsteroidal anti inflammatory drugs"
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"abstract": "A 65-year-old female with diabetes mellitus but otherwise good health in the past suffered from cough with occasional blood-stained sputum during initial presentation. The patient was diagnosed with pulmonary poorly differentiated adenocarcinoma with an epidermal growth factor receptor (EGFR) exon 19 deletion and hence received afatinib therapy for 25 months without obvious adverse events except for a grade 1-2 acneiform rash. The disease was stabilized after subsequent cycles of chemotherapy with pemetrexed and carboplatin followed by maintenance pemetrexed. The patient was rechallenged with afatinib treatment as a named-patient drug in July 2014 (after approval) and later received afatinib in combination with palliative radiation. A blood test confirmed the presence of the T790M mutation and the patient was on osimertinib as part of a compassionate use program. The patient experienced good drug tolerance and eventually had a significant drop in tumor marker levels. This case provides insight into the use of afatinib in first-line setting of EGFR-mutated lung cancer.",
"affiliations": "Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.",
"authors": "Lee|Victor H F|VHF|",
"chemical_list": "D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077716:Afatinib; D066246:ErbB Receptors",
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"issue": "14 Suppl 1()",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "afatinib; epidermal growth factor receptor; lung adenocarcinoma",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000077716:Afatinib; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009154:Mutation; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents",
"nlm_unique_id": "101241430",
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"pages": "4-6",
"pmc": null,
"pmid": "29508939",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case sharing of a patient re-challenged with afatinib for EGFR-mutated advanced non-small cell lung cancer.",
"title_normalized": "case sharing of a patient re challenged with afatinib for egfr mutated advanced non small cell lung cancer"
} | [
{
"companynumb": "HK-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-170153",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
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{
"abstract": "Treatment of erectile dysfunction after radical prostatectomy includes intracavernous Caverject injections. We present the case of recurrent transient global amnesia in a man performing self-administration of Caverject after robotic radical prostatectomy. The correlation between the intracavernous injection and the neurological phenomenon was repeated and evident, yet the specific aetiology of transient global amnesia remains uncertain.",
"affiliations": "Humanitas University, Pieve Emanuele, MI, Italy.;Humanitas University, Pieve Emanuele, MI, Italy.;Humanitas Mater Domini, Castellanza, VA, Italy.;Humanitas Mater Domini, Castellanza, VA, Italy.;Humanitas Mater Domini, Castellanza, VA, Italy.;Humanitas University, Pieve Emanuele, MI, Italy.",
"authors": "Maffei|D|D|;Grizzi|F|F|;Zanoni|M|M|;Vota|P|P|;Justich|M|M|;Taverna|G|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2020.101184",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30072-3\n10.1016/j.eucr.2020.101184\n101184\nFunctional Medicine\nRecurrent transient global amnesia after intracavernous Caverject injection in erectile dysfunction after robotic prostatectomy\nMaffei D. a Grizzi F. a Zanoni M. b Vota P. b Justich M. b Taverna G. gianluigi.taverna@humanitas.itab∗1 a Humanitas University, Pieve Emanuele, MI, Italy\nb Humanitas Mater Domini, Castellanza, VA, Italy\n∗ Corresponding author. Humanitas University, Pieve Emanuele, MI, Italy. gianluigi.taverna@humanitas.it1 Present address: Istituto Clinico Humanitas, via Manzoni 56, Rozzano (MI), Italy.\n\n\n02 4 2020 \n7 2020 \n02 4 2020 \n31 10118419 3 2020 26 3 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/).Treatment of erectile dysfunction after radical prostatectomy includes intracavernous Caverject injections. We present the case of recurrent transient global amnesia in a man performing self-administration of Caverject after robotic radical prostatectomy. The correlation between the intracavernous injection and the neurological phenomenon was repeated and evident, yet the specific aetiology of transient global amnesia remains uncertain.\n\nKeywords\nTransient global amnesiaCaverject injectionErectile dysfunctionRobotic prostatectomyAbbreviations\nTGA, Transient Global IschemiaED, Erectile dysfunction\n==== Body\nIntroduction\nErectile dysfunction (ED) is a well-known complication following robotic radical prostatectomy (RARP)1 and intracavernous injections of Caverject remains one of the pharmacologic standard treatments.2\n\nTransient global amnesia (TGA) is a rare and frightening condition whose underlying pathophysiological basis has not been understood, yet it most commonly remains an isolated event. Some authors have postulated it may be related to cerebral vein thrombosis and epileptic events. Several inciting factors have been reported, such as pain, anxiety, exercise, which have been hypothesized to be connected by a Valsalva maneuver.3\n\nWe would like to report on a case of recurrent transient global amnesia as an adverse drug reaction in a patient performing Caverject injections after RARP.\n\nCase presentation\nA 66-year-old male, EM, underwent RARP at our institution in 2016 for treatment of localized prostate cancer. Since surgery, no evidence of recurrence has been observed. His medical history includes right bundle branch block and his medications are limited to aspirin for primary prevention. No drug allergies reported.\n\nTreatment of ED following RARP in this patient consisted in oral PDE5 inhibitors and, upon therapeutic failure, intracavernous injections of Caverject, first at 10mg and then 20mg. The patient would perform 2–4 injections per month, generally obtaining sufficient erection for successful penetrative intercourse.\n\nIn March 2019, the patient experienced an episode of transient global transient amnesia which occurred during a sexual intercourse with his wife aided by an intracavernous injection with Caverjet 20mg. As the partner recalls, the patient performed the injection mid-afternoon with satisfactory results in terms of erection, being able to complete a satisfactory intercourse. About 2 hours after the drug administration, the patient became confused, paranoid and was not able to recall recent events or his whereabouts, while continuously repeating the same questions to his partner. The patient remained alert and had insight of the episode, while not being able to calm down nor reply to his wife's questions about events happened in the last few weeks to months.\n\nAfter a period of 4 hours from the injection, the patient started recovering, and he regained full memory of previous recent events within 24h. The patient was however unable to remember anything occurring during the first 4 hours following the Caverject injection.\n\nEM was subjected to a cardiological and neurological check up, including 24h Holter Blood-pressure monitoring, Elettroencephalography, Brain MRI and coronarography, which excluded organic causes of the event.\n\nAfter a period of abstinence from sexual activity and Caverject use, the patient started performing Caverject injections in August 2019. On 23rd Jan 2020, after about having performed 20 Caverject self-administrations, EM experienced a second analogous episode of TGA. The patient has not performed any more administration.\n\nDiscussion\nTGA represents an important and worrisome clinical phenomenon, that may results in socially dangerous events. The case we have hereby reported highlights a repeated correlation between the administration of Caverject, the singular therapeutic efficacy of such administrations and the appearance of TGA, managed thanks to the presence of the patient's partner. As far as we are concerned, we cannot establish whether the cause lies in the drug administered or the sexual vigor allowed by the particularly efficacious response to therapy at the time. During other Caverject self-administrations, the patient's erectile response had resulted similarly valid without the appearance of the neurologic phenomenon. In any case, being unable to foresee precisely the response to treatment, which varies from administration to administration, we have endorsed the patient's decision to interrupt the pharmacoprotesis.\n\nConclusions\nIn conclusion, recurrent episodes of TGA have been observed after intracavernous Carverject injections. It is yet to be understood whether the inciting cause is secondary to the active principle (Alprostadil), any of the eccipients or episodic sexual vigor.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.\n==== Refs\nReferences\n1 Shabataev V. Saadat S.H. Eletrman D.S. Management of erectile dysfunction and LUTS/incontinence: the two most common, long-term side effects of prostate cancer treatment Can J Urol 27 1S1 2020 Feb 17 24 32101696 \n2 Philippou Y.A. Jung J.H. Steggall M.J. Penile rehabilitation for postprostatectomy erectile dysfunction Cochrane Database Syst Rev 10 2018 Oct 23 CD012414 30352488 \n3 Tynas R. Panegyres P.K. Factors determining recurrence in transient global ischemia BMC Neurol 2020 1 2020 Mar 6 83\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "31()",
"journal": "Urology case reports",
"keywords": "Caverject injection; ED, Erectile dysfunction; Erectile dysfunction; Robotic prostatectomy; TGA, Transient Global Ischemia; Transient global amnesia",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101184",
"pmc": null,
"pmid": "32280597",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports",
"references": "30352488;32101696;32143587",
"title": "Recurrent transient global amnesia after intracavernous Caverject injection in erectile dysfunction after robotic prostatectomy.",
"title_normalized": "recurrent transient global amnesia after intracavernous caverject injection in erectile dysfunction after robotic prostatectomy"
} | [
{
"companynumb": "IT-PFIZER INC-2020157719",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALPROSTADIL"
},
"drugadditional": "1",
... |
{
"abstract": "The American College of Chest Physicians and American Hepato-Pancreato-Biliary Association recommend using low-molecular-weight heparin for 28 days postoperatively for venous thromboembolism prophylaxis after cancer surgery. Dabigatran is a once daily oral anticoagulant that is FDA approved for venous thromboembolism prophylaxis after orthopedic surgery, uses fixed dosing, and has an antidote.\n\n\n\nPatients undergoing surgery for malignant pancreatic tumors (neuroendocrine excluded) from January 2017 to January 2018 were converted to dabigatran 220 mg daily on discharge until postoperative day 28; patients with medical or insurance contraindications were converted to enoxaparin or another direct oral anticoagulant. The primary endpoint was bleeding complications through 90 days.\n\n\n\nA total of 134 patients were considered for this study (median age 67 ± 10; 58.9% male). Eighty-seven (82.9%) patients received dabigatran and 18 (17.1%) received another form of anticoagulation. There were 19 (4.2%) patients not prescribed dabigatran due to medical or inpatient contraindications. Four patients experienced bleeding complications after discharge while on dabigatran. Two (2%) were major bleeds (Clavien-Dindo IV and V), and 2 (2%) were minor (Clavien-Dindo I). Patient compliance was excellent, with 93% of prescribed patients fully completing their prophylaxis. There were 2 patients that developed symptomatic deep vein thrombosis.\n\n\n\nThe use of a direct oral anticoagulant as extended venous thromboembolism prophylaxis after major gastrointestinal surgery has not been studied to date. These results show dabigatran to be a safe alternative to low-molecular-weight heparin for extended venous thromboembolism prophylaxis with regard to bleeding complications.",
"affiliations": "Division of Gastrointestinal & Endocrine Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Ave - 8th Floor, New York, NY, 10032, USA.;Division of Gastrointestinal & Endocrine Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Ave - 8th Floor, New York, NY, 10032, USA.;Division of Gastrointestinal & Endocrine Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Ave - 8th Floor, New York, NY, 10032, USA.;Division of Gastrointestinal & Endocrine Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Ave - 8th Floor, New York, NY, 10032, USA.;Division of Gastrointestinal & Endocrine Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Ave - 8th Floor, New York, NY, 10032, USA.;Division of Gastrointestinal & Endocrine Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Ave - 8th Floor, New York, NY, 10032, USA.;Division of Gastrointestinal & Endocrine Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Ave - 8th Floor, New York, NY, 10032, USA. mk2462@cumc.columbia.edu.",
"authors": "Rashid|M Farzan|MF|;Jackson|Terri L|TL|;Morgan|Jheanell A|JA|;Dwyer|Franklin A|FA|;Schrope|Beth A|BA|;Chabot|John A|JA|;Kluger|Michael D|MD|0000-0003-4311-078X",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1007/s11605-018-3936-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1091-255X",
"issue": "23(6)",
"journal": "Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract",
"keywords": "Dabigatran; Pancreas; Postoperative hemorrhage; Quality improvement; Surgical oncology; Venous thromboembolism",
"medline_ta": "J Gastrointest Surg",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000991:Antithrombins; D000069604:Dabigatran; D005260:Female; D006801:Humans; D008297:Male; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D011183:Postoperative Complications; D016896:Treatment Outcome; D054556:Venous Thromboembolism",
"nlm_unique_id": "9706084",
"other_id": null,
"pages": "1166-1171",
"pmc": null,
"pmid": "30187331",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "10535437;10737280;11919306;12393647;15925818;16371741;16881934;18574271;19572068;19919878;20333493;21155702;21691924;22186771;22762398;22859911;23146958;23313542;23594983;24608305;24687760;24888461;25202884;25908111;26489742;26567148;27688212;28366422;29231094",
"title": "Dabigatran (Pradaxa) Is Safe for Extended Venous Thromboembolism Prophylaxis After Surgery for Pancreatic Cancer.",
"title_normalized": "dabigatran pradaxa is safe for extended venous thromboembolism prophylaxis after surgery for pancreatic cancer"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-045201",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "A 62-year-old woman who was treated with daratumumab, bortezomib and dexamethasone for multiple myeloma, developed a skin tumor on her back. Histologic examination of a biopsy from the nodule revealed cutaneous plasmacytoma. Secondary plasmacytoma is an indicator of poor prognosis.",
"affiliations": "Maasstad Ziekenhuis, Rotterdam. Afd. Interne Geneeskunde.;Maasstad Ziekenhuis, Rotterdam. Afd. Interne Geneeskunde.;Maasstad Ziekenhuis, Rotterdam. Afd. Pathologie.",
"authors": "Sandberg|Yorick|Y|;Sprenger|Reinier|R|;den Bakker|Michael A|MA|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; C556306:daratumumab; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "164()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D000069286:Bortezomib; D003907:Dexamethasone; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007167:Immunotherapy; D008875:Middle Aged; D009101:Multiple Myeloma; D010954:Plasmacytoma; D011379:Prognosis; D012878:Skin Neoplasms",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32391990",
"pubdate": "2020-03-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A woman with a progressive skin tumor during immunotherapy.",
"title_normalized": "a woman with a progressive skin tumor during immunotherapy"
} | [
{
"companynumb": "NL-ASPEN-GLO2020NL005475",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "Massive perivillous fibrin deposition of the placenta (MPFD) or maternal floor infarction (MFI) is a serious condition associated with recurrent complications including fetal death and severe fetal growth restriction. There is no method to evaluate the risk of adverse outcome in subsequent pregnancies, or effective prevention. Recent observations suggest that MFI is characterized by an imbalance in angiogenic/anti-angiogenic factors in early pregnancy; therefore, determination of these biomarkers may identify the patient at risk for recurrence. We report the case of a pregnant woman with a history of four consecutive pregnancy losses, the last of which was affected by MFI. Abnormalities of the anti-angiogenic factor, sVEGFR-1, and soluble endoglin (sEng) were detected early in the index pregnancy, and treatment with pravastatin corrected the abnormalities. Treatment resulted in a live birth infant at 34 weeks of gestation who had normal biometric parameters and developmental milestones at the age of 2. This is the first reported successful use of pravastatin to reverse an angiogenic/anti-angiogenic imbalance and prevent fetal death.",
"affiliations": "a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .;a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .;a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .;a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .;a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .;f Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD , USA .;f Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD , USA .;g Perinatal Unit , Winchester Obstetrics and Gynecology, Winchester Medical Center , Winchester , VA , USA , and.;a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .;a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .;a Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD and Detroit , MI , USA .",
"authors": "Chaiworapongsa|Tinnakorn|T|;Romero|Roberto|R|;Korzeniewski|Steven J|SJ|;Chaemsaithong|Piya|P|;Hernandez-Andrade|Edgar|E|;Segars|James H|JH|;DeCherney|Alan H|AH|;McCoy|M Cathleen|MC|;Kim|Chong Jai|CJ|;Yeo|Lami|L|;Hassan|Sonia S|SS|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016756:Immunoglobulins, Intravenous; D040281:Vascular Endothelial Growth Factor Receptor-1; D017035:Pravastatin",
"country": "England",
"delete": false,
"doi": "10.3109/14767058.2015.1022864",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": "29(6)",
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": "Angiogenic factors; maternal floor infarction; placental growth factor; preeclampsia; proton pump inhibitor; soluble endoglin; soluble vascular endothelial growth factor receptor-1",
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": "D000026:Abortion, Habitual; D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016756:Immunoglobulins, Intravenous; D010922:Placenta Diseases; D017035:Pravastatin; D011247:Pregnancy; D040281:Vascular Endothelial Growth Factor Receptor-1",
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "855-62",
"pmc": null,
"pmid": "25893545",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17990939;19265171;19234141;19556010;23746925;23841577;23747588;23331974;23906160;23905710;24070396;23749761;24287098;24503248;24591337;24412113;24066977;24681146;24963809;24657242;24397483;21951517;12652302;16563347;16421767;16957146;17166218;17261644;19900040;19909254;19916710;19965971;20434767;20567176;20634190;20948996;21048973;20459337;22981320;23344286;23411799;23437230;23333542;23333548;23460290;23594919;14506648;14612202;14764923;15485113;6624805;4018779;3195520;2403172;1442990;8164938;8946557;9025835;9391746;9895405;15546153;15708122;15804781;15837060;16105786;16163683;16391409;16463429;16506120;17515455;18175241;18175242;17956952;18285616;18446652;21187414;21326865;21317220;21793744;21778140;12576248;11910510;12066949;22083058;22092404;22106179;22390808;22340745;21867402;22594519;12618519;12628270",
"title": "Pravastatin to prevent recurrent fetal death in massive perivillous fibrin deposition of the placenta (MPFD).",
"title_normalized": "pravastatin to prevent recurrent fetal death in massive perivillous fibrin deposition of the placenta mpfd"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0070316",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAVASTATIN\\PRAVASTATIN SODIUM"
},
"dru... |
{
"abstract": "Allogeneic hematopoietic stem cell transplantation (HSCT) is the recommended treatment for children with very high risk acute lymphoblastic leukemia (ALL), but it requires adequate institutional infrastructure, experience, and expertise, especially for alternative donor HSCT. We review our experience with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (APBSCT), followed by post-APBSCT maintenance chemotherapy for children with very high risk ALL. Between August 1997 and November 2012, our institute was not successful with HLA-haploidentical HSCT. Thus, if patients lacked HLA-matched allogeneic donors or cord blood donors, we treated them with HDCT and APBSCT with carmustine, etoposide, cytarabine, and cyclophosphamide, followed by post-APBSCT maintenance chemotherapy with vincristine, oral prednisolone, methotrexate, and 6-mercaptopurine.Ten patients underwent HDCT and APBSCT due to relapse, biphenotype leukemia, Philadelphia translocation, MLL rearrangement, hypodiploidy, and initial white blood cell count above 20.0 × 109/L. At a median 7.4 years from HDCT to APBSCT, overall survival (OS) was 70.0% ± 14.5% and event-free survival (EFS) was 70.0% ± 14.5%. Adverse events were tolerable, without treatment-related mortality.This historical analysis may be a useful reference when allogeneic HSCT including alternative donor HSCT cannot be performed for children with very high risk ALL.",
"affiliations": "Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. kanghj@snu.ac.kr.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.;Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.",
"authors": "Hong|Che Ry|CR|;Kang|Hyoung Jin|HJ|;Park|Kyung Duk|KD|;Shin|Hee Young|HY|;Ahn|Hyo Seop|HS|",
"chemical_list": "D014750:Vincristine; D003520:Cyclophosphamide; D002330:Carmustine; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-017-2355-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "107(3)",
"journal": "International journal of hematology",
"keywords": "Autologous; Leukemia; Maintenance chemotherapy; Transplantation",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D064592:Autografts; D002330:Carmustine; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D060046:Maintenance Chemotherapy; D008297:Male; D036102:Peripheral Blood Stem Cell Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011241:Prednisone; D012306:Risk; D014182:Transplantation, Autologous; D014750:Vincristine",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "355-362",
"pmc": null,
"pmid": "29052026",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "8298555;18408773;15778727;1672260;15077135;25255163;10996522;12176883;7581142;14716339;26465987;22209888;7909913",
"title": "High-dose chemotherapy and autologous peripheral blood stem cell transplantation with BCVAC regimen followed by maintenance chemotherapy for children with very high risk acute lymphoblastic leukemia.",
"title_normalized": "high dose chemotherapy and autologous peripheral blood stem cell transplantation with bcvac regimen followed by maintenance chemotherapy for children with very high risk acute lymphoblastic leukemia"
} | [
{
"companynumb": "KR-TEVA-2018-KR-877289",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Hoarseness of voice following supraclavicular brachial plexus block is a rare complication and is seen in 1.3% of cases. It has been reported in cases of right supraclavicular brachial block exclusively. The reason for this is the course of recurrent laryngeal nerve which is not the same in the left and right sides. Here we report a case of left supraclavicular brachial plexus block following which the patient developed hoarseness of voice.",
"affiliations": "Department of Anesthesiology, AIIMS, Patna, Bihar, India.;Department of Anatomy, AIIMS, Patna, Bihar, India.;Department of Anesthesiology, AIIMS, Patna, Bihar, India.;Department of Anesthesiology, SKMCH, Muzaffarpur, Bihar, India.",
"authors": "Naaz|Shagufta|S|;Asghar|Adil|A|;Jha|Nandan K|NK|;Ozair|Erum|E|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/sja.SJA_440_19",
"fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Wolters Kluwer - Medknow India SJA-14-10910.4103/sja.SJA_440_19Case ReportA unique case of hoarseness of voice following left supraclavicular brachial plexus block Naaz Shagufta Asghar Adil 1Jha Nandan K. Ozair Erum 2Department of Anesthesiology, AIIMS, Patna, Bihar, India1 Department of Anatomy, AIIMS, Patna, Bihar, India2 Department of Anesthesiology, SKMCH, Muzaffarpur, Bihar, IndiaAddress for correspondence: Dr. Shagufta Naaz, Department of Anesthesiology, AIIMS, Patna, Bihar, India. E-mail: drshaguftanaaz@gmail.comJan-Mar 2020 06 1 2020 14 1 109 111 12 7 2019 14 7 2019 Copyright: © 2020 Saudi Journal of Anesthesia2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Hoarseness of voice following supraclavicular brachial plexus block is a rare complication and is seen in 1.3% of cases. It has been reported in cases of right supraclavicular brachial block exclusively. The reason for this is the course of recurrent laryngeal nerve which is not the same in the left and right sides. Here we report a case of left supraclavicular brachial plexus block following which the patient developed hoarseness of voice.\n\nHoarsenessrecurrent laryngeal nervevocal cords\n==== Body\nIntroduction\nSupraclavicular brachial plexus block is a nerve block frequently performed for the surgery distal to the midarm. Here, the nerve trunks are densely located, and hence it is performed with ease and there are high chances of success. Complications such as pneumothorax, arterial puncture, hematoma formation, diaphragmatic palsy, local anesthetic toxicity, and hoarseness of voice are associated with this block.[1] Ultrasound guidance helps in performing nerve blocks with accuracy and has reduced the rates of complications. But experience and acquaintance with the anatomy is highly required. Hoarseness of voice is a rare complication of this block and has been always reported in case of right-sided block. Here, we report a case in which hoarseness of voice was complained after ultrasound-guided left supraclavicular brachial plexus nerve block which is very unlikely and has never been reported in the literature.\n\nCase Report\nA 14-year-old boy weighing 50 kg and with American Society of Anesthesiologists (ASA) grade 1 had to undergo corrective surgery for postburn syndactyly in the third and fourth finger webs. Preoperative investigations were found within normal limit. After explaining the procedure and taking consent for the supraclavicular brachial plexus block, he was taken inside the operation room. The standard ASA monitors were attached and baseline parameters were recorded. Taking all aseptic precautions, supraclavicular block was performed under ultrasonography (USG) guidance using high-frequency linear transducer of SonoSite M-Turbo ultrasound machine just above the clavicle at approximately its midpoint. By in-plane technique, a 50-mm, 22-G Stimuplex needle was passed posterolateral to the brachial plexus in a lateral-to-medial direction. Being convinced with the location of needle, 10 mL of 0.5% bupivavaine plain and 10 mL of 2% lignocaine with adrenaline (1:200,000) were instilled after repeated negative aspiration. The block was effective and the patient's hand was anesthetized. He also complained of difficulty in speech and there was hoarseness in his voice which was not there before. The child became very anxious because of this. He had no other problem like breathlessness or drop in oxygen saturation. His hemodynamic parameters were unaltered and there were no electrocardiogram changes. As the patient became very anxious, we decided to place supraglottic device (I gel no. 3; Intersurgical Ltd, Wokingham, UK) and ventilate him mechanically. Injection dexamethasone 8 mg was given. The surgery lasted for 3 h. After the completion of surgery, we examined the vocal cords of the patient using a fiberoptic laryngoscope. Both the vocal cords could be seen moving, the left one little less and looking smaller in length than right, though they were not adducting completely as the patient was deeply sedated. We also ruled out pneumothorax, clinically by seeing the symmetry of his chest, bilateral chest rise, auscultation, and using ultrasound where lung sliding could be seen. We took a view of the supraclavicular fossa using ultrasound [Figure 1]. The drug deposition could be seen laterally and it also seemed that either there was blood or some drug had reached to the medial of subclavian artery. Recurrent laryngeal nerve (RLN) or vagus nerve block of the side of the procedure was considered. The patient was extubated, and after that there was no hoarseness of voice or any other complication. He was pain-free for about 12 h. Again the left supraclavicular fossa of the patient was examined the next day using ultrasound and then the image was clear which indicated that there was drug deposition medially which was absorbed by that time and no hematoma formation [Figure 2].\n\nFigure 1 Ultrasound image 3 h after nerve block\n\nFigure 2 Ultrasound image 18 h after block\n\nDiscussion\nThe complications associated with USG-guided supraclavicular block depend on the level of block although they are few and infrequent in experienced hands. RLN block is commonly seen during interscalene brachial plexus block but is quite unusual following supraclavicular approach. According to Neal et al., the incidence of the RLN block during supraclavicular approach is seen in 1.3% of patients.[2] Gupta et al. reported a case of RLN block after right supraclavicular block.[3] Balaji et al. reported hoarseness of voice and Horner's syndrome in a single patient following right supraclavicular brachial plexus block and attributed it to tourniquet application in that arm.[4] Whenever reported earlier RLN block or even palsy have been reported in right-sided supraclavicular block and the reason is obvious.[5] The right and left RLNs follow different courses[6] [Figure 3]. The right one encircles the right subclavian artery and is in its close proximity. So there are chances of its involvement in rare cases when large amount of local anesthetic is deposited near the artery where the RLN is located. But left RLN is much medial in relation to the left subclavian artery running closer to trachea and esophagus. It is the left vagus nerve which runs near the subclavian artery. The mechanism by which the nerve block occurred in our case was the exclusive block of the fibers of RLN present in the vagus nerve or unilateral vagus nerve as the drug deposited moved medial to the subclavian artery [Figure 1] and since the RLN is located farther. Visualization of the tip of the needle throughout the procedure is of utmost importance as this prevents the puncture of unwanted structures preventing complications and increases the chances of success of the procedure by deposition of local anesthetic at exact location.[789] The fascial sheath surrounding the brachial plexus which is a derivative of deep cervical fascia terminates by merging with the medial intermuscular septum of the arm. After injection, the local anesthetic spreads up and down the nerves in a longitudinal manner and this fascial sheath limits the circumferential spread.[10] But proximal spread of local anesthetic via fascial sheath is not likely cause of RLN block because the RLN is anterior and outside this fascial sheath surrounding the brachial plexus which merges with the prevertebral fascia. Balaji et al. and Gupta et al. in two different case reports of right RLN block have attributed the hoarseness of voice to proximal spread of excessive local anesthetic.[34] There is remote possibility of aberrant left RLN (incident 0.04%) when it is known as nonrecurrent inferior laryngeal nerve.[11] It runs closer to the subclavian artery and is always associated with aberrant vessels like arteria lusoria, right aortic arch, and situs inversus. Vascular anomaly was ruled out in this case clinically, by X-ray chest and color Doppler. Unilateral RLN block is not of much clinical significance except that it leads to patient discomfort. But it is of significance in patients who already have contralateral RLN palsy either due to previous neck dissection or any other reason. Cases have been reported of respiratory obstruction as a result of unilateral supraclavicular brachial plexus block in such situation.[12] For similar reason, interscalene brachial plexus block should be avoided.[13]\n\nFigure 3 Anatomical relationship of recurrent laryngeal nerve right and left. Downloaded from nejm.org at BROWN UNIVERSITY on March 25, 2019\n\nThis case can only be explained as a case of block of medial fibers of vagus nerve, that is, fibers of left RLN present in vagus nerve or unilateral vagus nerve block. When performing nerve blocks, care should be taken to inject lesser dose of local anesthetic because these days nerve blocks are performed using ultrasound and the location where the drug is deposited is more accurate. The tip of the needle should be visualized right from introduction till the whole of the drug is injected so that drugs may not be deposited elsewhere and chances of complications are minimized.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Finucane BT Tsui BC Complications of brachial plexus anesthesia Complications of Regional Anesthesia 2007 New York, NY Springer 121 48 \n2 Neal JM Gerancher JC Hebl JR Ilfeld BM McCartney CJ Franco CD Upper extremity regional anesthesia: Essentials of our current understanding, 2008 Reg Anesth Pain Med 2009 34 134 70 Review. Erratum in: Reg Anesth Pain Med 2010;35:407 19282714 \n3 Gupta M Jain P Bhalla S Upadhyay N Hoarseness of voice after supraclavicular ultrasound-guided subclavian perivascular brachial plexus block Indian Anaesth Forum 2017 18 86s \n4 Balaji RM Sherfudeen KM Kumar S Double trouble: Hoarseness and Horner's after supraclavicular brachial plexus block S Afr J Anaesth Analg 2017 23 24 5 \n5 Sahu SK Badole U A rare complication in ultrasound-guided supraclavicular brachial plexus block Res Innov Anesth 2016 1 30 1 \n6 Andersen DK Raphael EP Billiar T Dunn D Hunter J Matthews J Brunicardi FC Schwartz's Principles of Surgery 9th ed McGraw Hill Professional; 2009. ISBN 978-0-07-154769-7 \n7 Vade Boncouer TR Weinberg GL Oswald S Angelov F Early detection of intravascular injection during ultrasound-guided supraclavicular brachial plexus block Reg Anesth Pain Med 2008 33 278 9 18433687 \n8 Loubert C Williams SR Hélie F Arcand G Complication during ultrasound-guided regional block: Accidental intravascular injection of local anesthetic Anesthesiology 2008 108 759 60 18362609 \n9 Schafhalter-Zoppoth I Zeitz ID Gray AT Inadvertent femoral nerve impalement and intraneural injection visualized by ultrasound Anesth Analg 2004 99 627 8 \n10 Thompson GE Rorie DK Functional anatomy of the brachial plexus sheaths Anesthesiology 1983 59 117 22 6869868 \n11 Kamath S Rathnakar P Shetty K Nonrecurrent laryngeal nerve: Rare entity NUJHS 2012 2 42 4 \n12 Rollins M McKay WR Eshima RE Airway difficulty after subclavian perivascular block Anesth Analg 2003 96 1191 2 12651683 \n13 Plit ML Chhajed PN MacDonald P Cole IE Harrison GA Bilateral vocal cord palsy following interscalene brachial plexus block Anaesth Intensive Care 2002 30 499 501 12180594\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "14(1)",
"journal": "Saudi journal of anaesthesia",
"keywords": "Hoarseness; recurrent laryngeal nerve; vocal cords",
"medline_ta": "Saudi J Anaesth",
"mesh_terms": null,
"nlm_unique_id": "101500601",
"other_id": null,
"pages": "109-111",
"pmc": null,
"pmid": "31998030",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "6869868;12651683;18433687;12180594;18362609;15271763;19282714",
"title": "A unique case of hoarseness of voice following left supraclavicular brachial plexus block.",
"title_normalized": "a unique case of hoarseness of voice following left supraclavicular brachial plexus block"
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"abstract": "Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.\n\n\n\nPatients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.\n\n\n\nOf 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.\n\n\n\nSteroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).",
"affiliations": "Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Radiology, Johns Hopkins University, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.;Pulmonology and Critical Care Medicine, Johns Hopkins Medicine School of Medicine, Baltimore, Maryland, USA.;Pulmonology and Critical Care Medicine, Johns Hopkins Medicine School of Medicine, Baltimore, Maryland, USA.;Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA jnaidoo1@jhmi.edu.",
"authors": "Balaji|Aanika|A|0000-0001-6697-3364;Hsu|Melinda|M|;Lin|Cheng Ting|CT|0000-0003-0275-8037;Feliciano|Josephine|J|;Marrone|Kristen|K|;Brahmer|Julie R|JR|;Forde|Patrick M|PM|;Hann|Christine|C|;Zheng|Lei|L|0000-0003-4163-2541;Lee|Valerie|V|;Illei|Peter B|PB|;Danoff|Sonye K|SK|;Suresh|Karthik|K|;Naidoo|Jarushka|J|0000-0002-3470-8686",
"chemical_list": null,
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"doi": "10.1136/jitc-2020-001731",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n33414264\njitc-2020-001731\n10.1136/jitc-2020-001731\nClinical/Translational Cancer Immunotherapy\n1506\n2435\nOriginal researchSteroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes\nhttp://orcid.org/0000-0001-6697-3364\nBalaji Aanika 12\nHsu Melinda 12\nhttp://orcid.org/0000-0003-0275-8037\nLin Cheng Ting 3\nFeliciano Josephine 12\nMarrone Kristen 12\nBrahmer Julie R 12\nForde Patrick M 12\nHann Christine 12\nhttp://orcid.org/0000-0003-4163-2541\nZheng Lei 12\nLee Valerie 12\nIllei Peter B 14\nDanoff Sonye K 5\nSuresh Karthik 5\nhttp://orcid.org/0000-0002-3470-8686\nNaidoo Jarushka 12\n1 Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA\n2 The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA\n3 Radiology, Johns Hopkins University, Baltimore, Maryland, USA\n4 Division of Pathology, Johns Hopkins University, Baltimore, MD, USA\n5 Pulmonology and Critical Care Medicine, Johns Hopkins Medicine School of Medicine, Baltimore, Maryland, USA\nCorrespondence to Jarushka Naidoo; jnaidoo1@jhmi.edu\n2021\n6 1 2021\n9 1 e00173129 11 2020\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2022\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.\n\nBackground\n\nImmune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis.\n\nMethods\n\nPatients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression.\n\nResults\n\nOf 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3–12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone.\n\nConclusions\n\nSteroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients’ treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality).\n\nimmunotherapy\ninflammation\nprogrammed cell death 1 receptor\nspecial-featureunlocked\n==== Body\npmcHighlights\n\nSteroid-refractory immune-checkpoint inhibitor (ICI)-pneumonitis constitutes 18.5% of patients referred for multidisciplinary care of immune-related toxicity.\n\nSteroid-refractory ICI-pneumonitis most commonly presents as diffuse alveolar damage on chest CT.\n\nPatients treated with intravenous immunoglobulin had fewer fatalities (43%), improvements in patient oxygenation, and level-of-care.\n\nIntroduction\n\nImmune-checkpoint inhibitor pneumonitis (ICI-pneumonitis) is the most frequently fatal toxicity from PD-(L)1 (PD-(L)1: programmed cell death protein-1/programmed death ligand-1) monotherapies.1 ICI-pneumonitis typically develops within the first 3 months (range: 9 days to 19 months) of ICI initiation, clinically improve with corticosteroids therapy within 48–72 hours, and require a median of 12 weeks to taper off corticosteroids completely.2–5 However, a subset of patients with ICI-pneumonitis do not clinically improve with corticosteroids alone and require further immunosuppression. This phenomenon, termed steroid-refractory ICI-pneumonitis, is defined as a lack of clinical improvement in ICI-pneumonitis after 48 hours to 2 weeks of corticosteroid treatment.6–9 However, the clinical and radiographic features of steroid-refractory ICI-pneumonitis are poorly understood and limited to individual cases and small case series.10–13 Additionally, patients who develop steroid-refractory ICI-pneumonitis almost universally succumb to this toxicity or the infectious complications of immunosuppressive management.2 14\n\nPublished guidelines recommend a variety of potential treatments for steroid-refractory ICI-pneumonitis including infliximab, intravenous immunoglobulin (IVIG), cyclophosphamide, or mycophenolate mofetil.4 15 16 However, the data supporting these choices are based largely on their use in other steroid-refractory irAEs.4 15 16 Infliximab, a TNF (Tumor-necrosis factor)-alpha inhibitor, has been used successfully to treat steroid-refractory ICI-colitis.17 18 IVIG is an admixture of antibodies from human sera that produces an immunomodulatory effect19 and has resulted in clinical improvements for patients with ICI-myasthenia gravis and ICI-thrombocytopenia.20 21 Thus, the optimum choice of immunosuppressive therapy for patients who develop steroid-refractory ICI-pneumonitis has yet to be established.\n\nGiven these gaps in our knowledge, we provide the first comprehensive report of the incidence, features, management, and outcomes of patients with steroid-refractory ICI-pneumonitis at a single, high-volume academic institution.\n\nMethods\n\nStudy approval\n\nCollection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.\n\nPatient selection\n\nWe retrospectively identified patients who developed steroid-refractory ICI-pneumonitis after referral to an institutional immune-related multidisciplinary team or a dedicated pulmonary outpatient clinic for ICI-pneumonitis at the Johns Hopkins Hospital between January 2011 and January 2020. Patients may have been given ICIs either as part of a clinical trial or standard-of-care.\n\nIncidence\n\nIncidence of steroid-refractory ICI-pneumonitis was calculated by dividing the total number of steroid-refractory ICI-pneumonitis cases by the total ICI-pneumonitis cases referred internally for multidisciplinary input (inpatient and outpatient) between January 2011 and January 2020 at the Johns Hopkins Hospital.\n\nSteroid-refractory ICI-pneumonitis definition and diagnosis\n\nThe diagnosis of ICI-pneumonitis was made by the treating medical oncologist and confirmed by a multidisciplinary team comprised of a pulmonologist, radiologist, second medical oncologist, and pathologist.22 ICI-pneumonitis was defined as clinical and radiographic lung inflammation either during or after anti-PD-(L)1 therapy. Patients with confirmed alternative diagnoses, such as cancer progression, radiation pneumonitis,23 or lung infection, were excluded with appropriate laboratory testing, diagnostic imaging and pathological evaluation. Steroid-refractory ICI-pneumonitis was defined as a failure of clinical improvement of ICI-pneumonitis after a minimum of 48 hours of high-dose corticosteroids (prednisone 1–2 g/kg/day or more) to up to 14 days of corticosteroids.4 15 16 Clinical improvement in steroid-refractory ICI-pneumonitis was defined a reduction in either level-of-care or oxygen supplementation for ICI-pneumonitis. Death from steroid-refractory ICI-pneumonitis was defined as death attributed to ICI-pneumonitis or its management. Laboratory testing, radiologic imaging, and diagnostic bronchoscopy with bronchoalveolar lavage were performed at the discretion of the treating physician.\n\nRadiology\n\nSerial radiologic imaging including chest CT for steroid-refractory ICI-pneumonitis was captured and tumor radiologic response was assessed by RECIST (Response evaluation criteria in solid tumors) V.1.1 (v. 4.03) guidelines. Infiltrate types of steroid-refractory ICI-pneumonitis were categorized as diffuse alveolar damage (DAD), organizing pneumonia (OP), or non-specific by a board-certified thoracic radiologist (CTL), blinded to the clinical course of each patient. Radiologic DAD pattern of ICI-pneumonitis was defined as findings of ground glass opacities (GGOs) with or without intralobular lines (“crazy-paving”),24–26 traction bronchiectasis, and perilobular sparing; while the OP pattern was defined as lung parenchymal consolidation (occasionally with “reverse halo sign”) with traction bronchiectasis, and perilobular sparing.27 Non-specific findings included those that did not clearly demonstrate DAD or OP; including extensive nodularity with associated GGOs (pneumonitis not otherwise specified)2 and bronchial wall thickening with centrilobular tree-in-bud nodularity and consolidation (pneumonitis not-otherwise-specified).2\n\nLevel-of-care\n\nThe level-of-care received by each patient from the day of diagnosis of steroid-refractory ICI-pneumonitis was recorded and categorized as oncology floor/intermediate care, intensive care unit (ICU) without mechanical ventilation, or ICU with mechanical ventilation.28\n\nOxygen supplementation\n\nThe highest level of oxygen supplementation required for each patient, from the day of diagnosis of steroid-refractory ICI-pneumonitis, was recorded. The categories of oxygen supplementation required included: (1) no oxygen supplementation, (2) oxygen supplementation with nasal cannula, (3) high-flow nasal cannula (HFNC) or non-rebreather mask (NRB), (4) non-invasive positive-pressure ventilation (NIPPV; including bi-level positive airway pressure or continuous positive airway pressure), or (5) intubation with mechanical ventilation. A numerical value for the highest level of oxygen supplementation required per patient per hospitalization day was assigned. The percent time spent within each level of oxygen supplementation was calculated by aggregating individual patient data by immunosuppressive treatment group (IVIG alone, infliximab alone, combination of IVIG and infliximab (“combination”)). Additionally, the hospitalization time was subdivided into three categories: preimmunosuppression, during immunosuppression, or postimmunosuppression. Differences in percent hospitalization time by oxygen level were compared within immunosuppressive treatment groups by preimmunosuppression and postimmunosuppression hospitalization days, with the days of administration of immunosuppression (“during immunosuppression”) not included. Baseline supplemental oxygen requirement by patients and recorded increased oxygen use was calculated as a change from baseline.28 29\n\nFor patients who were readmitted to the hospital for steroid-refractory ICI-pneumonitis after an initial hospitalization for ICI-pneumonitis, time before reinitiation of immunosuppression during the second hospitalization was classified as preimmunosuppression. Patients who received more than one course of immunosuppressive therapy during the same hospitalization were classified as “postimmunosuppression” after the first immunosuppressive agent was administered if the half-life of the first dose of immunosuppressive therapy given overlapped the second (half-life IVIG: 21 days, half-life infliximab: 9.5 days).30 31\n\nStatistical analysis\n\nStudy data were summarized using descriptive statistics using Stata V.16.1 (StataCorp). Results are reported with means with ranges, as appropriate. Categorical and ordinal variables were summarized as percentages.\n\nResults\n\nIncidence\n\nThe incidence of steroid-refractory ICI-pneumonitis in patients referred to a multidisciplinary immune-related toxicity team or pulmonary outpatient clinic for ICI-pneumonitis after multidisciplinary referral was 18.5% (12/65). Twenty-three patients (35.4%) were referred while receiving inpatient care and 42 (64.6%) were referred in the outpatient setting. The majority of referred patients with steroid-refractory ICI-pneumonitis had high grade toxicity at initial presentation of ICI-pneumonitis (grade 3+: 50.8%, n=33/65) while a minority had grade 2 (43.1%) and grade 1 toxicity (6.2%).\n\nIn the 12 patients who developed steroid-refractory ICI-pneumonitis, ICI-pneumonitis eventually resolved in four patients, while eight patients died either from steroid-refractory ICI-pneumonitis or its complications.\n\nStudy population\n\nBaseline characteristics of patients who developed steroid-refractory ICI-pneumonitis, including subgroup characteristics based on immunosuppressive treatment received (IVIG only=7, infliximab only=2, combination=3), are depicted in table 1. Complete patient-level details are shown in online supplemental table 1.\n\n10.1136/jitc-2020-001731.supp1 Supplementary data\n\nTable 1 Baseline characteristics of patients with steroid-refractory ICI-pneumonitis by immunosuppressive treatment\n\nTherapy type\tIntravenous immunoglobulin\tInfliximab\tCombination\t\nTotal patients, n (%)\t7\t2\t3\t\nBaseline characteristics\t\n Age at ICI-pneumonitis diagnosis (mean, years)\t66\t66\t68\t\n Sex\t\n Male\t4 (57)\t0 (0)\t2 (67)\t\n Female\t3 (43)\t2 (100)\t1 (33)\t\n Race\t\n Caucasian\t6 (86)\t2 (100)\t3 (100)\t\n African-American\t1 (14)\t0 (0)\t0 (0)\t\n Smoking status\t\n Never\t3 (43)\t0 (0)\t0 (0)\t\n Current/former\t4 (57)\t2 (100)\t3 (100)\t\n Pack year history (mean, years)\t29.4\t37.5\t32.5\t\n Tumor histology\t\n Lung carcinoma\t5 (71)\t2 (100)\t2 (67)\t\n Non-small cell lung carcinoma\t4 (80)\t2 (100)\t2 (100)\t\n Small cell lung carcinoma\t1 (20)\t0 (0)\t0 (0)\t\n Oropharyngeal squamous cell carcinoma\t0 (0)\t0 (0)\t1 (33)\t\n Renal cell carcinoma\t0 (0)\t0 (0)\t0 (0)\t\n Pancreatic adenocarcinoma\t0 (0)\t0 (0)\t0 (0)\t\n Initial cancer stage*\t\n II\t1 (14)\t1 (50)\t1 (33)\t\n III\t3 (43)\t0 (0)\t0 (0)\t\n IV\t3 (43)\t1 (50)\t2 (67)\t\nAnticancer therapy\t\n Prior chemotherapy\t6 (86)\t2 (100)\t3 (100)\t\n Initial surgery\t1 (14)\t0 (0)\t1 (33)\t\n Prior chest radiation therapy†\t4 (57)\t1 (50)\t2 (67)\t\n PD-1/PD-L1 monotherapy\t2 (29)\t1 (50)\t3 (100)\t\n Durvalumab\t2 (100)\t0 (0)\t1 (33)\t\n Nivolumab\t0 (0)\t1 (100)\t1 (33)\t\n Pembrolizumab\t0 (0)\t0 (0)\t1 (33)\t\n PD-1/PD-L1-based combinations\t5 (71)\t1 (50)\t0 (0)\t\n Pembrolizumab+chemotherapy\t4 (80)\t0 (0)\t0 (0)\t\n Nivolumab+ipilimumab\t1 (20)\t1 (100)\t0 (0)\t\n ICI response at 3 months‡\t\n Partial response\t1 (14)\t1 (50)\t1 (33)\t\n Stable disease\t4 (57)\t0 (0)\t0 (0)\t\n Progressive disease\t2 (29)\t1 (50)\t2 (67)\t\n*AJCC staging system.\n\n†Dose of chest radiation in the range of 8–66 Gy given 276–739 days prior to steroid-refractory ICI-pneumonitis onset.\n\n‡As defined by RECIST V.1.1 criteria.\n\nICI, immune-checkpoint inhibitor; PD, progressive disease.\n\nWe identified 12 patients with steroid-refractory ICI-pneumonitis. The mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35–85 years), 50.0% (6/12) patients were male, 83.3% were Caucasian, 75.0% were current/former smokers. The majority of patients had lung carcinoma (75%, 9/12), predominantly non-small cell lung carcinoma (8/9). Nearly all patients had received prior chemotherapy (91.6%). Seven patients (58.3%) had a distant history of chest radiotherapy (range: 8–66 Gy) administered 276–739 days prior to onset of ICI-pneumonitis. Antitumor response to ICI assessed at 3 months post ICI-start demonstrated that 25.0% of patients had a partial response (PR) to therapy, 33.3% had stable disease (SD), and 41.7% had progressive disease (PD) by RECIST V.1.1.\n\nClinical features\n\nThe clinical features of patients who developed steroid-refractory ICI-pneumonitis are outlined in table 2. All patients were symptomatic (grade 2+) at initial diagnosis of ICI-pneumonitis (grade 2, 25%, n=3/12; grade 3, 75%, n=9/12) and developed ICI-pneumonitis early in their treatment course (mean number of ICI doses: 5, range: 3–12). Steroid-refractory ICI-pneumonitis developed between 40 and 127 days (median: 85 days) after the first dose of ICI and resulted in a hospitalization of between 6 and 35 total days (median: 14 days) All patients were treated with high-dose corticosteroids (median dose of prednisone equivalents: 75 mg/day (range: 50–237.5 mg/day) prior to receiving additional immunosuppressive therapy. Pulmonary medicine specialists were consulted in all cases, and infectious disease specialists in 58.3% (7/12) of cases.\n\nTable 2 Clinical features and management of steroid-refractory ICI-pneumonitis by immunosuppressive treatment\n\nTherapy type\tIntravenous immunoglobulin\tInfliximab\tCombination\t\nTotal patients, n (%)\t7\t2\t3\t\nSteroid-refractory pneumonitis features\t\n Initial CTCAE grade\t\n 2\t3 (43)\t0 (0)\t0 (0)\t\n 3\t4 (57)\t2 (100)\t3 (100)\t\n ICI doses (mean, range)\t5 (3–10)\t7 (1–13)\t2 (2–3)\t\n ICI start to steroid-refractory pneumonitis onset, days (mean, range)\t127 (39–208)\t98 (14–182)\t40 (21–77)\t\n Hospital length of stay, days (mean, range)\t21 (6–48)\t13.5 (13–14)\t20 (8–31)\t\nSteroid-refractory pneumonitis management\t\n Corticosteroid duration, days (mean, range)\t59 (14–122)\t58 (19–97)\t26 (5–41)\t\n First corticosteroid dose to first immunosuppression dose, days (mean, range)\t17 (2–96)\t8 (4–12)\t2 (1–5)\t\n Intubation for SRCIP\t1 (14)\t1 (50)\t1 (33)\t\n Diagnostic bronchoscopy with bronchoalveolar lavage\t4 (57)\t1 (50)\t1 (33)\t\n Pulmonology consult\t7 (100)\t2 (100)\t3 (100)\t\n Infectious disease consult\t4 (57)\t1 (50)\t2 (67)\t\nSteroid-refractory pneumonitis outcomes\t\n CTCAE grade after immunosuppression\t\n 2\t3 (43)\t0 (0)\t0 (0)\t\n 3\t3 (43)\t1 (50)\t2 (67)\t\n 4\t1 (14)\t1 (50)\t1 (33)\t\n Infection after immunosuppression\t1* (14)\t1† (50)\t0 (0)\t\n Clinical outcome\t\n Improved\t2 (29)\t0 (0)\t0 (0)\t\n Worsened\t2 (29)\t0 (0)\t0 (0)\t\n Death from steroid-refractory pneumonitis\t3 (43)\t2 (100)\t3 (100)\t\n*Herpes Zoster Shingles.\n\n†Parainfluenza pneumonia.\n\nCTCAE, common terminology criteria for adverse events; ICI, immune-checkpoint inhibitor; SRCIP, steroid-refractory ICI-pneumonitis.\n\nPatients were treated with either IVIG alone, infliximab alone, or a combination of IVIG and infliximab. Patients given IVIG generally had concerns for a superimposed infectious process due to immunosuppression from long-term corticosteroid use.\n\nSteroid-refractory ICI-pneumonitis-related deaths were most frequent in those with PD at 3 months post-ICI (n=4/5, 80%), compared with SD (n=2/4, 50%) or PR (n=1/3, 33%). Following a similar pattern, fewer patients who had PD demonstrated clinical improvement after immunosuppression (n=1/5, 20%) than those who had PR (n=3/3, 100%) or SD (n=3/4, 75%).\n\nRadiographic features\n\nWe examined serial CT imaging of patients who developed steroid-refractory ICI-pneumonitis at four timepoints: pre-ICI, at initial ICI-pneumonitis diagnosis, postcorticosteroids, and postadditional immunosuppression (up to 4 weeks). Representative CT images of patients within each treatment group (IVIG, infliximab, and combination), stratified by clinical improvement or lack thereof are shown in figure 1. Specific CT findings of our cohort are described in online supplemental figure 1. Radiographic features at the time of ICI-pneumonitis diagnosis consisted predominantly of a DAD pattern across all immunosuppressive treatments received (50%, 6/12), with OP (33.3%, 4/12) and other (16.7%, 2/12) patterns identified in a minority of cases. Most cases of steroid-refractory ICI-pneumonitis demonstrated disease in bilateral lung fields (75%, 9/12).\n\n10.1136/jitc-2020-001731.supp2 Supplementary data\n\nFigure 1 Serial radiologic imaging in patients with steroid-refractory ICI-pneumonitis. Illustrative images from six cases, each representing one patient treated with IVIG, infliximab, or combination immunosuppression and either demonstrated improvement with immunosuppression or did not have improvement with immunosuppression. Images are taken at 1: Pre-ICI: before immune checkpoint inhibitor therapy start, 2: Initial dx ICI-pneumonitis scan: CT scan at the time of diagnosis of ICI-pneumonitis, 3: Poststeroids: postcorticosteroids, prior to additional immunosuppression, 4: Postadditional IS: within 4 weeks of administration of additional immunosuppression as outlined in top panel. Red circles in panel (2) show diagnostic features of ICI-pneumonitis. Blue circles in panel (4) show areas of worsening ICI-pneumonitis in patients whose steroid-refractory ICI-pneumonitis. Corresponding patient labels are noted in the bottom right hand corner of each image. IVIG, intravenous immunoglobulin; ICI, immune-checkpoint inhibitor; dx, diagnosis; IS, immunosuppression. The infiltrate classification is depicted in online supplemental figure 1.\n\nImmunosuppressive management and outcomes\n\nIntravenous immunoglobulin\n\nAfter lack of clinical improvement with high-dose corticosteroids, seven patients were treated with IVIG (0.4 g/kg/day) over 5 days in accordance with institutional practices. IVIG was administered a mean of 17 days after corticosteroid initiation (range: 1–96 days). Once completing IVIG therapy, two patients (29%, n=2/7) sustained an improvement in ICI-pneumonitis grade (grade 3 to grade 2), while two patients (29%) had their ICI-pneumonitis clinically stabilize (grade 2=1; grade 3=1), and three patients worsened to grade 5 (43%, n=3/7).\n\nPatient level details are depicted in figure 2. All patients, excluding one, required ICU-level care. Patient 2 did not require ICU-level care as oxygen levels were maintained with HFNC. Shortly after discharge, he was admitted to a palliative care service. Most patients (5/7, 71.4%) received one course of IVIG during their hospitalization. Patient 6 received two doses of IVIG during a prolonged hospital stay, but only had an improvement in level-of-care after the first dose only. Patient 3 received IVIG during each of three separate hospitalizations and sustained a clinical benefit (reduced oxygen requirements) after each administration of IVIG.\n\nFigure 2 Clinical course of steroid-refractory immune-checkpoint inhibitor pneumonitis (ICI- pneumonitis) stratified by additional immunosuppressive treatment received after corticosteroids. CTCAE ICI-pneumonitis grade, immunosuppressive therapy, level-of-care, and clinical ICI-pneumonitis outcome are shown over time during days of hospitalization. Yellow shaded areas indicate admission to the oncology unit, orange shaded areas represent admission to the ICU without the need for mechanical ventilation, red shaded areas show admission to the ICU with mechanical ventilation, and gray areas represent time between hospitalizations if a patient was discharged then readmitted for further treatment. White squares within each hospitalization bar represent when IVIG was given and white triangles show when infliximab was given. The lightning bolt following hospitalization bars indicate death from SRCIP/SRCIP-related care. Pt., patient; no., number; Gr, grade; ICU, intensive care unit; ICI, immune checkpoint inhibitor; IVIG, intravenous immunoglobulin; SRCIP, steroid-refractory ICI-pneumonitis.\n\nOxygen supplementation requirements for patients treated with IVIG alone are depicted in figure 3. As a group, patients were hospitalized for 49 days total (n=7 patients) prior to IVIG administration and no patients required oxygen supplementation at baseline. During the majority of hospitalization time, patients treated with IVIG required oxygen supplementation via nasal cannula (51%, n=25/49 days), HFNC/NRB (30.6%, n=15/49 days), no oxygen supplementation (14.3%, n=7/49 days), or mechanical ventilation (4.1%, n=2/49 days). After administration, patients receiving IVIG were hospitalized for 86 days total. After IVIG was administered, we observed that no patients required mechanical ventilation, fewer patients required HFNC/NRB (25.6%), and some required no oxygen supplementation (15.1%).\n\nFigure 3 Oxygen supplementation required preimmunosuppression and postimmunosuppression as a percentage of hospitalization days. Groups were separated by additional immunosuppression given (IVIG, infliximab, or combination). Excluded 41 hospitalization days from the IVIG group, 2 hospitalization days from the infliximab group, and 15 hospitalization days from the combination group from the calculation. supp, supplemental; O2, oxygen; HFNC, high-flow nasal cannula; IVIG, intravenous immunoglobulin; NRB, non-rebreather mask; NIPPV, non-invasive positive pressure ventilation; MV, mechanical ventilation.\n\nIn terms of clinical irAE outcome, two patients (29%, n=2/7) clinically improved and were discharged from the hospital and two patients whose ICI-pneumonitis stabilized (29%, n=2/7) subsequently died from progression of cancer (n=3). For three patients whose ICI-pneumonitis worsened (43%), steroid-refractory ICI-pneumonitis was the cause of death. Patient 3 developed infectious complications after receiving IVIG (Herpes zoster shingles), however, ultimately died from cancer progression.\n\nInfliximab\n\nTwo patients received infliximab 8 days (range: 7–8 days) after commencement of high-dose corticosteroids. All patients in our series receiving infliximab were given one dose (5 g/kg), which is in accordance with current published literature describing successful use of infliximab for steroid-refractory ICI-pneumonitis in selected cases.10 13 After receiving infliximab, steroid-refractory ICI-pneumonitis worsened in one patient (grade 3 to grade 4) and improved in the other (grade 4 to grade 3).\n\nBoth patients in the cohort received infliximab only receiving ICU-level care, one of which (patient 8) required mechanical ventilation (figure 2). This patient was weaned off the ventilator after infliximab administration and transitioned to the oncology floor. Patient 9 required escalation to ICU-level care after receiving infliximab and was transitioned to palliative care shortly thereafter.\n\nNeither patient required oxygen supplementation prior to the diagnosis of ICI-pneumonitis. Prior to infliximab administration, both patients contributed 12 total days of hospitalization. Of this time, the majority was spent with a requirement for oxygen supplementation by nasal cannula (75%, n=9/12 days), followed by HFNC/NRB (16.7%, n=2/12 days), and mechanical ventilation (8.3%, n=1/12 days). After infliximab administration, the proportion of time spent requiring nasal cannula and mechanical ventilation decreased, while time spent requiring HFNC/NRB increased by 30% (nasal cannula: 46.7%; HFNC/NRB: 46.7%; mechanical ventilation: 7%). Patient 9 had a new oxygen supplementation requirement on discharge.\n\nBoth patients died from complications of steroid-refractory ICI-pneumonitis. After discharge, Patient 9 passed from respiratory failure secondary to steroid-refractory ICI-pneumonitis in hospice. Patient 8 developed parainfluenza pneumonia related to infliximab therapy and died from respiratory complications.\n\nCombination immunosuppression\n\nThree patients were treated with sequential IVIG and infliximab. Once hospitalized, patients were administered IVIG (0.5 g/kg/day) a mean of 2 days and infliximab (5 g/kg) a mean of 9 days after commencing high-dose corticosteroids. Two patients received IVIG first in their hospital course (patient 10=day 4, patient 12=day 2), followed by infliximab (patient 10=day 9, patient 12=day 15), while patient 11 received infliximab first (day 4), followed by IVIG (day 8). All three patients had a worsening in ICI-pneumonitis grade (grade 3 to grade 5) after administration of both immunosuppressive therapies and died from the complications of steroid-refractory ICI-pneumonitis.\n\nAll three patients required ICU-level care (figure 2). Initially, patient 10 improved clinically after receiving combination immunosuppression and was discharged for 14 days with a new oxygen requirement. However, this patient developed worsening symptoms (increasing shortness of breath) warranting readmission. Patient 11 received both immunosuppressive agents sequentially while mechanically ventilated, but was not able to be weaned off ventilation, transitioned to palliative care, and died from steroid-refractory ICI-pneumonitis. Patient 12 had early clinical benefit (downgrade from ICU to oncology floor) after administration of IVIG, however, this patient’s ICI-pneumonitis subsequently worsened. The patient was administered infliximab before a return transfer to the ICU but died from steroid-refractory ICI-pneumonitis 16 days after infliximab administration.\n\nIn terms of oxygen requirement (figure 3), only patient 12 had a baseline oxygen requirement prior to hospitalization. In total, patients contributed 14 hospitalization days before administration of their first immunosuppressive agent. The majority of this time was spent requiring HFNC/NRB (64.3%, n=9/14 days). A minority of time was spent requiring nasal cannula (21.4%) and NIPPV (14.2%). After administration of immunosuppressive therapy, the group contributed 41 hospitalization days and required more invasive methods of oxygen supplementation. The percentage of hospitalization days requiring nasal cannula (21.4% to 19.5%) and NIPPV (14.3% to 2.4%) decreased after administration of immunosuppressive therapy, while the time spent requiring HFNC/NRB increased (by 6.4%) and time spent requiring mechanical ventilation (0% to 7.3%) increased.\n\nTaken together, all patients treated with infliximab, either alone (n=2) on as part of combination immunosuppressive therapy (n=3), died due to steroid-refractory ICI-pneumonitis or infectious complications of infliximab therapy.\n\nDiscussion\n\nIn this, the first comprehensive cohort study of patients with steroid-refractory ICI-pneumonitis, we identify several clinically relevant findings. First, the incidence of steroid-refractory ICI-pneumonitis in those referred for multidisciplinary care was 18.5%. Second, we observe that steroid-refractory ICI-pneumonitis tends to occur early in a patient’s treatment course, and exhibits a radiographic pattern of bilateral DAD. Third, we identify that when treated with IVIG, infliximab, or the combination—patients with steroid-refractory ICI-pneumonitis exhibit very different clinical courses. Patients treated with IVIG generally demonstrated improvements in level-of-care and a reduced oxygen requirement, while those treated with infliximab monotherapy or the combination had an increased level-of-care and oxygen requirement. Finally, we observed a higher rate of fatality from steroid-refractory ICI-pneumonitis or its complications, in those treated with an infliximab-containing approach.\n\nSteroid-refractory ICI-pneumonitis is a fatal clinical phenomenon, and its incidence is poorly understood.10 11 A recent abstract by Beattie et al estimated that 0.5% of all patients with irAEs received additional immunosuppression.12 In our study, we estimate the incidence of steroid-refractory ICI-pneumonitis among patients referred for multidisciplinary care, at a surprisingly high 18.5%. Prior studies have described the radiographic features of steroid-refractory ICI-pneumonitis in individual patient cases,13 and we provide the largest experience to date, of 12 patients. Our study is the first to demonstrate that IVIG may be used successfully to treat steroid-refractory ICI-pneumonitis in multiple patients; with only one prior study in which a single case of steroid-refractory ICI-pneumonitis demonstrated improvement with IVIG.11\n\nImportantly, our study is the first to objectively quantify the clinical outcomes of treatment of steroid-refractory ICI-pneumonitis, by assessing patient level-of-care and oxygen supplementation preimmunosuppressive and postimmunosuppressive treatment. Wiertz et al recently depicted clinical improvements in steroid-refractory hypersensitivity pneumonitis after cyclophosphamide therapy, using pulmonary function test metrics (forced vital capacity).32 More recently, a randomized control trial comparing normobaric versus hyperbaric oxygen therapy for COVID-19 utilized oxygen supplementation levels as metric of clinical improvement.33 Building on this experience, our analysis demonstrates that patients treated with IVIG alone had improved oxygenation. This was aligned with an overall improvement in level-of-care, ICI-pneumonitis grade, and fewer deaths from steroid-refractory ICI-pneumonitis in these patients.\n\nWhile our study has several strengths, there were also important limitations. First, the retrospective nature of this study may limit its generalizability to other centers and clinical situations. Second, there is no standard definition for steroid-refractory ICI-pneumonitis, therefore, our study may have included patients whose ICI-pneumonitis was either steroid-dependent or steroid-resistant. This highlights the need to elucidate clearer definitions for these terms. Our estimate of the incidence of steroid-refractory ICI-pneumonitis is derived from those referred for multidisciplinary care, who likely represent more complex cases of ICI-pneumonitis, and thus may be an overestimation of the true incidence of this phenomenon. Improvement in steroid-refractory ICI-pneumonitis was assessed clinically, and in some cases, without imaging, therefore, some patients did not have CT imaging after receiving steroid therapy. Importantly, the conclusions of this study are limited by small patient numbers and the clinical status of patients at the time of immunosuppressive treatment. That is, patients treated with IVIG may have had less severe steroid-refractory ICI-pneumonitis at baseline (having less need for invasive oxygen supplementation), which may have contributed to the overall improved clinical findings for this group. Finally, since there are multiple guideline-based treatment options for this phenomenon, there was a lack of an established paradigm for patients being treated with either IVIG, infliximab, or the combination. This limits our ability to identify an immunosuppressive treatment that is truly preferable. The poorer outcomes faced by those who received infliximab (either as monotherapy or combination) may thus be due to confounding by indication and reflect timing of therapy or severity of steroid-refractory ICI-pneumonitis rather than a lack of efficacy of infliximab itself. We attempt to address some of these limitations by assessing the functional impact of ICI-pneumonitis through evaluation of oxygen requirement and level-of-care across all cases. A prospective trial is currently underway in order to evaluate these therapies for steroid-refractory ICI-pneumonitis (NCT04438382).\n\nIn conclusion, we report the incidence, clinical, radiologic features, management and outcomes of a cohort of patients with steroid-refractory ICI-pneumonitis. Steroid-refractory cases occurred in 18.5% among patients diagnosed with ICI-pneumonitis referred to a multidisciplinary team. The development of steroid-refractory ICI-pneumonitis occurred early in patients’ treatment course and demonstrated radiologic patterns of bilateral DAD. Importantly, patients treated with IVIG both demonstrated improvement in their oxygen requirements and level-of-care and also had reduced fatalities from steroid-refractory ICI-pneumonitis, while those treated with an infliximab-containing regimen had poorer outcomes. Prospective data from clinical trials in this area are needed to identify the optimum immunosuppressive approach for steroid-refractory ICI-pneumonitis.\n\nData availability statement\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nCollection of clinical, radiographic, and pathological data was approved by the local IRB at Johns Hopkins Hospital.\n\nTwitter: @AanikaBalaji, @DrJNaidoo\n\nAB and MH contributed equally.\n\nKS and JN contributed equally.\n\nCorrection notice: This article has been corrected since it was first published online. The dosage unit mg/kg has been amended to g/kg.\n\nContributors: AB, MH, CTL, JF, KM, JRB, PMF, CH, LZ, VL, PBI, SKD, KS, JN: identification, analysis, and interpretation of patient data. CTL: radiological data analysis and interpretation. AB, MH, JN, KS: study design, conceptualization, and manuscript writing. All authors read and approved the final manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 Wang DY, Salem J-E, Cohen JV, et al . Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018;4 :1721–8. 10.1001/jamaoncol.2018.3923 30242316\n2 Naidoo J, Wang X, Woo KM, et al . Pneumonitis in patients treated with Anti-Programmed Death-1/Programmed death ligand 1 therapy. J Clin Oncol 2017;35 :709–17. 10.1200/JCO.2016.68.2005 27646942\n3 Nishino M, Chambers ES, Chong CR, et al . Anti–PD-1 inhibitor–related pneumonitis in non-small cell lung cancer. 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Clinical outcomes of Anti-programmed death-1 Antibody–Related pneumonitis in patients with non-small cell lung cancer. SN Compr Clin Med 2020;2 :570–8. 10.1007/s42399-020-00259-3\n10 Andruska N, Mahapatra L, Hebbard C, et al . Severe pneumonitis refractory to steroids following anti-PD-1 immunotherapy. BMJ Case Rep 2018;366 :bcr-2018. 10.1136/bcr-2018-225937\n11 Petri CR, Patell R, Batalini F, et al . Severe pulmonary toxicity from immune checkpoint inhibitor treated successfully with intravenous immunoglobulin: case report and review of the literature. Respir Med Case Rep 2019;27 :100834. 10.1016/j.rmcr.2019.100834 31008047\n12 Beattie J, Fuentes P, Rizvi H, et al . Success and failure of additional immunosuppressants in steroid-refractory pneumonitis related to immune checkpoint blockade. J Clin Oncol 2020;38 :3078. 10.1200/JCO.2020.38.15_suppl.3078\n13 Nishino M, Sholl LM, Hodi FS, et al . Anti-PD-1–related pneumonitis during cancer immunotherapy. N Engl J Med 2015;373 :288–90. 10.1056/NEJMc1505197 26176400\n14 Kyi C, Hellmann MD, Wolchok JD, et al . Opportunistic infections in patients treated with immunotherapy for cancer. J Immunother Cancer 2014;2 :19. 10.1186/2051-1426-2-19 24991413\n15 Puzanov I, Diab A, Abdallah K, et al . Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for immunotherapy of cancer (SITC) toxicity management Working group. J Immunother Cancer 2017;5 :95. 10.1186/s40425-017-0300-z 29162153\n16 Brahmer JR, Lacchetti C, Schneider BJ, et al . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline. J Clin Oncol 2018;36 :1714–68. 10.1200/JCO.2017.77.6385 29442540\n17 Merrill SP, Reynolds P, Kalra A, et al . Early administration of infliximab for severe ipilimumab-related diarrhea in a critically ill patient. Ann Pharmacother 2014;48 :806–10. 10.1177/1060028014528152 24651165\n18 Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm 2009;24 :321–5. 10.1089/cbr.2008.0607 19538054\n19 Hallowell RW, Amariei D, Danoff SK. Intravenous immunoglobulin as potential adjunct therapy for interstitial lung disease. Ann Am Thorac Soc 2016;13 :1682–8. 10.1513/AnnalsATS.201603-179PS 27482830\n20 Shiuan E, Beckermann KE, Ozgun A, et al . Thrombocytopenia in patients with melanoma receiving immune checkpoint inhibitor therapy. J Immunother Cancer 2017;5 :8. 10.1186/s40425-017-0210-0 28239462\n21 Lau KHV, Kumar A, Yang IH, et al . Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle Nerve 2016;54 :157–61. 10.1002/mus.25141 27065302\n22 Naidoo J, Zhang J, Lipson EJ, et al . A multidisciplinary toxicity team for cancer Immunotherapy-Related adverse events. J Natl Compr Canc Netw 2019;17 :712–20. 10.6004/jnccn.2018.7268 31200355\n23 Bledsoe TJ, Nath SK, Decker RH. Radiation pneumonitis. Clin Chest Med 2017;38 :201–8. 10.1016/j.ccm.2016.12.004 28477633\n24 Akira M, Ishikawa H, Yamamoto S. Drug-induced pneumonitis: thin-section CT findings in 60 patients. Radiology 2002;224 :852–60. 10.1148/radiol.2243011236 12202725\n25 Johkoh T, Itoh H, Müller NL, et al . Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology 1999;211 :155–60. 10.1148/radiology.211.1.r99ap10155 10189465\n26 Rossi SE, Erasmus JJ, McAdams HP, et al . Pulmonary drug toxicity: radiologic and pathologic manifestations. Radiographics 2000;20 :1245–59. 10.1148/radiographics.20.5.g00se081245 10992015\n27 Kligerman SJ, Franks TJ, Galvin JR. From the radiologic pathology archives: organization and fibrosis as a response to lung injury in diffuse alveolar damage, organizing pneumonia, and acute fibrinous and organizing pneumonia. Radiographics 2013;33 :1951–75. 10.1148/rg.337130057 24224590\n28 Bhatraju PK, Ghassemieh BJ, Nichols M, et al . Covid-19 in Critically Ill Patients in the Seattle Region - Case Series. N Engl J Med 2020;382 :2012–22. 10.1056/NEJMoa2004500 32227758\n29 Weekley MS, Bland LE. Oxygen administration. In: StatPearls. Treasure Island, FL: StatPearls Publishing, 2020.\n30 Melamed IR, Borte M, Trawnicek L, et al . Pharmacokinetics of a novel human intravenous immunoglobulin 10% in patients with primary immunodeficiency diseases: Analysis of a phase III, multicentre, prospective, open-label study. Eur J Pharm Sci 2018;118 :80–6. 10.1016/j.ejps.2018.03.007 29522908\n31 Federal Drug Administration. REMICADE (infliximab) for IV injection. Federal Drug Administration, 2009.\n32 Wiertz IA, van Moorsel CH, Van Moorsel CH, et al . Cyclophosphamide in steroid-refractory hypersensitivity pneumonitis and non-classifiable interstitial lung disease. Eur Respiratory Soc 2018;51 :1702519.\n33 Boet S, Katznelson R, Castelluci LA, et al . Protocol for a multicentre randomized controlled trial of normobaric versus hyperbaric oxygen therapy for hypoxemic COVID-19 patients. medRxiv 2020.\n\n",
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"issn_linking": "2051-1426",
"issue": "9(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "immunotherapy; inflammation; programmed cell death 1 receptor",
"medline_ta": "J Immunother Cancer",
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"nlm_unique_id": "101620585",
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"pmid": "33414264",
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"title": "Steroid-refractory PD-(L)1 pneumonitis: incidence, clinical features, treatment, and outcomes.",
"title_normalized": "steroid refractory pd l 1 pneumonitis incidence clinical features treatment and outcomes"
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"abstract": "Treatment options for anticoagulated patients presenting with ischemic stroke are limited. Off-label use of idarucizumab to rapidly reverse the anticoagulant effect of dabigatran may ensure eligibility for thrombolytic therapy with alteplase. This case describes a 77-year-old white male who presented to the hospital 89 minutes after sudden onset of right-sided hemiparesis, dysarthria, and facial palsy. Significant history included atrial fibrillation and previous right-sided cortical stroke. Medication reconciliation revealed he was taking dabigatran 150 mg twice a day, with the last dose being 179 minutes before presentation. Neuroimaging revealed no new infarct or hemorrhage, and 60 minutes after arrival, a decision was made to give idarucizumab to reverse the anticoagulant effect of dabigatran. In the absence of any contraindication, he was then treated with intravenous alteplase and idarucizumab. No adverse outcomes were noted, and at discharge, his new stroke symptoms were completely resolved.",
"affiliations": "Questions or comments about this article may be directed to Sheila Jala, MHSSMCN, at Sheila.Jala@health.nsw.gov.au. She is the Stroke Clinical Nurse Consultant, Neurology Department, Royal North Shore Hospital, St Leonards, Australia.",
"authors": "Jala|Sheila|S|;O'Brien|Elizabeth|E|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000931:Antidotes; D005343:Fibrinolytic Agents; C000594745:idarucizumab; D010959:Tissue Plasminogen Activator; D000069604:Dabigatran",
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"issue": "51(1)",
"journal": "The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses",
"keywords": null,
"medline_ta": "J Neurosci Nurs",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000931:Antidotes; D000069604:Dabigatran; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D020127:Recovery of Function; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "8603596",
"other_id": null,
"pages": "21-25",
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"pmid": "30489421",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Treatment With Intravenous Alteplase for Acute Ischemic Stroke After Reversal of Dabigatran With Idarucizumab: A Case Study.",
"title_normalized": "treatment with intravenous alteplase for acute ischemic stroke after reversal of dabigatran with idarucizumab a case study"
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"abstract": "To describe an adult patient with Rasmussen's disease with focal dystonia as the most disabling symptom and the good response to unilateral globus pallidus internus (GPi) deep brain stimulation (DBS).\n\n\n\nRetrospective review of clinical records and diagnostic tests.\n\n\n\nThe patient had displayedmild focal seizures with sensory and motor symptoms on the left arm and hemiface since the age of 22. Ten years later she experienced abrupt onset of focal left dystonia involving mainly the leg. Brain MRI showed progressive right hemisphere atrophy, and 18 fluorodeoxyglucose-positron emission tomography (18FDG-PET) showed right hypometabolism mainly over the frontal and insular regions. Brain biopsy confirmed chronic encephalitis. The dystonia became very severe and made walking extremely difficult. Different treatments including dopaminergic, anticholinergic, immunomodulatory drugs and botulinum toxin were ineffective. Finally the patient was treated with unilateral GPi DBS. Shortly after the onset of the stimulation, the dystonia started to improve. Parameters have been adjusted, and 18 months after surgery the patient is able to walk and run unaided, although a mild left leg dystonia persists.\n\n\n\nRasmussen's disease may be difficult to diagnose in adult patients. Associated movement disorders may be more disabling than seizures. Focal dystonia may be treated successfully with DBS.",
"affiliations": "Epilepsy Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain mcarreno@clinic.ub.es.;Movement Disorder Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.;Department of Pathology, Hospital Clínic, Barcelona, Spain.;Department of Neurology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.;Epilepsy Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.;Movement Disorder Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.;EMG Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.;Department of Radiology, Hospital Clínic, Barcelona, Spain.;Epilepsy Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.;Epilepsy Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.;Department of Nuclear Medicine, Hospital Clínic, Barcelona, Spain.;Epilepsy Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.;Movement Disorder Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.;Functional Neurosurgery Unit, Department of Neurosurgery, Hospital Clínic, Barcelona, Spain.;Department of Psychiatry and Psychology, Hospital Clínic, Barcelona, Spain.;Department of Psychiatry and Psychology, Hospital Clínic, Barcelona, Spain.;Department of Psychiatry and Psychology, Hospital Clínic, Barcelona, Spain.;Functional Neurosurgery Unit, Department of Neurosurgery, Hospital Clínic, Barcelona, Spain.",
"authors": "Carreño|Mar|M|;Martí|Maria José|MJ|;Aldecoa|Ibán|I|;Painous|Celia|C|;Conde|Estefanía|E|;Valldeoriola|Francesc|F|;Valls-Solé|Josep|J|;Bargalló|Núria|N|;Gil|Francisco|F|;Manzanares|Isabel|I|;Setoain|Xavier|X|;Donaire|Antonio|A|;Muñoz|Esteban|E|;Roldán|Pedro|P|;Boget|Teresa|T|;Pintor|Luis|L|;Bailles|Eva|E|;Rumià|Jordi|J|",
"chemical_list": "D000927:Anticonvulsants",
"country": "England",
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"issue": "90(1)",
"journal": "Journal of neurology, neurosurgery, and psychiatry",
"keywords": "autoimmune encephalitis; dystonia; electrical stimulation; epilepsy; pet",
"medline_ta": "J Neurol Neurosurg Psychiatry",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001706:Biopsy; D001921:Brain; D002908:Chronic Disease; D046690:Deep Brain Stimulation; D004421:Dystonia; D004569:Electroencephalography; D004576:Electromyography; D004660:Encephalitis; D005260:Female; D005917:Globus Pallidus; D006801:Humans; D007866:Leg; D008279:Magnetic Resonance Imaging; D049268:Positron-Emission Tomography; D012640:Seizures; D015899:Tomography, Emission-Computed, Single-Photon",
"nlm_unique_id": "2985191R",
"other_id": null,
"pages": "108-110",
"pmc": null,
"pmid": "29986904",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unilateral pallidal stimulation for disabling dystonia due to Rasmussen's disease.",
"title_normalized": "unilateral pallidal stimulation for disabling dystonia due to rasmussen s disease"
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"abstract": "To determine if a transversus abdominis plane (TAP) block with liposomal bupivacaine reduces total postoperative opioid use in the first 72 hrs following laparoscopic or robotic hysterectomy compared to port-site infiltration with 0.25% bupivacaine.\nPatients received either a true TAP block procedure with 266 mg liposomal bupivacaine and 50 mg of 0.25% bupivacaine and sham port infiltration or sham TAP block procedure with true port-site infiltration with 100-125 mg of 0.25% bupivacaine. All patients had a standardized, scheduled, non-opioid pain management plan. The primary outcome was total IV morphine equivalents used in the first 72 hrs following surgery. Secondary outcomes included assessment of postoperative pain over the study period and quality of recovery measures.\nPatients undergoing TAP blockade required fewer total opioid equivalents during the observation period than patients allocated to infiltration (median 21 versus 25 mg IV Morphine equivalents, P=0.03). Opioid use was highest in the first 24 hrs after surgery, with less difference between the groups during days 2 and 3 postoperatively. There were 5 in the TAP group and 0 in the infiltration group were opioid free at 72 hrs. Those in the TAP group had improved quality of recovery (QoR15) with no change in overall benefit of analgesia score.\nTAP blockade reduced the requirement for opioid pain medication in the first 72 hrs after surgery, had more patients opioid free at 72 hrs, and improved patients' quality of their recovery.",
"affiliations": "Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA.;Department of Obstetrics, Gynecology and Women's Health, Minneapolis, MN, USA.;Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA.;Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA.;Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, CO, USA.;Department of Obstetrics, Gynecology and Women's Health, Minneapolis, MN, USA.",
"authors": "Hutchins|Jacob|J|;Argenta|Peter|P|;Berg|Aaron|A|;Habeck|Jason|J|;Kaizer|Alexander|A|;Geller|Melissa A|MA|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/JPR.S193872",
"fulltext": "\n==== Front\nJ Pain ResJ Pain ResJPRjpainresJournal of Pain Research1178-7090Dove 19387210.2147/JPR.S193872Clinical Trial ReportUltrasound-guided subcostal transversus abdominis plane block with liposomal bupivacaine compared to bupivacaine infiltration for patients undergoing robotic-assisted and laparoscopic hysterectomy: a prospective randomized study Hutchins et alHutchins et alHutchins Jacob 1Argenta Peter 2Berg Aaron 1Habeck Jason 1Kaizer Alexander 3Geller Melissa A 21 Department of Anesthesiology, University of Minnesota, Minneapolis, MN, USA2 Department of Obstetrics, Gynecology and Women’s Health, Minneapolis, MN, USA3 Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, CO, USACorrespondence: Jacob HutchinsDepartment of Anesthesiology, University of Minnesota, Mayo Mail Code 290, 420 Delaware ST SE, Minneapolis, MN55455, USATel +1 612 624 9990Fax +1 612 626 2363 Email hutc0079@umn.edu04 7 2019 2019 12 2087 2094 08 11 2018 25 6 2019 © 2019 Hutchins et al.2019Hutchins et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nTo determine if a transversus abdominis plane (TAP) block with liposomal bupivacaine reduces total postoperative opioid use in the first 72 hrs following laparoscopic or robotic hysterectomy compared to port-site infiltration with 0.25% bupivacaine.\n\nMethods\nPatients received either a true TAP block procedure with 266 mg liposomal bupivacaine and 50 mg of 0.25% bupivacaine and sham port infiltration or sham TAP block procedure with true port-site infiltration with 100–125 mg of 0.25% bupivacaine. All patients had a standardized, scheduled, non-opioid pain management plan. The primary outcome was total IV morphine equivalents used in the first 72 hrs following surgery. Secondary outcomes included assessment of postoperative pain over the study period and quality of recovery measures.\n\nResults\nPatients undergoing TAP blockade required fewer total opioid equivalents during the observation period than patients allocated to infiltration (median 21 versus 25 mg IV Morphine equivalents, P=0.03). Opioid use was highest in the first 24 hrs after surgery, with less difference between the groups during days 2 and 3 postoperatively. There were 5 in the TAP group and 0 in the infiltration group were opioid free at 72 hrs. Those in the TAP group had improved quality of recovery (QoR15) with no change in overall benefit of analgesia score.\n\nConclusion\nTAP blockade reduced the requirement for opioid pain medication in the first 72 hrs after surgery, had more patients opioid free at 72 hrs, and improved patients’ quality of their recovery.\n\nKeywords\nacute painregional painTAP blockliposome bupivacaine\n==== Body\nIntroduction\nThe United States is in the midst of an opioid crisis which has placed even more importance on finding novel ways to minimize the amount of opioids patients need after surgery. Multimodal analgesia involves using two or more non-opioid medications to both minimize pain and minimize opioids after surgery. One component of that is the utilization of local anesthetics for postoperative pain control. It has been shown that using local anesthetics in transversus abdominis plane (TAP) blocks effectively provides analgesia for surgery-associated pain following abdominal surgery.1–4 Blocks can be performed before or after surgery and provide somatic analgesia for the anterior abdomen while decreasing the potential need for opioid pain medication.5–7 Our group recently reported both retrospective and prospective studies demonstrating that a group-wide transition from either bupivacaine local infiltration or bupivacaine TAP blocks to TAP blocks with liposomal bupivacaine was associated with lower postoperative pain scores, decreases in perioperative nausea, shorter length of hospitalization, and analgesia up through 72 hrs after surgery.8–10\n\nThe current study was undertaken to more rigorously test the hypothesis that regional TAP block, using liposomal bupivacaine and bupivacaine reduces perioperative opioid requirements compared to the most common technique, local port-site infiltration using 0.25% bupivacaine.\n\nMethods\nAfter obtaining approval from the University of Minnesota Institutional Review Board (IRB protocol 1508M77443) and registration with clinicaltrials.gov (NCT 02519023), we conducted a single institution, randomized, double-blinded, placebo-controlled study comparing TAP blocks with liposomal bupivacaine and 0.25% bupivacaine to port-site infiltration with 0.25% bupivacaine at a large, metropolitan, teaching hospital. We chose to compare TAP blocks with liposomal bupivacaine and 0.25% bupivacaine to port-site infiltration with 0.25% bupivacaine and not a higher concentration of bupivacaine because previous studies have demonstrated no difference in wound infiltration when using a higher concentration of local anesthetic.11,12 Patient consent was written informed consent and this trial was conducted in accordance with the Declaration of Helsinki. We do not intend to share deidentified participant data. Patients were randomly assigned after obtaining informed consent by a research assistant using a randomization sequence from www.random.org. Treatment allocation was 1:1 using block allocation. All women undergoing planned hysterectomy using a minimally invasive approach (laparoscopy or robotic-assisted) who were over the age of 18 and had an American Society of Anesthesiologists physical status of I–III were eligible for inclusion. Exclusion criteria included: contradiction to regional anesthesia, history of opioid usage for >3 weeks of continuous usage prior to surgery, patients with known chronic pain syndrome, and patients with an inability to understand the consent process. Because discharge rate was an endpoint, patients with a planned surgical start time after 5 PM were excluded from participation. All patients were operated on by one of six fellowship-trained gynecologic oncology surgeons. Patients who required conversion of a planned minimally invasive surgery to an open procedure were excluded from analyses. Demographic and medical histories were abstracted from the patients’ charts.\n\nEach patient underwent both a TAP procedure prior to initiation of surgery and local infiltration of the port sites at the conclusion of surgery. Patients randomized to the experimental arm underwent bilateral infiltration in the TAP as previously described5 using 10 mL of 0.25% bupivacaine with 1:200,000 epinephrine followed by 10 mL of 1.3% liposomal bupivacaine and 10 mL of saline per side (with the liposomal bupivacaine and saline injected as a 50/50 mixture) on each side. Under ultrasound guidance, a 22-gauge 30° beveled echogenic needle was inserted until the tip pierced the transversus abdominis fascia. There the injectate was deposited between the fascia and the transversus abdominis muscle. The port sites were infiltrated with up to 10 mL of sham treatment (normal saline) at the conclusion of surgery. Patients randomized to the control arm had a sham TAP procedure performed using 30 mL of normal saline per side before surgery and underwent local injections at each port site using 10 mL of 0.25% bupivacaine with 1:200,000 epinephrine per port site prior to extubation.\n\nBoth the patient and the treating team (surgeon, anesthesiologist, and nurses) were blinded to the treatment assignment; and medications were repackaged by our investigational pharmacy to precluded incidental identification. There were no alterations in the protocol during the course of this study.\n\nDuring the surgery and the postoperative care, all opioids were recorded. Pain was assessed using a 10-point numerical scale at 1 and 2 hrs postoperatively by the post-anesthesia unit nurses and at 6, 24, 48, and 72 hrs postoperatively by a research assistant; all assessors were also blinded to treatment allocation. Oxycodone (5 mg oral tablet) was given in the post-anesthesia care unit for a pain score of 5 or greater. Postoperatively, all subjects were instructed to take acetaminophen (1 g every 6 hrs), ibuprofen (800 mg every 8 hrs) scheduled for 72 hrs. They also were instructed to take oxycodone (5–10 mg every 4 hrs) only as needed for pain that rated above 5 on a 10-point numerical scale.\n\nPhone interviews were conducted for patients that were discharged prior to planned assessment points. Medication usage and complications, including respiratory suppression and modality-related complications, were assessed at each time point. All patients were administered a Quality of Recovery-15 (QoR15)13 and the Overall Benefit of Analgesia Score (OBAS)14 instruments to assess their subjective sense of recovery at 72 hrs. Complications and/or readmissions occurring up to postoperative day 17 (2 weeks from the conclusion of planned data acquisition) were recorded.\n\nThe primary endpoint was total opioid usage by 72 hrs postoperatively. Secondary endpoints included: postoperative pain scores at 24, 48, and 72 hrs; daily opioid usage, QoR15 score at 72 hrs, OBAS score at 72 hrs, incidence of nausea and emesis within 72 hrs, length of time in recovery, postoperative admission rates, and complication rates.\n\nSample size was determined using median and range of opioid consumption data from our previous trial, in which patients undergoing TAP procedure with liposomal bupivacaine for hysterectomy used a median of 24.9 mg IV morphine equivalentwith ranges of 0–86.9 Using the methods of Hozo et al to estimate the mean and standard deviation of that group using the median and range, we had an estimate mean of 34 and standard deviation of 24.15 Using an α of 0.05, we determined that 62 patient endpoints (31 in each group) were required to provide a β of 0.8 to detect an effect size of at least 0.8 in opioid usage among patients receiving the experimental arm relative to the control arm. Assuming a dropout rate of 20% and conversion to open at 10%, the study was approved to enroll 80 patients. Due to an increased number of conversions to an open procedure, loss to follow-up and screen fails, approval to enroll to up to 95 was obtained.\n\nMost continuous outcomes were not normally distributed (P<0.05 for Shapiro–Wilk test for normality), therefore comparisons used the Wilcoxon rank sum test. Chi-squared tests were used to compare dichotomous variables. P-values for secondary analyses were not adjusted for multiple comparisons. All analyses were completed with R-project Software version 3.3.1.\n\nResults\nA total of 87 patients were enrolled between July 2016 through April 2017, 49 in experimental and 38 in control arm. There were 201 patients evaluated with 62 reaching final analysis (Figure 1). Six patients did not receive the allocated intervention due to a change in surgical plan after allocation. One patient discontinued intervention and seven were lost to follow-up. Eleven patients required a conversion to laparotomy (nine in the experimental and two in the bupivacaine infiltration groups). Twenty-seven patients underwent laparoscopy and 35 patients underwent a robotic-assisted approach. Patient demographics are described in Table 1. The groups were well balanced for relevant risk factors.Table 1 Demographics\n\n\tExperimental median (range) N=31\tControl median (range) N=31\tP-value\t\nAge years\t58 (32,77)\t62 (32,88)\t0.331\t\nBMI kg/m2\t33.1 (20.1,51.5)\t32.4 (18.4,60.4)\t0.495\t\nWeight kg\t91.9 (59.8,149.0)\t80.3 (45.3,154.2)\t0.360\t\nSurgical approach (number)\t\t\nLaparoscopic\t15\t12\t\t\nRobotic\t16\t19\t\t\nReason For surgery (number)\t\t\nEndometrial cancer\t15\t13\t\t\nEndometrial hyperplasia\t8\t5\t\t\nPelvic/uterine mass\t3\t5\t\t\nHereditary cancer (ER+ breast cancerc gene [BRCA])\t2\t1\t\t\nCervical dysplasia\t1\t0\t\t\nEndometrial intraepithelial neoplasia\t1\t0\t\t\nCervical cancer\t0\t3\t\t\nOther\t1\t4\t\t\nNotes: Liposomal bupivacaine transversus abdominis plane is experimental. Bupivacaine infiltration is control. \n\nAbbreviations: BMI, body mass index; ER, estrogen receptor.\n\n\nFigure 1 CONSORT flow diagram.\n\n\n\n\nTotal opioid use over the 72 hrs following surgery was lower for the experimental group compared to the control group (median of 20.8 mg versus 25 mg IV morphine equivalents respectively, P=0.03) (Table 2). Opioid requirements were highest immediately following surgery and lower on postoperative days 2 and 3 for most patients. Notably, five patients (16.1%) assigned to the experimental group were opioid free at 72 hrs all while all patients in the control group required at least some opioid pain medication (P=0.062). Non-opioid pain management was similar for both groups, with no significant difference in acetaminophen or ibuprofen use. We examined both acetaminophen and ibuprofen use because while the patients were instructed to take these medications as scheduled and oxycodone as needed we discovered during our data analysis that not every patient took the non-opioid medications as scheduled for the full 72 hrs. Thus, we compared the amount used of each medication by each group to ensure the use of acetaminophen and ibuprofen did not influence the end results. There was a significant reduction in median maximal pain scores among patients allocated to the experimental group versus control on postoperative days 1 and 3 but were similar on postoperative day 2 (Table 3). The total maximal pain score which was the sum of maximal pain scores from day 1 through day 3 was significantly lower in the experimental group vs the control group (8.0 (0,29) vs 13.0 (3,30); P=0.022).Table 2 Opioid use and presence of nausea and vomiting\n\nVariables\tExperimental median (range) or N (%)\tControl median (range) or N (%)\tP-value\t\nPACU opioid use (MME)\t8.3 (0,36)\t10.0 (0,40)\t0.154\t\n0–24 hrs opioid use (MME)\t7.5 (0,55)\t22.5 (0,90)\t0.135\t\n24–48 hrs opioid use (MME)\t0 (0,45)\t7.5 (0,38)\t0.271\t\n48–72 hrs opioid use (MME)\t0 (0,25)\t5 (0,34)\t0.240\t\n0–72 hrs opioid us (MME)\t20.8 (0,66)\t25.0 (5,72)\t0.034\t\nOpioid-free patients\t5 (16%)\t0 (0%)\t0.062\t\nNumber of patients with nausea/vomiting\t10 (32.2%)\t16 (51.6%)\t0.198\t\nNotes: Liposomal bupivacaine transversus abdominis plane is experimental. Bupivacaine infiltration is control. Opioid use is in morphine milligram equivalents (MME).\n\n\nTable 3 Maximum pain scores\n\nTime period\tExperimental median (range)\tControl median (range)\tP-value\t\n0–24 hrs\t3.0 (0,10)\t5.0 (2,10)\t0.018\t\n24–48 hrs\t3.0 (0,9)\t4.0 (0,10)\t0.219\t\n48–72 hrs\t2.0 (0,10)\t3.0 (0,10)\t0.009\t\n0–72 hrs\t8.0 (0,29)\t13.0 (3,30)\t0.022\t\nNotes: Liposomal bupivacaine transversus abdominis plane is experimental. Bupivacaine infiltration is control.\n\n\n\n\nGlobal measures of clinical effectiveness were mixed; there were significant differences in the QoR15 scores favoring the experimental group over the control group (median 126 versus 115, P=0.02), but no significant difference in the OBAS score (median 2 versus 2, P=0.11). Indirect measures of pain management including patient satisfaction and length of PACU or hospital stay were similar between the groups (Table 4).Table 4 Postoperative and satisfaction values \n\nVariables\tExperimental median (range) or N (%)\tControl median (range) or N (%)\tP-value\t\nTotal OBAS\t2.0 (0,10)\t3.0 (0,11)\t0.105\t\nTotal QoR15\t126 (79,146)\t115 (65,136)\t0.021\t\nSatisfaction with pain management\t30 (96.8%)\t24 (77.4%)\t0.058\t\nAdmitted to hospital same day\t11 (35.5%)\t16 (51.6%)\t0.306\t\nLength of time in recovery (hours)\t3.3 (1,8)\t3.1 (1,9)\t0.978\t\nNotes: Liposomal bupivacaine transversus abdominis plane is experimental. Bupivacaine infiltration is control.\n\n\n\n\nComplications were rare and not significantly different between the groups. Four patients in the control group had urinary retention versus one in the experimental group. One patient in the control group had constipation and one patient in the experimental group had a postoperative urinary tract infection. The incidence of nausea and/or emesis were similar between the experimental and control groups during the study window (33% vs 53%, P=0.19).\n\nThe Cohen’s d effect size for the primary outcome of 0–72 hrs total opioid equivalents using the nonparametric Kruskal–Wallis test is 0.559 (ie, what would be considered a medium effect size).16\n\nDiscussion\nThis prospective randomized, double-blinded trial demonstrates that preoperatively applied TAP block with liposomal bupivacaine reduced opioid consumption in the first 72 hrs compared to port-site infiltration with bupivacaine in patients undergoing elective robotic or laparoscopic hysterectomy. Patients in the experimental group reported less pain, required fewer total opioids, had a higher quality of recovery score, and were more likely to be opioid free 72 hrs after surgery compared to the control group. Despite these improvements, patient-assessments of the overall benefit of analgesia score were not significantly different, possibly reflecting the general tolerability of minimally invasive approaches to hysterectomy or the multimodal approach to pain management applied to both study arms.\n\nThese data suggest that regional anesthesia may effectively improve postoperative recovery across a spectrum of surgeries, and are consistent with multiple reports suggesting benefit from including regional anesthesia (specifically TAP blocks) in enhanced recovery after surgery (ERAS) protocols in laparoscopic abdominal procedures.17–24 Most of these reports compare a pre- and post-intervention cohort, a strategy with multiple inherent biases, but multiple prospective head-to-head comparisons have been reported as well, making some comparisons possible.\n\nDespite multiple studies suggesting the efficacy of ERAS principles, there remains no clear consensus regarding a single “optimal” strategy for perioperative pain management after minimally invasive hysterectomy or the ideal outcome measure. A recent study by Gasanova et al showed the analgesic superiority of liposomal bupivacaine infiltration when compared to bupivacaine TAP blocks for open hysterectomy, finding that patients treated with liposomal bupivacaine infiltration had improved pain scores through 48 hrs and less opioid use through 24 hrs when compared to bupivacaine TAP.25 Similarly, Barron et al compared infiltration with liposomal bupivacaine to bupivacaine in laparoscopic hysterectomy, and found the liposomal bupivacaine group to have superior analgesic results on both postoperative day 2 and day 3 but no difference in opioid use.26 These data combined with our current results and previous study results from our institution suggest that the use of liposomal bupivacaine irrespective of modality provides superior analgesia compared to bupivacaine when used in gynecologic procedures.8,9\n\nSimilar results have been recently reported in the urologic and general surgery literature; Hutchins et al reported a prospective randomized trial that TAP blockade with liposomal bupivacaine provided superior analgesic effect in patients undergoing donor nephrectomy compared to bupivacaine TAP blocks.10 Another study by Fayezizadeh et al compared the use of liposomal bupivacaine TAP blocks to no TAP blocks in abdominal wall reconstruction and again found superior analgesic effects in the liposomal bupivacaine TAP block group.6 Additionally, Stokes et al showed in a retrospective analysis that patients who received liposomal bupivacaine TAP blocks for colorectal surgery had improved pain control compared to those who received bupivacaine TAP blocks.27 All of these studies illustrate what we found in our study that the use of a TAP block with liposomal bupivacaine tends to provide superior analgesia than when either no local anesthetic or bupivacaine is used.\n\nOur group previously reported a prospective trial demonstrating that liposomal bupivacaine provided superior pain control to bupivacaine hydrochloride when used in a TAP block for pain control after robotic hysterectomy.4 The TAP blockade technique was identical to that used in the present study and, reassuringly, the 72 hrs opioid usage was similar to what we observed in the TAP group of the current trial, demonstrating reproducibility of the results. Interestingly, analysis of secondary endpoints in both studies observed the highest pain scores and greatest discrepancy between the experimental and control arms in the first 24 hrs postoperatively. In both studies, we compared liposomal bupivacaine to 0.25% bupivacaine and not 0.5% or 0.75% bupivacaine. This is because previous studies have shown no difference in outcomes with the higher local anesthetic concentrations in either TAP blocks or wound infiltration.11,12,28,29 However, this has not been studied and compared to liposomal bupivacaine as such it is not known if there is a difference in comparing a higher concentration of bupivacaine infiltration to liposomal bupivacaine TAPs. The higher local anesthetic dose in our experimental group could explain the decreased opioid use and decreased pain scores. Thus, future studies should attempt to have a more similar total dose of local anesthetic in both groups to see if that has an impact on pain and opioid use. Gasanova et al did compare 0.5% bupivacaine TAP blocks to liposomal bupivacaine infiltration and still found the liposomal bupivacaine infiltration to be superior to the 0.5% TAP blocks.25\n\nThe strengths of this study include the prospective, randomized, sham-controlled, and blinded design. The balance of known risk factors suggests that the randomization was effective and the central blinding of the medications should preclude incidental observer or reporter bias. The effect size was defined a priori and at a level which was felt to be clinically relevant. The inclusion of multiple surgeons as well as both laparoscopic and robotic-assisted approaches suggests the data can be extrapolated to the most common used minimally invasive approaches. Finally, the study was completed over a relatively short period of time, precluding the potential impact of changes in surgical practice.\n\nDespite these strengths, there are multiple weaknesses which should be considered in analyzing these data. All surgeries were performed by experienced surgeons, but specific strategies, including the number of ports used were not mandated. It is hoped that randomization and blinding would mitigate these differences, but standardization would potentially have assured this. Though the infiltration strategies were specified in the protocol, compliance was not measured; however as both the TAP infusate and local infusate were labeled to preclude identification, it is thought that non-compliance was unlikely to bias our results. Another weakness is that we used between 100 and 125 mg of bupivacaine in the control group site vs 50 mg of bupivacaine and 266 mg of liposomal bupivacaine in the experimental group and this disparity of dosing may have impacted outcomes. Also, the sham TAP procedure may have resulted in unintended pain just from the saline expansion of the TAP space. Finally, as most patients were treated in an outpatient setting, we relied on patient reporting of opioid use. While the accuracy of the reports cannot be confirmed, blinding of both the observer and reporter in this case is thought to decrease potential bias.\n\nIn conclusion, our study provides high-level evidence that TAP blockade with liposomal bupivacaine prior to a minimally invasive hysterectomy results in lower opioid usage in the first 72 hrs following surgery, without impairment of the quality of recovery. The procedure adds both time and cost to a patient’s perioperative experience relative to local infusion but did not impact their operative time or complication rate. These findings are critical in light of the urgent need to decrease prescription opioids with the ongoing opioid epidemic due to the high risk of addiction with such drugs. Further study will be necessary to optimize both the technique and patient selection to optimize the cost:benefit ratio of using perioperative TAP blocks.\n\nAcknowledgments\nThe authors would like to acknowledge Melissa Cohen (data collection), Britt Erickson (contributing surgeon and study design), Sally Mullany (contributing surgeon and study design), Colleen Rivard (contributing surgeon and study design), and Boris Winterhoff (contributing surgeon and study design) for their contributions to this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Interim data from this work were presented at the 2017 European Society of Regional Anesthesia meeting on September 13-16, 2017 in Lugano, Switzerland.\n\nImplication statement\nThis study illustrates the analgesic and patient satisfaction benefit of TAP blocks with liposome bupivacaine when compared to surgeon infiltration with bupivacaine in robotic and laparoscopic hysterectomy procedures.\n\nAuthor contributions\nJ Hutchins and AB contributed to design, interpretation, writing, and editing. PA, MAG, J Habeck contributed to design, implementation of study, writing, and editing. AK contributed to data analysis and writing and editing. All authors contributed to drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\nJ Hutchins is a speaker and consultant for, and has received research funds from Pacira Pharmaceuticals, he is a consultant for and owns stock with Insitu Biologics, he is also a consultant and speaker for Acel RX, a consultant for Worrell and Johnson and Johnson, speaker for Sonosite, and a consultant and speaker for, and has received research funds from Avanos. AB is a consultant for Avnanos and Pacira Pharmaceuticals inc. and reports personal fees from Pacira Pharmaceuticals Inc., Halyard Health, outside the submitted work. The authors report no other conflicts of interest in this work.\n==== Refs\nReferences\n1. Rafi \nAN . Abdominal field block: a new approach via the lumbar triangle . Anaesthesia . 2001 ;56 :1024 –1026 .\n2. McDonnell \nJG , O’Donnell \nBD , Tuite \nD , Farrell \nT , Power \nC . The regional abdominal field infiltration (RAFI) technique computerized tomographic and anatomical identification of a novel approach to the transversus abdominis neuro-vascular fascial plain . Anesthesiology . 2004 ;101 :A899 .\n3. McDonnell \nJG , O’Donnell \nB , Curley \nG , Heffernan \nA , Power \nC , Laffey \nJG . The analgesic efficacy of transversus abdominis plane block after abdominal surgery: a prospective randomized controlled trial . Anesth Analg . 2007 ;104 :193 –197 . doi:10.1213/01.ane.0000250223.49963.0f 17179269 \n4. Hebbard \nP , Fujiwara \nY , Shibata \nY , Royse \nC . Ultrasound-guided transversus abdominis plane (TAP) block . Anaesth Intensive Care . 2007 ;35 :616 –617 .18020088 \n5. Hebbard \nP . Subcostal transversus abdominis plane block under ultra-sound guidance . Anesth Analg . 2008 ;106 :674 –675 . doi:10.1213/ane.0b013e318161a88f 18227342 \n6. Fayezizadeh \nM , Majumder \nA , Neupane \nR , Elliott \nHL , Novitsky \nYW . Efficacy of transversus abdomninis plane block with liposomal bupivacaine during open abdominal wall reconstruction . A J Surg . 2016 ;212 :399 –405 . doi:10.1016/j.amjsurg.2015.12.026 \n7. Abdallah \nFW , Laffey \nJG , Halpern \nSH , Brull \nR . Duration of analgesic effectiveness after the posterior and lateral transversus abdominis plane block techniques for transverse lower abdominal incisions: a meta-analysis . Br J Anaesth . 2013 ;111 :721 –735 . doi:10.1093/bja/aet214 23811424 \n8. Hutchins \nJ , Isaksson Vogel \nR , Ghebre \nR , et al. Ultrasound-guided subcostal transversus abdominis plane infiltration with liposomal bupivacaine for patients undergoing robotic-assisted hysterectomy . Int J Gynecol Cancer . 2015 ;25 :937 –941 . doi:10.1097/IGC.0000000000000429 25790044 \n9. Hutchins \nJ , Delaney \nD , Isaksson Vogel \nR , et al. Ultrasound guided subcostal transversus abdominis (TAP) infiltration with liposomal bupivacaine for patients undergoing robotic assisted hysterectomy: a prospective randomized controlled study . Gynecol Onc . 2015 ;138 :609 –613 . doi:10.1016/j.ygyno.2015.06.008 \n10. Hutchins \nJL , Kesha \nR , Blanco \nF , Dunn \nT , Hochhalter \nR . Ultrasound-guided subcostal transversus abdominis plane blocks with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after laparoscopic hand-assisted donor nephrectomy: a prospective randomised observer-blinded study . Anaesthesia . 2016 ;71 :930 –937 . doi:10.1111/anae.13502 27238859 \n11. Pettersson \nN , Berggren \nP , Larsson \nM , Westman \nB , Hahn \nRG . Pain relief by wound infiltration with bupivacaine or high-dose ropivacaine after inguinal hernia repair . Reg Anesth Pain Med . 1999 ;24 :569 –575 .10588564 \n12. Mulroy \nMF , Burgess \nFW , Emanuelsson \nBM . Ropivacaine 0.25% and 0.5% buty not 0.125% provide effective wound infiltration analgesia after outpatient hernia repair but with sustained plasma drug levels . Reg Anesth Pain Med . 1999 ;24 :136 –141 .10204899 \n13. Stark \nPA , Myles \nPS , Burke \nJA . Development and psychometric evaluation of a postoperative quality of recovery score: the QoR-15 . Anesthesiology . 2013 ;118 :1332 –1340 . doi:10.1097/ALN.0b013e318289b84b 23411725 \n14. Lehmann \nN , Joshi \nGP , Dirkmann \nD , et al. Development and longitudinal validation of the overall benefit of analgesia score: a simple multi-dimensional quality assessment instrument . Br J Anaesth . 2010 ;105 :511 –518 . doi:10.1093/bja/aeq186 20693179 \n15. Hozo \nSP , Djulbegovic \nB , Hozo \nI . Estimating the mean and variance from the median, range, and the size of a sample . BMC Med Res Methodol . 2005 ;5 :13 . doi:10.1186/1471-2288-5-27 15840177 \n16. Ivarsson \nA , Andersen \nMB , Johnson \nU , Lindwall \nM . To adjust or not adjust: nonparametric effect sizes, confidence intervals, and real-world meaning . Pyschol Sport Exerc . 2013 ;14 :97 –102 . doi:10.1016/j.psychsport.2012.07.007 \n17. Keller \nDS , Tahilramani \nRN , Flores-Gonzalez \nJR , Ibarra \nS , Haas \nEM . Pilot study of a novel pain management strategy: evaluating the impact on patient outcomes . Surg Endosc . 2016 ;30 :2192 –2198 . doi:10.1007/s00464-015-4459-4 26275549 \n18. Alvarez \nMP , Foley \nKE , Zebley \nDM , Fassler \nSA . Comprehensive enhanced recovery pathway significantly reduces postoperative length of stay and opioid usage in elective laparoscopic colectomy . Surg Endosc . 2015 ;29 :2506 –2511 . doi:10.1007/s00464-014-4006-8 25480622 \n19. Keller \nDS , Ermlich \nBO , Schiltz \nN , et al. The effect of transversus abdominis plane blocks on postoperative pain in laparoscopic colorectal surgery: a prospective, randomized, double-blind trial . Dis Colon Rectum . 2014 ;57 :1290 –1297 . doi:10.1097/DCR.0000000000000211 25285696 \n20. Pisarka \nM , Pedziwiatr \nM , Major \nP , et al. Laparoscopic gastrectomy with enhanced recovery after surgery protocol: single-center experience . Med Sci Monit . 2017 ;23 :1421 –1427 . doi:10.12659/msm.898848 28331173 \n21. Helander \nEM , Webb \nMP , Bias \nM , Whang \nEE , Kaye \nAD , Urman \nRD . Use of regional anesthesia techniques: analysis of institutional enhanced recovery after surgery protocols for colorectal surgery . J Laparoendosc Adv Surg Tech . 2017 ;27 :898 –902 . doi:10.1089/lap.2017.0339 \n22. Pirrera \nB , Alagna \nV , Lucchi \nA , et al. Transversus abdominis plane (TAP) block versus epidural analgesia (TEA) in laparoscopic colon surgery in the ERAS program . Surg Endosc . 2018 ;32 :376 –382 . doi:10.1007/s00464-017-5686-7 28667547 \n23. Pedrazzani \nC , Menestrina \nN , Moro \nM , et al. Local wound infiltration plus transversus abdominis plane (TAP) block versus local infiltration in laparoscopic colorectal surgery and ERAS program . Surg Endosc . 2016 ;30 :5117 –5125 . doi:10.1007/s00464-016-4862-5 27005290 \n24. Kim \nAJ , Young \nRJ , Urman \nRD . The role of transversus abdominis plane blocks in enhanced recovery after surgery pathways for open and laparoscopic colorectal surgery . J Laparoendosc Adv Surg Tech . 2017 ;27 :909 –914 . doi:10.1089/lap.2017.0337 \n25. Gasanova \nI , Alexander \nJ , Ogunnaike \nB , et al. Transversus abdominis plane block versus surgical site infiltration for pain management after open total abdominal hysterectomy . Anesth Analg . 2015 ;121 :1383 –1388 . doi:10.1213/ANE.0000000000000909 26252171 \n26. Barron \nKI , Lamvu \nGM , Schmidt \nRC , Fisk \nM , Blanton \nE , Pantanwala \nI . Wound infiltration with extended-release versus short-acting bupivacaine before laparoscopic hysterectomy: a randomized controlled trial . JMIG . 2017 ;24 :286 –292 .\n27. Stokes \nAL , Adhikary \nSD , Quintili \nA , et al. Liposomal bupivacaine use in transversus abdominis plane blocks reduces pain and postoperative intravenous opioid requirement after colorectal surgery . Dis Colon Rectum . 2017 ;60 :170 –177 . doi:10.1097/DCR.0000000000000747 28059913 \n28. Ng \nSC , Habib \nAS , Sodha \nS , Carvalho \nB , Sultan \nP . High-dose versus low-dose local anaesthetic for transversus abdominis plane block post-caesarean delivery analgesia: a meta-analysis . Br J Anaesth . 2018 ;120 :252 –263 . doi:10.1016/j.bja.2017.11.084 29406174 \n29. Jalil \nRMA , Yahya \nN , Sulaiman \nO , et al. Comparing the effectiveness of ropivacaine 0.5% versus ropivacaine 0.2% for transabdominis plane block in providing postoperative analgesia after appendectomy . Acta Anaesthesiol Taiwan . 2014 ;42 :49 –53 . doi:10.1016/j.aat.2014.05.007\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7090",
"issue": "12()",
"journal": "Journal of pain research",
"keywords": "TAP block; acute pain; liposome bupivacaine; regional pain",
"medline_ta": "J Pain Res",
"mesh_terms": null,
"nlm_unique_id": "101540514",
"other_id": null,
"pages": "2087-2094",
"pmc": null,
"pmid": "31308734",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "10204899;10588564;11576144;15840177;17179269;18020088;18227342;20693179;23411725;23811424;25016507;25285696;25480622;25790044;26056753;26252171;26275549;27005290;27156796;27238859;27856385;28059913;28331173;28667547;28742434;28742435;29406174",
"title": "Ultrasound-guided subcostal transversus abdominis plane block with liposomal bupivacaine compared to bupivacaine infiltration for patients undergoing robotic-assisted and laparoscopic hysterectomy: a prospective randomized study.",
"title_normalized": "ultrasound guided subcostal transversus abdominis plane block with liposomal bupivacaine compared to bupivacaine infiltration for patients undergoing robotic assisted and laparoscopic hysterectomy a prospective randomized study"
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"companynumb": "US-PACIRA-201900250",
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"abstract": "Farber disease (FD) is a rare, lysosomal storage disorder caused by deficient acid ceramidase activity. FD has long been considered a fatal disorder with death in the first three decades of life resulting either from respiratory insufficiency as a consequence of airway involvement or from progressive neurodegeneration because of nervous system involvement. Peripheral symptoms associated with FD, including inflammatory joint disease, have been described to improve relatively rapidly after hematopoietic cell transplantation (HCT).\n\n\n\nTo evaluate the disease-specific status and limitations in the long-term follow-up after HCT, investigate genotype/phenotype correlations and the benefit of allogeneic HCT in FD patients with nervous system involvement.\n\n\n\nTransplant- and disease-related information of ten FD patients was obtained by using a questionnaire, physicians' letters and additional telephone surveys. ASAH1 gene mutations were identified to search for genotype/phenotype correlations.\n\n\n\nAfter mainly busulfan-based preparative regimens, all patients engrafted with one late graft loss. The inflammatory symptoms resolved completely in all patients. Abnormal neurologic findings were present pre-transplant in 4/10 patients, post-transplant in 6/10 patients. Mutational analyses revealed new mutations in the ASAH1 gene and a broad diversity of phenotypes without a genotype/phenotype correlation. With a median follow-up of 10.4 years, overall survival was 80% with two transplant-related deaths.\n\n\n\nAllogeneic HCT leads to complete and persistent resolution of the inflammatory aspects in FD patients. It appears to have no beneficial effect on progression of nervous system involvement. New mutations in the acid ceramidase gene were identified. A genotype/phenotype correlation could not be established.",
"affiliations": "Department of Pediatric Hematology and Oncology, University Medicine Greifswald, Ferdinand, Sauerbruch-Strasse, D-17475 Greifswald, Germany.;Cancer Research Centre of Toulouse, INSERM UMR1037, Toulouse, France.;Department Unit of Rare Diseases, Gaslini Institute, Genoa, Italy.;Department Unit of Rare Diseases, Gaslini Institute, Genoa, Italy.;Department of Stem Cell Transplantation, Children's Hospital at Dr von Haunersches Kinderspital, University of München, Munich, Germany.;Department of Pediatric Palliative Care, Children's Hospital at Dr von Haunersches Kinderspita, University of München, Munich, Germany.;Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt am Main, Germany.;Department of Stem Cell Transplantation, University Children's Hospital Zürich, Zürich, Switzerland.;Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany.;Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.",
"authors": "Ehlert|Karoline|K|;Levade|Thierry|T|;Di Rocco|Maja|M|;Lanino|Edoardo|E|;Albert|Michael H|MH|;Führer|Monika|M|;Jarisch|Andrea|A|;Güngör|Tayfun|T|;Ayuk|Francis|F|;Vormoor|Josef|J|",
"chemical_list": "C526693:ASAH1 protein, human; D055573:Acid Ceramidase",
"country": "United States",
"delete": false,
"doi": "10.1002/jimd.12043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0141-8955",
"issue": "42(2)",
"journal": "Journal of inherited metabolic disease",
"keywords": null,
"medline_ta": "J Inherit Metab Dis",
"mesh_terms": "D055573:Acid Ceramidase; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D055577:Farber Lipogranulomatosis; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D038622:Internationality; D008297:Male; D009154:Mutation; D015996:Survival Rate; D019172:Transplantation Conditioning",
"nlm_unique_id": "7910918",
"other_id": null,
"pages": "286-294",
"pmc": null,
"pmid": "30815900",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Allogeneic hematopoietic cell transplantation in Farber disease.",
"title_normalized": "allogeneic hematopoietic cell transplantation in farber disease"
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{
"companynumb": "DE-ASPEN-GLO2019DE003758",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
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"druga... |
{
"abstract": "BACKGROUND\nWith expanding applications and increasingly aggressive stress protocols, concerns about the safety of dobutamine stress echocardiography (DSE) have arisen. The purpose of this study was to analyse prospectively the safety, adverse event profile and complication rate of DSE.\n\n\nMETHODS\nProspective data were recorded in a consecutive series of 474 patients undergoing DSE. Dobutamine was administered intravenously in graded infusion, each stage over 3 min, at 10, 20, 40 and, if required, 50 micrograms/kg/min. Atropine (1 mg) was administered thereafter if the response remained suboptimal.\n\n\nRESULTS\nThe mean dose of dobutamine was 42 micrograms/kg/min, with 111 patients (23%) receiving 50 micrograms/kg/min. Atropine was required for 27 patients (6%). No patient died or suffered a myocardial infarction. Sustained ventricular tachycardia occurred in one patient, angina pectoris in 127 (27%), non-sustained ventricular tachycardia in eight (2%) and supraventricular tachycardia in 19 (4%). Profound bradycardia requiring cessation of the test occurred in one patient. Pulmonary oedema developed in one patient. A hypotensive response requiring cessation of the test was seen in one patient. Test termination because the patient complained of nausea, tremor or headache was not required.\n\n\nCONCLUSIONS\nDSE is safe. Side effects are rare and when they occur, are usually minor. Ischaemic pain is effectively treated by termination of the test and sublingual administration of nitrates.",
"affiliations": "Cardiovascular Research Group, Mater Misericordiae Hospital, Dublin, Ireland.",
"authors": "Hennessy|T G|TG|;Codd|M B|MB|;Kane|G|G|;McCarthy|C|C|;McCann|H A|HA|;Sugrue|D D|DD|",
"chemical_list": "D002316:Cardiotonic Agents; D004280:Dobutamine",
"country": "England",
"delete": false,
"doi": "10.1097/00019501-199703000-00009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6928",
"issue": "8(3-4)",
"journal": "Coronary artery disease",
"keywords": null,
"medline_ta": "Coron Artery Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris; D001145:Arrhythmias, Cardiac; D002316:Cardiotonic Agents; D003327:Coronary Disease; D004280:Dobutamine; D004452:Echocardiography; D004562:Electrocardiography; D005080:Exercise Test; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012449:Safety",
"nlm_unique_id": "9011445",
"other_id": null,
"pages": "175-8",
"pmc": null,
"pmid": "9237028",
"pubdate": "1997",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety of dobutamine stress echocardiography in 474 consecutive studies.",
"title_normalized": "safety of dobutamine stress echocardiography in 474 consecutive studies"
} | [
{
"companynumb": "IE-PFIZER INC-2021267495",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOBUTAMINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "A 66-year-old man was diagnosed with advanced type 2 gastric cancer and underwent total gastrectomy. The pathological diagnosis was T3N2H0P0CY0M0, stage ⅢB gastric cancer. Consequently, the patient received adjuvant S-1 therapy for 12 months. Thirty months after the operation, para-aortic lymph node recurrence was evident by computed tomography (CT). As a result, combination chemotherapy with paclitaxel, 5-fluorouracil, and cisplatin was initiated. However, after three courses of chemotherapy, abdominal CT showed progressive disease of the recurrent lymph node. Thereafter, radiotherapy at a total dose of 56 Gy was performed. After the radiotherapy treatment, abdominal CT demonstrated a remarkable reduction of the recurrent lymph node. The patient remains alive, with no signs of relapse, 70 months later. Therefore, this case suggests that radiotherapy may represent an effective treatment for localized remote lymph node recurrence of gastric cancer.",
"affiliations": "Dept. of Surgery, Niigata Cancer Center Hospital.",
"authors": "Migita|Kazuhiro|K|;Nashimoto|Atsushi|A|;Yabusaki|Hiroshi|H|;Matsuki|Atsushi|A|;Aizawa|Masaki|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000005:Abdomen; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001011:Aorta; D005743:Gastrectomy; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D012008:Recurrence; D013274:Stomach Neoplasms; D013997:Time Factors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1207-9",
"pmc": null,
"pmid": "26489550",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Abdominal Para-Aortic Lymph Node Recurrence of Gastric Cancer Treated with Radiotherapy, Surviving More Than 5 Years.",
"title_normalized": "a case of abdominal para aortic lymph node recurrence of gastric cancer treated with radiotherapy surviving more than 5 years"
} | [
{
"companynumb": "JP-BAUSCH-BL-2016-001665",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Adenovirus (ADV) infection after kidney transplantation (KT) causes significant morbidity. Patient characteristics and outcomes of ADV infection in KT recipients were investigated.\nAll adult KT recipients with ADV infection between January 2015 and June 2019 were included. ADV infection/disease was defined as detection of ADV DNA in clinical specimens/plus symptoms. Clinical and laboratory findings, treatments, and outcomes were assessed.\nAdenovirus infection was diagnosed in 24 of 751 (3.2%) KT recipients. Twenty (83%) were male with a median age of 47 years (interquartile range [IQR], 36-58). Fifteen (63%) underwent deceased donor KT, and 13 (54%) received induction therapy. Twenty-one (88%) and 4 (17%) patients developed hemorrhagic cystitis and disseminated disease, respectively. There were equal distributions of early-onset (EOI) (≤3 months) and late-onset (LOI) (>3 months) infections. Patients who were diagnosed with EOI had lower median absolute lymphocyte counts compared with those with LOI (735/mm3 [IQR, 543-1123] vs 1122/mm3 [IQR, 784-1344], P = .04). All achieved resolution after reduction of their immunosuppression regimen and 13 (54%) received cidofovir therapy. Eighteen (75%) developed allograft dysfunction, of which 67% were transient. One (4%) underwent nephrectomy for allograft failure and 1 (4%) died (non-ADV-related). Patients with EOI were more likely to receive cidofovir therapy (75% vs 33%, P = .04) and develop other opportunistic infections (75% vs 8%, P < .001).\nAdenovirus infection after KT typically involves a genitourinary system and transiently impairs an allograft function. Those who developed early infection tend to have more lymphopenia, coinfection, and receive antiviral therapy.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Excellence Center of Organ Transplantation, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Excellence Center of Organ Transplantation, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Bruminhent|Jackrapong|J|;Worawichawong|Suchin|S|;Tongsook|Chutatip|C|;Pasomsub|Ekawat|E|;Boongird|Sarinya|S|;Watcharananan|Siriorn P|SP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofz489",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofz489\nofz489\nMajor Article\nEpidemiology and Outcomes of Early-Onset and Late-Onset Adenovirus Infections in Kidney Transplant Recipients\nBruminhent Jackrapong 12 Worawichawong Suchin 23 Tongsook Chutatip 4 Pasomsub Ekawat 4 Boongird Sarinya 25 Watcharananan Siriorn P 1 1 \nDivision of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand\n2 \nExcellence Center of Organ Transplantation, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand\n3 \nDepartment of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand\n4 \nDivision of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand\n5 \nDivision of Nephrology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand\nCorrespondence: Jackrapong Bruminhent, MD, Division of Infectious Diseases, Department of Medicine and the Excellence Center of Organ Transplantation, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd., Ratchathewi, Bangkok, 10400, Thailand. Email: jbruminhent@gmail.com\n12 2019 \n13 11 2019 \n13 11 2019 \n6 12 ofz48913 8 2019 06 11 2019 11 11 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nObjective\nAdenovirus (ADV) infection after kidney transplantation (KT) causes significant morbidity. Patient characteristics and outcomes of ADV infection in KT recipients were investigated.\n\nMethod\nAll adult KT recipients with ADV infection between January 2015 and June 2019 were included. ADV infection/disease was defined as detection of ADV DNA in clinical specimens/plus symptoms. Clinical and laboratory findings, treatments, and outcomes were assessed.\n\nResults\nAdenovirus infection was diagnosed in 24 of 751 (3.2%) KT recipients. Twenty (83%) were male with a median age of 47 years (interquartile range [IQR], 36–58). Fifteen (63%) underwent deceased donor KT, and 13 (54%) received induction therapy. Twenty-one (88%) and 4 (17%) patients developed hemorrhagic cystitis and disseminated disease, respectively. There were equal distributions of early-onset (EOI) (≤3 months) and late-onset (LOI) (>3 months) infections. Patients who were diagnosed with EOI had lower median absolute lymphocyte counts compared with those with LOI (735/mm3 [IQR, 543–1123] vs 1122/mm3 [IQR, 784–1344], P = .04). All achieved resolution after reduction of their immunosuppression regimen and 13 (54%) received cidofovir therapy. Eighteen (75%) developed allograft dysfunction, of which 67% were transient. One (4%) underwent nephrectomy for allograft failure and 1 (4%) died (non-ADV–related). Patients with EOI were more likely to receive cidofovir therapy (75% vs 33%, P = .04) and develop other opportunistic infections (75% vs 8%, P < .001).\n\nConclusions\nAdenovirus infection after KT typically involves a genitourinary system and transiently impairs an allograft function. Those who developed early infection tend to have more lymphopenia, coinfection, and receive antiviral therapy.\n\nabsolute lymphocyte countcidofovircytomegalovirushemorrhagic cystitishuman adenoviruslymphopenia\n==== Body\nINTRODUCTION\nAdenovirus (ADV) is a nonenveloped double-stranded DNA virus that can cause a wide variety of clinical symptoms in humans. Adenovirus infection usually is asymptomatic or mild in immunocompetent individuals, but it can cause substantial morbidity in immunocompromised individuals [1]. In kidney transplant (KT) patients, ADV can cause localized and invasive end-organ diseases, including hemorrhagic cystitis, nephritis, pneumonitis, hepatitis, and gastroenteritis, which occasionally result in severe disseminated infection affecting multiple organs [2]. Only a few published reports mention the epidemiology of ADV infection in adult KT recipients. Our team retrospectively reviewed the incidence of ADV infection in adult KT recipients, and it was approximately 4.9% [3, 4]. As well as clinical and histopathological findings, nucleic acid amplification testing (NAAT) has been utilized for the diagnosis and monitoring of ADV infection after KT [2]. Virus-specific immune monitoring has recently been explored in the management of solid organ transplant (SOT) recipients [5, 6]. A low absolute lymphocyte count (ALC) is associated with early ADV infection resulting in significant morbidity after KT [3]. In a recent study, the restoration of ALC and ADV-specific T-cell immunity was correlated with viral clearance in KT recipients [7]. The management of ADV infection in SOT recipients mainly involves the reduction of their immunosuppression regimen combined with cidofovir therapy. For the last few years, NAAT and cidofovir have been accessible more at our transplant center. In the present study, we investigated the incidence of ADV infection after KT, aspects of its epidemiology, diagnosis, and management, and patient outcomes during the study period. Severe or disseminated ADV infection can require cidofovir therapy, but clinicians may hesitate to administer it to KT recipients in view of potential drug-related nephrotoxicity. Herein, we report our experiences in the management of ADV infection in KT recipients using cidofovir, in terms of clinical and virological resolutions, adverse reactions, allograft outcomes, and rates of rejection after therapy.\n\nMETHODS\nAll adult KT recipients diagnosed with ADV infection between January 2015 and June 2019 at a single transplant center in Bangkok, Thailand, were included in the present study. At our center, trimethoprim/sulfamethoxazole for pneumocystis prophylaxis, acyclovir for herpes simplex virus prophylaxis, and isoniazid for latent tuberculous infection therapy (regardless of status) were prescribed in all patients. Surveillance testing for cytomegalovirus (CMV) infection was performed due to a high prevalence of CMV-seropositive recipients, except for those requiring antithymocyte globulin induction therapy when (val)ganciclovir prophylaxis was implemented. Instead, surveillance for ADV infection was not performed routinely. Only patients clinically suspected of ADV infection or exhibiting a consistent etiology underwent investigation, and other pathogens that were potentially responsible for their symptoms were excluded in the patients included in the study. Adenovirus infection was defined as detection of ADV by NAAT in plasma or organ-specific specimens. Adenovirus disease was defined as ADV infection combined with at least 1 specific organ symptom. Disseminated ADV disease was defined as ADV disease with the involvement of at least 2 specific organs. Early (EOI) and late (LOI) onset ADV infection was defined as the occurrence within and after 3 months, respectively. Adenovirus DNA loads in plasma and urine specimens were measured via quantitative real-time polymerase chain reaction (PCR) assays (Adenovirus R-Gene US Real-Time PCR kit, bioMérieux, Marcy l’Etoile, France, from January 2015 until August 2018, and Adenovirus ELITe MGB Kit, ELITech Group SpA, Turin, Italy, thereafter). Adenovirus DNA load was reported as log10 copies/mL with limits of quantification of 2.0–6.0 log10 copies/mL for the R-Gene kit and 2.4–6.0 log10 copies/mL for the ELITe MGB kit. Adenovirus DNA in respiratory specimens was measured via qualitative PCR assays (xTAG Respiratory Viral Panel, Luminex Corporation, Austin, TX). Imaging and histopathologic analyses were performed as appropriate based on clinical indications. Plasma ADV DNA loads were determined at the time of diagnosis and twice weekly after treatment until no ADV DNA load was detected in 2 consecutive tests. Clinical resolution was defined as resolution of all symptoms. Virological resolution was defined as undetectable ADV DNA load in plasma or urine on 2 consecutive occasions. Demographic, clinical, laboratory, and virological data pertaining to all patients were recorded, as were treatment details. Intravenous (IV) cidofovir at a dose of 5 mg/kg, 1 mg/kg 3 times weekly, or 0.5 mg/kg 3 times weekly (those with creatinine clearance <50 mL/min) and IV immunoglobulin (IVIG) therapy at doses ranging from 0.5–2.0 g/kg was prescribed based on current guidelines [8]. Outcomes were recorded, including clinical and virological resolution, patient survival, allograft function, and opportunistic infection other than ADV. Allograft function was calculated as the estimated glomerular filtration rate as determined via either the Cockcroft‐Gault Formula, the Modification of Diet in Renal Disease Study Equation, or the Chronic Kidney Disease Epidemiology Collaboration equation. Transient allograft dysfunction was defined as any estimated glomerular filtration rate (eGFR) reduction compared to baseline that subsequently returned to baseline after the resolution of infection. Allograft failure and loss was defined as an irreversible estimated glomerular filtration rate reduction requiring chronic hemodialysis and/or retransplantation. The Institutional Review Board of the Faculty of Medicine of Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, approved the study protocol and waived the requirement to obtain any informed consent.\n\nStatistical Analyses\nPatient demographic data and clinical characteristics were assessed via descriptive analysis. Categorical data were described as absolute and relative frequencies, and continuous data were described as medians with interquartile ranges (IQRs). Clinical and laboratory findings, treatments, and outcomes in those with EOI and LOI were compared via the Mann-Whitney test and χ 2 test for continuous and categorical data, respectively. P values <.05 determined via a 2-tailed test were considered statistically significant. Statistical analyses were performed with Stata statistical software (version 15, StataCorp, LLC, College Station, TX).\n\nRESULTS\nEpidemiology and Demographic Data\nDuring the study period, 751 KTs were performed at our transplant center, and of these, 24 (3.2%) patients subsequently were diagnosed with ADV infection. Each and overall patient characteristics are shown in Table 1 and 2, respectively. Twenty (83%) patients were male and the median age was 47 years (IQR 36–58 years). Twenty-three (96%) patients received their first KT, and 15 patients (63%) received an allograft from a deceased donor. The most common etiology of end-stage renal disease was unknown (67%). Thirteen patients (54%) received induction therapy, including 12 (50%) who received antithymocyte globulin (ATG) and 1 (4%) who received interleukin-2 receptor antagonist. The majority was followed by maintenance therapy, including tacrolimus (75%), mycophenolate mofetil (83%), and prednisolone (100%). All donors and recipients were seropositive for CMV; hence, preemptive CMV monitoring was undertaken after KT in the majority of cases. One patient underwent a second KT requiring ATG induction therapy and received IV ganciclovir prophylaxis during admission and subsequently was switched to preemptive approaches for 3 months after KT. Trimethoprim/sulfamethoxazole for pneumocystis prophylaxis, acyclovir for herpes simplex virus prophylaxis, and isoniazid for latent tuberculous infection therapy were prescribed in all patients.\n\nTable 1. Baseline Characteristics of 24 Kidney Transplant Recipients\n\nCharacteristics, n (%)\tN = 24\t\nAge (median, IQR; years)\t47 (36–58)\t\nMale sex \t20 (83)\t\nEtiologies of end-stage renal disease\t\n- Diabetic nephropathy\t2 (8)\t\n- IgA nephritis\t3 (13)\t\n- Lupus nephritis\t2 (8)\t\n- Chronic glomerulonephritis\t1 (4)\t\n- Unknown etiology\t16 (67)\t\nDeceased-donor kidney transplantation\t15 (63)\t\nImmunosuppressive regimens\t\nInduction therapy\t\n- None\t11 (46)\t\n- Antithymocyte globulin \t1 (4)\t\n- Interleukin-2 receptor antagonist\t12 (50)\t\nMaintenance therapy\t\n- Tacrolimus\t18 (75)\t\n- Cyclosporine\t6 (25)\t\n- Mycophenolate mofetil\t20 (83)\t\n- Mycophenolate sodium \t3 (13)\t\n- Everolimus\t1 (4)\t\n- Prednisolone\t24 (100)\t\nAbbreviations: ADV, adenovirus; Ig, immunoglobulin; IQR, interquartile range.\n\nTable 2. Patient Characteristics, Management, and Outcomes in 24 Kidney Transplant Recipients Diagnosed With Adenovirus Infection\n\nPatient\tAge (Years)\tSex\tType of KT\tInduction Regimen\tMaintenance Regimens\tOnset After KT (Months)\tDiagnosis\tPlasma/urine Peak ADV DNA Load (Log Copies/mL)\tCidofovir\tIVIG\tClinical Outcome/Other Infections\tAllograft Outcome\tSurvived\t\n1\t37\tM\tLRKT\tIL2RA\tTAC Everolimus Pred\t0.50\tADV-associated hemorrhagic cystitis\t5.4/ > 6.0\tYes, 3 mg/kg/wk (divided as 3 times a wk) at wk 0 without oral probenecid\tYes, 0.5 g/kg at week 1\tResolved\tTransient allograft dysfunction\tYes\t\n2\t45\tM\tDDKT\tIL2RA\tTAC MMF Pred\t0.50\tDisseminated ADV disease (hemorrhagic cystitis, right epididymo-orchitis)\t> 6.0/> 6.0\tYes, 1.5–3.0 mg/kg/wk (divided as 3 times a wk) at wk 0,1 with oral probenecid\tYes, 2 g/kg (in 5 divided doses daily)\tResolved/ asymptomatic CMV infection\tTransient allograft dysfunction\tYes\t\n3\t38\tF\tDDKT\tIL2RA\tTAC MMF Pred\t0.50\tADV-associated hemorrhagic cystitis\t4.2/> 6.0\tYes, 1.5–3.0 mg/kg/wk (divided as 3 times a wk) at wk 0,1 with oral probenecid\tNo\tResolved\tTransient allograft dysfunction\tYes\t\n4\t58\tM\tLRKT\tIL2RA\tCsA MMF Pred\t0.75\tADV-associated hemorrhagic cystitis\t> 6.0/> 6.0\tYes, 5 mg/kg/wk at wk 0,1 with oral probenecid\tNo\tResolved/ asymptomatic CMV infection\tAllograft dysfunction\tYes\t\n5\t42\tM\tLRKT\tIL2RA\tTAC MMF Pred\t1\tAsymptomatic ADV infection\t3.6/4.6\tNo\tNo\tResolved/asymptomatic CMV infection\tNo allograft dysfunction\tYes\t\n6\t34\tF\tRe-DDKT\tATG\tTAC MMF Pred\t1\tADV-associated hemorrhagic cystitis, ADV interstitial nephritis\t> 6.0/> 6.0\tYes, 1.5 mg/kg/wk (divided as 3 times a wk) at wk 0,1,2 with oral probenecid\tYes, 2.8 g/kg (in 7 divided doses daily)\tResolved, human parainfluenza URI, E. coli UTI\tAllograft failure, acute antibody-mediated and T-cell–mediated rejection/graft loss\tYes\t\n7\t60\tM\tLRKT\tNone\tCsA MMF Pred\t1\tADV pneumonitis\t< LLOQ/not detected\tNo\tNo\tOrganizing pneumonia, resolved/asymptomatic CMV infection\tTransient allograft dysfunction\tNo (non-ADV – related)\t\n8\t56\tM\tLRKT\tNone\tCsA MMF Pred\t1.50\tADV-associated hemorrhagic cystitis\t5.1/> 6.0\tNo\tNo\tResolved\tTransient allograft dysfunction\tYes\t\n9\t42\tM\tLRKT\tIL2RA\tCsA MMF Pred\t1.50\tADV-associated hemorrhagic cystitis\t> 6.0/> 6.0\tYes, 5 mg/kg/wk at wk 0,1 without oral probenecid\tNo\tResolved/ESBL- producing E. coli UTI\tAllograft dysfunction, acute T-cell–mediated rejection\tYes\t\n10\t36\tM\tDDKT\tIL2RA\tTAC MMF Pred\t2\tDisseminated ADV disease (hemorrhagic cystitis, left epididymo-orchitis, pneumonitis, hepatitis)\t> 6.0/> 6.0\tYes, 3 mg/kg/wk (divided as 3 times a wk) at wk 0,1 with oral probenecid\tYes, 2 g/kg (in 5 divided doses daily)\tResolved/asymptomatic CMV infection\tTransient allograft dysfunction\tYes\t\n11\t59\tF\tDDKT\tIL2RA\tTAC MMF Pred\t2\tADV-associated hemorrhagic cystitis\t5.7/> 6.0\tYes, 5 mg/kg/wk at wk 0,1 with oral probenecid\tNo\tResolved/Enterococcus spp. UTI, BKVAN\tNo allograft dysfunction\tYes\t\n12\t30\tM\tLRKT\tNone\tCsA MMF Pred\t3\tADV syndrome (fever with leukopenia)\t5.5/N/A\tYes, 5 mg/kg/wk at wk 0, 1, 3, 5 with oral probenecid\tNo\tResolved/asymptomatic CMV infection\tNo allograft dysfunction\tYes\t\n13\t53\tM\tDDKT\tIL2RA\tTAC MMF Pred\t12\tADV-associated hemorrhagic cystitis, ADV interstitial nephritis\t5.4/> 6.0\tYes, 3 mg/kg/wk (divided as 3 times a wk) at wk 0,1 without oral probenecid\tYes, 2 g/kg (in 5 divided doses daily)\tResolved\tAllograft dysfunction\tYes\t\n14\t55\tF\tDDKT\tNone\tTAC MMF Pred\t16\tADV-associated hemorrhagic cystitis\t> 6.0/5.0\tYes, 3 mg/kg/wk (divided as 3 times a wk) at wk 0, then 5 mg/kg/wk at wk 1, 3, 5 without oral probenecid\tNo\tResolved\tNo allograft dysfunction\tYes\t\n15\t29\tM\tLRKT\tNone\tTAC MMF Pred\t15\tDisseminated ADV disease (hemorrhagic cystitis, hepatitis)\t> 6.0/> 6.0\tYes, 5 mg/kg/wk at wk 0,1 with oral probenecid\tNo\tResolved\tTransient allograft dysfunction\tYes\t\n16\t43\tM\tDDKT\tNone\tCsA MMF Pred\t22\tDisseminated disease (hemorrhagic cystitis, gastroenteritis, upper respiratory tract infection)\t5.7/> 6.0\tNo\tYes, 1 g/kg (in 3 divided doses daily)\tResolved/CMV syndrome, BKVAN\tTransient allograft dysfunction\tYes\t\n17\t49\tM\tDDKT\tIL2RA\tTAC MMF Pred\t22\tADV-associated hemorrhagic cystitis\t< LLOQ/5.6\tNo\tNo\tResolved\tTransient allograft dysfunction\tYes\t\n18\t62\tM\tDDKT\tNone\tTAC MPS Pred\t27\tADV-associated hemorrhagic cystitis\t5.3/> 6.0\tYes, 3 mg/kg/wk (divided as 3 times a wk) at wk 0 with oral probenecid\tNo\tResolved\tNo allograft dysfunction\tYes\t\n19\t59\tM\tDDKT\tNone\tTAC MMF Pred\t36\tADV-associated hemorrhagic cystitis\t> 6.0/> 6.0\tNo\tNo\tResolved\tTransient allograft dysfunction\tYes\t\n20\t54\tM\tDDKT\tIL2RA\tTAC MPS Pred\t39\tADV-associated hemorrhagic cystitis\t5.0/> 6.0\tNo\tNo\tResolved\tAllograft dysfunction\tYes\t\n21\t57\tM\tDDKT\tNone\tTAC MMF Pred\t40\tADV-associated hemorrhagic cystitis\t> 6.0/> 6.0\tNo\tNo\tResolved\tNo allograft dysfunction\tYes\t\n22\t67\tM\tDDKT\tNone\tTAC MPS Pred\t47\tADV-associated hemorrhagic cystitis\t3.9/> 6.0\tNo\tNo\tResolved\tTransient allograft dysfunction\tYes\t\n23\t24\tM\tLRKT\tNone\tTAC MMF Pred\t59\tADV-associated hemorrhagic cystitis\t5.1/> 6.0\tNo\tNo\tResolved\tTransient allograft dysfunction\tYes\t\n24\t34\tM\tDDKT\tIL2RA\tTAC MMF Pred\t63\tADV-associated hemorrhagic cystitis\t5.3/> 6.0\tNo\tNo\tResolved\tAllograft dysfunction, acute T-cell–mediated rejection\tYes\t\nAbbreviations: ADV, adenovirus; ALC, absolute lymphocyte count; ATG, antithymocyte globulin; BKVAN, BK polyomavirus-associated nephropathy; CMV, cytomegalovirus; CsA, cyclosporine; DDKT, deceased-donor kidney transplantation; DNA, deoxyribonucleic acid; ESBL, extended-spectrum beta-lactamase; F, female; IL2RA, interleukin-2 receptor antagonist; IVIG, intravenous immunoglobulin; LLOQ, lower limit of quantification; M, male; MMF, mycophenolate mofetil; MPS, mycophenolate sodium; LRKT, living-related kidney transplantation; N/A, not applicable; Pred, prednisolone; TAC, tacrolimus; UTI, urinary tract infection; wk, week.\n\nDiagnosis of Adenovirus Infection\nThe distribution of ADV infection onset after KT included 7 (29%) patients who developed infection within 1 month after KT, 5 (21%) between 1 and 3 months, and 12 (50%) after 1 year. There were equal distributions of patients diagnosed with EOI and LOI. Seven (29%) and 17 (71%) patients developed infection during a wet season (June to October) and a dry season (November to May), respectively. Among 7 patients (no respiratory symptoms) who underwent an investigation for possible route of acquisition, nasopharyngeal (NP) swab for ADV PCR was detectable in 2 (29%) patients. Among the LOI group, there was no patients who developed rejection within 3 months prior to ADV infection.\n\nThe infections were classified as asymptomatic ADV (4%), ADV disease (4%), hemorrhagic cystitis (88%), upper respiratory tract infection (4%), lower respiratory tract infection (8%), gastroenteritis (4%), hepatitis (8%), interstitial nephritis (8%), epididymo-orchitis (8%), and disseminated disease (17%). Initial presentations included dysuria (83%), gross hematuria (83%), fever (46%), sore throat/runny nose (4%), shortness of breath (8%), reduced allograft function (8%), and testicular pain (8%). Urinalysis results included pyuria (n = 7), microscopic hematuria (n = 8), and proteinuria (n = 10). Twenty-two (92%) patients had a detectable plasma ADV DNA load. Among those, the median initial plasma ADV load was 5.3 log copies/mL (IQR, 3.5–6.0 log copies/mL), then it increased to a median peak plasma ADV load of 5.5 log copies/mL (IQR, 5.3–6.0 log copies/mL). Twenty (83%) patients had detectable ADV DNA in urine and the majority (85%) had a urine ADV load of 6.0 log copies/mL or more. Two (17%) had detectable ADV DNA in respiratory specimens. At diagnosis, the median total white blood cell count was 6255/mm3 (IQR, 4208–10498/mm3) and the median ALC was 883/mm3 (IQR, 704–1398/mm3). Probable ADV pneumonitis was diagnosed via the detection of ADV DNA from bronchoalveolar lavage fluid via PCR, histopathology revealed no viral cytopathic change, and ADV in situ hybridization was not detected. Adenovirus interstitial nephritis was defined as the detection of viral cytopathic changes in tubular cells; ADV in situ hybridization was detected in 1 patient (proven) and it was inconclusive in another. In 2 patients, a diagnosis of probable epididymo-orchitis was supported by compatible symptoms, Doppler ultrasonography, and detectable ADV DNA in urine without histopathological confirmation that was deemed to be invasive. Clinical, radiological, and histopathological findings of representative patients who were diagnosed with hemorrhagic cystitis, pneumonitis, epididymo-orchitis, and interstitial nephritis are shown in Figure 1.\n\nFigure 1. Clinical, Radiographic, and Histopathology Findings in Kidney Transplant Recipients Diagnosed With Adenovirus Infection A, Gross hematuria. B, computed tomography of the chest showed newly developed patchy ground glass opacities with overlying consolidation opacity as well as several scattering solid nodules in both lungs. C, Doppler ultrasonography of the testes showed relatively enlarged size and increased vascularity of the right testis without mass or abnormal echogenicity. D, histopathology findings of the renal allograft biopsy showed lymphoplasmacytic infiltration in the interstitium with tubular injury and focal tubulitis. (PAS X 400).\n\nPatients who were diagnosed with LOI were slightly more frequent to present with hemorrhagic cystitis compared to EOI (100% vs 75%, P = .06) Table 3. Patients who were diagnosed with EOI were more likely to be febrile compared with those with LOI, but this was not statistically significant (83% vs 58%, P = .18). Patients with EOI had lower median absolute lymphocyte counts (ALCs) than those with LOI (735/mm3 [IQR, 543–1123] vs 1122/mm3 [IQR, 784–1344], P = .04). There was no different in median peak plasma and urine ADV DNA load between 2 groups.\n\nTable 3. Clinical, Laboratory, Management, and Outcome Data Derived From 24 Kidney Transplant Recipients Who Were Diagnosed with Early and Late Onset ADV Infection\n\n\tEarly onset (n = 12)\tLate onset (n = 12)\t\nP value\t\n\nADV infection, n (%)\n\t\n- Asymptomatic infection\t1 (8)\t0\t.30\t\n- Hemorrhagic cystitis\t9 (75)\t12 (100)\t.06\t\n- Interstitial nephritis\t1 (8)\t1 (8)\t>.999\t\n- Hepatitis\t1 (8)\t1 (8)\t>.999\t\n- Upper respiratory tract infection\t0\t1 (8)\t.30\t\n- Pneumonitis\t2 (17)\t0\t.14\t\n- Gastroenteritis\t0\t1 (8)\t.30\t\n- Epididymo-orchitis\t2 (17)\t0\t.14\t\n- ADV syndrome\t1 (8)\t0\t.30\t\n- Disseminated infection\t2 (17)\t2 (17)\t>.999\t\n\nClinical presentations, n (%)\n\t\n- Fever\t10 (83)\t7 (58)\t.18\t\n- Dysuria\t9 (75)\t11 (92)\t.27\t\n- Gross hematuria\t9 (75)\t11 (92)\t.27\t\n- Testicular pain\t2 (17)\t0\t.14\t\n- Shortness of breath\t2 (17)\t0\t.14\t\n\nLaboratory findings at diagnosis, median (IQR)\n\t\n- Total white blood cell count (cells/mm3)\t7670 (4013–10658)\t6050 (4208–7423)\t.37\t\n- Absolute lymphocyte count (cells/mm3)\t735 (543–1122)\t1122 (784–1344)\t.04\t\n- Peak urine ADV DNA load (log10 copies/mL)\t6.0 (6.0–6.0)\t6 (6.0–6.0)\t>.999\t\n- Peak plasma ADV DNA load (log10 copies/mL)\t5.7 (5.1–6.0)\t5.4 (5.1–6.0)\t.70\t\n\nTreatment, n (%)\n\t\n- Cidofovir\t9 (75)\t4 (33)\t.04\t\n- Intravenous immunoglobulin\t4 (25)\t2 (17)\t.35\t\n\nOutcome, n (%)\n\t\n- Time to virological resolution (median, IQR; days)\t56 (35–60)\t43 (28–52)\t.24\t\n- Time to clinical resolution (median, IQR; days)\t10 (5–17)\t6 (5–11)\t.30\t\n- Opportunistic infection other than ADV\t9 (75)\t1 (8)\t<.001\t\n- Cytomegalovirus coinfection\t6 (50)\t1 (8)\t.03\t\n- Normal allograft function\t3 (25)\t3 (25)\t1.00\t\n- Transient allograft dysfunction\t6 (50)\t6 (50)\t1.00\t\n- Allograft dysfunction\t2 (17)\t3 (25)\t.62\t\n- Allograft failure\t1 (8)\t0\t.30\t\n- Acute T-cell–mediated rejection\t2 (17)\t1 (8)\t.54\t\n- Antibody-mediated rejection\t1 (8)\t0\t.30\t\n- Hemodialysis required after transplantation\t1 (8)\t0\t.30\t\n- Mortality (non-ADV–related)\t1 (8)\t0\t.30\t\nAbbreviations: ADV, adenovirus; DNA, deoxyribonucleic acid; IQR, interquartile range; RBC, red blood cell.\n\nManagement\nAfter diagnosis the immunosuppression regimen was reduced in all patients. Mycophenolic acid was discontinued. The median dose reduction of mycophenolate mofetil was 1.5 g (IQR, 1.25–1.50 g). Calcineurin inhibitors were reduced to maintained trough levels of 3–5 ng/mL in patients who were on tacrolimus and 50–100 ng/mL in patients who were on cyclosporine. Prednisolone was maintained as tolerated, to a median dose of 7.5 mg/day (IQR, 5–15 mg/day). Thirteen (54%) patients received IV cidofovir with prehydration and posthydration with 1 L of 0.9% normal saline solution, and, of those patients, 10 (77%) received oral probenecid with dosing of a total of 4 g oral probenecid,with 2 g 3 hours prior to infusion, 1 g 2 hours after infusion, and 1 g 8 hours after infusion. The details of cidofovir dosing are shown in Table 2. Five patients received weekly IV cidofovir at a dose of 5 mg/kg, 5 patients received 1 mg/kg 3 times per week, and 3 patients received 0.5 mg/kg 3 times per week (those with creatinine clearance <50 mL/min) for 2 consecutive weeks followed by every other week until clinical and viral clearance in most cases. Different doses of cidofovir was selected on clinician preference based on the doses that were recommended by an international guideline. Patients diagnosed with EOI were more likely to receive IV cidofovir therapy (75% vs 33%, P = .04) compared with those who diagnosed with LOI. Among 13 patients who received IV cidofovir, the creatinine increased in 9 (69%) patients after therapy and 5 (38%) returned to baseline. Allograft dysfunction occurred more frequently in patients who received IV cidofovir therapy compared with those withheld from therapy (38% vs 18%, P = .66) as well as those received once weekly (40%) compared with thrice-weekly regimen (40% vs 25%, P = .57), though the trends were not statistically significant. No patients developed uveitis, significant neutropenia, anemia, or proteinuria, or adverse reactions to probenecid, including fever, rash, headache, or nausea.\n\nSix (25%) patients received IVIG at doses ranging from 0.5–2.0 g/kg as adjunctive therapy. After resolution, all patients were restarted gradually on mycophenolic acid closed to baseline dosing. Calcineurin inhibitors were kept at appropriate trough levels and low dose prednisolone was maintained.\n\nOutcome\nIn all patients, the median time from diagnosis to clinical resolution of 9 days (IQR, 5–13 days) was significantly shorter than virological resolution of 46 days (IQR, 30–60 days) (P < .001). Infection completely resolved without complications in 23 patients (96%). One patient was diagnosed with probable ADV pneumonitis that was subsequently complicated by organizing pneumonia requiring a tapered course of prednisolone therapy. Recurrence with low-level ADV DNAemia that was not clinically significant occurred in 1 patient (4%) after the resumption of immunosuppressant. Ten patients (42%) developed opportunistic infections other than ADV, including CMV (including asymptomatic CMV infection; n=6), CMV syndrome (n=1), BK polyomavirus-associated nephropathy (n=2), human para-influenza virus upper respiratory tract infection (n=1), urinary tract infection with Enterococcus spp. (n=1), Escherichia coli (n=1), and extended-spectrum beta-lactamase-producing E. coli (n=1). Patients diagnosed with EOI were more likely to develop opportunistic infection other than ADV (75% vs 8%, P < .001), including CMV coinfection (50% vs 8%, P = .03), compared with those diagnosed with LOI.\n\nEighteen (75%) patients developed allograft dysfunction, and 67% of these were transient. Three (13%) patients developed acute T-cell–mediated allograft rejection after therapy, and 1 (4%) of them developed concurrent antibody-mediated rejection. One patient (4%) underwent nephrectomy for allograft failure and 1 (4%) died from a non-ADV–related cause.\n\nDISCUSSION\nHerein, we have reported the most recent and comprehensive data on the epidemiology, clinical characteristics, management, and outcomes of ADV infection in KT recipients from a retrospectively analyzed cohort at a single transplant center. The genitourinary tract was the most commonly involved system, followed by some unusual presentations rarely seen in clinical practice. Nucleic acid amplification testing with or without histopathological testing is the main diagnostic tool used to achieve a diagnosis. Patients who developed ADV infection early posttransplant seem to have more lymphopenia at diagnosis, opportunistic infection (other than ADV), and receive cidofovir therapy. Although reduction of the immunosuppression regimen combined with IV cidofovir evidently can achieve a favorable clinical and virological outcome, transient allograft dysfunction remains a substantial consideration.\n\nKidney transplant recipients have been considered to be at low to moderate risk of ADV infection compared with those who undergo liver or thoracic organ transplantation, likely due to less intense immunosuppression [9]. A large cohort study of KT performed previously at our center provided an opportunity to investigate this uncommon infection after KT. The prevalence of ADV infection in KT recipients were decreased slightly during 2 periods of time approximately a decade apart, 4.9% from 2007 to 2010 [3], and 3.2% during the current study period of 2015 to 2019. Time to diagnosis varied similarly in the 2 studies, ranging widely from a few months to years after KT [3]. Although ADV infection can occur all year round without seasonal variability [10], the majority of ADV infection in our cohort occurred during the wet season. Kidney transplant recipients with ADV infection can present with symptoms ranging from absent or mild to severe disseminated disease [8]. The present cohort was concordant with previous studies with regard to similar initial presentations and organ involvement of ADV infection with hemorrhagic cystitis in the majority of patients. Nanmoku et al [11] recently reported a high incidence of ADV genitourinary tract infection (4.5%) in their cohort. In contrast, we also detected uncommon presentations of ADV infection that are somewhat unique and specific to immunocompromised patients, such as pneumonitis, epididymo-orchitis, and interstitial nephritis, due to the availability of NAAT and immunohistochemical testing at our institution, in which clinicians who are managing these patients should be aware of. In the present study, median initial and peak ADV loads were both >5 log copies/mL, which is greater than they were in a previous study [3].\n\nObservations in the present study were concordant with our previous study in which patients with early infection (onset within 3 months after KT) that was more severe tended to have lower ALCs at weeks 1 and 3 than patients with late infections [3]. In the present cohort, half of the patients developed ADV infection within 3 months post-KT, and these patients exhibited variable ALCs. Nierenberg et al [12] reported that lymphopenia (<500 cells/mm3) measured prior to transplantation is a potential tool for predicting opportunistic infection after liver transplantation. Absolute lymphocyte count indirectly represents impairment of nonspecific cell-mediated immunity (CMI) in these patients. Our team recently reported low nonspecific CMI as indicated by the total lymphocyte count and lymphocyte subset proportions (CD4+ and CD8+ T-cells), as well as ADV-specific CMI in patients diagnosed with ADV infection, wherein this immunity was later restored after resolution [7]. Because there is no commercial assay available for measuring ADV-specific immunity in clinical practice, we encourage the use of a practical and simple tool to at least stratify and predict those who may develop severe infection.\n\nAlthough no ideal management strategy for ADV infection has been established, all patients underwent reduction of their immunosuppression regimen as recommended in a current guideline [8], including discontinuation of mycophenolate, maintenance of low calcineurin inhibitor trough level, and the lowest dose of prednisolone tolerated [2] in the present study. More than half of the patients received IV cidofovir (compared with a quarter in a previous study [13]) due to the recent increased availability of the medication at our institution. Cidofovir was considered to be cost-prohibitive in our resource-limited setting. Some patients were able to complete the induction phase but not the maintenance phase as recommended in the aforementioned guideline [8]. However, both early clinical and virological improvement in those patients would be less likely to require further treatment. The combination of an anti-ADV agent and optimized immunosuppression has been shown to improve clinical and virological outcomes, and the strategy reportedly facilitates more rapid clinical resolution although it takes approximately 2 months to achieve virological clearance. The present patients tolerated IV cidofovir well, without hematological or ocular toxicities. We found those who received IV cidofovir were more likely to develop allograft dysfunction. However, the majority of the patients developed transient increases in serum creatinine, which is known to be derived from multifactorial etiologies, including cidofovir exposure, but the incidence of permanent damage in this context is reportedly low [14]. Patients diagnosed with EOI were more likely to receive IV cidofovir therapy; this could be explained by the complexity of the infection during a period with more intense immunosuppression. We found less allograft dysfunction had occurred in those who received a once-weekly regimen compared with the thrice-weekly regimen (40% vs 25%) and a true explanation for this different outcome has been elucidating. However, we did not observe other significant complications apart from nephrotoxicity in our cohort.\n\nAlthough a few patients did not receive oral probenecid (because a high urine drug concentration was achieved in order to treat ADV genitourinary tract infection), the allograft outcome was acceptable. This may have been due to aggressive IV saline hydration concomitantly with cidofovir therapy. However, it is important to monitor renal function closely (including proteinuria) both before and during treatment.\n\nAnti-ADV agents were implemented in the majority of the current patients who were diagnosed with ADV disease, facilitating evaluation of the efficacy of these agents. Cidofovir with and without IVIG has been reported to be effective in some SOT, including KT recipients diagnosed with disseminated disease [15, 16]. The true efficacy of cidofovir and/or IVIG is difficult to assess based on outcome, because all patients underwent reduction of their immunosuppression regimen. Because there has been no randomized control trial of cidofovir and IVIG to support efficacy, a current guideline suggested considering those agents for severe or disseminated ADV disease and hypogammaglobulinemia, respectively [8].\n\nApart from antiviral agents and adjunctive therapies, it has been reported that ADV-specific immunity is related to ADV clearance in KT recipients [5, 7]. Allograft rejection may occur as a consequence of reduction of an immunosuppressive regimen. Therefore, 1 goal is to balance immunosuppression during infection and maintain the allograft by resuming immunosuppression as soon as the infection is controlled. A future study measuring specific ADV-specific immunity in order to facilitate optimal management in this setting is encouraged. Although KT recipients with disseminated disease are at a high risk of mortality, there were no cases of disseminated disease-associated mortality in the present study. That was likely due to early diagnosis, prompt reduction of an immunosuppressive regimen, and vigilant management [6].\n\nThe current study had some limitations. There is an inherent possibility of bias due to the retrospective nature of the study. The true incidence of ADV infection likely was underestimated due to a lack of preemptive ADV load monitoring, which would have facilitated the diagnosis of asymptomatic ADV infection. Such preemptive ADV load monitoring currently is not advocated, and, in Humar et al [17], half of the patients developed transient and self-limiting reactivation without clinical significance. Accordingly, preemptive monitoring is not recommended in the aforementioned guidelines [8]. Additionally, approximately one-third of patients had CMV coinfection, a sole effect of each pathogen that contributes to the idea that the symptoms could be limited. An immunomodulatory effect of CMV infection is known to place patients at risk of infection from another opportunistic pathogen [18]. Last, because the rarity of the disease could limit a sample size, independent risk factors analyzed from multivariate analysis to investigate from this small cohort would not be allowed.\n\nDuring recent years, ADV has remained a relatively uncommon pathogen that can cause genitourinary tract infection in adult KT recipients. Low ALC at the time of diagnosis may predict an increased risk of ADV infection in KT recipients early post KT. Effective management is facilitated by early diagnosis and is assisted by readily available NAAT, supportive care, and reduction of immunosuppression. This combination evidently can achieve favorable clinical and virological outcomes. Although transient worsening of allograft function may occur, it is not associated with high mortality.\n\nAcknowledgments\nWe thank Darunee Chotiprasitsakul, Nantanee Rungpethwong, Subencha Pinsai, and Charat Thongprayoon for their helpful participation in discussions. We also thank the Ramathibodi Kidney Transplant Cohort Study team: Vasant Sumethkul, Somnuek Domrongkitchaiporn, Surasak Kantachuvesiri, Bunyong Phakdeekitcharoen, Chagriya Kitiyakara, Sinee Disthabanchong, Atiporn Ingsathit, Arkom Nongnuch, Montira Assanatham, and Punlop Wiwattanathum.\n\n\nAuthor contributions. J.B. and S.P.W. conceptualizatized this work. J.B., S.W., and C.T. performed data collection. J.B. analyzed the data and composed the original draft of the manuscript. This manuscript was revised and edited by J.B., S.W., C.T., E.P., S.B., and S.P.W. \n\n\nFinancial support. None reported.\n\n\nPotential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nBruminhent J , Watcharananan SP \nAdenovirus beyond “pink eye”\n. J Infect Dis Antimicrob Agents 2018 ; 35 :191 –4\n.\n2. \nFlorescu DF , Stohs EJ \nApproach to infection and disease due to adenoviruses in solid organ transplantation\n. Curr Opin Infect Dis 2019 ; 32 :300 –6\n.31116132 \n3. \nWatcharananan SP , Avery R , Ingsathit A , et al. \nAdenovirus disease after kidney transplantation: course of infection and outcome in relation to blood viral load and immune recovery\n. Am J Transplant 2011 ; 11 :1308 –14\n.21449944 \n4. \nWatcharananan SP , Junchotikul P , Srichanrusmi C , et al. \nAdenovirus infection after kidney transplantation in Thailand: seasonal distribution and potential route of acquisition\n. Transplant Proc 2010 ; 42 :4091 –3\n.21168635 \n5. \nSester M , Leboeuf C , Schmidt T , Hirsch HH \nThe “ABC” of virus-specific T cell immunity in solid organ transplantation\n. Am J Transplant 2016 ; 16 :1697 –706\n.26699950 \n6. \nFlorescu MC , Miles CD , Florescu DF \nWhat do we know about adenovirus in renal transplantation?\nNephrol Dial Transplant 2013 ; 28 :2003 –10\n.23493328 \n7. \nBruminhent J , Apiwattanakul N , Hongeng S , Kantachuvesiri S , Watcharananan SP \nAbsolute lymphocyte count and human adenovirus-specific T-cell immune restoration of human adenovirus infection after kidney transplantation\n. J Med Virol 2019 ; 91 :1432 –9\n.30905076 \n8. \nFlorescu DF , Schaenman JM ; AST Infectious Diseases Community of Practice \nAdenovirus in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice\n. Clin Transplant 2019 ; e13527 . 30859626 \n9. \nFlorescu DF , Kwon JY , Dumitru I \nAdenovirus infections in heart transplantation\n. Cardiol Rev 2013 ; 21 :203 –6\n.23535527 \n10. \nIson MG \nAdenovirus infections in transplant recipients\n. Clin Infect Dis 2006 ; 43 :331 –9\n.16804849 \n11. \nNanmoku K , Ishikawa N , Kurosawa A , et al. \nClinical characteristics and outcomes of adenovirus infection of the urinary tract after renal transplantation\n. Transpl Infect Dis 2016 ; 18 :234 –9\n.26919131 \n12. \nNierenberg NE , Poutsiaka DD , Chow JK , et al. \nPretransplant lymphopenia is a novel prognostic factor in cytomegalovirus and noncytomegalovirus invasive infections after liver transplantation\n. Liver Transpl 2014 ; 20 :1497 –507\n.25205044 \n13. \nBruminhent J , Rotjanapan P , Watcharananan SP \nEpidemiology and outcome of ganciclovir-resistant cytomegalovirus infection after solid organ transplantation: a single transplant center experience in Thailand\n. Transplant Proc 2017 ; 49 :1048 –52\n.28583524 \n14. \nNeofytos D , Ojha A , Mookerjee B , et al. \nTreatment of adenovirus disease in stem cell transplant recipients with cidofovir\n. Biol Blood Marrow Transplant 2007 ; 13 :74 –81\n.17222755 \n15. \nSaquib R , Melton LB , Chandrakantan A , et al. \nDisseminated adenovirus infection in renal transplant recipients: the role of cidofovir and intravenous immunoglobulin\n. Transpl Infect Dis 2010 ; 12 :77 –83\n.19761559 \n16. \nBruminhent J , Athas DM , Hess BD , Flomenberg P \nDisseminated adenovirus disease in heart transplant recipient presenting with conjunctivitis\n. Transpl Infect Dis 2015 ; 17 :125 –8\n.25571908 \n17. \nHumar A , Kumar D , Mazzulli T , et al ; PV16000 Study Group \nA surveillance study of adenovirus infection in adult solid organ transplant recipients\n. Am J Transplant 2005 ; 5 :2555 –9\n.16162207 \n18. \nRazonable RR , Humar A \nCytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice\n. Clin Transplant 2019 ; 33 :e13512 .30817026\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "6(12)",
"journal": "Open forum infectious diseases",
"keywords": "absolute lymphocyte count; cidofovir; cytomegalovirus; hemorrhagic cystitis; human adenovirus; lymphopenia",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofz489",
"pmc": null,
"pmid": "32128332",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": "23535527;21168635;25571908;30859626;16804849;19761559;28583524;30817026;30905076;16162207;26919131;26699950;31116132;23493328;17222755;21449944;25205044",
"title": "Epidemiology and Outcomes of Early-Onset and Late-Onset Adenovirus Infections in Kidney Transplant Recipients.",
"title_normalized": "epidemiology and outcomes of early onset and late onset adenovirus infections in kidney transplant recipients"
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"companynumb": "NVSC2020TH054361",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"abstract": "The COVID-19 pandemic has strained the healthcare system worldwide, leading to an approach favoring judicious resource allocation. A focus on resource preservation can result in anchoring bias and missed concurrent diagnosis. Coinfection of Mycobacterium tuberculosis (TB) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has implications beyond morbidity at the individual level and can lead to unintended TB exposure to others. We present six cases of COVID-19 with newly diagnosed cavitating pulmonary tuberculosis to highlight the significance of this phenomenon and favorable outcomes if recognized early.",
"affiliations": "Department of Medicine, Hamad Medical Corporation, Doha, Qatar.;Department of Medicine, Hamad Medical Corporation, Doha, Qatar.;Medicine, Reading Hospital, Tower Health Medical Group, West Reading, United States.;Dresden International University, Dresden, (DIU), Germany.;Department of Infectious Disease, Hamad Medical Corporation, Qatar.;Department of Infectious Disease, Hamad Medical Corporation, Qatar.;Dresden International University, Dresden, (DIU), Germany.;Department of Medicine, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Yousaf|Zohaib|Z|;Khan|Adeel A|AA|;Chaudhary|Haseeb A|HA|;Mushtaq|Kamran|K|;Parengal|Jabeed|J|;Aboukamar|Mohamad|M|;Khan|Muhammad Umair|MU|;Mohamed|Mouhand F H|MFH|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.idcr.2020.e00973",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(20)30281-X\n10.1016/j.idcr.2020.e00973\ne00973\nCase Report\nCavitary pulmonary tuberculosis with COVID-19 coinfection\nYousaf Zohaib zohaib.yousaf@gmail.com\nab1⁎\nKhan Adeel A. a1\nChaudhary Haseeb A. c1\nMushtaq Kamran bd1\nParengal Jabeed e1\nAboukamar Mohamad e1\nKhan Muhammad Umair bd1\nMohamed Mouhand F.H. ab1\na Department of Medicine, Hamad Medical Corporation, Doha, Qatar\nb Dresden International University, Dresden, (DIU), Germany\nc Medicine, Reading Hospital, Tower Health Medical Group, West Reading, United States\nd Department of Gastroenterology and Hepatology, Hamad Medical Corporation, Doha, Qatar\ne Department of Infectious Disease, Hamad Medical Corporation, Qatar\n⁎ Corresponding author at: Department of Medicine, Hamad Medical Corporation, Doha, Qatar. zohaib.yousaf@gmail.com\n1 Institution: Hazm Mebaireek General Hospital, Hamad Medical Corporation, Qatar.\n\n28 9 2020\n2020\n28 9 2020\n22 e0097313 7 2020\n25 9 2020\n25 9 2020\n© 2020 The Author(s)\n2020\nThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nThe COVID-19 pandemic has strained the healthcare system worldwide, leading to an approach favoring judicious resource allocation. A focus on resource preservation can result in anchoring bias and missed concurrent diagnosis. Coinfection of Mycobacterium tuberculosis (TB) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has implications beyond morbidity at the individual level and can lead to unintended TB exposure to others. We present six cases of COVID-19 with newly diagnosed cavitating pulmonary tuberculosis to highlight the significance of this phenomenon and favorable outcomes if recognized early.\n\nKeywords\n\nSAR-CoV-2\nCOVID-19\nMycobacterium tuberculosis\nTB\nCo-infection\nPulmonary tuberculosis\n==== Body\nBackground\n\nThe modern-day medical practice uses William Osler’s principles of clinical reasoning. “Occam’s razor” advocates a simplistic approach where all symptoms are attributed to a single disease [1]. The counterargument to this diagnostic parsimony is “Hickam's dictum,\" which favors disease plurality in a single patient. Numerous shortcomings in the current COVID-19 pandemic have skewed our practice in favor of the former principle to preserve resources. This practice has led to anchoring bias and overlooking of other concomitant diseases [2]. Historical evidence suggests higher mortality in patients with concurrent infection of TB and respiratory viruses, such as influenza [3,4]. We present six COVID-19 patients who were co-infected with pulmonary TB with a favorable outcome. All patients had an initial working diagnosis of COVID-19 pneumonia on triage. It was on a detailed review that the probability of pulmonary TB coinfection became apparent leading to isolation from other COVID-19 patients.\n\nCase presentations\n\nSubjects\n\nWe performed a retrospective analysis of the six male patients co-infected with TB and COVID-19 (software utilized: Jamovi version 1.1.9, available at www.jamovi.org). Extracted data included baseline demographics, clinical characteristics, laboratory values, imaging, and microbiologic findings.\n\nPatient characteristics\n\nAll patients were male owing to the preponderance of male immigrant population in Qatar. The mean age of patients was 35.5 years. All patients were from TB endemic area of south-east Asia. Only one patient had previous diagnosis of diabetes mellitus (DM). Other patients had no previous co-morbidities. The mean duration of symptoms prior to hospitalization was 14 days. Detailed information is shown in Table 1.Table 1 Patient’s characteristics.\n\nTable 1Characteristics\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\t\nAge\t34\t32\t50\t35\t27\t35\t\nSex\tMale\tMale\tMale\tMale\tMale\tMale\t\nNationality\tNepalese\tNepalese\tIndian\tBangladeshi\tIndian\tBangladeshi\t\nPast Medical History\tNone\tNone\tDiabetes Mellites\tNone\tNone\tNone\t\nDuration of symptoms (days)\t10\t8\t21\t30\t5\t10\t\nSymptoms\tFever, productive cough, myalgias\tDry cough, fatigue.\tDry cough\tdry cough, fever\tFever, myalgias, headache\tDry cough\t\nB-Type symptoms\tSubjective weight loss\t5 % Weight loss over 6 months\tSubjective weight loss\t5 % weight loss over 3months\tNone\tSubjective weight loss\t\n\nSymptomatology and lab results\n\nThe most common symptoms were cough (83.3 %), followed by fever (50 %), myalgias (33.3 %), headache (16.6 %) and fatigue (16.6 %). None of our patients reported diarrhea, vomiting, loss of smell, or taste. The main B-type symptom was weight-loss (83.3 %). Lab results included a mean neutrophil count 7.6*103 cells/mm3, lymphocyte count 1.3*103 cells/mm3 and ALT 28.1 U/l. Neutrophil/lymphocyte ratio (NLR) was more than 3.13 in all patients. Screening for hepatitis B, hepatitis C, and human immunodeficiency viruses (HIV) was negative in all patients. All patients had cavitary lesions identified on imaging (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6). Patient 6 also had pleural effusion which turned out to be lymphocytic exudative with a positive nucleic acid amplification test for TB (Fig. 1e).Fig. 1 Bilateral infiltrates with multiple cavitary lesions.\n\nFig. 1\n\nFig. 2 Predominantly right middle zone infiltrates with multiple cavitary lesions.\n\nFig. 2\n\nFig. 3 Bilateral infiltrates with extensive involvement on right side with multiple cavitary lesions.\n\nFig. 3\n\nFig. 4 Bilateral infiltrates, more prominent in right upper zone with multiple cavitary lesions.\n\nFig. 4\n\nFig. 5 Bilateral infiltrates with multiple cavitary lesion.\n\nFig. 5\n\nFig. 6 Bilateral infiltrates with left middle zone cavitary lesion and left sided pleural effusion.\n\nFig. 6\n\nDiagnosis\n\nThe diagnosis of pulmonary TB in patients 1–6 was initially based on a positive sputum smear for acid-fast bacilli (AFB). Later, the TB culture from sputum sample turned out to be positive in all patients. All patients were smear-negative by 6 weeks of treatment with median of 3 weeks (Table 2).Table 2 Diagnosis.\n\nTable 2\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\t\nIGRA for TB\tNegative\tIndeterminate\tIndeterminate\tIndeterminate\tPositive\tPositive\t\nAFB smear status\tPositive from sputum\tPositive from sputum\tPositive from sputum\tPositive from sputum\tPositive from sputum\tPositive from sputum\t\nAFB culture status\tPositive from sputum\tPositive from sputum\tPositive from sputum\tPositive from sputum\tPositive from sputum\tPositive from sputum\t\nTB Diagnosis\tPulmonary TB\tPulmonary TB\tPulmonary TB\tPulmonary TB\tPulmonary TB\tPulmonary and pleural TB\t\nSARS-CoV-2 RT-PCR (Nasopharyngeal Swab)\tPositive\tPositive\tPositive\tPositive\tPositive\tPositive\t\nNumber of days for negative SARS-CoV-2 RT-PCR\t42\t42\t14\t72\t28\t21\t\nNumber of days for negative AFB smear/TB PCR\t42\t14\t28\t21\t21\t14\t\nNew Diagnosis during hospitalization\tPre-Diabetes\tDiabetes Mellites\tAnemia\tPre-diabetes\tAnemia\tNone\t\n(IGRA: Interferon Gamma Release Assay, AFB: Acid Fast Bacillus, TB: Tuberculosis, SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus-2, RT-PCR: Reverse Transcriptase-Polymerase Chain Reaction).\n\nAll patients tested positive for SARS-CoV-2 RNA by RT-PCR of the nasopharyngeal swab. Follow-up COVID-19 oropharyngeal and nasopharyngeal swabs were initially repeated two weeks from diagnosis and then weekly until negative. The clearance of virus was variable, but two patients had positive SARS-CoV-2 RT-PCR beyond four weeks (Table 2).\n\nTreatment\n\nAll patients received five days of Ceftriaxone, Azithromycin, and Hydroxychloroquine for COVID-19 pneumonia, according to the local COVID-19 management guidelines at that time. All patients also received first-line anti-tuberculous therapy (ATT) consisting of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol with Pyridoxine.\n\nPrognosis and outcome\n\nAll patients admitted from the emergency improved with treatment and were discharged in a stable condition from the hospital.\n\nDiscussion\n\nThere is a paucity of data reported on TB and SARS-CoV-2 coinfection, which is likely due to under-reporting. However, missed diagnosis, early mortality, and limited testing facilities for SARS-CoV-2 may also be responsible [5]. None of our patients had a known history of direct exposure to TB; however, all of them belonged to areas where TB is endemic i.e. South-Asian descent. The exact mechanism underlying COVID-19 and TB coinfection is unknown. An interplay of various interleukins (IL) triggered by inflammatory response to viral infection that affect T-cell Immune response is an argument found in the literature [6]. Type-I interferon (IFN) has antiviral properties, but detrimental effects of inappropriate or mistimed type-I IFN response in viral infections also exist that may promote susceptibility to TB infection [7].\n\nOther factors, such as dysregulated glucose metabolism, predispose patients to an excessive uncontrolled inflammatory response, which leads to a higher risk of developing COVID-19 pneumonia and rapid disease progression [8]. Additionally, DM also increases the risk of developing active tuberculosis infection by two to four folds [9]. Only one of our patients had established diagnosis of DM. However, 66.6 % of our patients had impaired glucose metabolism with an average HbA1c of 6.48. It is also important to note that a population with low socioeconomic status may carry a higher risk of exposure and disease spread [10,11], as seen in our case series.\n\nIn terms of risk stratification, Ai-Ping Yang et al. have studied neutrophil to lymphocyte ratio (NLR) and age as an independent biomarker for poor clinical outcome in COVID-19 patients [12]. All our patients had an NLR greater than 3.3 with a mean ferritin level of 1686 ug/L and CRP 98.7 mg/L denoting at least moderate disease severity in an otherwise healthy young population (Table 2). The limitation to interpreting these parameters is coinfection with TB that makes it difficult to assess COVID-19 related disease severity.\n\nDetecting patients with this coinfection has implications for patient management. Cohorting COVID-19 patients with patients who have undiagnosed MTB may lead to its nosocomial transmission. COVID-19 patients with pulmonary TB coinfection will require airborne isolation, even if they do not receive invasive or non-invasive mechanical ventilation. This may affect the length of stay and pose a challenge in a limited resource setting.\n\nConclusion\n\nCoinfection with COVID-19 and Mycobacterium tuberculosis may alter disease course and management. A high index of suspicion is required for detection of this coinfection especially in population at high risk for TB or belonging to endemic areas. Coinfection may not correlate with worse outcomes if recognized early.\n\nAuthor contributions\n\nThe first three authors contributed equally to this article. ZY conceived the topic idea, identified the cases, and managed some of the cases. Additionally, he performed the initial literature review, data analysis, and wrote the initial manuscript. AAK assisted in the literature review and wrote up the manuscript. HAC critically reviewed and revised the final manuscript. KM, MUK and MFHM assisted in analyzing the cases and critically revising the manuscript. JB and SAK were involved in managing the cases and reviewed the data as infectious disease experts. All authors approved the final version for submission.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nCRediT authorship contribution statement\n\nZohaib Yousaf: Conceptualization, Methodology, Project administration, Writing - original draft. Adeel A. Khan: Writing - original draft. Haseeb A. Chaudhary: Writing - review & editing. Kamran Mushtaq: Writing - review & editing. Jabeed Parengal: Supervision. Mohamad Aboukamar: Supervision. Muhammad Umair Khan: Project administration. Mouhand F.H. Mohamed: Writing - review & editing.\n\nDeclaration of Competing Interest\n\nThe authors declare no conflict of interest.\n\nAcknowledgment\n\nThe publication of this article was funded by the Qatar National Library.\n==== Refs\nReferences\n\n1 Wildner M. In memory of William of Occam - the lancet [internet] [cited Jun 4]. Available from: 2020 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)77085-9/fulltext\n2 Whyte M.B. An argument against the use of Occam’s razor in modern medical education Med Teach 40 1 2018 99 100 28395579\n3 Oei W. Nishiura H. The relationship between tuberculosis and influenza death during the influenza (H1N1) pandemic from 1918-19 Comput Math Methods Med 2012 2012 124861\n4 Walaza S. Influenza virus infection is associated with increased risk of death amongst patients hospitalized with confirmed pulmonary tuberculosis in South Africa, 2010-2011 BMC Infect Dis 15 January 27 2015 26 25623944\n5 Giri A.K. Rana D.R.S.B.B. Charting the challenges behind the testing of COVID-19 in developing countries: nepal as a case study Biosafety Health [Internet] 2020 May 13 [cited 2020 Jun 4]; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219426/\n6 Redford P.S. Influenza a virus impairs control of Mycobacterium tuberculosis coinfection through a type I interferon receptor–Dependent pathway J Infect Dis [Internet] 209 2 2014 270 274 Jan 15 [cited 2020 Jun 4], Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873785/\n7 Type I interferons in the pathogenesis of tuberculosis: molecular drivers and immunological consequences [Internet] 2020 [cited Sep 7]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711827/\n8 Guo W. Li M. Dong Y. Zhou H. Zhang Z. Tian C. Diabetes is a risk factor for the progression and prognosis of COVID-19 Diabetes Metab Res Rev March 31 2020 e3319 32233013\n9 Al-Rifai R.H. Pearson F. Critchley J.A. Abu-Raddad L.J. Association between diabetes mellitus and active tuberculosis: a systematic review and meta-analysis PLoS One 12 11 2017 e0187967\n10 Coronavirus (COVID-19) related deaths by ethnic group 2020 England and Wales - Office for National Statistics [Internet] [cited Jun 4]. Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/articles/coronavirusrelateddeathsbyethnicgroupenglandandwales/2march2020to10april2020\n11 Rimmer A. Covid-19: Two thirds of healthcare workers who have died were from ethnic minorities BMJ 369 April 23 2020 m1621 32327412\n12 Yang A.P. Liu J.P. Tao W.Q. Li H.M. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients Int Immunopharmacol 84 2020 106504 10.1016/j.intimp.2020.106504\n\n",
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"keywords": "COVID-19; Co-infection; Mycobacterium tuberculosis; Pulmonary tuberculosis; SAR-CoV-2; TB",
"medline_ta": "IDCases",
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"pages": "e00973",
"pmc": null,
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"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "Cavitary pulmonary tuberculosis with COVID-19 coinfection.",
"title_normalized": "cavitary pulmonary tuberculosis with covid 19 coinfection"
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"abstract": "Diffuse large B-cell lymphoma (DLBCL) is a common indication for autologous stem cell transplantation (auto-SCT).\n\n\n\nThis prospective noninterventional study aimed to evaluate the impact of mobilization characteristics and graft cellular content on hematologic recovery and outcome after auto-SCT among 68 patients with DLBCL.\n\n\n\nBetter mobilization capacity as manifested by blood CD34+ cell count >32 × 106 /L and CD34+ cell yield of the first apheresis >2.75 × 106 /kg correlated with faster neutrophil (P = .005 and P = .017) and platelet (P = .002 and P < .001) recovery. A higher number of infused CD34+ cells (> 2.65 × 106 /kg) was associated with better 5-year overall survival (OS; 95% vs 67%, P = .012). The graft CD34+ CD133+ CD38- cell count >0.07 × 106 /kg was predictive of better 5-year OS (87% vs 63%; P = .008) and higher graft CD3+ cell count (>23.1 × 106 /kg) correlated also with better 5-year OS (80% vs 40%, P = .008). In multivariate analysis only disease status of CR I at auto-SCT was associated with better progression-free survival (P = .014) and OS (P = .039).\n\n\n\nThe mobilization capacity of CD34+ cells impacted on early hematologic recovery in patients with DLBCL after auto-SCT. Higher graft CD34+ cell count and both CD34+ CD133+ CD38- and CD3+ cells were also associated with better OS. The effect of optimal graft cellular composition on outcome in DLBCL should be evaluated in a randomized study.",
"affiliations": "Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Department of Oncology, Central Hospital of Central Finland, Jyväskylä, Finland.;Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.;Department of Oncology, Oulu University Hospital, Oulu, Finland.;Department of Medicine, Central Hospital of Savonlinna, Savonlinna, Finland.;Department of Oncology, Tampere University Hospital, Tampere, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.;Eastern Finland Laboratory Centre, Kuopio, Finland.;Eastern Finland Laboratory Centre, Kuopio, Finland.;Department of Medicine, Kymenlaakso Central Hospital, Kotka, Finland.;Department of Medicine, Kuopio University Hospital, Kuopio, Finland.",
"authors": "Partanen|Anu|A|0000-0002-5634-2582;Turunen|Antti|A|;Valtola|Jaakko|J|;Pyörälä|Marja|M|;Vasala|Kaija|K|;Kuittinen|Outi|O|;Kuitunen|Hanne|H|;Penttilä|Karri|K|;Keskinen|Leena|L|;Kuittinen|Taru|T|;Mäntymaa|Pentti|P|;Pelkonen|Jukka|J|;Varmavuo|Ville|V|;Jantunen|Esa|E|",
"chemical_list": "D018952:Antigens, CD34; D017252:CD3 Complex; D003561:Cytarabine; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D005047:Etoposide; D003520:Cyclophosphamide; D000069585:Filgrastim; D008558:Melphalan; D002330:Carmustine",
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"issue": "61(2)",
"journal": "Transfusion",
"keywords": "CD34+ cell mobilization; autograft cellular composition; diffuse large B-cell lymphoma; hematologic recovery; outcome",
"medline_ta": "Transfusion",
"mesh_terms": "D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D000971:Antineoplastic Combined Chemotherapy Protocols; D001772:Blood Cell Count; D017252:CD3 Complex; D002330:Carmustine; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003561:Cytarabine; D018572:Disease-Free Survival; D005047:Etoposide; D064147:Febrile Neutropenia; D005260:Female; D000069585:Filgrastim; D005500:Follow-Up Studies; D006085:Graft Survival; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D011092:Polyethylene Glycols; D000077982:Progression-Free Survival; D011446:Prospective Studies; D012074:Remission Induction; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0417360",
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"pages": "516-525",
"pmc": null,
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"pubdate": "2021-02",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Mobilization characteristics, blood graft composition, and outcome in diffuse large B-cell lymphoma after autologous stem cell transplantation: Results from the prospective multicenter GOA study.",
"title_normalized": "mobilization characteristics blood graft composition and outcome in diffuse large b cell lymphoma after autologous stem cell transplantation results from the prospective multicenter goa study"
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"abstract": "Predicting the risk of posthepatectomy liver failure is important when performing extended hepatectomy. However, there is no established method to evaluate liver function and improve preoperative liver function in pediatric patients.\n\n\n\nWe show the clinical features of pediatric patients who underwent living donor liver transplant for posthepatectomy liver failure in hepatoblastoma. The subjects were 4 patients with hepatoblastoma who were classified as Pretreatment Extent of Disease III, 2 of whom had distal metastasis (chest wall and lung).\n\n\n\nHepatic right trisegmentectomy was performed in 3 patients and extended left hepatectomy in 1 patient. The median alpha-fetoprotein level at the diagnosis of hepatoblastoma was 986300 ng/mL (range, 22500-2726350 ng/mL), and the median alpha-fetoprotein level before hepatectomy was 8489 ng/mL (range, 23-22500 ng/mL). The remnant liver volume after hepatectomy was 33.3% (range, 20% to 34.9%). Four patients had cholangitis after hepatectomy and progressed to posthepatectomy liver failure. The peak serum total bilirubin after hepatectomy was 11.4 mg/dL (range, 8.7-14.6 mg/dL). Living donor liver transplant was performed for these 4 patients with posthepatectomy liver failure, and they did not have a recurrence.\n\n\n\nWhen the predictive remnant liver volume by computed tomography-volumetry before extended hepatectomy for patients with hepatoblastoma is less than 40%, the possibility of posthepatectomy liver failure should be recognized.",
"affiliations": ">From the Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University, Shimotsuke City, Tochigi, Japan.",
"authors": "Hirata|Yuta|Y|;Sanada|Yukihiro|Y|;Omameuda|Takahiko|T|;Katano|Takumi|T|;Miyahara|Go|G|;Yamada|Naoya|N|;Okada|Noriki|N|;Onishi|Yasuharu|Y|;Sakuma|Yasunaru|Y|;Sata|Naohiro|N|",
"chemical_list": null,
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"doi": "10.6002/ect.2019.0323",
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"issue": "18(5)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
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"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D005260:Female; D006498:Hepatectomy; D018197:Hepatoblastoma; D006801:Humans; D007223:Infant; D007564:Japan; D017093:Liver Failure; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D012086:Reoperation; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
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"pages": "612-617",
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"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Liver Transplant for Posthepatectomy Liver Failure in Hepatoblastoma.",
"title_normalized": "liver transplant for posthepatectomy liver failure in hepatoblastoma"
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"abstract": "The author presents a case of diffuse alveolar hemorrhage in a woman consuming Ginkgo biloba extract and ginseng. The patient had no illnesses or exposures that would predispose to diffuse alveolar hemorrhage, and an extensive evaluation revealed no etiology. The patient has had no further bleeding since discontinuing Ginkgo biloba extract and ginseng 1 year ago.",
"affiliations": "*Department of Medicine, University of Oklahoma Health Sciences Center †Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.",
"authors": "Carlile|Paul V|PV|",
"chemical_list": "D010936:Plant Extracts",
"country": "United States",
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"issue": "22(2)",
"journal": "Journal of bronchology & interventional pulmonology",
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"medline_ta": "J Bronchology Interv Pulmonol",
"mesh_terms": "D005260:Female; D020441:Ginkgo biloba; D006470:Hemorrhage; D006801:Humans; D008171:Lung Diseases; D008875:Middle Aged; D005894:Panax; D010936:Plant Extracts; D011859:Radiography",
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"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unexplained alveolar hemorrhage associated with Ginkgo and ginseng use.",
"title_normalized": "unexplained alveolar hemorrhage associated with ginkgo and ginseng use"
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"activesubstancename": "KONJAC MANNAN"
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"abstract": "Antibiotic-resistant infections remain to be a major issue for all over the world. Although appropriate diagnosis and rapid treatment initiation are crucially important particularly in immunocompromised patients, selection of antibiotics without identification of causative bacteria is often challenging. A 44-year-old woman with acute myeloid leukemia (AML) under myelosuppression suffered from teicoplanin-resistant gram-positive cocci bacteremia. Taking severe neutropenia due to chemotherapy and glycopeptide-resistance into account, teicoplanin was empirically substituted with daptomycin, which led to prompt defervescence. This microorganism later turned out to be Leuconostoc lactis (L. Lactis), and daptmycin was continued to use based on antimicrobial susceptibility tests. As a result, empiric use of daptomycin successfully controlled glycopeptide-resistant gram-positive cocci bacteremia under neutropenia. This is the first report of daptomycin treatment for L. lactis bacteremia in a patient with AML under neutropenia. Our findings suggest that daptomycin would be a suitable treatment option for glycopeptide-resistant gram-positive cocci bloodstream infections, especially in myelosuppressive patients.",
"affiliations": "Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Infection Control and Prevention, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Infection Control and Prevention, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Infection Control and Prevention, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan; Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Electronic address: kurokawa-tky@umin.ac.jp.",
"authors": "Matsuda|Kensuke|K|;Koya|Junji|J|;Toyama|Kazuhiro|K|;Ikeda|Mahoko|M|;Arai|Shunya|S|;Nakamura|Fumihiko|F|;Okugawa|Shu|S|;Moriya|Kyoji|K|;Kurokawa|Mineo|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D017334:Teicoplanin; D014640:Vancomycin; D017576:Daptomycin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2017.06.010",
"fulltext": null,
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"issn_linking": "1341-321X",
"issue": "23(11)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Acute myeloid leukemia; Bacteremia; Chemotherapy; Daptomycin; Leuconostoc lactis",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D064146:Chemotherapy-Induced Febrile Neutropenia; D017576:Daptomycin; D024881:Drug Resistance, Bacterial; D016983:Enterococcus; D005260:Female; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007934:Leuconostoc; D015470:Leukemia, Myeloid, Acute; D008826:Microbial Sensitivity Tests; D017334:Teicoplanin; D014640:Vancomycin",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "788-790",
"pmc": null,
"pmid": "28743428",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A therapeutic benefit of daptomycin against glycopeptide-resistant gram-positive cocci bloodstream infections under neutropenia.",
"title_normalized": "a therapeutic benefit of daptomycin against glycopeptide resistant gram positive cocci bloodstream infections under neutropenia"
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"abstract": "Lung cancer has been the leading cause of cancer-related deaths in both developed and developing countries, with most primary lung cancers being non-small cell lung carcinomas. Treatment for this condition is sometimes individualized. With developments in modern treatment and phase III clinical trial results, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and ALK-TKI have proven thier superior effectivity in comparison with the standard platinum-based doublet and are commonly approved as first-line indications in previously untreated advanced non-small cell lung cancer (NSCLC) patients with EGFR or ALK mutations. In the majority of cases, the presence of the ALK rearrangement mutation does not overlap with other mutations in NSCLC. Here, we report a patient with concomitant ALK rearrangement and EGFR mutation treated with a combination of TKIs: osimertinib and ceritinib.",
"affiliations": "Department of Medical Oncology, Vietnam National Cancer Hospital, Hanoi, Vietnam.;Oncology, Ho Chi Minh City Oncology Hospital, Ho Chi Minh City, Vietnam.;Department of Medical Oncology, Vietnam National Cancer Hospital, Hanoi, Vietnam.;Trauma and Orthopedic Department, Thong Nhat Hospital, Ho Chi Minh City, Vietnam.",
"authors": "Nguyen|Thai Hoa Thi|THT|;Pham|Xuan Dung|XD|;Dao|Khanh Linh|KL|;Vo|Thanh Toan|TT|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1159/000516404",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\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\n10.1159/000516404\ncro-0014-1085\nCase Report\nResponse to a Combination of Full-Dose Osimertinib and Ceritinib in a Non-Small Cell Lung Cancer Patient with EML4-ALK Rearrangement and Epidermal Growth Factor Receptor Co-Mutation\nNguyen Thai Hoa Thi a\nPham Xuan Dung b*\nDao Khanh Linh a\nVo Thanh Toan c\naDepartment of Medical Oncology, Vietnam National Cancer Hospital, Hanoi, Vietnam\nbOncology, Ho Chi Minh City Oncology Hospital, Ho Chi Minh City, Vietnam\ncTrauma and Orthopedic Department, Thong Nhat Hospital, Ho Chi Minh City, Vietnam\n*Xuan Dung Pham, phxdung@yahoo.com\nMay-Aug 2021\n8 7 2021\n8 7 2021\n14 2 10851091\n30 3 2021\n1 4 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.\nLung cancer has been the leading cause of cancer-related deaths in both developed and developing countries, with most primary lung cancers being non-small cell lung carcinomas. Treatment for this condition is sometimes individualized. With developments in modern treatment and phase III clinical trial results, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and ALK-TKI have proven thier superior effectivity in comparison with the standard platinum-based doublet and are commonly approved as first-line indications in previously untreated advanced non-small cell lung cancer (NSCLC) patients with EGFR or ALK mutations. In the majority of cases, the presence of the ALK rearrangement mutation does not overlap with other mutations in NSCLC. Here, we report a patient with concomitant ALK rearrangement and EGFR mutation treated with a combination of TKIs: osimertinib and ceritinib.\n\nKeywords\n\nOsimertinib\nCeritinib\nTyrosine kinase inhibitors\nNon-small cell lung cancer\n==== Body\nIntroduction\n\nAccording to worldwide and Vietnam statistics, non-small cell lung cancer (NSCLC) accounts for approximately 75–80% of the total number of lung cancers. Currently, the treatment of this disease depends on many factors, such as stage, comorbidities, and associated pathology. For the advanced stage, the molecular characteristics of the tumour are very important in treatment and prognosis. Based on these characteristics, targeted therapies are expected to increase the effectiveness of the treatment compared to systemic chemotherapy. Recently, the results achieved in phase III clinical trials showed that NSCLC with epidermal growth factor receptor (EGFR) or ALK mutations have good results with tyrosine kinase inhibitors (TKIs) [1, 2, 3, 4]. According to a study in Vietnam, EGFR and ALK mutations account for 32.3 and 5.4% of all mutations, respectively, and the rate of 2 mutations occurring simultaneously is 1.4% [5]. Treatment for this condition is sometimes individualized, with no standard treatment considered for this rare group of patients.\n\nCase Presentation\n\nA 39-year-old male patient who was a non-smoker with no comorbidities arrived at our hospital in August 2019 and presented with dry cough for 6 months and a weight loss of 5 kg per month. The patient had no previous chest pain or dyspnoea. A physical examination was also performed. Computed tomography (CT) of the thorax revealed many bilateral lung lesions of approximately 4–9 mm with enlargement of the mediastinum, hilar and supravicular, and abdominal lymph nodes with the largest size of 28 × 31 mm. The brain MRI showed that the lesion in the frontal region located in the top left and right frontal lobe had the largest diameter of approximately 24 mm, causing oedema. Moreover, bone scintigraphy showed numerous bone metastases in the spine and bilateral pelvis. A CT-guided fine-needle biopsy of the lung tumour was also performed, and the histological identification illustrated lung invasive adenocarcinoma with both TTF1 and napsin A. The patient was diagnosed with stage IVC lung adenocarcinoma (brain, bone, and abdominal lymph nodes). Tissue samples were tested for next-generation sequencing. According to the results, the patient had both types of EGFR exon 19 deletion mutation mixed rearrangement ALK (ALK-EML4 fusion). In September 2019, we decided to use a second-generation ALK inhibitor, ceritinib (alectinib is not available in Vietnam), instead of EGFR-TKIs for the initial treatment of the patient. The patient's brain lesions were also closely monitored.\n\nWithin 3 months of treatment, the patient's clinical symptoms markedly improved. The patient did not experience cough or chest pain. The CT scan indicated that lesions of the bilateral lungs, as well as the mediastinal and abdominal lymph nodes were greatly reduced and exhibited partial response (Fig. 1).\n\nNevertheless, brain MRI showed that metastatic tumours responded poorly to treatment. Thus, the patient underwent stereotactic radiosurgery with one fraction at a dose of 18 Gy on the brain lesion for local control, whilst continuing with ceritinib.\n\nHowever, the patient's condition started to worsen at 4 months. He began to experience chest tightness and coughing with increasing breathing difficulty. The CT showed massive bilateral pleural effusion and a low degree of pericardial effusion (Fig. 2).\n\nWe identified progressive disease and decided to choose erlotinib, a first-generation EGFR-TKI, for the second-line treatment. Three months after the therapy, the patient's respiratory symptoms clinically improved, such as cough relief, chest pain relief. Moreover, the chest CT exhibited partial response, but the patient had 2 seizures in the right half of the body. Brain MRI indicated metastatic damage to the frontal lobe; the left apex increased in size to approximately 27 × 40 mm, causing increased oedema with at least 5 lesions with less peripheral drug absorption (Fig. 3).\n\nAt this time, second gamma-knife surgery was considered, and at the same time, the patient was administered the third-generation TKI osimertinib, with the hope that the brain damage would be better controlled. After a month of treatment with osimertinib, we evaluated the patient with a total examination; the brain lesion was stable, and the mediastinal lymph nodes had increased in size (Fig. 4).\n\nThe patient's condition at that time was also very poor, with an Eastern Cooperative Oncology Group performance status index of 3. The patient felt exhausted and had difficulties tolerating chemotherapy. Therefore, we decided to incorporate ceritinib and osimertinib (starting in April 2020). The disease was assessed as exhibiting partial response 2 months after treatment when the mediastinal lymph nodes exhibited a decrease on the CT chest scan and the brain metastasis exhibited stability on the cranial MRI (Fig. 5).\n\nTo date, the patient has undergone 11 months of treatment with this regimen. Clinically, the patient's respiratory symptoms have significantly improved. The patient ceased coughing and exhibited improvements in chest pain and the mild paralysis in the right half of the body, as well as an improved quality of life. The pulmonary and lymph node lesions on chest CT tended to decrease, brain metastases were stable, and brain oedema decreased compared to the period before treatment. In terms of tolerance, the following adverse events were observed: grade I skin rash, mild fatigue, and grade I passing twice daily, which was well-controlled with loperamide.\n\nDiscussion\n\nDetecting the molecular profile of tumours, particularly the identification of activating mutations of EGFR and ALK genes, is becoming very important in finding effective treatments for NSCLC. According to the literature, these 2 types of mutations are often found independently [6]. However, in reality, a number of authors have reported cases of concurrence of these 2 mutations.\n\nRecent data show that between 1.3 and 1.6% of patients with NSCLC have both EGFR mutations and ALK translocations [7, 8]. To date, there have been no optimal treatment protocols for these patients. In patients with driver mutations, numerous phase III clinical trials have demonstrated the superior efficacy of targeted therapy compared with chemotherapy containing platinum, in terms of improved response rates and progression-free survival [1, 2, 3, 4]. The remarkable point of this treatment over chemotherapy is the ability of the TKIs to cross the blood-brain barrier, making the drug effective in patients with CNS metastases [9].\n\nAt present, there are insufficient data to decide whether to choose an anti-EGFR or ALK as primary therapy in patients with concurrent EGFR and ALK mutations. A 100-case review found that ALK-TKIs seem to elicit a higher response rate than EGFR-TKIs [10]. By contrast, as reported by Schmid et al. [11] EGFR inhibition may be more effective than ALK-TKI in patients with concomitant EGFR-ALK mutations.\n\nIn our patient, we decided to use the selective ALK-TKI ceritinib for first-line treatment because the patient had brain metastases and because osimertinib is not approved for use in Vietnam. However, despite a rapid clinical response, the patient's disease progressed only after 4 months. When the treatment was switched from an ALK-TKI to an EGFR-TKI (erlotinib), the patient experienced a partial response. However, the response time was only a few months. According to Schmid et al. [11], their patient was initially treated with ALK-TKI and exhibited progression after 1.3, 5.7, and 7.3 months. According to them, an initial treatment with EGFR-TKI achieves an mPFS of 5.8 months, which is lower than the results of previous phase III trials [1, 3, 4]. In contrast, Yang et al. [8] reported an mPFS of 11.2 months amongst patients on first-line treatment with EGFR-TKI. Thus, the hypothesis of rapid progression with TKI treatment is also inconsistent in the previous studies; nevertheless, according to a review of 100 cases with this concomitant mutation, many cases rapidly progress after TKI treatment [10].\n\nAfter failure with monotherapy, the combination of both EGFR and ALK-TKIs, osimertinib and ceritinib, continued to elicit a response. In terms of drug tolerance, our patient experienced well-controlled adverse effects, and the patient's quality of life also significantly improved. After 10 months of treatment, the disease remains stable.\n\nFrom this case, we would like to raise a few points for discussion. First is the choice of sequential treatment with TKIs or an initial combination of 2 types of TKIs. In our patient, after failing with ALK-TKI, the EGFR treatment elicited a good response; however, the response time of ALK-TKI and EGFR-TKI is only 3–4 months. It appears that the remaining mutant cell lines of ALK or EGFR continue to grow if we use only one of the 2 types of TKIs.\n\nMoreover, in our patient, the response and tolerance to the two-target combination was good and had been more likely to be more effective in prolonging the response time than sequential treatment. To date, the problem of combination treatment with 2 targets, ALK and EGFR, has not been fully addressed in terms of efficacy and toxicity.\n\nThe last point is with regard to CNS Response. In this patient's case, both ALK-TKI and EGFR-TKI treatment did not achieve a substantial intracranial response; nevertheless, the extracerebral response was excellent. Therefore, stereotactic radiosurgery has been performed to control the size and symptoms of the brain metastases, which are very common in patients with ALK and EGFR mutations. New-generation TKIs have also been shown to elicit a high response rate to CNS metastases [12, 13]. However, with the unexpected brain response results in our patient, we have reviewed the literature; unfortunately, the CNS response in patients with these 2 mutations remains unclear.\n\nConclusions\n\nConcurrent EGFR mutation with ALK reassortment is a relatively uncommon case amongst patients with advanced NSCLC, therefore, understanding the molecular characterisation of genes via gene profiles is necessary. Currently, there have been some reports on the use of EGFR-TKI or ALK antagonists in monotherapies as lines of treatment. However, there is no clinical evidence proving the efficacy or safety of the combination of EGFR and ALK inhibitors or multi-targeted TKIs. Furthermore, the response of the central nervous system remains unclear, and which TKI generation should be used for highest efficiency still needs follow-up assessment.\n\nStatement of Ethics\n\nThe written informed consent was obtained from the patient for the publication of this case report and the accompanying images.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nThere is no funding source or sponsor to report.\n\nAuthor Contributions\n\nT.H.T.N. and X.D.P. contributed substantially to the conception and design of the case report, as well as to the acquisition, analysis, and interpretation of the patient data. T.H.T.N. drafted the manuscript. X.D.P., K.L.D., and T.T.V. critically reviewed and revised the manuscript for important intellectual content and gave their final approval.\n\nFig. 1 Chest CT images before (a) and after 3 months of treatment with certinib (b). Before treatment with second-generation ALK-KI, CT showed that numerous mediastinal lymph nodes exhibited heterogeneous drug absorption after injection. Figure b was taken after 3 months of treatment with ceritinib and shows no abnormal mediastinal lymph nodes. CT, computed tomography.\n\nFig. 2 Chest CT images were taken 4 months after ceritinib treatment. At this time, the patient developed difficulty breathing due to massive bilateral pleural effusion and pericardial effusion. CT, computed tomography.\n\nFig. 3 Chest CT, cranial magnetic resonance imaging before (a, c) and after 3 months of treatment with erlotinib (b, d). The lung nodules, mediastinal lymph nodes, pleural fluid, and pericardial fluid have decreased compared to the untreated time; however, the brain lesions tended to progress in terms of size, and a number of brain metastases were accompanied by oedema. CT, computed tomography.\n\nFig. 4 CT scan images before (a) and after (b) administration of osimertinib. This time, the mediastinal lymph nodes returned and enlarged the bronchi and the mediastinal vessels. CT, computed tomography.\n\nFig. 5 CT scans of the chest (a) and cranial MRI (b) were recorded 2 months after treatment with the TKI combination of osimertinib and ceritinib. Mediastinal lymph nodes rapidly decreased and brain metastases stabilized, with a decrease in size and oedema of the surrounding brain. TKI, tyrosine kinase inhibitor; CT, computed tomography.\n==== Refs\nReferences\n\n1 Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Engl J Med 2009 Sep 3 361 (10) 947 57 19692680\n2 Shaw AT Kim DW Nakagawa K Seto T Crinó L Ahn MJ Crizotinib versus chemotherapy in advanced ALK-positive lung cancer N Engl J Med 2013 Jun 20 368 (25) 2385 94 23724913\n3 Soria JC Tan DSW Chiari R Wu YL Paz-Ares L Wolf J First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study Lancet 2017 Mar 4 389 (10072) 917 29 28126333\n4 Zhou C Wu YL Chen G Feng J Liu XQ Wang C Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study Lancet Oncol 2011 8 12 (8) 735 42 21783417\n5 Dang AH Tran VU Tran TT Thi Pham HA Le DT Nguyen L Actionable mutation profiles of non-small cell lung cancer patients from Vietnamese population Sci Rep 2020 Feb 17 10 (1) 2707 32066856\n6 Soda M Choi YL Enomoto M Takada S Yamashita Y Ishikawa S Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer Nature 2007 Aug 2 448 (7153) 561 6 17625570\n7 Ulivi P Chiadini E Dazzi C Dubini A Costantini M Medri L Nonsquamous, non-small-cell lung cancer patients who carry a double mutation of EGFR, EML4-ALK or KRAS: frequency, clinical-pathological characteristics, and response to therapy Clin Lung Cancer 2016 9 17 (5) 384 90 26712101\n8 Yang JJ Zhang XC Su J Xu CR Zhou Q Tian HX Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation Clin Cancer Res 2014 Mar 1 20 (5) 1383 92 24443522\n9 Saboundji K Auliac JB Pérol M François G Janicot H Marcq M Efficacy of osimertinib in EGFR-mutated non-small cell lung cancer with leptomeningeal metastases pretreated with EGFR-tyrosine kinase inhibitors Target Oncol 2018 8 13 (4) 501 7 30039345\n10 Lo Russo G Imbimbo M Corrao G Proto C Signorelli D Vitali M Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases Oncotarget 2017 Aug 29 8 (35) 59889 900 28938691\n11 Schmid S Gautschi O Rothschild S Mark M Froesch P Klingbiel D Clinical outcome of ALK-positive non-small cell lung cancer (NSCLC) patients with de novo EGFR or KRAS co-mutations receiving tyrosine kinase inhibitors (TKIs) J Thorac Oncol 2017 4 12 (4) 681 8 28007627\n12 Camidge DR Dziadziuszko R Peters S Mok T Noe J Nowicka M Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study J Thorac Oncol 2019 7 14 (7) 1233 43 30902613\n13 Koba T Kijima T Takimoto T Hirata H Naito Y Hamaguchi M Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: two case reports Medicine 2017 2 96 (6) e6087 28178168\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(2)",
"journal": "Case reports in oncology",
"keywords": "Ceritinib; Non-small cell lung cancer; Osimertinib; Tyrosine kinase inhibitors",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1085-1091",
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"pmid": "34326746",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "28007627;26712101;21783417;24443522;28178168;30039345;19692680;32066856;28938691;28126333;23724913;30902613;17625570",
"title": "Response to a Combination of Full-Dose Osimertinib and Ceritinib in a Non-Small Cell Lung Cancer Patient with EML4-ALK Rearrangement and Epidermal Growth Factor Receptor Co-Mutation.",
"title_normalized": "response to a combination of full dose osimertinib and ceritinib in a non small cell lung cancer patient with eml4 alk rearrangement and epidermal growth factor receptor co mutation"
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"abstract": "BACKGROUND\nActinomycetes can rarely cause intracranial infection and may cause a variety of complications. We describe a fatal case of intracranial and intra-orbital actinomycosis of odontogenic origin with a unique presentation and route of dissemination. Also, we provide a review of the current literature.\n\n\nMETHODS\nA 58-year-old man presented with diplopia and progressive pain behind his left eye. Six weeks earlier he had undergone a dental extraction, followed by clindamycin treatment for a presumed maxillary infection. The diplopia responded to steroids but recurred after cessation. The diplopia was thought to result from myositis of the left medial rectus muscle, possibly related to a defect in the lamina papyracea. During exploration there was no abnormal tissue for biopsy. The medial wall was reconstructed and the myositis responded again to steroids. Within weeks a myositis on the right side occurred, with CT evidence of muscle swelling. Several months later he presented with right hemiparesis and dysarthria. Despite treatment the patient deteriorated, developed extensive intracranial hemorrhage, and died. Autopsy showed bacterial aggregates suggestive of actinomycotic meningoencephalitis with septic thromboembolism. Retrospectively, imaging studies showed abnormalities in the left infratemporal fossa and skull base and bilateral cavernous sinus.\n\n\nCONCLUSIONS\nIn conclusion, intracranial actinomycosis is difficult to diagnose, with potentially fatal outcome. An accurate diagnosis can often only be established by means of histology and biopsy should be performed whenever feasible. This is the first report of actinomycotic orbital involvement of odontogenic origin, presenting initially as bilateral orbital myositis rather than as orbital abscess. Infection from the upper left jaw extended to the left infratemporal fossa, skull base and meninges and subsequently to the cavernous sinus and the orbits.",
"affiliations": "Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands. g.hotte@oogziekenhuis.nl.;Department of Oral and Maxillofacial Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Neurology, Franciscus Gasthuis and Vlietland, Rotterdam, The Netherlands.;Department of Oral and Maxillofacial Surgery, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands.;Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.",
"authors": "Hötte|G J|GJ|;Koudstaal|M J|MJ|;Verdijk|R M|RM|;Titulaer|M J|MJ|;Claes|J F H M|JFHM|;Strabbing|E M|EM|;van der Lugt|A|A|;Paridaens|D|D|",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 440810.1186/s12879-019-4408-2Case ReportIntracranial actinomycosis of odontogenic origin masquerading as auto-immune orbital myositis: a fatal case and review of the literature Hötte G. J. g.hotte@oogziekenhuis.nl 12Koudstaal M. J. m.koudstaal@erasmusmc.nlmaarten.koudstaal@sll.se 3Verdijk R. M. r.verdijk@erasmusmc.nl 4Titulaer M. J. m.titulaer@erasmusmc.nl 5Claes J. F. H. M. j.claes@franciscus.nl 6Strabbing E. M. e.strabbing@erasmusmc.nl 3van der Lugt A. a.vanderlugt@erasmusmc.nl 7Paridaens D. d.Paridaens@oogziekenhuis.nl 121 000000040459992Xgrid.5645.2Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands 2 0000 0001 0009 7699grid.414699.7Department of Orbital Oculoplastic and Lacrimal Surgery, The Rotterdam Eye Hospital, PO box 70030, 3000 LM Rotterdam, The Netherlands 3 000000040459992Xgrid.5645.2Department of Oral and Maxillofacial Surgery, Erasmus Medical Center, Rotterdam, The Netherlands 4 000000040459992Xgrid.5645.2Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands 5 000000040459992Xgrid.5645.2Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands 6 0000 0004 0459 9858grid.461048.fDepartment of Neurology, Franciscus Gasthuis and Vlietland, Rotterdam, The Netherlands 7 000000040459992Xgrid.5645.2Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands 2 9 2019 2 9 2019 2019 19 76327 5 2019 25 8 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\nActinomycetes can rarely cause intracranial infection and may cause a variety of complications. We describe a fatal case of intracranial and intra-orbital actinomycosis of odontogenic origin with a unique presentation and route of dissemination. Also, we provide a review of the current literature.\n\nCase presentation\nA 58-year-old man presented with diplopia and progressive pain behind his left eye. Six weeks earlier he had undergone a dental extraction, followed by clindamycin treatment for a presumed maxillary infection. The diplopia responded to steroids but recurred after cessation. The diplopia was thought to result from myositis of the left medial rectus muscle, possibly related to a defect in the lamina papyracea. During exploration there was no abnormal tissue for biopsy. The medial wall was reconstructed and the myositis responded again to steroids. Within weeks a myositis on the right side occurred, with CT evidence of muscle swelling. Several months later he presented with right hemiparesis and dysarthria. Despite treatment the patient deteriorated, developed extensive intracranial hemorrhage, and died. Autopsy showed bacterial aggregates suggestive of actinomycotic meningoencephalitis with septic thromboembolism. Retrospectively, imaging studies showed abnormalities in the left infratemporal fossa and skull base and bilateral cavernous sinus.\n\nConclusions\nIn conclusion, intracranial actinomycosis is difficult to diagnose, with potentially fatal outcome. An accurate diagnosis can often only be established by means of histology and biopsy should be performed whenever feasible. This is the first report of actinomycotic orbital involvement of odontogenic origin, presenting initially as bilateral orbital myositis rather than as orbital abscess. Infection from the upper left jaw extended to the left infratemporal fossa, skull base and meninges and subsequently to the cavernous sinus and the orbits.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12879-019-4408-2) contains supplementary material, which is available to authorized users.\n\nKeywords\nActinomycosisIntracranial infectionIntraorbital infectionOdontogenic originOrbital myositisissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nMost odontogenic infections are self-limiting and localized. In some cases however, they may cause a variety of complications [1, 2]. Infections can spread intracranially, leading to life-threatening complications such as brain abscess, meningitis or meningoencephalitis, orbital abscess and cavernous sinus thrombosis [1, 3].\n\nIn the order of Actinomycetales, Actinomyces is a genus of the Actinomycetaceae family, whereas Nocardia is a genus of the Nocardiaceae family. Both genera belong to the normal commensal flora of the oropharyngeal cavity and are known to rarely cause intracranial infection of odontogenic origin [4].\n\nIn this report we describe a fatal case of presumed intracranial and presumed intra-orbital actinomycosis of odontogenic origin. To our best knowledge, this specific case shows a presentation and clinical course not reported on before.\n\nCase presentation\nA 58-year-old man first presented with pain in the left upper jaw. Medical history included polyarthrosis with secondary arthritis treated with hydroxychloroquine. After 2 weeks, the upper left second molar was extracted by his dentist. Three days later, routine blood examination by the rheumatologist showed a highly increased C-reactive protein (CRP) level, which was interpreted as a maxillary infection and treated with clindamycin for 5 days.\n\nSix weeks later he experienced sudden diplopia and progressive pain in the left temporal/frontal region and behind the left eye. On Magnetic Resonance Imaging (MRI) of the brain and jaw region only a small uncomplicated lipoma near the parotid gland was found. He was admitted to the rheumatology department on suspicion of giant cell arthritis. Erythrocyte sedimentation rate (ESR) was normal, CRP was only mildly elevated and biopsy of the temporal artery was negative. Nonetheless, the pain and diplopia responded well to a three-day course of high dose intravenous steroids (1000 mg/day).\n\nWithin a week after cessation of steroids he experienced an increase in pain and diplopia and was admitted to the neurology department for further evaluation. On neurologic examination, there was an abduction deficit but no signs of meningitis. Cerebral spinal fluid (CSF) was normal and MR Venography (MRV) showed no pathology of the dural venous sinuses. Serologic tests were negative for Borrelia burgdorferi and Treponema pallidum (Venereal Disease Research Laboratory test and Rapid Plasma Reagin test). Ophthalmic examination was unremarkable but orthoptic evaluation confirmed the abduction deficit with over-elevation in adduction of the left eye, suggestive of a mechanical component (Fig. 1a). Computed Tomography (CT) imaging of the orbit showed a defect in the left lamina papyracea, closely related to the left medial rectus muscle, with prolapse of orbital fat into the ethmoid sinus. Also, the medial rectus muscle was slightly enlarged (Fig. 1b). The findings were interpreted to be either an occult trauma to the medial orbital wall with reactive myositis, or an auto-immune orbital myositis. Oral steroids (60 mg initially) were prescribed and he was referred to the department of oral and maxillofacial surgery for evaluation. On examination, the extraction site of the upper left second molar was unremarkable and there were no complaints in that region. During surgical exploration of the left medial wall region there were no signs of infection or abnormal tissue for biopsy. The appearance of the bony defect corresponded well to the suspected traumatic cause and the medial wall was uneventfully reconstructed using a polydioxanone (PDS) sheet. Postoperatively the ocular motility improved and prisms were prescribed. The headaches, however, returned and he was referred back to the neurologist for further evaluation.\nFig. 1 a Orthoptic evaluation shows an impaired abduction with over-elevation in adduction of the left eye, suggesting a mechanical component. b CT image (coronal reconstruction) which demonstrates a defect in the left lamina papyracea\n\n\n\nAfter 2 weeks the diplopia worsened as the steroids were tapered to 20 mg. In addition to the slight residual abduction deficit of the left eye, orthoptic evaluation now demonstrated impaired abduction and elevation of the right eye (Fig. 2a). Neurological examination was otherwise unremarkable. ESR and white blood cell (WBC) count were increased (58 mm/h and 23.7 × 109/L respectively), while anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA) were negative. New MRI and CT scans were performed which showed enlargement of the inferior rectus muscle of the right eye, surrounded by an inflammatory fat infiltration (Fig. 2b). These findings fitted the previous suspected diagnosis of (auto-immune) orbital myositis. Steroid dosage was initially increased to 60 mg and then tapered.\nFig. 2 a Orthoptic evaluation now shows impaired elevation and abduction of the right eye. b CT image (coronal reconstruction) which shows enlargement of the right inferior rectus muscle with inflammatory fat infiltration surrounding the muscle\n\n\n\nSeven months after the initial presentation, he presented with a transient right hemiparesis and dysarthria. On a CT scan a slightly increased density in the suprasellar cistern was found but no signs of cerebral ischemia or hemorrhage. A Fludeoxyglucose Positron Emmision Tomography (FDG-PET) scan showed increased cerebral activity and at the skull base, but no evident vasculitis. One out of six blood cultures showed Staphylococcus aureus growth, which was considered to be a contamination.\n\nAfter being transferred to the university hospital, further evaluation was initiated. Protein levels in the CSF were elevated 25 times the normal value and cytology showed signs of an acute inflammation with increased neutrophil levels, but no microorganisms could be identified through Gram stain and culture. On a new MRI scan, abnormalities at the skull base, cerebrum and brainstem were found, indicating basal meningitis, together with bilateral thalamic infarcts. Also it now showed a lesion in the right orbit, suggestive of an abscess (Fig. 3). The imaging results and the highly increased protein levels in the CSF suggested tuberculous meningitis. However, as he had recently travelled to Indonesia, other viral/bacterial aetiologies were considered and broad-spectrum antibiotics (amoxicillin and ceftriaxone) and aciclovir together with antimycobacterial therapy (isoniazid, rifampicin, pyrazinamide and ethambutol) and dexamethasone was commenced. The orbital abscess fitted the presumed diagnosis of tuberculosis but, more importantly, his poor clinical condition did not permit biopsy of the lesion for confirmation. Further evaluation for tuberculous meningitis was initiated. For both CSF and sputum, Auramine staining and polymerase chain reaction (PCR) for Mycobacterium tuberculosis were negative. Interferon-gamma release assay was uninterpretable. Bacterial, mycobacterial and fungal cultures were obtained from blood, CSF and sputum. Serologic testing for toxoplasmosis showed increased IgG-, but normal IgM-levels, together with negative PCR for Toxoplasma gondii in CSF, indicating an earlier exposure but no current infection. To rule out lymphoma, CSF samples showed no monoclonal B-cell or abnormal T-cell populations. Despite treatment the patient deteriorated. After 2 weeks there was an acute clinical deterioration and CT showed an extensive intracranial hemorrhage. All treatment was discontinued and he deceased shortly after (Additional file 1).\nFig. 3 a T1w fat-suppressed post-gadolineum MRI scan which shows contrast enhancement at the surface of the basal brain structures compatible with basal meningitis (arrow). b Diffusion-weighted image shows high signal, which represents diffusion restriction caused by an acute brain infarct, bilaterally in the thalamus (arrow indicated by asterisk). In addition the high signal posterior in the ventricles is suggestive of ventricular empyema (arrow indicated by double asterisk). c and d Pre and post-gadolineum T1w MRI scan demonstrating a lesion in the right orbit with ring enhancement compatible with an abscess\n\n\n\nPost-mortem the mycobacterial cultures of CSF, sputum and blood were negative.16S rRNA PCR returned positive for the CSF samples, but further sequencing was uninterpretable. During autopsy there were no signs of mycobacterial infection. There were, however, signs of meningoencephalitis with vasculitis and septic thromboembolism based on gram-positive filamentous microbes such as Actinomyces or Nocardia (Fig. 4). Further distinction between the two could not be made histologically and the paraffin embedded specimens allowed no further genetic determination by sequencing. Unfortunately, the autopsy application lacked information on the orbital lesions and as such this region was not explored during the autopsy.\nFig. 4 Autopsy samples from the brain showed gram-positive filamentous microbes\n\n\n\nAll imaging studies were reexamined. In two of the MRI scans (performed 2 months after the initial presentation) a soft tissue mass was now identified in the left infratemporal fossa, together with subtle abnormal signal intensities at the left skull base and the left cavernous sinus (Fig. 5a–c). In an MRI scan performed at a later stage, the abnormal intensity at the infratemporal fossa and skull base was less evident, but there was bilateral enlargement of the cavernous sinus and involvement of the pituitary gland (Fig. 5d–f). We concluded that the intracranial and intraorbital actinomycotic infection appeared to have originated from an odontogenic maxillary infection.\nFig. 5 Reexamination of imaging studies. a–c\nT1w MRI scans from 2 months after the initial presentation show (a) a soft tissue mass in the left infratemporal fossa (arrow), with (b) decreased signal intensity in the left central skull base (arrow) and (c) a low signal intensity in the left cavernous sinus (arrow). d–f T1w MRI scan performed at a later stage revealed (d) resolution of the lesion in the infratemporal fossa (arrow), but there is bilateral enlargement of the cavernous sinus (arrows) and involvement of the pituitary gland on the coronal post-gadolinium T1w scan (e) and the T2w Scan (f)\n\n\n\nDiscussion and conclusions\nActinomyces and Nocardia, belong to the normal commensal flora of the oropharyngeal cavity [4–6]. Although the name Actinomyces translates to “ray fungus”, these pathogens are in fact branching filamentous prokaryotic bacteria related to mycobacteria [4, 5, 7, 8]. Although some are microaerophilic, most Actinomyces species require strict anaerobic conditions to grow, whereas Nocardia grows best in aerobic conditions [5, 8]. Although this patient used hydroxychloroquine, Actinomycetes do not appear to have a predilection toward immunocompromised patients. They have low virulence but can lead to actinomycosis if there is disruption of the mucosal barrier [4, 5].\n\nAs outlined by Van Dellen, actinomycosis can disseminate intracranially through direct invasion, along fascial planes and by extension through the base of the skull or meninges. Also, it can spread through perineural extension or by hematogenous route [4]. Although the first report of intracranial actinomycotic infection dates back to as early as 1882 by Ponfick, it is in fact a very rare finding (3% of actinomycotic cases) [4, 5].\n\nFive different orbital complications of odontogenic infection have been outlined by Allan et al.: preseptal cellulitis, orbital cellulitis, orbital subperiosteal abscess, orbital abscess and cavernous sinus thrombosis [9, 10]. Although an orbital abscess was present at a later stage, this is the first report of actinomycotic orbital involvement presenting initially as an orbital myositis.\n\nMoreover, while bilateral cavernous sinus involvement has been reported, the route of dissemination in this particular case is of interest. The infection presumably started near the upper left second molar and extended to the left infratemporal fossa, skull base and meninges. Next, infection must have spread to the left cavernous sinus, the sellar region and subsequently to the right cavernous sinus. The cavernous sinus is connected with nearby regions (such as the maxillary dentition) by valveless veins, allowing infections to spread bidirectionally [1, 11]. As such, the infection extended from the cavernous sinuses to the left and subsequently right orbit, evidenced by the muscle enlargement, fat infiltration and, later, orbital abscess. Involvement of the cavernous sinus first, with subsequent retrograde bilateral spread to the orbits has not yet been described in actinomycosis. An uncertainty in our report is the fact that, unfortunately, the orbits were not explored during autopsy. As such, actinomycotic involvement of this region could not be confirmed. The relationship between the defect in the lamina papyracea and the orbital myositis is unclear. The medial rectus inflammation might have weakened the thin medial wall, making it more fragile, causing fracture at rubbing, but this is speculative. It could well have been a chance finding, which clouded the initial diagnostic process.\n\nFew case reports describe painful ophthalmoplegia, characterized by periorbital pain and paralysis of the oculomotor nerves, as the presenting sign of actinomycosis with cavernous sinus involvement [12–14]. In our case however, despite cavernous sinus involvement, the restriction of ocular motility seemed not paralytic but rather mechanical or restrictive in nature. This raises the question as to why bilateral involvement of the cavernous sinus did not lead to apparent clinical or radiological signs of orbital congestion or evident paralysis of the oculomotor nerves. Possibly, the cavernous sinus infection resulted from direct extension from the infratemporal regions, rather than being caused by infected thrombi [11]. The eventual cause of death was shown to have been the intracranial hemorrhage, which resulted from vasculitis and thromboembolism, together with meningoencephalitis. Koda et al. describe a case of actinomycotic meningitis in which secondary necrotizing arteritis lead to the perforation of a pseudoaneurysm and subsequent subarachnoid hemorrhage [15]. In fact, odontogenic infections have been shown to be involved in the pathogenesis of ruptured cerebral aneurysms [16, 17].\n\nRetrospectively, the history of maxillary pain and possible molar infection should have been emphasized more. Possibly, the recognition of the infection was hampered by several obscuring clinical findings. Furthermore, unlike in the patient reported by Sullivan there were no apparent infectious foci for biopsy until late stages of the disease [18]. In addition, subtle radiological features that pointed at disease were overlooked and only diagnosed at a late stage.\n\nFrom an ophthalmological point of view, at first it appeared to be a clinically apparent case of idiopathic or reactive orbital myositis; i.e. enlargement of the extraocular muscles and tendons with surrounding infiltration of the orbital fat and corresponding painful impairment of ocular motility. As idiopathic orbital myositis is a diagnosis per exclusionem, the question is raised as to when one can assume an infection is sufficiently excluded. Clinical and radiological findings in infectious myositis are similar to those of auto-immune myositis [19] and initially CRP, ESR, WBC and CSF were not suggestive of infectious disease. Although there is no consensus on diagnostic criteria for idiopathic orbital myositis, the above-mentioned clinical features are in line with what can be expected in this disease entity. The fact that it responded well to steroid therapy strengthened this assumption [20]. Mombaerts et al. state that many orbital disorders respond well to steroids initially and thus is a weak tool in identifying the cause of orbital inflammation. Therefore they advocate early tissue biopsy to exclude other causes, with the exception of lesions located in the orbital apex or extraocular muscles [21]. .For orbital myositis, the initial treatment of choice mostly is a trial of steroids, while biopsies are done in non-responsive patients or those presenting with clinical recurrence. In line with these guidelines, we performed surgical exploration of the affected area in the left orbit as the diplopia recurred after cessation of steroids. However, no abnormal tissue was found for biopsy. It is likely that the courses of steroids have supported the dissemination of the infection [12]. .Also, it is questionable if the PDS sheet that was used could have served as a foreign body that has aggravated the infection.\n\nAt a later stage, the findings of the CSF and imaging led us to believe it could be tuberculous meningitis and, although broad-spectrum antibiotics and aciclovir were initiated also because of a recent travel history, antimycobacterial treatment was emphasized alike. At this stage imaging also showed an abscess in the right orbit, which fitted the presumed diagnosis of tuberculosis. More importantly, however, his clinical condition did not permit biopsy of the lesion for confirmation. It is likely that this orbital abscess would have evolved in an earlier stage if steroids had not been prescribed for a prolonged period of time. If so, his condition at that time probably would have permitted biopsy of the lesion, allowing for adequate treatment early into the clinical course. Unfortunately also, the broad range 16S rRNA PCR in the CSF did not return positive until after death, confirming the presence of bacteria.16S rRNA PCR is rarely positive in tuberculous meningitis and, in fact, Mycobacterium tuberculosis has been used as a negative control to measure specificity of the assay [22]. As such, earlier availability of this result would have questioned the diagnosis. An uncertainty in our report is the fact that, due to poor quality DNA derived from the formalin fixated paraffin embedded obduction sample, sequencing for the genetic subclassification of the gram-positive filamentous microbes was not possible. Additional targeted 16S rRNA assays, in order to distinguish Actinomyces from Nocardia, turned out negative due to poor quality of the RNA.\n\nActinomycosis is characterized by a long duration of mild, nonspecific, constitutional symptoms with or without fever; a true silent assassin [4, 23]. Van Dellen states that actinomycosis should be considered based on several features: (1) chronicity, (2) progression across tissue boundaries, (3) masslike features, (4) disease features that resolve and recur, and (5) refractory or relapsing infection after a short course of therapy [4].\n\nEven when suspected based on the above mentioned features, actinomycosis is notably difficult to diagnose [4]. Although not specific to actinomycosis, imaging can show abnormalities such as cerebral and/or orbital abscess, meningitis and subdural/epidural empyema [4]. Interestingly, Sato et al. recently described FDG-PET scan findings identifying an odontogenic infection as the cause of a brain abscess [24] Unfortunately, in our case no such findings were seen on the FDG-PET scan. Actinomycetes are extremely difficult to culture [5, 25]. It is therefore best to use PCR techniques in addition to cultures. Although this does not test for antibiotic susceptibility, it could aid to alter empiric antibiotic coverage [25]. In our case, the results were indeed positive but unfortunately only after death. Besides 16S rRNA PCR, Wilson et al. recently suggested metagenomics to identify the right pathogen [26]. Eventually, diagnosis is often made histologically, showing sulfur granules, which are composed of aggregates of microbes, often featuring the Splendore-Hoeppli Phenomenon, and contain calcium phosphate [23].\n\nAfter establishing the diagnosis, the treatment of actinomycosis poses an even bigger challenge. High dose intravenous penicillin or amoxicillin for a prolonged period of time is the treatment of choice, although tetracyclines and clindamycin can be used as alternatives [4, 27]. At initial presentation, clindamycin was prescribed but only shortly and the specific species could have been resistant to clindamycin [27]. Moreover, clindamycin does not cross the blood-brain barrier making it impractical for the treatment of intracranial actinomycosis. At a later stage we commenced amoxicillin as part of broad-spectrum coverage. Although penicillin resistance is almost nonexistent, the vasculitis leading to the eventual fatal hemorrhage probably was too well advanced at this point [8, 27]. Also, Actinomyces aggregates into tight polymicrobial rosettes thereby preventing antibiotics from reaching the microbes within the aggregate. This further provides resistance against phagocytosis and accommodates ideal anaerobic conditions for growth [5, 25]. As such successful antibiotic treatment is difficult and surgical drainage is often required, if feasible [4, 23].\n\nIn conclusion, this is the first report of probable actinomycotic orbital involvement of odontogenic origin, presenting initially as an orbital myositis. Intracranial actinomycosis is a rare complication, notoriously difficult to diagnose and treat, with potentially fatal outcome. Imaging is aspecific and cultures are clouded by high false-negative results. Therefore, it is imperative to vigorously explore all recent medical history as this may be the only clue leading to the right diagnosis. When such rare infection is included in the differential diagnosis and the clinician is aware of the potential mode of spread, the cavernous sinus location of infectious masses would be more readily identified, thus allowing for earlier adequate treatment. Moreover, one should remain aware of the fact that idiopathic orbital myositis is a diagnosis per exclusionem. Therefore, an accurate diagnosis can only be established by means of histology and biopsy should be performed whenever feasible.\n\nAdditional file\n\nAdditional file 1: Timeline of the relevant data. (PNG 132 kb)\n\n \n\n\nAbbreviations\nANAAnti Nuclear Antibodies\n\nANCAAnti Neutrophil Cytoplasmic Antibodies\n\nCRPC-reactive Protein\n\nCSFCerebrospinal Fluid\n\nCTComputed Tomography\n\nESRErythrocyte Sedimentation Rate\n\nFDG-PETFludeoxyglucose Positron Emission Tomography\n\nMRIMagnetic Resonance Imaging\n\nMRVMagnetic Resonance Venography\n\nPCRPolymerase Chain Reaction\n\nPDSPolydioxanone\n\nrRNARibosomal Ribonucleic Acid\n\nWBCWhite Blood Cell\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nN/A\n\nAuthors’ contributions\nAll authors read and approved the final manuscript. GH analyzed the clinical course of the case and wrote the manuscript. MK provided additional insights in the clinical course of the case and assisted in writing the manuscript. RV provided background information on the pathological processes of the disease, provided insights the clinical course of the case and assisted in writing the manuscript. MT provided additional insights in the clinical course of the case and assisted in writing the manuscript. FC provided additional insights in the clinical course of the case and assisted in writing the manuscript. ES provided additional insights in the clinical course of the case and assisted in writing the manuscript. AL aided in the interpretation of the radiological images, provided additional insights in the clinical course of the case and assisted in writing the manuscript. DP provided additional insights in the clinical course of the case and was a major contributor in writing the manuscript.\n\nAuthors’ information\nN/A\n\nFunding\nN/A\n\nAvailability of data and materials\nN/A\n\nEthics approval and consent to participate\nN/A\n\nConsent for publication\nWritten consent for publication was obtained from the subject’s relatives.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Bali RK Sharma P Gaba S Kaur A Ghanghas P A review of complications of odontogenic infections Natl J Maxillofac Surg 2015 6 2 136 143 10.4103/0975-5950.183867 27390486 \n2. Ryan P McMahon G Severe dental infections in the emergency department Eur J Emerg Med 2012 19 4 208 213 10.1097/MEJ.0b013e32834ddb68 22127295 \n3. Smego RA Jr Actinomycosis of the central nervous system Rev Infect Dis 1987 9 5 855 865 10.1093/clinids/9.5.855 3317731 \n4. Van Dellen JR Actinomycosis: an ancient disease difficult to diagnose World Neurosurg 2010 74 2–3 263 264 10.1016/j.wneu.2010.06.012 21492553 \n5. Haggerty CJ Tender GC Actinomycotic brain abscess and subdural empyema of odontogenic origin: case report and review of the literature J Oral Maxillofac Surg 2012 70 3 e210 e213 10.1016/j.joms.2011.09.035 22209103 \n6. Palonta F Preti G Vione N Cavalot AL Actinomycosis of the masseter muscle: report of a case and review of the literature J Craniofac Surg 2003 14 6 915 918 10.1097/00001665-200311000-00015 14600635 \n7. Bennhoff DF Actinomycosis: diagnostic and therapeutic considerations and a review of 32 cases Laryngoscope 1984 94 9 1198 1217 10.1288/00005537-198409000-00013 6381942 \n8. Valour F Senechal A Dupieux C Karsenty J Lustig S Breton P Actinomycosis: etiology, clinical features, diagnosis, treatment, and management Infect Drug Resist 2014 7 183 197 25045274 \n9. Allan BP Egbert MA Myall RW Orbital abscess of odontogenic origin. 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Sullivan TJ Aylward GW Wright JE Actinomycosis of the orbit Br J Ophthalmol 1992 76 8 505 506 10.1136/bjo.76.8.505 1390538 \n19. Kubota Toshinobu Orbital Myositis Idiopathic Inflammatory Myopathies - Recent Developments 2011 \n20. Fraser CL Skalicky SE Gurbaxani A McCluskey P Ocular myositis Curr Allergy Asthma Rep 2013 13 3 315 321 10.1007/s11882-012-0319-7 23093472 \n21. Mombaerts I Rose GE Garrity JA Orbital inflammation: biopsy first Surv Ophthalmol 2016 61 5 664 669 10.1016/j.survophthal.2016.03.002 26994870 \n22. Couble A Rodriguez-Nava V de Montclos MP Boiron P Laurent F Direct detection of Nocardia spp. in clinical samples by a rapid molecular method J Clin Microbiol 2005 43 4 1921 1924 10.1128/JCM.43.4.1921-1924.2005 15815019 \n23. Akhaddar A Elouennass M Baallal H Boucetta M Focal intracranial infections due to Actinomyces species in immunocompetent patients: diagnostic and therapeutic challenges World Neurosurg 2010 74 2–3 346 350 10.1016/j.wneu.2010.05.029 21492568 \n24. Sato J Kuroshima T Wada M Satoh A Watanabe S Okamoto S Use of FDG-PET to detect a chronic odontogenic infection as a possible source of the brain abscess Odontology 2016 104 2 239 243 10.1007/s10266-015-0218-1 26497357 \n25. Moazzam AA Rajagopal SM Sedghizadeh PP Zada G Habibian M Intracranial bacterial infections of oral origin J Clin Neurosci 2015 22 5 800 806 10.1016/j.jocn.2014.11.015 25800939 \n26. Wilson MR Shanbhag NM Reid MJ Singhal NS Gelfand JM Sample HA Diagnosing Balamuthia mandrillaris encephalitis with metagenomic deep sequencing Ann Neurol 2015 78 5 722 730 10.1002/ana.24499 26290222 \n27. Steininger C Willinger B Resistance patterns in clinical isolates of pathogenic Actinomyces species J Antimicrob Chemother 2016 71 2 422 427 10.1093/jac/dkv347 26538502\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "19(1)",
"journal": "BMC infectious diseases",
"keywords": "Actinomycosis; Intracranial infection; Intraorbital infection; Odontogenic origin; Orbital myositis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000196:Actinomycosis; D001327:Autoimmune Diseases; D020806:Central Nervous System Bacterial Infections; D003937:Diagnosis, Differential; D004172:Diplopia; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008439:Maxillary Diseases; D008875:Middle Aged; D055622:Orbital Myositis; D011183:Postoperative Complications; D014081:Tooth Extraction",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "763",
"pmc": null,
"pmid": "31477035",
"pubdate": "2019-09-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "11883847;12850413;1390538;14600635;15330828;15815019;16679798;1761876;21492553;21492568;22127295;22209103;23093472;23761916;25045274;25800939;25838693;26290222;26497357;26538502;26724261;26929556;26994870;27390486;3317731;6381942",
"title": "Intracranial actinomycosis of odontogenic origin masquerading as auto-immune orbital myositis: a fatal case and review of the literature.",
"title_normalized": "intracranial actinomycosis of odontogenic origin masquerading as auto immune orbital myositis a fatal case and review of the literature"
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"companynumb": "NL-TEVA-2019-NL-1132128",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "4",
... |
{
"abstract": "Chimeric antigen receptor (CAR) T-cells, engineered autologous T-cells that target antigens found in leukemia, have shown durable remissions in relapsed acute lymphoblastic leukemia (ALL). Infant ALL with KMT2A rearrangements (KMT2Ar) is a rare, aggressive form of leukemia associated with extramedullary disease both at diagnosis and at relapse, and overall outcomes for these patients are dismal. Here we report the successful use of tisagenlecleucel, a CAR T-cell product approved for relapsed/refractory ALL, in a patient with KMT2Ar infant ALL who was treated for combined marrow and extramedullary (renal) relapse.",
"affiliations": "Department of Pediatrics, Division of Hematology/Oncology/Blood and Marrow Transplantation, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI.;Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Department of Pediatric Radiology, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI.;Department of Pediatrics, Division of Hematology/Oncology/Blood and Marrow Transplantation, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI.;Department of Pediatrics, Division of Hematology/Oncology/Blood and Marrow Transplantation, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI.",
"authors": "Moskop|Amy|A|0000-0002-5110-004X;Pommert|Lauren|L|;Thakrar|Pooja|P|;Talano|Julie|J|;Phelan|Rachel|R|",
"chemical_list": "C497422:KMT2A protein, human; D000076962:Receptors, Chimeric Antigen; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "68(1)",
"journal": "Pediatric blood & cancer",
"keywords": "ALL; ALL relapse; immunotherapy; pediatric hematology/oncology",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D019046:Bone Marrow Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D016219:Immunotherapy, Adoptive; D007223:Infant; D007680:Kidney Neoplasms; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein; D009364:Neoplasm Recurrence, Local; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D000076962:Receptors, Chimeric Antigen",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28739",
"pmc": null,
"pmid": "33009894",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Chimeric antigen receptor T-cell therapy for marrow and extramedullary relapse of infant acute lymphoblastic leukemia.",
"title_normalized": "chimeric antigen receptor t cell therapy for marrow and extramedullary relapse of infant acute lymphoblastic leukemia"
} | [
{
"companynumb": "US-TEVA-2021-US-1910275",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORINOSTAT"
},
"drugadditional": "3",
... |
{
"abstract": "Spontaneous pneumothorax can be classified into primary and secondary variants. A 58-year-old patient presented with a 7-week history of severe coughing and chest pain. He noticed progressive swelling of the face and the upper part of the body. His medical history revealed osteoporosis and severe rheumatoid arthritis treated with steroids and disease-modifying antirheumatic drugs. Computed tomography of the thorax revealed complete rupture of the thoracic wall through costae 9 and 10 with lung herniation. The defect was closed using dual mesh and the pneumothorax was treated. Two weeks after surgery, the subcutaneous emphysema resolved and the patient was discharged from the hospital.",
"affiliations": "Department of Intensive Care Medicine, Elisabeth-Tweesteden Hospital, Tilburg, the Netherlands.;Department of Intensive Care Medicine, Elisabeth-Tweesteden Hospital, Tilburg, the Netherlands.;Department of Intensive Care Medicine, Elisabeth-Tweesteden Hospital, Tilburg, the Netherlands. Electronic address: sjaakpwls@gmail.com.",
"authors": "van Schaik|Eva|E|;Ramnarain|Dharmanand|D|;Pouwels|Sjaak|S|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2021.01.051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "112(4)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases; D011030:Pneumothorax; D011239:Prednisolone; D012132:Respiratory Muscles; D012422:Rupture, Spontaneous; D035441:Thoracic Wall",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e237-e239",
"pmc": null,
"pmid": "33592182",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumothorax Due to a Nontraumatic Thoracic Wall Rupture Due to Steroid-Induced Muscle Wasting.",
"title_normalized": "pneumothorax due to a nontraumatic thoracic wall rupture due to steroid induced muscle wasting"
} | [
{
"companynumb": null,
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"drugadministratio... |
{
"abstract": "A post-marketing surveillance study is investigating the safety and effectiveness of stiripentol during real-world clinical use in Japanese patients with Dravet syndrome (DS).\n\n\n\nThe safety and effectiveness of stiripentol were prospectively investigated over 104 weeks in all patients with DS who were administered the drug from November 2012 through July 2019 in Japan. Patients administered stiripentol for the first time after its approval were defined as \"new patients,\" and those who continued to take the drug after participating in domestic clinical studies were defined as \"continuous-use patients.\" The responder rate was defined as the proportion of patients with a ≥50 % decrease in seizure episodes at the time of assessment of stiripentol effectiveness compared with the 4 weeks before starting stiripentol. Overall improvement was evaluated by the physician in charge based on the comprehensive assessment of the patient's condition after stiripentol treatment.\n\n\n\nOf 411 patients whose information was collected, 410 patients (376 new and 34 continuous-use) were included in the safety analysis set, and 409 (376 new and 33 continuous-use) were included in the effectiveness analysis set. The median age of new patients was 7 years (range: 0.5-50 years) at the time of stiripentol initiation; 99 % of patients were taking concomitant sodium valproate and 93 % clobazam. Adverse drug reactions occurred in 70 % of new patients; the most common were somnolence (39 %) and loss of appetite (25 %). No new safety concerns due to stiripentol were observed. The responder rate in new patients was 43 % (110/257 patients) for convulsive seizures (tonic-clonic and/or clonic convulsions), 55 % (58/105 patients) for focal impaired awareness seizures, and 62 % (56/90 patients) for generalized myoclonic seizures and/or generalized atypical absence seizures. Overall improvement (after 104 weeks or at the time of drug discontinuation) was rated as marked or moderate in 160/353 of new patients (45 %).\n\n\n\nStiripentol is safe and effective during long-term use in patients with DS in routine clinical practice.",
"affiliations": "Safety Vigilance & Management Dept., Reliability & Quality Assurance Division, Meiji Seika Pharma Co., Ltd., Tokyo, Japan. Electronic address: miyuki.yamada@meiji.com.;Safety Vigilance & Management Dept., Reliability & Quality Assurance Division, Meiji Seika Pharma Co., Ltd., Tokyo, Japan. Electronic address: katsuyoshi.suzuki.aa@meiji.com.;Safety Vigilance & Management Dept., Reliability & Quality Assurance Division, Meiji Seika Pharma Co., Ltd., Tokyo, Japan. Electronic address: daisuke.matsui@meiji.com.;Department of Clinical Research, National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan. Electronic address: yinoue-jes@umin.net.;Department of Child Neurology, Asahigawaso Rehabilitation and Medical Center, Okayama, Japan. Electronic address: ohtsuka@okayama-u.ac.jp.",
"authors": "Yamada|Miyuki|M|;Suzuki|Katsuyoshi|K|;Matsui|Daisuke|D|;Inoue|Yushi|Y|;Ohtsuka|Yoko|Y|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.eplepsyres.2020.106535",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "170()",
"journal": "Epilepsy research",
"keywords": "Adverse drug reaction; Dravet syndrome; Prospective study; Real world effectiveness; Seizures; Stiripentol",
"medline_ta": "Epilepsy Res",
"mesh_terms": null,
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "106535",
"pmc": null,
"pmid": "33388609",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term safety and effectiveness of stiripentol in patients with Dravet syndrome: Interim report of a post-marketing surveillance study in Japan.",
"title_normalized": "long term safety and effectiveness of stiripentol in patients with dravet syndrome interim report of a post marketing surveillance study in japan"
} | [
{
"companynumb": "JP-VISTAPHARM, INC.-VER202101-000543",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOBAZAM"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nHepatitis E is an infectious disease due to inflammation of the liver caused by hepatitis E virus (HEV) and represents one of the most common causes of acute hepatitis and jaundice in the world. Although data of hepatitis E infection in patients with rheumatoid arthritis (RA) are accumulating, little is known on the course of HEV infection. We reported, for the 1st time, a case of patient with RA with hepatitis E that developed during leflunomide therapy in combination with low-dose steroids.\nWe present a 39-year-old woman, affected by RA and treated with leflunomide, reported diffuse itching and persistent fatigue laboratory data revealed elevated liver enzyme levels.\n\n\nMETHODS\nPositivity for anti-HEV IgM and IgG was observed. HEV-RNA of the genotype 3 was detected, indicating acute E hepatitis.\n\n\nRESULTS\nLeflunomide was stopped and restarted 5 months after the initial diagnosis at the same dosage, with a close clinical and laboratory follow-up. The virus was eradicated from the serum without chronic transformation. The patient is alive and well 7 months after the initial diagnosis.\n\n\nCONCLUSIONS\nTo our knowledge, this report is the 1st case of acute E hepatitis in a patient with RA developed during leflunomide therapy in combination with low-dose steroids. Moreover, geoepidemiology of infection is important, due to the fact that Abruzzo, a central region of Italy, has the highest HEV seroprevalence in general population, related to the zoonotic transmission of the infection from domestic and wild animals. Our case highlighted that immunosuppressive therapy, and in particular leflunomide, could be safely reintroduced after the resolution of the infection and the clearance of the virus. Further studies are needed to evaluate potential advantages in serologic testing for HEV infection as a part of the routine workup done to patients with rheumatic diseases and selected for immunosuppressive therapy.",
"affiliations": "Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila.;Infectious Disease Department, S. Salvatore Hospital, L'Aquila, Italy.;Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila.;Infectious Disease Department, S. Salvatore Hospital, L'Aquila, Italy.;Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila.;Infectious Disease Department, S. Salvatore Hospital, L'Aquila, Italy.;Infectious Disease Department, S. Salvatore Hospital, L'Aquila, Italy.;Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila.",
"authors": "Carubbi|Francesco|F|;Picchi|Giovanna|G|;Di Bartolomeo|Salvatore|S|;Ricciardi|Alessandra|A|;Cipriani|Paola|P|;Marola|Laura|L|;Grimaldi|Alessandro|A|;Giacomelli|Roberto|R|",
"chemical_list": "D007166:Immunosuppressive Agents; D000077339:Leflunomide",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000016399",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31415347MD-D-19-0051110.1097/MD.0000000000016399163996900Research ArticleClinical Case ReportHepatitis E infection in a patient with rheumatoid arthritis treated with leflunomide A case report with emphasis on geoepidemiologyCarubbi Francesco MD, PhDab∗Picchi Giovanna MDcDi Bartolomeo Salvatore MDaRicciardi Alessandra MDcCipriani Paola MD, PhDaMarola Laura MDcGrimaldi Alessandro MDcGiacomelli Roberto MD, PhDaNA. \na Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L’Aquila\nb Department of Medicine, ASL1 Avezzano-Sulmona-L’Aquila\nc Infectious Disease Department, S. Salvatore Hospital, L’Aquila, Italy.∗ Correspondence: Francesco Carubbi, University of L’Aquila, L’Aquila, Italy (e-mail: francescocarubbi@libero.it).8 2019 16 8 2019 98 33 e1639918 1 2019 5 5 2019 13 6 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0\nAbstract\nRationale:\nHepatitis E is an infectious disease due to inflammation of the liver caused by hepatitis E virus (HEV) and represents one of the most common causes of acute hepatitis and jaundice in the world. Although data of hepatitis E infection in patients with rheumatoid arthritis (RA) are accumulating, little is known on the course of HEV infection. We reported, for the 1st time, a case of patient with RA with hepatitis E that developed during leflunomide therapy in combination with low-dose steroids.\n\nPatient concerns:\nWe present a 39-year-old woman, affected by RA and treated with leflunomide, reported diffuse itching and persistent fatigue laboratory data revealed elevated liver enzyme levels.\n\nDiagnosis:\nPositivity for anti-HEV IgM and IgG was observed. HEV-RNA of the genotype 3 was detected, indicating acute E hepatitis.\n\nInterventions and outcomes:\nLeflunomide was stopped and restarted 5 months after the initial diagnosis at the same dosage, with a close clinical and laboratory follow-up. The virus was eradicated from the serum without chronic transformation. The patient is alive and well 7 months after the initial diagnosis.\n\nLessons:\nTo our knowledge, this report is the 1st case of acute E hepatitis in a patient with RA developed during leflunomide therapy in combination with low-dose steroids. Moreover, geoepidemiology of infection is important, due to the fact that Abruzzo, a central region of Italy, has the highest HEV seroprevalence in general population, related to the zoonotic transmission of the infection from domestic and wild animals. Our case highlighted that immunosuppressive therapy, and in particular leflunomide, could be safely reintroduced after the resolution of the infection and the clearance of the virus. Further studies are needed to evaluate potential advantages in serologic testing for HEV infection as a part of the routine workup done to patients with rheumatic diseases and selected for immunosuppressive therapy.\n\nKeywords\nhepatitis E infectionhepatitis E virusleflunomiderheumatoid arthritisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nHepatitis E virus (HEV) is a nonenveloped single-stranded positive RNA virus belonging to Hepeviridae family.[1] There are at least 4 human pathogenic HEV-genotypes (GT1–4), which display a specific geographical distribution.[1,2] In particular, GT1 and GT2 infect only humans, are spread by the fecal-oral route, and are prevalent in regions with low sanitation standards. GT3 and GT4 are the most prevalent strains in industrialized countries, and the infection with such strains is considered a zoonosis, being pigs, wild boars, and deers the major source of infection. Although rare, interhuman infection seems possible, in particular through blood products.[3]\n\n\nHepatitis E is an infectious disease due to inflammation of the liver caused by HEV and represents one of the most common causes of acute hepatitis and jaundice in the world.[2] The course of HEV infection is variable, from a clinically asymptomatic and self-limiting condition in the vast majority of cases, to a mild self-limiting hepatitis, with fatigue, nausea, itching, and jaundice, the latter occurring only in a small percentage of patients, mainly old males.[4] Acute liver failure is a rare complication, mainly occurring in patients with chronic liver disease, and being fatal in 0.5% to 3% of young adults. However, it can account for up to 30% of mortality in pregnant women in the 3rd trimester.[2] Chronic infection, described with GT3 and GT4 genotypes, is defined as the persistence of detectable HEV-RNA in serum for 6 months in immunocompetent and 3 months in immunocompromised patients.[4] In particular, solid organ transplant receivers may develop a chronic infection in >50% of cases,[5,6] and data concerning its incidence in individuals infected with the human immunodeficiency virus, or patients with hematologic or rheumatic disorders receiving immunosuppressive therapy, are accumulating in the literature.[7,8,9] In these patients, chronic infection can rapidly lead to liver cirrhosis and failure.\n\nIn addition, several extra-hepatic manifestations, in particular neurologic, renal, hematologic, and rheumatic, have been reported in association with HEV infection.[10,11,12]\n\n\nHepatic involvement is one of the most common complications of immunosuppressive treatment in patients with rheumatoid arthritis (RA). Reactivation of viruses such as hepatitis B (HBV) and hepatitis C (HCV) viruses, or de novo hepatic infection can occur as side effect of conventional synthetic (cs) or biologic (b) disease-modifying antirheumatic drug (DMARD) therapy.[13,14,15]\n\n\nWe report a case of acute hepatitis E in a patient with RA during immunosuppressive treatment with leflunomide and a stable dose of prednisone and receiving hepatitis B prophylaxis with entecavir.\n\n2 Case presentation\nIn January 2018, a 39-year-old woman with severe arthritis of wrists and metacarpophalangeal joints was admitted to our Rheumatology Unit. The affected joints were warm, erythematous, swollen, and painful, but fever was not detected, and the general physical examination found no abnormalities, except a systolic murmur on the left 4° intercostal space. She was born in Albania, has been living in L’Aquila, a city of the Abruzzo region of central Italy, for 8 years, and did not travel abroad over the previous months. Her medical history was remarkable for a chronic autoimmune thyroiditis, a congenital subaortic defect of the interventricular septum, and a previously resolved, HBV infection. She had a 13-year history of rheumatoid factor-positive and anticitrullinated protein antibody-positive RA with joint erosions. In the past, she had been treated with subcutaneous injections of methotrexate 15 mg/wk, with good response, until May 2017, when she was admitted to Pneumology Unit of our hospital due to the occurrence of fever, worsening dyspnea, and nonproductive cough. High resolution computed tomography of the lungs revealed limited areas of ground glass opacity in the upper right and left lobes. Cultures of bronchoalveolar lavage fluid were negative for most common bacteria, including mycobacteria. Methotrexate was stopped, and a prolonged course of corticosteroids and broad-spectrum antibiotics were started.\n\nOn current hospital admission, treatment for RA included prednisone 5 mg/d; other chronic medications were l-thyroxine 50 μg/d, esomeprazole 40 mg/d, inhaled fluticasone furoate/vilanterole 92/22 μg/d, cholecalciferol 25,000 IU/mo. Figure 1 displays a summary of the clinical and laboratory course of the patient. The activity (DAS28-C-reactive protein [CRP] 5.22) and severity (namely seropositivity and erosive disease) of RA required the reintroduction of DMARD treatment. However, in consideration of the medium–high risk of these drugs on reactivation of HBV (anti-Hbc and anti-Hbs positive patient with negative HBV-DNA), she started prophylactic therapy with entecavir 0.5 mg/d. One month after, leflunomide 20 mg/d was added.\n\nFigure 1 Course of liver enzymes and disease activity, considering HEV infection and immunosuppressive treatment for rheumatoid arthritis. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DAS28-CRP = disease activity score 28-C-reactive protein, ENT = entecavir, HEV = hepatits E virus, LEF = leflunomide, PDN = prednisone, γ-GT = gamma-glutamyl-transferase.\n\nIn March 2018, 1 month after starting treatment with leflunomide and 2 months after starting treatment with entecavir, she complained diffuse itching and persistent fatigue. Laboratory data revealed elevated liver enzyme levels, and she was admitted to Infectious Diseases Unit of our hospital. Two hypotheses were proposed: firstly, a drug-induced liver injury hence with possible hepatotoxic drugs including leflunomide was stopped; secondly, a reactivation of occult hepatitis B despite therapy with entecavir, so HBV-DNA was tested. Blood counts, total protein, albumin, total bilirubin, electrolytes, renal tests, CRP, and coagulation test results were within normal ranges. Antinuclear antibodies and other autoimmune hepatitis serologic markers were also negative. An ultrasound scan of the abdomen showed no abnormalities of the liver or gallbladder, no dilation of the intrahepatic or extrahepatic bile ducts and no evidence of thrombosis of the suprahepatic veins or portal venous system. A broad spectrum of other hepatotropic viruses, including hepatitis A and hepatitis C viruses, herpes simplex virus, cytomegalovirus, Epstein–Barr virus, human immunodeficiency virus, and parvovirus B19, was also tested but recent infections could be ruled out. HBV-DNA was also negative. Interestingly, positivity for anti-HEV IgM (1.99 IU/mL) and IgG (0.86 IU/mL) was observed. HEV-RNA of the GT3 genotype was 724 IU/mL indicating acute E hepatitis. The patient reported a consumption of undercooked pig sausages some weeks before the onset of symptoms. During the follow-up, her clinical conditions gradually improved, the transaminase levels diminished within 3 weeks, no specific antiviral therapy was started and she was discharged.\n\nAfter the resolution of the infection and the clearance of the virus, because of persistent articular complaints, leflunomide was restarted at the same dosage, with a close clinical and laboratory follow-up to rapidly reveal any sign of liver injury. Seven months later, liver enzyme levels were normal. Anti-HEV IgG persisted, and anti-HEV IgM decreased to the threshold value. HEV-RNA was negative in the serum.\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\n3 Discussion\nThere are several causes of increased liver function tests in patients with rheumatic diseases, including drug toxicity, liver involvement by the rheumatic disease itself, concomitant autoimmune hepatic disease, or infections, and an accurate differential diagnosis is important to choose the best treatment for the patient.[13,14,15] In the case we described here, the occurrence of acute liver injury could be associated with the introduction of leflunomide and entecavir, giving suspect for a drug toxicity. However, we detected ongoing acute E hepatitis and such finding underscores that in immunocompromised patients with liver cytolysis, investigations for HEV infection must be performed routinely, especially in high endemic areas, as is the case for Abruzzo region.\n\nThe HEV is an ubiquitous virus and outbreaks occur against an endemic background in areas with inadequate drinking water safety and sanitation.[1,2] Although the difference in test sensitivity and the frequently asymptomatic course of the disease, HEV seroprevalence in Europe could be estimated ranging from 7.5% to 31.9%, with an average rate of 19.16%.[16] A recent critical review estimated that HEV seroprevalence varied from 0.12% to 49% in Italy, with the highest rates being reported from the central region of Italy.[17] In particular, Abruzzo region seems to have the highest seroprevalence in general population.[17,18] In Italy, GT3 genotype occurs in the majority of the locally acquired acute HEV infection, related to the zoonotic transmission of the infection from domestic and wild animals. The majority of autochthonous cases of HEV infection were clearly related to the ingestion of raw or undercooked local pork meat.[19] In our patient, we were not able to identify a certain the source of infection; in particular, she did not have recent travel history or exposure to blood products, and no other family members complained symptoms or clinical signs related to hepatitis. However, patient referred to regularly eat pork sausages and, in particular, she reported a consumption of undercooked pig sausages some weeks before the onset of symptoms.\n\nInterestingly, although several observations show that acute polyarthritis should be added to the systemic manifestations of HEV infection,[20] in our patient, we did not observe a worsening of RA, in terms of patient-related symptoms or disease activity measured by DAS28-CRP.\n\nTwenty-six cases of hepatitis E developed during the treatment of RA with DMARDs were reported in a recent literature review.[21] In particular, 20 patients were treated with targeted synthetic (ts) or bDMARDs with or without csDMARDs and 6 patients with csDMARDs, namely methotrexate, bucillamine, mizoribine, actarit, and tacrolimus; low-dose steroids were used in 16 cases. Interestingly, our case showed for the 1st time a HEV infection related to the treatment with leflunomide with low-dose steroids.\n\nUnfortunately, we did not have stored serum samples from earlier times to confirm whether our patient developed hepatitis as a result of primary acute or chronic infection of HEV. However, the clinical course of our patient was self-limiting, the virus was eradicated from the serum without chronic transformation, and we did not observe recurrence of hepatitis nor persistent infection of HEV infection during the following 7 months, even after the reintroduction of leflunomide.\n\nIn general, the outcome of HEV infection seems favorable in patients with inflammatory arthritides treated with immunosuppressants, with no evolution to chronic hepatitis or fulminant liver failure.[22] In case of hepatitis E occurrence, discontinuation of DMARDs is recommended, and administration of ribavirin may be necessary in high-risk patients.[4] Our case highlighted that csDMARDs, and in particular leflunomide, could be safely reintroduced after the resolution of the infection and the clearance of the virus, with a close monitoring of hepatic function tests and HEV-RNA.\n\n4 Conclusion\nAlthough case reports of hepatitis E infection in patients with RA are accumulating,[9,21,22,23] little is known on the course of HEV infection in patients with inflammatory rheumatic disorders. We reported a case of patients with RA with hepatitis E that developed during leflunomide therapy in combination with low-dose steroids. In immunocompromised patients with unexplained liver cytolysis, investigations for HEV infection must be performed routinely, including not only tests for IgG and IgM antibodies, but also RT-PCR assays for HEV-RNA in blood and stool specimens, due to the fact that these patients may have no detectable antibodies even when the virus is present.[24] Likewise, the reintroduction of immunosuppressive drugs can be considered once the polymerase chain reaction tests for HEV-RNA revert to negative in blood and/or stool specimens. Further studies are needed to evaluate potential advantages in serologic testing for HEV infection as a part of the routine workup done to patients with rheumatic diseases and selected for DMARD therapy.\n\nAuthor contributions\n\nConceptualization: Francesco Carubbi.\n\n\nData curation: Francesco Carubbi, Giovanna Picchi, Salvatore Di Bartolomeo, Alessandra Ricciardi, Paola Cipriani, Laura Marola.\n\n\nFormal analysis: Francesco Carubbi.\n\n\nInvestigation: Francesco Carubbi, Giovanna Picchi, Salvatore Di Bartolomeo, Alessandra Ricciardi, Paola Cipriani.\n\n\nSupervision: Alessandro Grimaldi, Roberto Giacomelli.\n\n\nValidation: Giovanna Picchi.\n\n\nWriting – original draft: Francesco Carubbi, Salvatore Di Bartolomeo.\n\n\nWriting – review & editing: Giovanna Picchi, Alessandra Ricciardi, Paola Cipriani.\n\nAbbreviations: ACPA = anticitrullinated protein antibody, CRP = C-reactive protein, DAS = disease activity score, DMARDs = disease-modifying antirheumatic drugs, GT = genotype, HBV = hepatitis B virus, HCV = hepatitis C virus, HEV = hepatitis E virus, RA = rheumatoid arthritis.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] \nGuerra JAAA Kampa KC Morsoletto DGB \nHepatitis E: a literature review . J Clin Transl Hepatol \n2017 ;5 :376 –83 .29226104 \n[2] \nNimgaonkar I Ding Q Schwartz RE \nHepatitis E virus: advances and challenges . Nat Rev Gastroenterol Hepatol \n2018 ;15 :96 –110 .29162935 \n[3] \nHewitt PE Ijaz S Brailsford SR \nHepatitis E virus in blood components: a prevalence and transmission study in southeast England . Lancet \n2014 ;384 :1766 –73 .25078306 \n[4] \nDalton HR Kamar N Baylis SA \nEuropean Association for the Study of the Liver. EASL Clinical Practice Guidelines on hepatitis E virus infection . J Hepatol \n2018 ;68 :1256 –71 .29609832 \n[5] \nKamar N Selves J Mansuy JM \nHepatitis E virus and chronic hepatitis in organ-transplant recipients . NEJM \n2008 ;358 :811 –7 .18287603 \n[6] \nFang SY Han H \nHepatitis E viral infection in solid organ transplant patients . Curr Opin Organ Transplant \n2017 ;22 :351 –5 .28582320 \n[7] \nDebes JD Pisano MB Lotto M \nHepatitis E virus infection in the HIV-positive patient . J Clin Virol \n2016 ;80 :102 –6 .27243210 \n[8] \nO’Gorman J Burke Á O’Flaherty N \nHepatitis E virus - key points for the clinical haematologist . Br J Haematol \n2018 ;181 :579 –89 .29468650 \n[9] \nKobayashi D Ito S Takai C \nType-E hepatitis in rheumatoid arthritis patients . Mod Rheumatol Case Rep \n2017 ;1 :30 –4 .\n[10] \nKamar N Marion O Abravanel F \nExtrahepatic manifestations of hepatitis E virus . Liver Int \n2016 ;36 :467 –72 .27005692 \n[11] \nPischke S Hartl J Pas SD \nHepatitis E virus: Infection beyond the liver? \nJ Hepatol \n2017 ;66 :1082 –95 .27913223 \n[12] \nMclean BN Gulliver J Dalton HR \nHepatitis E virus and neurological disorders . Pract Neurol \n2017 ;17 :282 –8 .28647707 \n[13] \nSmolen JS Landewé R Bijlsma J \nEULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update . Ann Rheum Dis \n2017 ;76 :960 –77 .28264816 \n[14] \nCraig E Cappelli LC \nGastrointestinal and hepatic disease in rheumatoid arthritis . Rheum Dis Clin North Am \n2018 ;44 :89 –111 .29149929 \n[15] \nRadovanović-Dinić B Tešić-Rajković S Zivkovic V \nClinical connection between rheumatoid arthritis and liver damage . Rheumatol Int \n2018 ;38 :715 –24 .29627896 \n[16] \nHartl J Otto B Madden RG \nHepatitis E seroprevalence in Europe: a meta-analysis . Viruses \n2016 ;8 :E211 .27509518 \n[17] \nMauceri C Grazia Clemente M Castiglia P \nHepatitis E in Italy: a silent presence . J Infect Public Health \n2018 ;11 :1 –8 .28864359 \n[18] \nLucarelli C Spada E Taliani G \nHigh prevalence of anti-hepatitis E virus antibodies among blood donors in central Italy, February to March 2014 . Euro Surveill \n2016 ;21 : \n[19] \nTarantino G Bagnarelli P Marzioni M \nHepatitis E in a region of Italy: an emerging autochthonous infection? \nDig LiverDis \n2016 ;48 :1340 –5 .\n[20] \nSerratrice J Disdier P Colson P \nAcute polyarthritis revealing hepatitis E . Clin Rheumatol \n2007 ;26 :1973 –5 .17340044 \n[21] \nIkeuchi H Koinuma K Nakasatomi M \nHepatitis E during tocilizumab therapy in a patient with rheumatoid arthritis: case report and literature review . Case Rep Rheumatol \n2018 ;2018 :6873276 .30147981 \n[22] \nBauer H Luxembourger C Gottenberg JE \nOutcome of hepatitis E virus infection in patients with inflammatory arthritides treated with immunosuppressants: a French retrospective multicenter study . Medicine (Baltimore) \n2015 ;94 :e675 .25860212 \n[23] \nThodou V Buechter M Manka P \nCourse of hepatitis E infection in a patient with rheumatoid arthritis and autoimmune hepatitis: a case report . Medicine (Baltimore) \n2017 ;96 :e9407 .29390558 \n[24] \nBihl F Negro F \nChronic hepatitis E in the immunosuppressed: a new source of trouble? \nJ Hepatol \n2009 ;50 :435 –7 .19070913\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "98(33)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D001172:Arthritis, Rheumatoid; D005260:Female; D016751:Hepatitis E; D016752:Hepatitis E virus; D006801:Humans; D007166:Immunosuppressive Agents; D007558:Italy; D000077339:Leflunomide; D016036:Seroepidemiologic Studies",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e16399",
"pmc": null,
"pmid": "31415347",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis E infection in a patient with rheumatoid arthritis treated with leflunomide: A case report with emphasis on geoepidemiology.",
"title_normalized": "hepatitis e infection in a patient with rheumatoid arthritis treated with leflunomide a case report with emphasis on geoepidemiology"
} | [
{
"companynumb": "IT-SA-2019SA238791",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "OBJECTIVE\nTo analyze the applicability of US-guided rectus sheath block and to find out the efficacy of analgesia provided using this method without the need for opioids in conventional Hypertrophic pyloric stenosis (HPS) surgery in infants.\n\n\nBACKGROUND\nThis study describes the provision of intra- as well as postoperative analgesia by the use of an ultrasound-guided rectus sheath block in infants undergoing conventional HPS surgery under general anesthesia.\n\n\nMETHODS\nThe anesthetic protocols of 26 infants undergoing HPS surgery were reviewed retrospectively.\n\n\nRESULTS\nThe weight of the infants ranged from 2.6 to 4.6 kg. The rectus sheath block was regarded as successful in all patients as there was no heart rate increase upon surgical skin incision in any of the patients. Two out of 26 (7.6%) babies needed additional intraoperative rescue analgesia and were administered fentanyl at 20 and 40 min after skin incision. Two more (a total of 4; 15.3%) babies required postoperative analgesia and were administered tramadol droplets and liquid ibuprofen at 15, 120 and 150 min postoperatively. Duration of surgery was significantly longer in those two patients who required intraoperative rescue analgesia (Wilcoxon-Mann-Whitney test: P < 0.05). These were also the only two patients who received one intra- and one postoperative dose of opioid each (7.6%).\n\n\nCONCLUSIONS\nUS-guided rectus sheath block seems to be a simple and quick method for the provision of intra- and postoperative analgesia in infants undergoing conventional HPS surgery.",
"affiliations": "Department of Anaesthesia, Klinikum Klagenfurt, Klagenfurt, Austria.",
"authors": "Breschan|Christian|C|;Jost|Robert|R|;Stettner|Haro|H|;Feigl|Georg|G|;Semmelrock|Sandra|S|;Graf|Gudrun|G|;Likar|Rudolf|R|",
"chemical_list": "D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014147:Tramadol; D005283:Fentanyl; D007052:Ibuprofen",
"country": "France",
"delete": false,
"doi": "10.1111/pan.12267",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "23(12)",
"journal": "Paediatric anaesthesia",
"keywords": "hypertrophic pyloric stenosis; infant; ultrasound-guided rectus sheath block",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D000701:Analgesics, Opioid; D000768:Anesthesia, General; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005260:Female; D005283:Fentanyl; D006339:Heart Rate; D006801:Humans; D007052:Ibuprofen; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009407:Nerve Block; D010149:Pain, Postoperative; D011182:Postoperative Care; D011183:Postoperative Complications; D011300:Preoperative Care; D011446:Prospective Studies; D046248:Pyloric Stenosis, Hypertrophic; D014147:Tramadol; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "1199-204",
"pmc": null,
"pmid": "24112798",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ultrasound-guided rectus sheath block for pyloromyotomy in infants: a retrospective analysis of a case series.",
"title_normalized": "ultrasound guided rectus sheath block for pyloromyotomy in infants a retrospective analysis of a case series"
} | [
{
"companynumb": "AT-JNJFOC-20140903495",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nNeurotrophic receptor tyrosine kinase fusions cause overexpression or activation of kinase and are believed to confer oncogenic potential in some non-rhabdomyosarcoma soft tissue sarcomas. TRK inhibitors have recently been shown to induce responses in these tumours though current experience with these agents is still limited.\n\n\nMETHODS\nWe report a case of an adolescent with treatment-refractory non-rhabdomyosarcoma soft tissue sarcomas, carrying a novel DCTN1-NTRK1 gene fusion whose progressive disease was treated with multi-kinase and TRK inhibitors.Management and outcome: Our patient was started on pan-TRK inhibitor larotrectinib, as his disease progressed after chemotherapy, radiation therapy and surgery, based on next-generation sequencing test showing DCTN1-NTRK1 gene fusion. He responded quickly to larotrectinib with the improvement of symptoms and reduction of masses. However, this response was short-lived due to the development of acquired solvent front resistance mutation. This patient did not respond to next-generation TRK inhibitor selitrectinib and eventually succumbed to his disease.\n\n\nCONCLUSIONS\nThe initial rapid and drastic response of our patient to larotrectinib was not sustained due to the development of acquired resistance. This case emphasizes the need for upfront and periodic next-generation sequencing testing to guide treatment of patients with refractory non-rhabdomyosarcoma soft tissue sarcomas.",
"affiliations": "Department of Pharmacy, KK Women's and Children's Hospital, Singapore, Singapore.;Department of Paediatric Subspecialties, Haematology-Oncology Service, KK Women's and Children's Hospital, Singapore, Singapore.;Duke-NUS Medical School, Singapore, Singapore.;Department of Diagnostic and Interventional Imaging, KK Women's and Children's Hospital, Singapore, Singapore.;Duke-NUS Medical School, Singapore, Singapore.;Department of Paediatric Subspecialties, Haematology-Oncology Service, KK Women's and Children's Hospital, Singapore, Singapore.",
"authors": "Goh|Xue Na|XN|https://orcid.org/0000-0001-9414-7983;Seng|Michaela Su-Fern|MS|;Loh|Amos Hong Pheng|AHP|;Gupta|Achint|A|;Chang|Kenneth Tou En|KTE|;Iyer|Prasad|P|",
"chemical_list": "D000970:Antineoplastic Agents; D001372:Aza Compounds; C000606360:DCTN1 protein, human; D000072159:Dynactin Complex; C000611485:NTRK1 protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C000629855:selitrectinib; D020917:Receptor, trkA; C000609083:larotrectinib",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220938849",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(2)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Neurotrophic receptor tyrosine kinase fusions; TRK inhibitor resistance; larotrectinib; non-rhabdomyosarcoma soft tissue sarcomas; selitrectinib",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D001372:Aza Compounds; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D000072159:Dynactin Complex; D017809:Fatal Outcome; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D020917:Receptor, trkA; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "485-489",
"pmc": null,
"pmid": "32693686",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Larotrectinib followed by selitrectinib in a novel DCTN1-NTRK1 fusion undifferentiated pleomorphic sarcoma.",
"title_normalized": "larotrectinib followed by selitrectinib in a novel dctn1 ntrk1 fusion undifferentiated pleomorphic sarcoma"
} | [
{
"companynumb": "SG-BAYER-2020-168526",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAROTRECTINIB"
},
"drugadditional": "1",
... |
{
"abstract": "Pancytopenia and neutropenia due to coronavirus disease 2019 (COVID-19) are rare. Here we report a case of neutropenia as a sequela of COVID-19 with concern for bone marrow infiltration. The patient was successfully treated with granulocyte colony-stimulating factor.",
"affiliations": "University of South Florida, Morsani College of Medicine, Department of Internal Medicine, Tampa, Florida, USA.;University of South Florida, Morsani College of Medicine, Department of Internal Medicine, Tampa, Florida, USA.;University of South Florida, Morsani College of Medicine, Department of Internal Medicine, Tampa, Florida, USA.;University of South Florida, Morsani College of Medicine, Department of Internal Medicine, Tampa, Florida, USA.;University of South Florida, Morsani College of Medicine, Department of Internal Medicine, Tampa, Florida, USA.;Tampa General Hospital, Esoteric Testing, Research & Development, and Microbiology Laboratories, Tampa, Florida, USA.;University of South Florida, Morsani College of Medicine, Department of Internal Medicine, Tampa, Florida, USA.",
"authors": "Hernandez|Jarelys M|JM|https://orcid.org/0000-0003-2048-894X;Quarles|Ross|R|;Lakshmi|Seetha|S|;Casanas|Beata|B|;Eatrides|Jennifer|J|;McCoy|Erin|E|;Somboonwit|Charurut|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofab017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2328-8957",
"issue": "8(2)",
"journal": "Open forum infectious diseases",
"keywords": "COVID-19; GCSF; SARS-CoV-2; neutropenia; pancytopenia",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofab017",
"pmc": null,
"pmid": "33604404",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "32755847;32791509;32776573;32849654;32839624;32419212;32615155;32535707",
"title": "Pancytopenia and Profound Neutropenia as a Sequela of Severe SARS-CoV-2 Infection (COVID-19) With Concern for Bone Marrow Involvement.",
"title_normalized": "pancytopenia and profound neutropenia as a sequela of severe sars cov 2 infection covid 19 with concern for bone marrow involvement"
} | [
{
"companynumb": "US-SLATE RUN PHARMACEUTICALS-21US000530",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional"... |
{
"abstract": "Patients who receive or have received anti-programmed cell-death-1 (PD-1) monoclonal antibodies can develop immune-related adverse events due to activation of the immune system.\nWe report a case of a patient who received pembrolizumab and presented with cardiac tamponade. Despite pericardial drainage, she persisted with refractory arterial hypotension due to secondary adrenal insufficiency. After initiating corticosteroid therapy, the patient recovered successfully.\nThe association of pericarditis, hypophysitis and thyroid dysfunction support the diagnosis of a life-threatening immune-related adverse event due to pembrolizumab. In case of immune-related adverse events secondary to anti-PD-1 monoclonal antibodies, corticosteroid therapy should be promptly initiated in order to avoid major complications.",
"affiliations": "Department of Cardiology, Hospital Universitario Vall d'Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Paseo Vall d'Hebrón, Barcelona, Spain.;Department of Cardiology, Hospital Universitario Vall d'Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Paseo Vall d'Hebrón, Barcelona, Spain.;Department of Oncology, Hospital Universitario Vall d'Hebrón, Vall d'Hebrón Institute of Oncology, Paseo Vall d'Hebrón, Barcelona, Spain.;Department of Oncology, Hospital Universitario Vall d'Hebrón, Vall d'Hebrón Institute of Oncology, Paseo Vall d'Hebrón, Barcelona, Spain.",
"authors": "Oristrell|Gerard|G|;Bañeras|Jordi|J|;Ros|Javier|J|;Muñoz|Eva|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/yty038",
"fulltext": "\n==== Front\nEur Heart J Case RepEur Heart J Case RepehjcrEuropean Heart Journal: Case Reports2514-2119Oxford University Press 10.1093/ehjcr/yty038yty038Case ReportsCardiac tamponade and adrenal insufficiency due to pembrolizumab: a case report Oristrell Gerard 1Bañeras Jordi 1Ros Javier 2Muñoz Eva 21 Department of Cardiology, Hospital Universitario Vall d'Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Paseo Vall d'Hebrón, Barcelona, Spain2 Department of Oncology, Hospital Universitario Vall d'Hebrón, Vall d'Hebrón Institute of Oncology, Paseo Vall d'Hebrón, Barcelona, SpainCorresponding author. Tel: +34 93 274 61 34, Fax: +34 93 274 60 03, Email: gerard.oristrell@gmail.com. This case report was reviewed by Timothy C. Tan and Marco De Carlo.6 2018 03 4 2018 03 4 2018 2 2 yty03818 11 2017 4 3 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nIntroduction\nPatients who receive or have received anti-programmed cell-death-1 (PD-1) monoclonal antibodies can develop immune-related adverse events due to activation of the immune system.\n\nCase presentation\nWe report a case of a patient who received pembrolizumab and presented with cardiac tamponade. Despite pericardial drainage, she persisted with refractory arterial hypotension due to secondary adrenal insufficiency. After initiating corticosteroid therapy, the patient recovered successfully.\n\nDiscussion\nThe association of pericarditis, hypophysitis and thyroid dysfunction support the diagnosis of a life-threatening immune-related adverse event due to pembrolizumab. In case of immune-related adverse events secondary to anti-PD-1 monoclonal antibodies, corticosteroid therapy should be promptly initiated in order to avoid major complications.\n\nPericarditisCardiac tamponadeAdrenal insufficiencyPembrolizumabCorticosteroidsCase report\n==== Body\nLearning points\nImmune-checkpoint inhibitors (ICIs) can induce several immune-related adverse events, including thyroid dysfunction, hypophysitis, and pericarditis.\n\nImmune-mediated pericarditis secondary to ICIs is rare, but can be the first clinical manifestation of a wide spectrum of immune-related adverse events.\n\nPrompt recognition of immune-related adverse events and the early use of corticosteroid therapy are crucial in order to avoid major complications.\n\n\n\n\nIntroduction\nImmune-checkpoint inhibitors (ICIs) have demonstrated antitumor response in melanoma, non-small cell lung cancer and renal cell cancer, and are being tested in other tumours. However, a wide spectrum of immune-related adverse events has been observed, including pneumonitis, colitis, hypophysitis, hepatitis, or hypothyroidism. Occasional cases of cardiotoxicity, including myocarditis, heart block or pericarditis, have also been reported.\n\nAlthough corticosteroids are not recommended as first-line treatment for acute pericarditis because of the risk of favouring a chronic evolution of the disease and promoting drug dependence,1 immune-mediated cardiotoxicity secondary to ICIs needs prompt steroid treatment to ensure favourable clinical outcomes.2\n\nTimeline\nTime\tEvents\t\nMarch–September 2016\tThe patient received treatment with pembrolizumab\t\nMarch 2017: Day 1\tPatient presented with cardiac tamponade.\t\nPericardiocentesis—260 mL of pericardial fluid was drained.\t\nDay 2\tMaintained hypotension despite pericardiocentesis.\t\nEchocardiogram showed signs of constrictive pericarditis\t\nDay 2 (12 a.m.)\tAnterior pericardiectomy\t\nDay 2 (1 p.m.)\tNoradrenaline was started due to refractory hypotension\t\nDay 4 (12 a.m.)\tNegative pericardial cultures: a bacterial infection of the pericardium was ruled out.\t\nFirst dose of corticosteroids (2 mg/kg)\t\nDay 4 (6 p.m.)\tNoradrenaline stopped—blood pressure recovered\t\nDay 6\tA hormonal study of the pituitary confirmed a secondary adrenal insufficiency\t\nCase presentation\nA 55-year-old woman was admitted to the Acute Cardiac Care Unit with the diagnosis of cardiac tamponade. She was a current smoker and was diagnosed with an infiltrating ductal carcinoma of the left breast cT2cN1cM0 in February 2016. Soon after, she enrolled in a clinical trial and received neoadjuvant chemotherapy based on five cycles of pembrolizumab (200 mg/tw), nab-paclitaxel (100 mg/m2) and carboplatin and four cycles of adriamycin (60 mg/m2) and cyclophosphamide (600 mg/m2), finishing the treatment in September 2016. The patient did not exhibit any relevant toxicity during chemotherapy. In October 2016, a lumpectomy and an axillary-lymph-node dissection were performed, followed by radiation therapy.\n\nIn March 2017, the patient presented to the emergency department with pericardial chest pain. She did not report shortness of breath or fever. On admission, blood pressure (BP) was 90/55 mmHg, pulse was 105 b.p.m., baseline oxygen saturation was 97% and temperature was 36°C. A pericardial rub was present, and lungs were clear. An electrocardiogram showed sinus tachycardia and decreased electrocardiographic voltage. During the first hours, the patient had transient episodes of severe hypotension, requiring fluid therapy. Pulsus paradoxus was present and an urgent transthoracic echocardiogram (TTE) showed moderate pericardial effusion and right atrial systolic collapse. Left ventricular ejection fraction (LVEF) was 55%, and troponin I levels were in the normal range. Emergent pericardiocentesis was performed, and 260 mL of pericardial fluid was drained. Then, BP increased transiently to 112/64 mmHg. Analysis of the fluid showed an exudate with 4.3 g/dL of proteins, 36 mg/dL of glucose, a lactate-dehydrogenase value of 1543 UI/L, and abundant cellularity (19 × 109 cells/L) with a predominant acute inflammatory component (93% neutrophils).\n\nDespite pericardiocentesis, episodes of arterial hypotension (BP 65/45 mmHg) persisted during the following 12 h. However, pericardial drainage flow rate was low, urine output was preserved, and lactate levels were <2 mmol/L. Another TTE showed mild pericardial effusion and ventricular septal shift with preserved LVEF. The Doppler registry showed increased hepatic vein flow reversal with expiration (Figure 1 and Supplementary material online, Video S1). Due to the persistence of haemodynamic instability and the suspicion of constrictive pericarditis, an emergent anterior pericardiectomy was performed. The macroscopic evaluation showed a slightly thickened pericardium but without inflammation of the visceral layer so visceral pericardiectomy was not necessary. Histologic examination of the pericardium showed a huge infiltration of neutrophils, but no fibrous tissue or granulomatous inflammation (Figure 2).\n\n\nFigure 1 (A) Pulsed Doppler recording of left ventricular inflow showing reduced early diastolic filling with inspiration. (B) Pulsed Doppler recording of pulmonary vein flow showing a prominent diastolic filling phase. (C) Subcostal view showing a dilated inferior vena cava reflecting the elevated right atrial pressure. (D) Pulsed Doppler recording of hepatic vein flow showing increased hepatic vein flow reversal with expiration.\n\nFigure 2 (A) Acute pericarditis, haematoxylin, and eosin staining. (B) CD3+ infiltrated in the pericardium. (C, D) Huge infiltration in pericardium with predominance of neutrophils, although there are some lymphocytes.\n\nDespite cardiac surgery, severe hypotension persisted requiring increasing doses of noradrenaline up to 0.5 mcg/kg/min. Moreover, acute pancytopenia appeared and haemoglobin, leucocytes and platelets fell from 11.9 to 7.6 g/dL (range 12–15 g/dL), 7.44 to 1.29 × 109/L (range 4–11 × 109/L) and 189 to 105 × 109/L (range 140–400 × 109/L), respectively. C-reactive protein increased to 28 mg/dL (normal < 0.5 mg/dL). Other blood investigations showed a low sodium level of 132.3 mmol/L (range 136–146 mmol/L) and a normal serum potassium of 4.32 mmol/L (range 3.5–5.1 mmol/L).\n\nAs cultures of the pericardial fluid, as well as antinuclear and antineutrophil cytoplasmic antibodies, were negative and no malignant cells were detected in the pericardial fluid, an immune-mediated pericarditis associated with adrenal insufficiency secondary to pembrolizumab was suspected and empiric treatment with intravenous corticosteroids 2 mg/kg/day was started.\n\nResponse to corticosteroids treatment was rapid. Blood pressure recovered and noradrenaline could be promptly stopped. Prior to steroid treatment, a hormonal study of the pituitary confirmed a secondary adrenal insufficiency [cortisol 0.93 μg/dL (range 5.27–22.45 μg/dL) and corticotropin <1.6 pg/mL (range 4.7–48.8 pg/mL)] and primary hypothyroidism [TSH 16.819 mU/L (range 0.55–4.78 mU/L) and T4 0.79 pg/mL (range 0.8–1.76 pg/mL)]. There was no other impaired pituitary secretion and a brain magnetic resonance ruled out metastasis to the pituitary gland. Adrenal insufficiency was treated with physiologic steroid replacement. A cardiac magnetic resonance (Figure 3) showed normal LVEF and diffuse pericardial thickening with diffuse pericardial enhancement, indicating pericardial inflammation. No myocardial delayed-contrast enhancement was observed. The patient was discharged a few days later. Six months after discharge, she has not developed any other immune-related adverse event and is doing well on low doses of corticosteroids.\n\n\nFigure 3 (A) Four-chamber and (B) two-chamber end-diastole cine-RM images show a thickened pericardium without pericardial effusion (arrows). Note mild bilateral pleural effusion (asterisks). (C) Four-chamber short-tau inversion recovery (STIR) T2-weighted imaging shows diffuse pericardial hyperintensity suggesting pericardial oedema (arrows) and (D) two-chamber delayed-contrast-enhanced imaging depicts diffuse pericardial enhancement (arrows) indicating pericardial inflammation.\n\nDiscussion\nPericardial disease in oncological patients is relatively common. It may be secondary to cardiac metastases, as a consequence of radiotherapy, chemotherapy, or immunotherapy or it could also be bacterial or viral.3\n\nOur report describes a case of acute pericarditis and profound hypotension in a patient who has been previously treated with pembrolizumab. As the patient presented with pericardial chest pain and pericardial effusion, hypotension was firstly attributed to cardiac tamponade. However, hypotension persisted after pericardiocentesis. The association between pericardial effusion, profound hypotension, and the analysis of the pericardial fluid made us consider a bacterial infection, but cultures of the pericardial fluid were negative. Troponin I levels were normal and LVEF remained preserved following pericardial drainage, so myopericarditis and pericardial decompression syndrome were ruled out. Recent radiotherapy made us also consider constrictive pericarditis. Although the echocardiogram showed evidence of constrictive physiology, this might have been a temporary form of constriction.4 The absence of inflammation of the visceral layer of the pericardium in the surgical examination and the absence of pericardial fibrosis in the histological examination ruled out constrictive pericarditis.\n\nHypotension was finally explained by a secondary adrenal insufficiency, which was probably worsened by the stress of cardiac surgery. In this scenario, corticosteroid therapy was successful in treating both adrenal insufficiency and acute pericarditis. The association of pericarditis, adrenal insufficiency secondary to hypophysitis, and hypothyroidism support the diagnosis of an immune-related adverse event due to pembrolizumab.\n\nImmune-checkpoint inhibitors can induce several immune-related endocrinopathies, including thyroid dysfunction and hypophysitis.5 In addition, haematologic disorders, such as anaemia or thrombocytopenia, have also been described.6 Cardiotoxicity of ICIs is rare. Few cases of cardiac tamponade related to anti-programmed cell-death-1 immunotherapy have been reported,7–10 but none involve pembrolizumab. All cases were treated with pericardiocentesis and corticosteroids.7 Two cases of recurrent pleural effusion and cardiac tamponade secondary to nivolumab have been published. Both of them had a history of malignant pleural and pericardial effusions prior to treatment with nivolumab, mimicking disease progression.8 Moreover, two cases of late-onset cardiac tamponade related to ipilimumab (anti-CTLA4 antibody) have been published.9,10 In both cases, diagnosis was supported by the association of other immune-related adverse events.\n\nTo our knowledge, this is the first case report of cardiac tamponade and adrenal insufficiency secondary to pembrolizumab. Physicians treating patients with ICIs should be aware of their potentially late-onset cardiac and extracardiac effects. The early use of corticosteroids is crucial in order to avoid major complications. In our case, cardiac surgery might have been avoided.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal – Case Reports online.\n\nFunding\nThis work was funded by CIBERCV and co-financed by the European Regional Development Fund (ERDF-FEDER).\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: none declared.\n\nSupplementary Material\nSupplementary Data Click here for additional data file.\n==== Refs\nReferences\n1 \nImazio M , Gaita F. \nDiagnosis and treatment of pericarditis . Heart 2015 ;101 :1159 –1168 .25855795 \n2 \nWang DY , Okoye GD , Neilan TG , Johnson DB , Moslehi JJ. \nCardiovascular toxicities associated with cancer immunotherapies . Curr Cardiol Rep 2017 ;19 :21. 28220466 \n3 \nZamorano JL , Lancellotti P , Rodriguez Muñoz D , Aboyans V , Asteggiano R , Galderisi M , Habib G , Lenihan DJ , Lip GYH , Lyon AR , Lopez Fernandez T , Mohty D , Piepoli MF , Tamargo J , Torbicki A , Suter TM. \n2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) . Eur Heart J 2016 ;37 :2768 –2801 .27567406 \n4 \nGentry J , Klein AL , Jellis CL. \nTransient constrictive pericarditis: current diagnostic and therapeutic strategies . Curr Cardiol Rep 2016 ;18 :41. 26995404 \n5 \nByun DJ , Wolchok JD , Rosenberg LM , Girotra M. \nCancer immunotherapy—immune checkpoint blockade and associated endocrinopathies . Nat Rev Endocrinol 2017 ;13 :195 –207 .28106152 \n6 \nPföhler C , Eichler H , Burgard B , Krecké N , Müller CSL , Vogt T. \nA case of immune thrombocytopenia as a rare side effect of an immunotherapy with PD1-blocking agents for metastatic melanoma . Transfus Med Hemother 2017 ;44 :426 –428 .29344020 \n7 \nKushnir I , Wolf I. \nNivolumab-induced pericardial tamponade: a case report and discussion . Cardiology 2017 ;136 :49 –51 .27554835 \n8 \nKolla BC , Patel MR. \nRecurrent pleural effusions and cardiac tamponade as possible manifestations of pseudoprogression associated with nivolumab therapy—a report of two cases . J Immunother Cancer 2016 ;4 :80. 27895919 \n9 \nYun S , Vincelette ND , Mansour I , Hariri D , Motamed S. \nLate onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication . Case Rep Oncol Med 2015 ;2015 :794842. 25918658 \n10 \nDasanu CA , Jen T , Skulski R. \nLate-onset pericardial tamponade, bilateral pleural effusions and recurrent immune monoarthritis induced by ipilimumab use for metastatic melanoma . J Oncol Pharm Pract 2017 ;23 :231 –234 .26946531\n\n",
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"journal": "European heart journal. Case reports",
"keywords": "Adrenal insufficiency; Cardiac tamponade; Case report; Corticosteroids; Pembrolizumab; Pericarditis",
"medline_ta": "Eur Heart J Case Rep",
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"title": "Cardiac tamponade and adrenal insufficiency due to pembrolizumab: a case report.",
"title_normalized": "cardiac tamponade and adrenal insufficiency due to pembrolizumab a case report"
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"abstract": "Objective We report a case of pediatric thoracic tumor-induced osteomalacia (TIO) causing severe hypophosphatemic rickets with delayed diagnosis and emphasize on timely management of this rare entity. Case presentation A young boy presented with rickets since five years of age. Biochemical evaluation revealed hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase and normal calcium levels. Initially managed as hereditary hypophosphatemic rickets, he was given phosphorus supplements and calcitriol. Despite the therapy, skeletal deformities worsened requiring surgical corrections. Subsequently, he developed iatrogenic tertiary hyperparathyroidism for which he underwent total parathyroidectomy. Later on, he was found to have fibroblast growth factor-23 secreting thoracic mass (10.5 cm in largest dimension) which was excised with significant post operative improvement. Histopathology showed phosphaturic mesenchymal tumor-mixed connective tissue variant, confirming the diagnosis of TIO. Conclusion TIO, a correctable cause of hypophosphatemic rickets, should be considered in children presenting with hypophosphatemic rickets with evident mass on examination/imaging and in refractory cases.",
"affiliations": "Department of Endocrinology, Seth GS Medical College & KEM Hospital, Parel, Mumbai, India.;Department of Endocrinology, Seth GS Medical College & KEM Hospital, Parel, Mumbai, India.;Department of Endocrinology, Seth GS Medical College & KEM Hospital, Parel, Mumbai, India.;Department of Endocrinology, Seth GS Medical College & KEM Hospital, Parel, Mumbai, India.;Department of Pathology, Tata Memorial Center, Mumbai, Maharashtra, India.;Department of Endocrinology, Seth GS Medical College & KEM Hospital, Parel, Mumbai, India.;Department of Endocrinology, Seth GS Medical College & KEM Hospital, Parel, Mumbai, India.;Department of Endocrinology, Seth GS Medical College & KEM Hospital, Parel, Mumbai, India.",
"authors": "Kumar|Sandeep|S|;Shah|Ravikumar|R|;Patil|Virendra|V|;Ramteke-Jadhav|Swati|S|;Bal|Munita|M|;Lila|Anurag|A|;Shah|Nalini|N|;Bandgar|Tushar|T|",
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"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": "childhood TIO; thoracic TIO; tumor-induced osteomalacia; tumor-induced rickets",
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": null,
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"pmc": null,
"pmid": "32681779",
"pubdate": "2020-07-20",
"publication_types": "D002363:Case Reports",
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"title": "Tumor-induced rickets-osteomalacia: an enigma.",
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"abstract": "An 18-year-old man diagnosed with attention-deficit hyperactivity disorder was recently started on quetiapine in addition to regular methylphenidate, which he had been taking for a number of years. He presented with chest pain and inferolateral ST elevation, and underwent urgent coronary angiography, which showed normal coronary arteries. The initial troponin level was raised and an inpatient echocardiogram showed mild left ventricular systolic dysfunction with no evidence of regional wall motion abnormality. Cardiac MRI showed subepicardial late gadolinium enhancement, which was suggestive of myocarditis. Quetiapine and methylphenidate were discontinued and the patient was discharged home after 1 week. He was followed up within 8 weeks with complete recovery and no symptoms.",
"affiliations": "Department of Cardiology, Royal Wolverhampton Hospital, Wolverhampton, UK.;Department of Pharmacy, Royal Wolverhampton Hospital, Wolverhampton, UK.;Department of Cardiology, Royal Wolverhampton Hospital, Wolverhampton, UK.",
"authors": "Wassef|Nancy|N|;Khan|Nazish|N|;Munir|Shahzad|S|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D018765:Dopamine Uptake Inhibitors; D008774:Methylphenidate; D000069348:Quetiapine Fumarate",
"country": "England",
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"issue": "2015()",
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"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D001289:Attention Deficit Disorder with Hyperactivity; D001714:Bipolar Disorder; D002637:Chest Pain; D003937:Diagnosis, Differential; D003987:Dibenzothiazepines; D018765:Dopamine Uptake Inhibitors; D006801:Humans; D008297:Male; D008774:Methylphenidate; D009203:Myocardial Infarction; D009205:Myocarditis; D000069348:Quetiapine Fumarate; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
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"pmid": "25576507",
"pubdate": "2015-01-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12638679;17630867;11217818;24587933;19144938;22401481;19296063;19357408;10584719;11748583;8066913;21705357;12202290;16449736;16476862;17980265;11476122",
"title": "Quetiapine-induced myocarditis presenting as acute STEMI.",
"title_normalized": "quetiapine induced myocarditis presenting as acute stemi"
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"abstract": "Drug-induced thrombocytopenia is rarely associated with statin medications. We describe the case of a 69-year-old woman who developed refractory thrombocytopenia following atorvastatin use. To our knowledge, this is the fourth reported case of atorvastatin-induced thrombocytopenia and the first reported case of atorvastatin-induced refractory thrombocytopenia. Additionally, we summarize the cases of statin-induced thrombocytopenia reported in the medical literature.",
"affiliations": "Internal Medicine, University of Nevada, Reno School of Medicine, Reno, USA.;Internal Medicine, University of Nevada, Reno School of Medicine, Reno, USA.;Internal Medicine, Dr. D. Y. Patil Medical College, Hospital & Research Centre, Pimpri, IND.;Internal Medicine, University of Nevada, Reno School of Medicine, Reno, USA.;Internal Medicine, University of Nevada, Reno School of Medicine, Reno, USA.",
"authors": "Ghuman|Jasmine|J|;Manasewitsch|Nicholas T|NT|;Ghuman|Joban|J|;Antwi-Amoabeng|Daniel|D|;Chahal|Gurpreet|G|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.12502\nInternal Medicine\nHematology\nAtorvastatin-Induced Refractory Thrombocytopenia\nMuacevic Alexander Adler John R Ghuman Jasmine 1 Manasewitsch Nicholas T 1 Ghuman Joban 2 Antwi-Amoabeng Daniel 1 Chahal Gurpreet 1 \n1 \nInternal Medicine, University of Nevada, Reno School of Medicine, Reno, USA \n\n2 \nInternal Medicine, Dr. D. Y. Patil Medical College, Hospital & Research Centre, Pimpri, IND \n\nNicholas T. Manasewitsch nmanasewitsch@gmail.com\n5 1 2021 \n1 2021 \n13 1 e125025 1 2021 Copyright © 2021, Ghuman et al.2021Ghuman 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/47137-atorvastatin-induced-refractory-thrombocytopeniaDrug-induced thrombocytopenia is rarely associated with statin medications. We describe the case of a 69-year-old woman who developed refractory thrombocytopenia following atorvastatin use. To our knowledge, this is the fourth reported case of atorvastatin-induced thrombocytopenia and the first reported case of atorvastatin-induced refractory thrombocytopenia. Additionally, we summarize the cases of statin-induced thrombocytopenia reported in the medical literature.\n\nthrombocytopeniarefractorydrug-induced thrombocytopeniastatin-inducedatorvastatindrug reactionplateletpurpurahyperlipidemiapetechiaeThe 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\nAtorvastatin is used to treat dyslipidemia and the prevention of cardiovascular and cerebrovascular diseases, particularly in people who are unable to meet their lipid-lowering goals through lifestyle modifications [1-3]. It inhibits 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a key enzyme in cholesterol synthesis. The most common adverse effects of statins are dyspepsia, constipation, abdominal pain, flatulence, headache, and myalgia [4]. Myopathy, rhabdomyolysis, and liver enzyme abnormalities are rare, but major side effects seen with statin use [5,6]. A few case reports of statin-induced thrombocytopenia, specifically with atorvastatin, rosuvastatin, and simvastatin [7-15].\n\nThrombocytopenia can be either inherited or acquired. Acquired causes include drug-induced thrombocytopenia (DIT), viral or bacterial infections, malignancy, liver failure, and hypersplenism. Several mechanisms are proposed for DIT, but the most recent hypothesis suggests that weakly reactive platelet autoantibodies develop an increased affinity for platelet glycoprotein epitopes in the presence of the sensitizing drug [16]. Patients present with epistaxis, bruising, and petechiae [16]. In this case report, we present a probable temporal relationship between atorvastatin initiation and the onset of refractory thrombocytopenia.\n\nCase presentation\nA 69-year-old female with a history of hyperlipidemia presented to the hospital with atraumatic bruising, traumatic right knee hematoma, and multiple painless \"blood blisters\" on her buccal mucosa which she noticed one day prior. Her history was negative for bleeding disorders, anticoagulant use, and antiplatelet use. She started taking atorvastatin 20 mg daily about 10 weeks before presenting for hyperlipidemia. The patient's baseline low-density lipoprotein was between 125 and 146 mg/dL (reference range: < 100 mg/dL) and high-density lipoprotein was between 66 and 72 mg/dL (reference range: > 40 mg/dL). The patient was found to have profound thrombocytopenia on this admission with a platelet count of 2,000 / μL (reference range: 164,000-446,000/μL), and her other cell lines were within normal limits. Complete blood count from two months prior demonstrated a platelet count of 245,000 / μL. The patient was admitted for further workup.\n\nOur patient's coagulation studies, infectious panel, and autoimmune panel (anti-nuclear antibodies, rheumatoid factor, serum immunofixation test, serum protein electrophoresis including alpha and gamma globulins) were unremarkable. She received an infusion of two units of platelets with minimal increase in her platelet count. Suspecting immune-thrombocytopenic purpura (ITP), we subsequently treated her with two doses of intravenous immunoglobulin (IVIG) over two days and oral dexamethasone 40mg for four days. Her platelet counts improved to 55,000/μL, and she was discharged home with close follow-up. She continued taking atorvastatin 20mg.\n\nTwo days after discharge, the patient returned to the hospital, presenting with worsening fatigue and purpura. She was found to have a platelet count of 1,000 / μL and was readmitted. We discontinued her atorvastatin and started her on a regimen of IVIG for two days and prednisone 80mg for five days. Although she responded to this regimen, we added rituximab given our high suspicion for refractory thrombocytopenia, indicated by the lack of response to two or more treatments. Our patient's platelet count improved to 118,000 / μL, and she was discharged home in stable condition with instructions to complete seven days of 60 mg of prednisone and weekly doses of rituximab. The patient was not restarted on atorvastatin or any other statin. At follow-up five months after her hospital discharge and after completing four doses of rituximab, our patient's platelet count returned to baseline, and her purpura had resolved. A timeline of the variations in our patient's platelet count is illustrated in Figure 1. She currently manages her hyperlipidemia with diet and exercise.\n\nFigure 1 Temporal variations in platelet count after initiation of atorvastatin and response to interventions.\nIVIG- Intravenous mmunoglobulin\n\nDiscussion\nDIT presents with rapid symptomatic improvement following the discontinuation of the drug [16]. DIT has been associated with over 100 different mediations [16]. Two major pathologic mechanisms behind drug-induced thrombocytopenia include decreased platelet production via marrow suppression and peripheral platelet clearance [10]. Patients are exposed to the implicated medication for at least a week before developing clinical signs of thrombocytopenia [16]. DIT is suggested by rapid recovery following discontinuation of the implicated medication and the temporal relationship between symptom onset and medication exposure [7]. It is common practice to discontinue the medication and treat with steroid, and IVIG and plasma exchange may be considered for refractory cases [16]. Our patient's case was considered to be refractory given that she failed two or more treatments (steroids and IVIG), and the hematology-oncology consultant on the case agreed with this determination. We recognize that ITP may present similarly and that the resolution of our patient's thrombocytopenia may be attributed to rituximab initiation, rather than atorvastatin discontinuation alone [17].\n\nThe Naranjo Algorithm is a validated standardized questionnaire of 10 question items designed to estimate the probability of a drug causing an adverse clinical event. Scores greater than 8 are considered a definite reaction, 5 to 8 considered probable, 1 to 4 considered possible, and less than 1 considered doubtful [18,19]. Our patient’s Naranjo algorithm score of 8 (Table 1) suggests a probable association between initiation of atorvastatin and the onset of thrombocytopenia in this case.\n\nTable 1 The Naranjo Scale for assessing the association between atorvastatin use and the adverse drug reaction (ADR) of thrombocytopenia. Our patient had a probable ADR given a score of “8”. The reaction followed a reasonable temporal sequence after a drug, followed a recognized response to the suspected drug, was confirmed by withdrawal but not by exposure to the drug, and could not be reasonably explained by the known characteristics of the patient’s clinical state [16].\nNaranjo Question Item\tResponse\tScore\t\n1. Are there previous conclusive reports on this reaction?\tYes\t1\t\n2. Did the adverse event appear after the suspected drug was given?\tYes\t2\t\n3. Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was given?\tYes\t1\t\n4. Did the adverse reaction appear when the drug was re-administered?\tYes\t2\t\n5. Are there alternative causes that could have caused the reaction?\tNo\t2\t\n6. Did the reaction reappear when a placebo was given?\tN/A\t0\t\n7. Was the drug detected in any body fluid in toxic concentrations?\tN/A\t0\t\n8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?\tN/A\t0\t\n9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?\tN/A\t0\t\n10. Was the adverse event confirmed by any objective evidence?\tNo\t0\t\nScore\t \t8\t\nLovastatin has been found to dose-dependently induce platelet apoptosis via mitochondrial caspase activation. In mouse models, lovastatin impairs platelet function and reduces circulating platelets in vivo, suggesting the possible pathogenesis of thrombocytopenia and hemorrhage in patients treated with statins [20]. Given these findings, it is interesting that lovastatin-induced thrombocytopenia has not yet been reported in the literature.\n\nThe reported cases of statin-induced thrombocytopenia are summarized in Table 2. It is difficult to draw conclusions from a small set of case reports; however, statin-induced thrombocytopenia has been associated with atorvastatin, rosuvastatin, and simvastatin in the literature, two of which are lipophilic molecules. Additionally, the lipophilic statin lovastatin has been demonstrated to cause platelet apoptosis in vivo. Atorvastatin-induced thrombocytopenia has been reported three times in the literature, however, our case reports a refractory presentation [9].\n\nTable 2 Table summarizing reported cases of statin-induced thrombocytopenia in the literature.\nIVIG- Intravenous immunoglobulin; M- male; F- Female\n\nCase\tDrug\tDose\tAge / Gender\tLength of statin treatment\tClinical Symptoms\tLowest platelet count (/μL)\tTreatment regimen\tTime to resolution\tAlternate hyperlipidemia treatment\tTolerated another statin?\t\nPresent case\tAtorvastatin\t20mg\t69/F\t2.5 months\tDiffuse petechial rash, purpura, oral mucosal bleeding, traumatic knee hematoma\t1,000\tPlatelet transfusion, steroids, IVIG, rituximab\t5 months\tLifestyle modification\tNo\t\nMoitra et al (2016) [9]\tAtorvastatin\t10mg\t65/M\t6 days\tDiffuse petechial rash, gingival bleeding\t15,000\tPlatelet transfusion, steroids, IVIG\t10 days\tLifestyle modification\tNo\t\nCvetković et al (2013) [15]\tSimvastatin\t20mg\t78/F\t1 day\tGeneralized urticaria (immediate hypersensitivity reaction)\t85,000\tSteroids\t12 days\tUnspecified\tNo\t\nNarayanan et al (2010) [7]\tAtorvastatin\t20mg\t44/M\t6 months\tDiffuse petechial rash, gingival bleeding\t4,000\tSteroids\tUnspecified\tRosuvastatin\tYes, rosuvastatin\t\nVrettos et al (2009) [10]\tRosuvastatin\tUnspecified\t65/F\t1 year\tNone\t31,000\tNone (statin discontinuation only)\t6 months\tUnspecified\tNo / unknown\t\nAmes et al (2008) [11]\tSimvastatin\t10mg\t63/M\t2 months\tNone\t122,000\tNone (statin discontinuation only)\t1 month\tUnspecified\tNo / unknown\t\nGroneberg et al (2001) [12]\tSimvastatin\t10mg\t77/F\t11 months\tEpistaxis, easy bruising\t12,000\tNone (statin discontinuation only)\t3 weeks\tUnspecified\tNo / unknown\t\nGonzález-Ponte et al (1998) [8]\tAtorvastatin\t10mg\t46/M\t2 months\tWidespread purpura\t3,000\tPlatelet transfusion, steroids, IVIG\t1 month\tUnspecified\tYes, simvastatin\t\nYamada et al (1998) [13]\tSimvastatin\t5mg\t75/F\t3 years\tMultiple purpura of extremities and trunk\t2,000\tPlatelet transfusion, steroids\t2 months\tUnspecified\tNo / unknown\t\nPossamai et al (1992) [14]\tSimvastatin\t10mg\t64/F\t1 year\tEpistaxis, gingival bleeding, diffuse petechiae of trunk and limbs\t3,000\tPlatelet transfusion, steroids, IVIG\t3 weeks\tLifestyle modification\tNo\t\nConclusions\nTo our knowledge, this is the fourth reported case of atorvastatin-induced thrombocytopenia and the first reported case of atorvastatin-induced refractory thrombocytopenia. Clinicians need to be aware of this association and discontinue atorvastatin if thrombocytopenia develops. Future investigations into the relationship between statin medications and thrombocytopenia would prove useful to the medical literature.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Primary and secondary prevention of acute coronary syndromes: the role of the statins Recent Adv Cardiovasc Drug Discov Diamantis E Troupis T Mazarakis A Kyriakos G Diamanti S Troupis G Skandalakis P 97 105 9 2014 26152179 \n2 Statins in stroke Curr Med Chem Aznaouridis K Masoura C Vlachopoulous C Tousoulis D 6174 6185 26 2019 31218948 \n3 Atorvastatin: its clinical role in cerebrovascular prevention Drugs Gaspardone A Area M 55 62 67 2007 17910521 \n4 An overview of the clinical safety profile of atorvastatin (lipitor), a new HMG-CoA reductase inhibitor Arch Intern Med Black DM Bakker-Arkema RB Nawrocki JW 577 584 158 1998 9521221 \n5 Prediction of pharmacokinetic drug-drug interactions causing atorvastatin-induced rhabdomyolysis using physiologically based pharmacokinetic modelling Biomed Pharmacother Li S Yu Y Jin Z 109416 119 2019 31518878 \n6 Statin-induced rhabdomyolysis, acute kidney injury, and hepatitis leading to death Am J Case Rep Mohamed MF Salameh OK Saeed AA 709 712 20 2019 31101801 \n7 Atorvastatin-related thrombocytopenic purpura BMJ Case Rep Narayanan D Kilpatrick ES 2010 \n8 Atorvastatin-induced severe thrombocytopenia Lancet González-Ponte ML González-Ruiz M Duvós E Gutiérrez-Iñiguez MA Olalla JI Conde E 1284 352 1998 \n9 Atorvastatin induced thrombocytopenia: a case report and review of literature Med J DY Patil Univ Moitra S Sen S Das P Banerjee I 117 120 9 2016 \n10 Rosuvastatin-induced thrombocytopenia South Med J Vrettos I Papageorgiou S Economopoulou C 676 678 103 2010 https://insights.ovid.com/article/00007611-201007000-00017 20531065 \n11 Simvastatin-induced thrombocytopaenia: a further case and a brief on its clinical relevance Ann Hematol Ames PRJ 773 774 87 2008 18386006 \n12 Simvastatin-induced thrombocytopenia Am J Hematol Groneberg DA Barkhuizen A Jeha T 277 67 2001 \n13 Severe thrombocytopenia caused by simvastatin in which thrombocyte recovery was initiated after severe bacterial infection Clin Drug Investig Yamada T Shinohara K Katsuki K 172 174 16 1998 \n14 Thrombocytopenic purpura during therapy with simvastatin Haematologica Possamai G Bovo P Santonastaso M 357 358 77 1992 https://pubmed.ncbi.nlm.nih.gov/1427446/ 1427446 \n15 Simvastatin and amlodipine induced thrombocytopenia in the same patient: double trouble and a literature review J Clin Pharm Ther Cvetković Z Suvajdžić‐Vuković N Todorović Z Panić M Nešković A 246 248 38 2013 23442182 \n16 Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management J Thromb Haemost Aster RH Curtis BR McFarland JG Bougie DW 911 918 7 2009 19344362 \n17 Long‐term follow‐up analysis after rituximab salvage therapy in adult patients with immune thrombocytopenia Am J Hematol Zaja F Volpetti S Chiozzotto M Puglisi S Isola M Buttignol S Fanin R 886 889 87 2012 22718483 \n18 A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther Naranjo CA Busto U Sellers EM 239 245 30 1981 https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1038/clpt.1981.154?sid=nlm%3Apubmed 7249508 \n19 Improving the assessment of adverse drug reactions using the Naranjo Algorithm in daily practice: the Japan adverse drug events study Pharmacol Res Perspect Murayama H Sakuma M Takahashi Y Morimoto T 1 7 6 2018 \n20 Lovastatin induces platelet apoptosis Environ Toxicol Pharmacol Zhao Q Li M Chen M 69 75 42 2016 26773364\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(1)",
"journal": "Cureus",
"keywords": "atorvastatin; drug reaction; drug-induced thrombocytopenia; hyperlipidemia; petechiae; platelet; purpura; refractory; statin-induced; thrombocytopenia",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e12502",
"pmc": null,
"pmid": "33564510",
"pubdate": "2021-01-05",
"publication_types": "D002363:Case Reports",
"references": "7249508;31218948;26152179;22750917;22718483;31101801;26773364;18370536;9788465;31518878;9521221;20531065;11443649;18386006;29417762;23442182;17910521;1427446;19344362",
"title": "Atorvastatin-Induced Refractory Thrombocytopenia.",
"title_normalized": "atorvastatin induced refractory thrombocytopenia"
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"abstract": "Isotretinoin a synthetic analogue of vitamin A is primarily used for cystic acne not responding to conventional treatment. Several ocular side effects including blurring of vision, decreased dark adaptation, corneal opacities and meibomian gland atrophy have been reported with prolonged use of isotretinoin. There have been reports of muscular damage caused by isotretinoin. Extra ocular myopathy as an adverse effect of long term used of isotretinoin has never been mentioned in literature. We report a case of a young male who presented to us with complaints of diplopia after using isotretinoin for a prolonged period. He was diagnosed as a case of presumed isotretinoin extraocular myopathy after imaging and other blood investigations.",
"affiliations": "Department of Orbit Oculoplasty Reconstructive and Aesthetic Services, Sankara Nethralaya, Medical Research Foundation, Chennai, Tamil Nadu, India.;Department of Orbit Oculoplasty Reconstructive and Aesthetic Services, Sankara Nethralaya, Medical Research Foundation, Chennai, Tamil Nadu, India.",
"authors": "Alam|Md Shahid|MS|;Agarwal|Swati|S|",
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"doi": "10.4103/0976-500X.195905",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-7-18710.4103/0976-500X.195905Case ReportPresumed isotretinoin-induced extraocular myopathy Alam Md. Shahid Agarwal Swati Department of Orbit Oculoplasty Reconstructive and Aesthetic Services, Sankara Nethralaya, Medical Research Foundation, Chennai, Tamil Nadu, IndiaAddress for correspondence: Md. Shahid Alam, 18, College Road, Nungambakkam, Chennai - 600 006, Tamil Nadu, India. E-mail: mshahidalam@gmail.comOct-Dec 2016 7 4 187 189 19 7 2016 31 7 2016 13 10 2016 Copyright: © 2016 Journal of Pharmacology and Pharmacotherapeutics2016This 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.Isotretinoin a synthetic analogue of vitamin A is primarily used for cystic acne not responding to conventional treatment. Several ocular side effects including blurring of vision, decreased dark adaptation, corneal opacities and meibomian gland atrophy have been reported with prolonged use of isotretinoin. There have been reports of muscular damage caused by isotretinoin. Extra ocular myopathy as an adverse effect of long term used of isotretinoin has never been mentioned in literature. We report a case of a young male who presented to us with complaints of diplopia after using isotretinoin for a prolonged period. He was diagnosed as a case of presumed isotretinoin extraocular myopathy after imaging and other blood investigations.\n\nKey words\nExtraocular musclesisotretinoinmyopathy\n==== Body\nINTRODUCTION\nIsotretinoin (13-cis-retinoic acid), a synthetic analog of Vitamin A, is used primarily for severe cystic acne and acne that has not responded to conventional treatments.[1] Ocular side effects of isotretinoin are usually dose related. They include abnormal meibomian gland secretion, blepharoconjunctivitis, corneal opacities, decreased dark adaptation, decreased tolerance to contact lens, decreased vision, increased tear osmolarity, keratitis, meibomian gland atrophy, myopia, ocular discomfort, ocular sicca, and photophobia.[2] Extraocular myopathy caused by isotretinoin has never been mentioned in literature. We herewith report a rare case of extraocular myopathy which was most likely caused by isotretinoin intake for a prolonged period.\n\nCASE REPORT\nA 31-year-old male presented to our oculoplasty clinic with chief complaints of gradual outward deviation of left eye and double vision in right gaze for the past 2 years. There was no history of pain, trauma, diurnal variation, diminution of vision, vomiting, or headache. He was not a known case of diabetes mellitus, hypertension, thyroid disorder, or any other chronic disease.\n\nVisual acuity of both eyes was 20/20. There was right face turn with left exotropia. Extraocular movements in left eye revealed complete limitation of adduction and mild limitation of depression [Figure 1]. There were no signs of thyroid ophthalmopathy. Rest of the anterior and posterior segment examination were within normal limits. A differential diagnosis of thyroid eye disease and ocular myasthenia gravis was considered and a thyroid function test (serum free T3, serum free T4, and serum thyroid stimulating hormone assay) and serum acetylcholine receptor antibody were ordered.\n\nFigure 1 External photograph of the patient showing left exotropia and complete limitation of adduction and mild limitation of depression in the left eye\n\nThyroid function test was within normal limits and serum acetylcholine receptor antibody was negative. Magnetic resonance imaging (MRI) of the brain and orbit showed hyperintensity in the belly of left medial and inferior rectus. There was no enlargement of the muscles and orbital fat content was normal [Figure 2a and b]. The features on MRI were neither suggestive of thyroid eye disease nor idiopathic orbital inflammation.\n\nFigure 2 (a) Magnetic resonance image, axial cut, T2 sequence showing hyperintensity in left medial rectus belly. The muscle belly is smooth without any enlargement. (b) Magnetic resonance image, coronal cut, T2 sequence showing hyperintensity in left medial rectus and inferior rectus belly (arrow). The muscle belly is smooth without any enlargement\n\nOn further inquiry, the patient gave history of isotretinoin intake for 3 months (1 mg/kg/day) for cystic acne just before the symptoms started and continued the drug for next 5 months. A provisional diagnosis of isotretinoin-induced myopathy was made and the patient was asked to stop isotretinoin. The patient was also started on a course of oral steroid in tapering fashion to take care of any associated inflammatory pathology. There was no improvement in extraocular motility after 3 months of oral steroids, and a repeat MRI showed no improvement, suggesting fibrosis. The patient was prescribed prism glasses to take care of his diplopia.\n\nDISCUSSION\nExact mechanism of action of isotretinoin is not known. It has been shown to induce apoptosis in various cells of the body including sebaceous glands, and thereby helping in the treatment of acne vulgaris.[3]\n\nOne study suggests that the drug amplifies production of neutrophil gelatinase-associated lipocalin in the skin, which has been shown to reduce sebum production by inducing apoptosis in sebaceous gland cells while exhibiting an antimicrobial effect on Propionibacterium acnes.[34] The drug decreases the size and sebum output of the sebaceous glands.\n\nAbout 15% of patients treated with isotretinoin have developed musculoskeletal symptoms and on rarer occasions increased creatine kinase (CK) activities.[5] There are reports of clinical and electromyographic evidence of muscle damage during treatment with isotretinoin. The acute muscle damage caused by isotretinoin was reversible on discontinuation of the drug.[6]\n\nMyalgia and muscle stiffness have been reported in 16%–51% of patients treated with isotretinoin while elevated serum CK levels have been found in up to 41% of patients.[7] There have been several reports of severe and debilitating muscular symptoms due to isotretinoin where CK levels were normal.[8] In such patients, myopathy or a disorder of myoneural junction was suggested by muscle biopsy.\n\nThe exact mechanism of isotretinoin-induced myopathy has not yet been elucidated; however, it has been hypothesized that all therapeutic as well as adverse effects of isotretinoin are caused by its “proapoptotic mechanisms” mediated by forkhead box O and its isoforms (Melnik). The latter are proteins that are involved in regulating gene expression in a variety of conditions including inflammatory and immune-mediated processes.\n\nRegarding the patient presented in this case report, there is a possible relationship between isotretinoin intake and his extraocular myopathy.\n\nDrug-induced myositis is a condition which implies the exclusion of other entities responsible for myositis such as infectious or autoimmune diseases or idiopathic cause. The three strong differentials in the present case were thyroid-related ophthalmopathy, ocular myasthenia gravis, and idiopathic orbital inflammatory disease. The thyroid eye disease was ruled out in view of normal thyroid levels, absence of ocular signs of thyroid eye disease, and no evidence of increase in size of extraocular muscles or orbital fat on MRI. Ocular myasthenia gravis was ruled out by the absence of diurnal variation in the symptoms, symptoms being stable for the past 2 years without any variability, and a negative serum acetylcholine receptor antibody assay.\n\nIdiopathic orbital inflammatory disease commonly presents with pain and the imaging shows diffuse irregular enlargement of extraocular muscles involving the whole length of the muscle. The present case did not have any pain and the MRI showed a smooth hyperintensity in the muscle belly without any enlargement. Thereby, considering the clinical and radiological findings, the most likely diagnosis in this case was an isotretinoin-induced myopathy. Isotretinoin has been reported to have some immunomodulating effects that may induce some autoimmune diseases such as Crohn's disease, immune-mediated diabetes, and Guillain–Barré syndrome.[910] There has been a case report regarding possible association between isotretinoin intake and concomitant autoimmune thyroiditis and ocular myasthenia gravis.[11]\n\nThere is considerable evidence in the literature that isotretinoin can induce an autoimmune reaction resulting in various autoimmune conditions;[91011] we presume that a similar mechanism would have been responsible to produce an autoimmune thyroid eye disease-like condition in the present case. Stopping the drug will result in cessation of the inflammatory response but the fibrosis induced by the inflammation would result in residual limitation of extraocular movements as in the present case.\n\nWe conclude that though rare, isotretinoin-induced extraocular myopathy should be considered in the differential diagnosis of any patient presenting with diplopia and extraocular motility restriction, with concomitant isotretinoin intake.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Merritt B Burkhart CN Morrell DS Use of isotretinoin for acne vulgaris Pediatr Ann 2009 38 311 20 19588674 \n2 Moy A McNamara NA Lin MC Effects of isotretinoin on meibomian glands Optom Vis Sci 2015 92 925 30 26154692 \n3 Nelson AM Cong Z Gilliland KL Thiboutot DM TRAIL contributes to the apoptotic effect of 13-cis retinoic acid in human sebaceous gland cells Br J Dermatol 2011 165 526 33 21564055 \n4 Nelson AM Gilliland KL Cong Z Thiboutot DM 13-cis retinoic acid induces apoptosis and cell cycle arrest in human SEB-1 sebocytes J Invest Dermatol 2006 126 2178 89 16575387 \n5 Dicken CH Retinoids: A review J Am Acad Dermatol 1984 11 4 Pt 1 541 52 6208221 \n6 Hodak E Gadoth N David M Sandbank M Muscle damage induced by isotretinoin Br Med J (Clin Res Ed) 1986 293 425 6 \n7 Heudes AM Laroche L Muscular damage during isotretinoin treatment Ann Dermatol Venereol 1998 125 94 7 9747221 \n8 Fiallo P Tagliapietra AG Severe acute myopathy induced by isotretinoin Arch Dermatol 1996 132 1521 2 8961893 \n9 Reddy D Siegel CA Sands BE Kane S Possible association between isotretinoin and inflammatory bowel disease Am J Gastroenterol 2006 101 1569 73 16863562 \n10 Pritchard J Appleton R Howard R Hughes RA Guillain-Barré syndrome seen in users of isotretinoin BMJ 2004 328 1537 15217870 \n11 Gursoy H Cakmak I Yildirim N Basmak H Presumed isotretinoin-induced, concomitant autoimmune thyroid disease and ocular myasthenia gravis: A case report Case Rep Dermatol 2012 4 256 60 23275770\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-500X",
"issue": "7(4)",
"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Extraocular muscles; isotretinoin; myopathy",
"medline_ta": "J Pharmacol Pharmacother",
"mesh_terms": null,
"nlm_unique_id": "101552113",
"other_id": null,
"pages": "187-189",
"pmc": null,
"pmid": "28163542",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "15217870;23275770;16863562;8961893;19588674;9747221;26154692;21564055;16575387;3091143;6208221",
"title": "Presumed isotretinoin-induced extraocular myopathy.",
"title_normalized": "presumed isotretinoin induced extraocular myopathy"
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"abstract": "Nitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.\n\n\n\nA single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.\n\n\n\nThirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = -2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66-100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54-100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31-92%) and 11 out of 12 chronic cluster headache (92%, 73-100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.\n\n\n\nIntravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.",
"affiliations": "Headache Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.;Headache Group, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.",
"authors": "Wei|Diana Y|DY|0000-0003-0644-7172;Goadsby|Peter J|PJ|0000-0003-3260-5904",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0333102421989617",
"fulltext": "\n==== Front\nCephalalgia\nCephalalgia\nCEP\nspcep\nCephalalgia\n0333-1024\n1468-2982\nSAGE Publications Sage UK: London, England\n\n33615843\n10.1177/0333102421989617\n10.1177_0333102421989617\nOriginal Articles\nComprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks\nhttps://orcid.org/0000-0003-0644-7172\nWei Diana Y 12\nhttps://orcid.org/0000-0003-3260-5904\nGoadsby Peter J 123\n1 Headache Group, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK\n2 NIHR Wellcome Trust King’s Clinical Research Facility, King’s College Hospital, London, UK\n3 Department of Neurology, University of California, Los Angeles, CA, USA\nPeter J Goadsby, Wellcome Foundation Building, King’s College Hospital, London SE5 9PJ, UK. Email: peter.goadsby@kcl.ac.uk\n20 2 2021\n7 2021\n41 8 913933\n6 9 2020\n28 10 2020\n17 11 2020\n© International Headache Society 2021\n2021\nInternational Headache Society\nhttps://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any 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).\nBackground\n\nNitroglycerin administration allows the study of cluster headache attacks in their entirety in a standardised way.\n\nMethods\n\nA single-blind, placebo-controlled, cross-over study using weight-calculated intravenous nitroglycerin administration at 0.5 µg/kg/min over 20 minutes to study cluster headache attacks, including accompanying non-headache symptoms and cranial autonomic symptoms.\n\nResults\n\nThirty-three subjects with cluster headache were included in the study; 24 completed all three study visits. Nitroglycerin-induced attacks developed in 26 out of 33 subjects (79%) receiving unblinded nitroglycerin infusion, and in 19 out of 25 subjects (76%) receiving single-blinded nitroglycerin infusion, compared with one out of 24 subjects (4%) receiving single-blinded placebo infusion. Episodic cluster headache subjects had a shorter latency period to a nitroglycerin-induced attack compared to the chronic cluster headache (CCH) subjects (U = 15, z = −2.399, p = 0.016). Sixteen of nineteen episodic cluster headache (mean, 84%; 95% confidence interval, 66–100%) and 11 of 14 chronic cluster headache subjects developed a nitroglycerin-induced attack (79%, 54–100%) following the unblinded nitroglycerin infusion. Following the single-blinded nitroglycerin infusion, eight out of 13 episodic cluster headache (62%, 31–92%) and 11 out of 12 chronic cluster headache (92%, 73–100%) subjects developed nitroglycerin-induced attacks. Nitroglycerin induced non-headache symptoms in the majority of subjects receiving it: 91% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visits, compared with 33% in the single-blinded placebo visit. Cranial autonomic symptoms were induced by nitroglycerin infusion, 94% in the open unblinded nitroglycerin visit and 84% in the single-blinded nitroglycerin visit, compared with 17% in the single-blinded placebo visit.\n\nConclusion\n\nIntravenous weight-adjusted nitroglycerin administration in both episodic cluster headache in bout and chronic cluster headache is effective and reliable in inducing cluster headache attacks, cranial autonomic symptoms and non-headache symptoms.\n\nCluster headache\nnitroglycerin\ncranial autonomic symptoms\nnon-headache symptoms\nnitroglycerin headache\nepisodic cluster headache\nchronic cluster headache\ntypesetterts2\n==== Body\nIntroduction\n\nDue to the episodic nature of acute attacks of cluster headache, a standardised and reliable method for triggering attacks is necessary for their complete study. There have been several substances used to trigger attacks, including histamine (1,2), meta-chloro-phenylpiperazine (mCPP) (3) and more recently calcitonin gene-related peptide (CGRP) (4). Nitroglycerin (NTG) is the most frequently employed substance in human experimental modelling of cluster headache attacks, being used since 1953 (2) (Table 1).\n\nTable 1. Review of studies using nitroglycerin to induce cluster headache attacks.\n\nStudy\tNumber of CH patients\tNTG dose and route\tControl\tPlacebo\tRate of induced CH attack\tLatency period before onset of headache\n(range in minutes)\t\nPeters 1953 (2)\t14\t1.3 mg sublingual\tNo, but compared with migraine, combination of CH and migraine, vasodilating head pain and tension headache\tNo, but compared with histamine and nicotinic acid\t78.6%\tNot reported\t\nEkbom 1968 (5)\t38 ECH: 28 in bout, 15 out of bout (of which five were tested in bout as well)\t1 mg sublingual\tNo\tNo\tIn bout ECH 100% (n = 28)\nOut of bout 0% (n = 15)\t12–72\t\nBarre 1982 (6)\t10 CH: two CCH, nine ECH in bout\t1 mg sublingual\tNo\tNo\t100%\t34–52\nMean 45.9\t\nDrummond et al. 1984 (7)\t29 CH\t0.9 mg sublingual\tNo\tNo\t76%\tWithin 90 min\t\nDrummond et al. 1985 (8)\t22 CH: 10 CCH, 12 ECH in bout\n\t0.9 mg sublingual\tYes, 10 in the control group without headache\tNo\tECH 75% (n = 9)\nCCH 60% (n = 6)\t9–90\nMean 44\t\nBogucki 1990 (9)\t21 ECH in bout\t1 mg sublingual\tNo\tNo\t67% (n = 14)\n\t30–65\t\nDahl et al. 1990 (10)\t15 ECH in bout\t1 mg sublingual\t10 healthy controls\tNo\t53% (n = 8)\nControls: not reported\t30–65\t\nHannerz et al. 1992 (11)\tEight ECH: five in bout and three out of bout\t1 mg sublingual\tNo\tNo\tIn bout ECH 100% (n = 5)\tNot reported\t\nFanciullacci et al. 1995 (12)\t18 in bout ECH, 12 out of bout ECH\t0.9 mg sublingual\tNo\tNo\tIn bout ECH 100% (n = 18)\nOut of bout ECH 0% (n = 12)\t39–86\t\nFanciullacci et al. 1997 (13)\t11 in bout ECH, eight out of bout ECH\t0.9 mg sublingual\tNo\tNo\tIn bout ECH 100% (n = 11)\nOut of bout ECH 0% (n = 8)\t18–50\t\nHsieh et al. 1996 (14)\tSeven ECH: four in bout ECH, three out of bout\t1 mg sublingual\tNo\tNo\tIn bout ECH 100%\nOut of bout ECH 0%\t18–35\t\nMay et al. 1998 (15)\tNine CCH, eight out of bout ECH\t1.0–1.2 mg spray\tNo\tNo\tCCH 100%\nOut of bout ECH 0%\tNot reported\t\nCosta et al. 2000 (16)\t15 CH: Six ECH, nine CCH\t0.9 mg sublingual\tNo\tNo\tECH 33% (n = 2)\nCCH 78% (n = 7)\t19–41\t\nCosta et al. 2003 (17)\t18 ECH in bout\t0.9 mg sublingual\tYes, 12 healthy sex and age-matched\tNo\tECH 67% (n = 12)\nControls 0%\t19–41\t\nSances et al. 2004 (18)\t42 CH: 29 ECH (11 out of bout), 13 CCH\t0.9 mg sublingual\tYes, 53 healthy controls\tNo\tIn bout ECH and CCH 81% (n = 25 out of 31)\nControls 7.5% developed headache in 7-hour post-NTG\tMean onset latency of 65.4 ± 54.7\t\n\nCluster headache patients suffer from recurrent episodes of severe unilateral pain in the trigeminal region; therefore, historically, the main emphasis has been centred around the pain onset of a cluster headache, and indeed this is often used as the indicator of the start of the attack. However, from clinical practice, there has been growing awareness of nonpainful symptoms preceding the onset of pain (19,20) and in recent years, the clinical phenotype of cluster headache has been further characterised by retrospective accounts (21–23) and prospective diaries (24,25).\n\nThe most frequent route of administration of NTG has been sublingual; however, the bioavailability of sublingual NTG is extremely variable (26). Therefore, we used a weight-calculated dose for intravenous infusion in a standardised single-blind, placebo-controlled study. NTG is a pro-drug of nitric oxide, with predominant actions on the cyclic guanylate phosphate (cGMP) pathway (27), and from pre-clinical studies there are indications of neural actions more centrally. This study is the first single-blind, placebo-controlled cross-over study using a weight-adjusted dose of nitroglycerin administered intravenously in cluster headache patients, thereby allowing comprehensive investigation of the various stages of the acute attack of cluster headache.\n\nMethods\n\nSubject selection and recruitment\n\nThe study was advertised on the UK cluster headache patient website OUCH (UK) (Organisation for the Understanding of Cluster Headache UK) (https://ouchuk.org/research/research-volunteers-needed) and in the tertiary Headache centre in King’s College Hospital, London. Subjects interested in participating would make contact via a dedicated research email. Subjects would then be screened for eligibility for the study via emails and a telephone call; those who met the criteria and were interested in participating were invited to attend the study visit. The study was approved by the London, City & East Research Ethics Committee (Ref Number 16/LO/0693). Data were collected from August 2016 until January 2019.\n\nThe subjects enrolled fulfilled the ICHD-3 beta criteria for cluster headache (28), and were between the ages of 18 and 60, with no significant previous medical history and no previous syncope or history of autonomic dysfunction. They had had a reliable response to high flow oxygen and/or subcutaneous sumatriptan during spontaneous attacks and normal brain neuroimaging. Women in child-bearing age were required to use reliable contraceptive methods during the study. Subjects were excluded if they were pregnant or breastfeeding, and who had any significant psychiatric disease, diagnosis of another primary headache type (other than migraine) or chronic pain syndrome, any medical history that would have contraindications to receiving NTG, use of preventive medication other than verapamil, or taking indomethacin for any reason, allergies to the medications used in the study or intolerance to high flow oxygen, and use of illicit drugs during the study.\n\nStudy visits\n\nThe study comprised of three visits in total, with each visit separated by a minimum of 1 week. During the first visit, subjects consented and a full headache history with a physical examination of the neurological and cardiovascular systems was performed, along with recordings of the baseline blood pressure, lying and standing blood pressure, heart rate, oxygen saturation, weight and electrocardiogram. Female subjects were required to have a urinary pregnancy test before the start of the infusion.\n\nOpen NTG infusion\n\nIf deemed eligible, subjects received an intravenous infusion of nitroglycerin at 0.5 µg/kg/min over 20 minutes. Subjects remained recumbent for 30 minutes before the infusion, and after the NTG infusion, subjects received 250 mL of 0.9% sodium chloride intravenously. The blood pressure and pulse were checked at the start of the infusion, and every 5 min during the infusion.\n\nPhenotypic characterisation\n\nEvery 5 minutes, subjects were asked to rate their pain level from a scale from no pain, mild, moderate to severe, where severe equates to their most severe attack, and they were asked a questionnaire of non-headache symptoms and cranial autonomic symptoms (CAS) (Figure 1). If the subject experienced pain, further details were obtained regarding the location and characteristic. Beyond the cluster headache attack, subjects were asked to report any other headache types and in particular NTG headache, which has been well described from migraine studies (29). The NTG headache was assessed for severity, phenotype, accompanying non-headache symptoms and duration. Subjects were actively encouraged to report any symptoms as and when they developed. Following the infusion, at 10 minute intervals, any developments in pain, non-headache symptoms and CAS were recorded for a total of 120 minutes after the infusion, based on the latency period reported from previous studies (Table 1).\n\nFigure 1. Questionnaire for non-headache and cranial autonomic symptoms.\n\nB: bilateral; R: right-sided; L: left-sided.\n\nSingle-blinded NTG and placebo infusions\n\nDuring the two single-blinded visits, subjects either received intravenous nitroglycerin at 0.5 µg/kg/min over 20 minutes or an equal volume of 0.9% sodium chloride at the same rate over 20 minutes, followed by the same 120 minutes of observations (Figure 2). The sequence was pre-determined using the randomise function in Excel; however, the investigator was able to amend this in certain situations if the subject was episodic and due to finish their bout.\n\nFigure 2. Outline of events from open unblinded nitroglycerin visit.\n\nBP: blood pressure; CAS: cranial autonomic symptoms; NTG: nitroglycerin; IV: intravenous.\n\nTreatment of acute attacks\n\nAcute treatment was administered at 20 minutes from the start of attack either with sumatriptan 6 mg subcutaneous injection (Imigran 6 mg/0.5 ml solution for injection pre-filled syringes, GlaxoSmithKline UK Ltd, or sumatriptan 6 mg/0.5 ml solution for injection pre-filled pens, Sun Pharmaceuticals Industries Europe B.V.) or with 15 L/min oxygen via a non-rebreather mask (O2Star™ non-rebreather oxygen mask M/L, Dräger). The visit was concluded only when the subject was pain free.\n\nStatistical analysis\n\nThe data was tabulated (Excel for Mac v 16.30), and descriptive statistics were performed to summarise data (SPSS Statistics version 26 for Mac and Excel). Mann-Whitney tests were performed on time until attack onset and time until CAS onset for those that developed NTG-triggered cluster headache attacks and CAS, comparing the differences in ECH with CCH subgroups. Kaplan-Meier survival graphs were used to examine the time until onset of event; that is, survival of no cluster headache attack status, or absence of CAS after NTG infusion for 140 minutes (20 minutes of infusion and 120 minutes of post-infusion observation), with log-rank statistical testing; P < 0.05 was considered significant. Graphs were made using SPSS and violin plots were made using GraphPad Prism 8 for Mac OS.\n\nResults\n\nDemography\n\nA total of 229 subjects were contacted to check for eligibility, of which 33 were included in the study; 24 completed all three study visits (Figure 3). All patients fulfilled the ICHD-3 beta criteria for cluster headache, 19 episodic cluster headache in bout (58%) and 14 chronic cluster headache (42%) (Table 2). The majority were male (n = 24, 73%) with a male: female ratio of 3:1. The average age was 41 (SD 10), with the mean age of females (34 years, SD 9) younger than in males (44 years, SD 9) in this cohort. Subjects had had the condition for a median of 9 years (IQR 5–16).\n\nFigure 3. Subject numbers throughout the study.\n\nTable 2. Subject characteristics.\n\nSubject\tAge\tSex\tSubtype\tSide of attacks\tTime since first attack (years)\tAverage attack frequency (per day)\tAverage attack duration when untreated (mins)\tAverage bout duration (weeks)\tVerapamil (total daily dose in mg)\t\n1\t55\tM\tChronic\tRight\t5\t2\t45\t–\t480\t\n2\t28\tF\tChronic\tRight\t12\t7\t150\t–\t–\t\n3\t40\tM\tEpisodic\tRight\t20\t3\t150\t8\t–\t\n4\t38\tF\tEpisodic\tLeft\t12\t2\t120\t4\t–\t\n5\t53\tM\tChronic\tLeft\t15\t4\t35\t–\t960\t\n6\t48\tM\tEpisodic\tLeft\t25\t5\t52.5\t5\t480\t\n7\t23\tM\tEpisodic\tLeft\t8\t2\t120\t10\t–\t\n8\t43\tM\tChronic\tRight\t9\t1\t40\t–\t–\t\n9\t43\tM\tEpisodic\tRight\t13\t3\t60\t5\t240\t\n10\t44\tM\tEpisodic\tRight\t27\t6\t45\t6\t–\t\n11\t47\tM\tEpisodic\tRight\t3\t1\t105\t20\t–\t\n12\t48\tM\tEpisodic\tLeft\t26\t3\t180\t10\t560\t\n13\t40\tM\tEpisodic\tRight\t5\t3\t60\t8\t–\t\n14\t50\tM\tEpisodic\tRight\t10\t2\t105\t8\t–\t\n15\t56\tM\tEpisodic*\tRight\t24\t1\t45\t–\t–\t\n16\t35\tM\tEpisodic\tLeft\t7\t2\t150\t6\t240\t\n17\t58\tM\tEpisodic\tLeft\t3\t1\t135\t24\t–\t\n18\t43\tM\tChronic\tLeft\t4\t2\t60\t–\t–\t\n19\t32\tM\tEpisodic\tLeft\t3\t3\t50\t12\t600\t\n20\t49\tF\tEpisodic\tRight\t8\t5\t50\t9\t–\t\n21\t49\tM\tChronic\tRight\t35\t2\t90\t–\t–\t\n22\t57\tM\tChronic\tRight\t20\t5\t65\t\t–\t\n23\t40\tF\tChronic\tLeft\t4\t1.5\t120\t–\t640\t\n24\t44\tM\tChronic\tRight\t6\t2\t90\t–\t720\t\n25\t23\tF\tEpisodic\tRight\t9\t2.5\t90\t6\t–\t\n26\t40\tM\tChronic\tLeft\t17\t1.5\t180\t–\t–\t\n27\t20\tF\tChronic\tRight\t6\t1.5\t150\t–\t–\t\n28\t31\tF\tEpisodic\tRight\t14\t2\t75\t11\t–\t\n29\t35\tM\tEpisodic\tLeft\t9\t2\t90\t3\t–\t\n30\t38\tF\tChronic\tLeft\t6\t1.5\t180\t–\t240\t\n31\t49\tM\tEpisodic\tLeft\t0.5\t1.5\t37.5\t21\t400\t\n32\t35\tF\tChronic\tLeft\t4\t0.3\t30\t–\t600\t\n33\t32\tM\tChronic\tLeft\t10\t6\t60\t–\t–\t\nM: male; F: female.\n\n*Subject was chronic but became episodic during study with no attacks in 6 months.\n\nClinical phenotyping of subjects by history\n\nPain features\n\nThere was a near-equal split between the laterality of attacks; 17 subjects had right-sided attacks (52%), and 16 subjects had left-sided attacks (49%). The median number of attacks per day was two (IQR 1.5–3) lasting a median of 90 minutes (IQR 50–128). Verapamil was the only preventive allowed on the study; 12 subjects (36%) were on verapamil ranging from 240 mg to 960 mg per day.\n\nMigraine, accompanying features and non-headache symptoms in spontaneous attacks\n\nIn this cohort, 58% (n = 19) had a concurrent migraine (28): five had migraine with aura, of which four had visual aura and one had facial sensory aura. Of the subjects who did not meet the diagnostic criteria for migraine (28) (n = 14, 42%), the majority had either migraine markers and/or a family history of migraine. Migraine markers were defined if subjects experienced: childhood cyclic nausea and vomiting, motion sickness, cold stimulus-induced headache, hangover headache and jetlag. Four subjects did not have migraine markers, and three subjects (9%) did not have either migraine marker or a family history of migraine. Subjects (n = 24, 73%) reported accompanying symptoms with their spontaneous attacks, the most common symptoms being cranial allodynia (n = 15), photophobia (n = 15), nausea (n = 11) and phonophobia (n = 10).\n\nNon-headache attack symptoms\n\nThe majority reported non-headache symptoms in the lead up to their spontaneous cluster headache attacks (n = 27, 82%), with the commonest symptoms being concentration difficulties (n = 18), mood changes (n = 15), neck stiffness (n = 13) and yawning (n = 8). The median onset time of symptoms was 10 minutes (IQR 2–30) before the onset of pain. Although most symptoms start before the onset of pain, five subjects only reported developing the symptoms during the attack.\n\nTwenty-eight subjects reported non-headache symptoms following their cluster headache attacks (85%), the commonest symptoms being tiredness (n = 27), mood changes (n = 13), concentration difficulties (n = 12), and neck stiffness (n = 7). The median duration of symptoms was 120 minutes (IQR 53–315).\n\nAttack triggers\n\nThe most commonly reported triggers for spontaneous attacks were alcohol ingestion (n = 22), followed by changes in temperature (n = 12), strong smells such as from nail varnish, paint (n = 11) followed by disrupted sleep (n = 4) and exercise (n = 3). Other triggers mentioned were stress (n = 2), caffeine (n = 2), changing time zones (n = 1), let down from stress (n = 1), being in a pressurised cabin on an airplane (n = 1), vardenafil (n = 1), and dehydration (n = 1). All subjects reported attacks within a few hours of alcohol ingestion, no one reported a next-day effect.\n\nClinical phenotyping of open NTG visit\n\nNTG triggered cluster headache-like attacks (n = 26, 79%), CAS (n = 31, 94%) and agitation (n = 24, 73%) during the open unblinded NTG visit. In the episodic cluster headache group, 16 out of 19 developed an NTG-induced attack (mean, 84%; 95% CI, 66–100%) and in the chronic cluster headache group, 11 out of 14 developed an NTG-induced attack (79%, 54–100%). Five out of the 31 subjects developed CAS, but did not develop an attack; of these subjects, three developed mild generalised pain, one developed restless legs, and one developed CAS on the contralateral side to the subject’s spontaneous attack phenotype, with a generalised headache. These cases were excluded.\n\nThe median onset time for CAS to develop from the start of the NTG infusion was 31 minutes (IQR 13–46). The median onset for an NTG-induced attack was 30 minutes (IQR 20–39) and the median time to maximum pain, if reached, was 51 minutes (IQR 39–70). The most common first cranial autonomic symptoms brought on by NTG infusion were nasal congestion (n = 10), conjunctival injection (n = 5), lacrimation (n = 4) and periorbital oedema (n = 3).\n\nClinical phenotyping of single-blinded NTG and placebo visit\n\nDuring the single-blinded visits, NTG induced attacks in 19 subjects (76%); three subjects did not have an attack (12%), two subjects developed migraine-like headache (8%) and one subject developed unilateral mild pain without CAS or agitation (4%) (Table 3). In the placebo group, only one developed an attack (4%), two subjects developed unilateral mild pain without CAS or agitation (8%) and two subjects experienced short-lived unilateral CAS (8%). Of the subjects receiving NTG, eight out of 13 ECH (mean, 62%; 95% CI, 31%-92%) and 11 out of 12 CCH (92%, 73–100%) developed NTG-induced attacks (Figure 4(a)).\n\nTable 3. Subject characteristics and comparison between spontaneous attack and triggered attack from single-blinded nitroglycerin visit, M = male, F = female, ECH = episodic cluster headache, CCH = chronic cluster headache, L = Left, R = Right, Y = Yes, N = No, VRS = verbal rating scale, mod = moderate, O2 = high flow oxygen via non-rebreather mask, suma = sumatriptan.\n\nSubject\tAge\tSex\tSubtype\tMigraine\tVerapamil (total daily dose in mg)\tSpontaneous attack\tTriggered attack- single-blinded NTG visit\t\nLaterality\tSeverity\tCAS\tAgitation\tLaterality\tSeverity/VRS\tCAS\tAgitation\tFeels like spontaneous attack\tTreatment\tLast spontaneous attack (days)\t\n1\t55\tM\tCCH\tN\t480\tR\t9/10\tConjunctival injection, nasal congestion, lacrimation. 3 months of R Horner’s syndrome in 2007, now resolved\tY\tR\t10/10\nVRS 3\tConjunctival injection, nasal congestion, lacrimation, periorbital oedema\tY\tY\tO2\t158\t\n2\t28\tF\tCCH\tY\n\t–\tR\t10/10\tPeriorbital oedema/ptosis, nasal congestion, dry eye then lacrimation\tY\tR\t10/10\nVRS 3\tPeriorbital oedema, nasal congestion, facial flushing\tY\tY\tO2\t128\t\n3\t40\tM\tECH\tN\t–\tR\t10/10\tLacrimation, rhinorrhoea, ptosis\tY\tR\t10/10\nVRS 3\tLacrimation, conjunctival injection, periorbital oedema, nasal congestion, aural fullness and facial droop\tY\tY\tSuma\t1\t\n4\t38\tF\tECH\tY\t–\tL\t10/10\tLacrimation, conjunctival injection, periorbital oedema, nasal congestion, ptosis, facial flushing\tY\tNo attack, developed generalised pain 4/10\tY\tN\tN/A\t1\t\n5\t53\tM\tCCH\tN\t960\tL\t10/10\tRhinorrhoea, ptosis\tY\tL\t10/10\nVRS 3\tConjunctival injection, eye grittiness, lacrimation\tY\tY\tO2\t4\t\n6\t48\tM\tECH\tN\n\t480\tL\t8/10\tNasal congestion, lacrimation\tY\tDid not attend\t\n7\t23\tM\tECH\tY\t–\tL\t10/10\tLacrimation, conjunctival injection, nasal congestion, ptosis, facial flushing\tY\tDid not attend\t\n8\t43\tM\tCCH\tN\t–\tR\t10/10\tNasal congestion, rhinorrhoea, lacrimation, facial flushing\tY\tR\t10/10\nVRS 3\tNasal congestion, conjunctival injection, eye grittiness\tY\tY\tSuma\t<1\t\n9\t43\tM\tECH\tN\t240\tR\t10/10\tLacrimation, conjunctival injection, facial flushing, ptosis, facial droop\tY\tDid not attend\t\n10\t44\tM\tECH\tN\t–\tR\t10/10\tNasal congestion, ptosis, periorbital oedema, lacrimation, flushing\tY\tNo attack, L mild hangover like headache, with nasal congestion.\nAfter study visit felt nauseous and vomited, then slept, headache free at 7pm\tN\tN\tO2- no response\t<1\t\n11\t47\tM\tECH\tN\t–\tR\tSevere attacks 10/10\tNasal congestion, aural fullness\tY\tR\t7/10\nVRS 2/3 moderate/\nsevere\tNasal congestion, conjunctival injection, aural fullness\tY\tY\tSuma\t13\t\n12\t48\tM\tECH\tN\t560\tL\t10/10\tLacrimation, nasal congestion, periorbital oedema\tY\tDid not attend\t\n13\t40\tM\tECH\tY\t–\tR\t10/10\tNasal congestion, ptosis, conjunctival injection, lacrimation, throat tightness, rhinorrhoea\tY\tNo attack, bilateral mild headache 4/10 with nasal congestion\tY, brief (7 mins)\tN\tN/A\t19\t\n14\t50\tM\tECH\tY\t–\tR\t10/10\n\tLacrimation, periorbital oedema, nasal congestion, rhinorrhoea\tY\tDid not attend\t\n15\t56\tM\tECH\tY\t–\tR\t10/10\tLacrimation, rhinorrhoea, facial flushing, gritty eyes, conjunctival injection\tY with severe attacks\tDid not attend\t\n16\t35\tM\tECH\tY\t240\tL\t10/10\tNasal congestion, conjunctival injection, ptosis, lacrimation, rhinorrhoea\tY\tNot attack, milder than a shadow and no CAS\tN\tN\tN/A\t16\t\n17\t58\tM\tECH\tY\t–\tL\t10/10\tNasal congestion, rhinorrhoea, lacrimation, aural fullness, throat swelling\tY\tL\t7/10\nVRS 2–3 (mod-severe)\tNasal congestion, rhinorrhoea, voice change, lacrimation\tY\tY\tSuma\t1\t\n18\t43\tM\tCCH\tY\t–\tL (70%)\tMild 6/10, severe 10/10\tNasal congestion, periorbital oedema, aural fullness, facial flushing\tY\tL\tMild,\nVRS 1\tNasal congestion\tY\tY- shadow\tO2\t7\t\n19\t32\tM\tECH\tY\t600\tL\t10/10\tLacrimation, conjunctival injection, facial flushing\tY\tL\t7–8/10\nVRS 2–3\n(mod-severe)\tLacrimation, eye grittiness, nasal congestion, facial flushing\tY\tY\tO2\t<1\t\n20\t49\tF\tECH\tY\t–\tR\t10/10\tPtosis, periorbital oedema, lacrimation, nasal congestion, rhinorrhoea, (aural fullness with severe attacks)\tY\tR\t6–7/10\nVRS 2 mod\tNasal congestion, periorbital oedema, lacrimation, conjunctival injection\tY\tY\tO2\t7\t\n21\t49\tM\tCCH\tY\t–\tR\t4–10/10\tFacial flushing, nasal congestion, ptosis, lacrimation, rhinorrhoea, conjunctival injection\tY\tL\t8/10\nVRS 2–3\n(mod-severe)\n\tFacial flushing, lacrimation, periorbital oedema, conjunctival injection\tY\tY, but on L rather than R\tSuma\t<1\t\n22\t57\tM\tCCH\tN\t–\tR\t10/10\tLacrimation, conjunctival injection, nasal congestion, rhinorrhoea\tY\tNo attack, no pain and no CAS\tN\tN\tN/A\t26\t\n23\t40\tF\tCCH\tY\t640\tL\t10/10\n\tLacrimation, conjunctival injection, periorbital oedema, rhinorrhoea, ptosis, aural fullness\tY\tDid not attend\t\n24\t44\tM\tCCH\tN\t720\tR\t10/10\tLacrimation, conjunctival injection, periorbital oedema, facial flushing\tY\tDid not attend\t\n25\t23\tF\tECH\tY\t–\tR\t6–10/10\tNasal congestion, lacrimation, periorbital oedema. Rhinorrhoea and facial flushing with severe attacks\tY\tR\t7/10\nVRS 2\n(moderate)\tNasal congestion, periorbital oedema\tY\tY\tO2\t3\t\n26\t40\tM\tCCH\tY\t–\tL\tShadow 4/10, daytime attacks 6–7/10, full attack 10/10\tPtosis, aural fullness, lacrimation, conjunctival injection, periorbital oedema, nasal congestion\tY\tL\t8.5–9/10\nVRS 3 severe\tNasal congestion, periorbital oedema, lacrimation\tY\tY\tSuma\t3\t\n27\t20\tF\tCCH\tN\t–\tR\t8–9/10\tNasal congestion, lacrimation, rhinorrhoea, ptosis, aural fullness\tY\tR\t8/10\nVRS 3\nsevere\tNasal congestion, periorbital oedema\tY\tY\tO2\t<1\t\n28\t31\tF\tECH\tY\t–\tR\t10/10\tNasal congestion, periorbital oedema, rhinorrhoea, ptosis, aural fullness\tY\tR\t2/10\nVRS 1 (mild)\tNasal congestion, facial swelling\tY\tY, but milder\tSuma\t3\t\n29\t35\tM\tECH\tN\t–\tL\tMax pain 10/10\tNasal congestion, periorbital oedema, lacrimation, voice change (croaky). Facial flushing with severe attacks and rhinorrhoea after attack\tY\tL\t6–7/10\nVRS 2 (moderate)\tNasal congestion, lacrimation, conjunctival injection, voice change\tY\tY\tSuma\t<1\t\n30\t38\tF\tCCH\tY\t240\tL\t4–10/10\tLacrimation, rhinorrhoea, conjunctival injection, facial flushing. Ptosis with severe attacks\tY\tL\t6–7/10\nVRS 2 (moderate)\tAural fullness\tY\tY\tSuma\t1\t\n31\t49\tM\tECH\tY\t400\tL\t10/10\tNasal congestion, lacrimation, conjunctival injection, rhinorrhoea, ptosis, aural fullness. Prominent miosis after attack\tY\tNo attack, whole head felt heavy\tN\tN\tN/A\t10\t\n32\t35\tF\tCCH\tN\t600\tL\t4/10 (on verapamil),\n7/10 average\tPeriorbital oedema, eye grittiness, facial flushing, lacrimation\tY\tL\t7/10\nVRS 2–3\n(mod-severe)\tNasal congestion, conjunctival injection, facial flushing, lacrimation\tY\tY\tSuma\t1\t\n33\t32\tM\tCCH\tY\t–\tL\tSevere attacks 10/10\tLacrimation, ptosis, nasal congestion, conjunctival injection, ptosis, facial flushing, eye grittiness\tY\tL\t6/10\nVRS 2 (mod-severe)\tLacrimation, nasal congestion, ptosis\tY\tY\tSuma\t<1\t\n\nFigure 4. (a) Kaplan-Meier graph comparing time until cluster headache attack between the eight episodic cluster headache (ECH) and the 11 chronic cluster headache (CCH) subjects during single-blinded nitroglycerin (NTG) infusion, from the start of the infusion in minutes, log-rank P = 0.534. (b) Kaplan-Meier graph comparing time until cluster headache attack onset between the open unblinded (n = 33) and single-blinded (n =25) nitroglycerin (NTG) infusions with single-blinded placebo infusions (n = 24). Log-rank P = 0.000.\n\nThe median onset time to an induced attack was 33 minutes (IQR 15–42) from the start of the single-blinded NTG infusion, and in the single-blinded placebo visit only one subject developed an attack; the onset time was 10 minutes. On comparison of the attack onset time for the unblinded NTG, single-blinded NTG and single-blinded placebo visits, there was a difference between the placebo and NTG visits (P = 0.000, Figure 4(b)).\n\nNTG headache\n\nThe majority of subjects developed an NTG headache (n = 28, 85%) following the NTG infusion in the unblinded open visit, of which 27 subjects had a migraine diagnosis (n = 18), had migraine markers (n = 10) and a family history of migraine (n = 18); only one subject did not have migraine, migraine markers or a family history of migraine. The median time from the start of NTG infusion was 3 minutes (IQR 2–6), and the median duration of NTG headache was 26 minutes (IQR 14–41).\n\nOf the 25 subjects that went on to the single-blinded NTG visits, 18 (72%) developed NTG headache following NTG infusion, of which all had either migraine (n = 11), migraine markers (n = 7) or family history (n = 10). The median time of NTG headache onset from the start of NTG infusion in the blinded visit was 4 minutes (IQR 3–8), with a median duration of 26 minutes (IQR 9–45).\n\nIn the placebo visit, three of the 24 subjects (13%) developed NTG headache, median onset time was 13 minutes (range 1–18), and the median duration was 10 minutes (range 3–16).\n\nNon-headache symptoms\n\nThe majority of subjects reported non-headache symptoms in both the open unblinded NTG visit (n = 30, 91%) and the single-blinded NTG visit (n = 21, 84%) visits. In the single-blinded placebo visit, eight subjects (33%) reported non-headache symptoms. The most common non-headache symptoms from the open unblinded NTG visit were neck stiffness, photophobia, thirst and allodynia. The most common non-headache symptoms from the single-blinded NTG visit were neck stiffness, yawning, thirst and photophobia (Table 4). The median number of non-headache symptoms reported in the open unblinded NTG visit was three (IQR 2–5), and from the single-blinded NTG visit was three (IQR 2–6), compared with two (IQR 2–3) on-headache symptoms in the single-blinded placebo group.\n\nTable 4. Frequencies of non-headache symptoms reported during each visit.\n\nNon-headache symptom\tOpen unblinded NTG visit (n = 33)\tSingle-blinded NTG visit\n(n = 25)\tSingle-blinded placebo visit\n(n = 24)\t\nThirst\t15\t10\t3\t\nCraving\t0\t0\t0\t\nYawning\t8\t12\t4\t\nTiredness\t4\t3\t0\t\nMood changes\t5\t4\t1\t\nVisual blurring\t4\t3\t1\t\nNeck stiffness\t21\t15\t3\t\nIrritability\t3\t3\t0\t\nPhotophobia\t18\t10\t1\t\nConcentration difficulties\t6\t4\t1\t\nPhonophobia\t4\t6\t0\t\nUrinary symptoms\t0\t0\t0\t\nSpeech disturbances\t0\t0\t0\t\nNausea\t6\t3\t0\t\nGastrointestinal discomfort\t0\t0\t0\t\nMovement sensitivity\t5\t5\t1\t\nAllodynia\t9\t8\t2\t\n\nIn the open unblinded NTG visit, the median onset time of non-headache symptoms from the start of the infusion was 9 minutes (IQR 4–17) with the median maximum duration of the symptoms being 50 minutes (IQR 24–64), the duration is calculated from the first symptom until the end of the last symptom. In the single-blinded NTG visit, the median onset time was 5 minutes (IQR 3–9) from the start of the infusion, and the median maximum duration of symptoms was 59 minutes (IQR 35–76). The outlier was a subject who developed allodynia and neck stiffness during their attack. For those that developed non-headache symptoms during the single-blinded placebo visit, the median onset time was 9 minutes (IQR 2–9), with a median duration of 16 minutes (IQR 6–34).\n\nCranial autonomic symptoms\n\nNTG triggered CAS in the majority of the subjects during the open unblinded NTG visit (n = 31, 94%). In all, five subjects out of the 31 (19%) developed unilateral CAS; however, they did not have a cluster headache attack. Two subjects had CAS with generalised headache, one had CAS without any pain, one subject developed CAS on the contralateral side to their attacks with mild generalised pain, and one subject with CAS developed restless leg symptoms, but no cluster headache attack. Of the subjects who developed unilateral CAS and cluster headache attack (n = 26, 79%), the median number of CAS was four (IQR 2–5), with the most common CAS being nasal congestion (n = 21), lacrimation (n = 16) and periorbital oedema (n = 15) (Table 5).\n\nTable 5. Frequencies of cranial autonomic symptoms reported in subjects who had attacks following NTG infusion.\n\nCranial autonomicsymptoms\tOpen unblinded NTG visit, total number of attacks (n = 26)\tSingle-blinded NTG visit, total number of attacks (n = 19)\t\nLacrimation\t16\t11\t\nConjunctival injection\t12\t9\t\nPeriorbital oedema\t15\t8\t\nEye grittiness/itchiness\t3\t3\t\nNasal congestion\t21\t16\t\nRhinorrhoea\t2\t1\t\nPtosis\t4\t1\t\nAural fullness\t5\t2\t\nFacial flushing\t7\t4\t\nSialorrhoea\t1\t0\t\nThroat swelling\t2\t0\t\nVoice change\t4\t2\t\nFacial swelling\t3\t1\t\n\nSimilarly, NTG brought on CAS in the majority of subjects during the single-blinded NTG visit (n = 21, 84%), of which two were not accompanied by a cluster headache attack, compared with four out of 24 in the single-blinded placebo group developing CAS (Figure 5(a)). One of the subjects from the single-blinded NTG group had a generalised headache similar to a hangover headache with unilateral CAS, and the other subject had a migraine-like headache with CAS. Of the 19 subjects (76%) that had unilateral CAS and a cluster headache attack, the median number of symptoms was three (IQR 2–4) and the most frequent symptoms were nasal congestion (n = 16), lacrimation ( n = 11) and conjunctival injection (n = 9) (Table 5). In comparing the time until all CAS onset between ECH and CCH after blinded NTG infusion, there was no difference between the two groups (log-rank P = 0.740; Figure 5(b)).\n\nFigure 5. (a) Kaplan-Meier graph showing time until onset of cranial autonomic symptoms (CAS) following open unblinded (n = 33) and single-blinded NTG (n = 25) infusions compared with the single-blinded placebo infusion (n = 24). Log-rank P = 0.000. (b) Kaplan-Meier graph showing the time until CAS onset in the single-blinded NTG visit, comparing episodic cluster headache (ECH) with chronic cluster headache (CCH). Log-rank P = 0.740.\n\nThe median time until CAS onset for those that developed cluster headache attacks was 31 min (IQR 13–46) in the open unblinded NTG visit and 12 min (IQR 6–30) in the single-blinded NTG visit. Subjects sequentially reported CAS development.\n\nDuring the single-blinded placebo visit, four subjects (17%) developed unilateral CAS, of which one subject developed a spontaneous attack, and three developed CAS but no pain. The median number of symptoms reported in the placebo group was two (IQR 1–2) and the symptoms reported were nasal congestion (n = 2), conjunctival injection (n = 1), periorbital swelling (n = 1), rhinorrhoea (n = 1) and aural fullness (n = 1).\n\nAgitation\n\nNitroglycerin brought on agitation in the majority of subjects, open unblinded NTG visit (n = 24, 73%) and single-blinded NTG visit (n= 20, 80%), compared with none in the single-blinded placebo visit.\n\nNon-headache symptoms post-attack\n\nThe non-headache symptoms were not studied here, as all attacks were treated with sumatriptan or oxygen after 20 minutes, thus altering the natural progression and development of symptoms.\n\nEpisodic cluster headache compared with chronic cluster headache\n\nFor the subjects that developed an NTG-induced attack following the single-blinded NTG infusion, the time until NTG-induced attack was shorter in the episodic cluster headache group compared with the chronic cluster headache group (U = 15, z = −2.399, P = 0.016). The time until CAS onset, in the subjects that developed CAS following single-blinded NTG infusion was not different between episodic cluster headache and chronic cluster headache groups (U = 38, z = −1.2000, P = 0.230).\n\nEffect of verapamil on NTG triggering\n\nThere were seven subjects on verapamil that attended the single-blinded NTG visits, of which two did not develop NTG-triggered cluster headache attacks (29%). Using χ2, there was no difference between verapamil and NTG triggering (χ2 (df = 1) = 0.111, P = 0.739).\n\nEffect of migraine on NTG-triggered attacks\n\nWithin the cohort that attended the single-blinded NTG visits, 15 had migraine (60%). There was no difference between the number of non-headache symptoms (U = 67, z = −0.449, P = 0.654) or number of CAS (U = 57, z = −1.019, P = 0.308), between the subjects with migraine and those without migraine. Furthermore, there was no association between subjects with migraine and NTG triggering (χ2 (df = 1) = 0.146, P = 0.702); similarly, there was no association between subjects with migraine and development of NTG headache (χ2 (df = 1) = 0.033, P = 0.856).\n\nDiscussion\n\nThis study demonstrates that weight-calculated intravenous NTG effectively triggers cluster headache attacks in both chronic cluster headache and episodic cluster headache subjects within bout when compared with placebo. The approach is reliable in terms of triggering a fully-featured attack that allows careful observation of symptoms and their development during acute attacks of cluster headache.\n\nThe benefit of weight-calculated intravenous NTG compared to intranasal and sublingual administration is that this is more reliable and has more stable bioavailability. The median time until cluster headache attack onset was 30 minutes (open unblinded NTG visit) and 33 minutes (single-blinded NTG visit), with the overall maximum onset time of 81 minutes. Subjects who did not develop an attack during the 140 minutes of observation were asked to report if they developed an attack later on that day, and none did. The median onset time is similar to the reported latency period reported in the literature (Table 1). The minimum onset time for NTG-induced attacks was 2 minutes, and this is less than reported from the sublingual route, where the shortest time until onset time was 9 minutes (8); this is expected, given the intravenous route has a half-life of 2.3–2.8 minutes (30,31). Two subjects started experiencing mild attack pain before the start of the NTG infusion, and within the placebo group we observed one subject who developed a spontaneous attack. Spontaneous attacks could be anticipated given the subjects are within bout; there were three subjects with only short-lasting CAS symptoms and two subjects who experienced a mild pain without CAS, similar to a shadow.\n\nThis study delineates the development of the various stages of an NTG-induced cluster headache attack, including the non-headache symptoms and CAS (Figure 6). The majority of subjects developed NTG headache shortly after the infusion started. This headache was generalised, mild and progressive in nature, predominantly in the bi-occipital and bi-temporal regions. Subjects described it as pressure-like or band-like ache, and they reported it to be distinct from their cluster headache attacks; if there were an overlap, the cluster headache attack would clearly ramp up and supersede the NTG headache. It is difficult to disentangle whether NTG headache developed because there was a high proportion of subjects with either a migraine diagnosis, migraine marker or family history of migraine. However, from a previous study with 25 healthy volunteers without a migraine diagnosis, 16 (64%) developed NTG headache following 0.5 mg NTG sublingual administration (32).\n\nFigure 6. Violin plots of the stages of cluster headache attack from the 19 subjects that developed cluster headache attacks and subdivided by chronicity. The timeline starts with 20 minutes of single-blinded nitroglycerin (NTG) infusion, followed by 120 minutes of post-infusion observation. CAS = cranial autonomic symptoms.\n\nFollowing the NTG headache, the majority of subjects reported non-headache symptoms in the lead-up to the onset of the pain from the attack and in some subjects, non-headache symptoms accompanied their attacks. The non-headache symptoms included homeostatic symptoms (thirst, cravings, yawning, frequency of urination), fatigue/cognitive symptoms (concentration difficulty, fatigue, memory impairment, mood changes, irritability) and sensitised sensory symptoms (neck stiffness, photophobia, phonophobia, osmophobia, nausea), as are reported in the premonitory phase of migraine (33). The most common symptoms were neck stiffness, photophobia and thirst. During their spontaneous attacks, subjects reported that non-headache symptoms would precede the attack at a median of 10 minutes (IQR 2–30) before the onset of pain, although it is known that there are discrepancies between retrospective and prospective reporting (25). Comparing the symptoms observed from NTG-induced attacks in this study with the prospective observational questionnaire study (24), the most reported general symptoms in the pre-pain phase in this study were concentration difficulties, photophobia and mood changes. Patients in the observational study also reported general symptoms during their attacks and postictal symptoms similar to the symptoms seen during the NTG-induced attacks and the reported symptoms by the subjects in this study during the postdrome phase of their spontaneous attacks. Non-headache symptoms such as photophobia, phonophobia, and localised allodynia were often reported during the attacks, as has been reported previously (21,34). In one semi-structured questionnaire study, they found a high proportion of cluster headache patients (73.2%) reported phonophobia or photophobia with their attacks (35), cluster headache patients with migraine did not more frequently report these symptoms compared with those without co-existing migraine. Furthermore, allodynia was more often reported in cluster headache patients with migraine. From pre-clinical studies, high dose NTG causes a sustained increase in spontaneous firing of Aδ and C-fibre trigeminal neurons (36), which migraine biology may unmask.\n\nSimilar to the prospective questionnaire study by Snoer and colleagues (24), in some subjects CAS presented before the onset of the attack pain (Figure 6). In this study, the median onset time for CAS was 31 minutes (IQR 13–46) in the open unblinded NTG visit and 12 minutes (IQR 6–30) in the single-blinded NTG visit, whereas the onset of NTG-induced attack was 30 minutes (IQR 20–39) in the open unblinded visit and 33 minutes (IQR 15–42) in the single-blinded NTG visit. From the open unblinded NTG visit, 38% presented with CAS before the attack, 15% presented with CAS with the onset of the attack, and from the single-blinded NTG visit, 58% presented with CAS before the attack and 16% presented with CAS with the onset of the attack.\n\nVollesen and colleagues used calcitonin gene-related peptide (CGRP) infusion to trigger cluster headache attacks, finding CGRP induced 50% of subjects with CCH and 89% for ECH subjects in bout (4). In our study, NTG induced attacks in 79% of the CCH subjects and 84% in ECH subjects in bout, in the open unblinded NTG visits, and 92% CCH and 62% ECH in bout in the single-blinded NTG visits. There are some differences in the number of chronic cluster headache subjects on verapamil between the studies; in this study, 33% of CCH subjects were on verapamil and in the study by Vollesen and colleagues, 57% of CCH subjects were on verapamil (of which one was on both verapamil and lithium) and one was on 4 mg melatonin. Vollesen and colleagues proposed that the CCH patients who did not develop an attack following CGRP infusion had a lower median attack frequency in the preceding 30 days prior to the study compared to the CCH patients that did develop an attack. However, in this study, subjects reported having their last attack as long ago as 128 and 158 days and still had NTG-induced attacks (Table 3).\n\nNTG is a pro-drug of nitric oxide (NO) and has effects on blood vessel dilation through mechanisms of the NO-cyclic guanylate phosphate (cGMP) pathway (27). However, the vasodilatory effects of NTG are not sufficient to explain the cluster headache attack that occurs after a latency and the central features associated with the attack. Indeed, experimental studies demonstrate that NTG has central effects (37,38). Interestingly, in studies where NO donors were administered in vivo and in vitro, there was a local release of CGRP (39–42). The difference in the rate of cluster headache attacks induced by NTG and CGRP in ECH and CCH subjects could reflect in part the underlying biological processes and systems that are more active in the different subtypes of cluster headache. The difference between ECH and CCH is also suggested by the treatment response to a CGRP monoclonal antibody, galcanezumab (43,44), and non-invasive vagal nerve stimulator (45,46).\n\nLimitations\n\nThe main limitations to the study were the recruitment of eligible subjects and the dropout rate at each stage due to the nature of the condition. Therefore, a pragmatic approach was taken with the study design regarding randomisation. Although there was a randomisation sequence, this was modified by the investigator if deemed necessary. This would be in the case of episodic cluster headache patients that were near the end of their bout missing the NTG visit if they followed the randomised sequence. For this reason, it was designed to be a single-blind cross-over study and not a double-blind and randomised study. Expectation bias was reduced by maintaining blinding of the subjects until the end of the study and having both infusions identical in volume, appearance and duration of infusion. Furthermore, given the stark difference between placebo and NTG, there was no difference between attack onset in the open unblinded compared with the single-blinded NTG visits (Figure 4(b)), is an indication that randomisation was not a factor in this study.\n\nConclusion\n\nWe present the results of the first placebo-controlled study using intravenous NTG administration to systematically study NTG-induced cluster headache attacks. We have shown that NTG can reliably bring on cluster headache attacks as well as the development of non-headache symptoms and CAS. This study highlights differences between NTG-induced attack onset times between the ECH and CCH subjects. Understanding the stages of cluster headache is essential; by recognising the non-headache symptoms in the lead up to the onset of pain and the underlying pathogenesis of this, we may be able to uncover new therapeutic targets to abort attacks before the onset of the severe and devastating pain experienced by our cluster headache patients.\n\nArticle highlights\n\nWeight-calculated standardised intravenous nitroglycerin administration is a reliable method to induce cluster headache attacks, cranial autonomic symptoms and non-headache symptoms that accompany cluster headache attacks.\n\nAccompanying non-headache symptoms in cluster headache attacks are important to recognise for both clinical and research purposes.\n\nThere may be inherent differences between episodic cluster headache and chronic cluster headache.\n\nAcknowledgement\n\nThis study would not have been possible without the support of OUCH(UK), all the cluster headache patients who were interested in helping us with this study and all the subjects who took part in this study.\n\nEthics or Institutional Review Board approval: This study 16/LO/0693 obtained approval from the London, City & East NHS Research Ethics Committee on 23 June 2016. This study was carried out in accordance with the World Medical Association Declaration of Helsinki (1964), the Research Governance Framework for Health and Social Care (2nd edition, 2005), the Data Protection Act (1998) and the Principles of Good Clinical Practice (GCP); all subjects gave informed consent before taking part.\n\nDeclaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DYW no reported competing interests. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli-Lilly and Company, grant from Celegene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, MundiPharma, Novartis, Pfizer, Praxis, Sanofi, Santara Therapeutics Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up-to-Date, Oxford University Press, and Wolters Kluwer; and a patent magnetic stimulation for headache assigned to eNeura without fee.\n\nFunding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part-funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London Maudsley Foundation Trust and King’s College London. 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"fulltext_license": "CC BY",
"issn_linking": "0333-1024",
"issue": "41(8)",
"journal": "Cephalalgia : an international journal of headache",
"keywords": "Cluster headache; chronic cluster headache; cranial autonomic symptoms; episodic cluster headache; nitroglycerin; nitroglycerin headache; non-headache symptoms",
"medline_ta": "Cephalalgia",
"mesh_terms": null,
"nlm_unique_id": "8200710",
"other_id": null,
"pages": "913-933",
"pmc": null,
"pmid": "33615843",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "31246132;9533604;12183331;7085264;2113834;29987329;23771276;14728706;31291515;13121092;4971733;30054443;2113833;19864020;22529192;2546144;9350388;31059165;12566974;7641257;30074545;9690407;12807519;2506503;1468905;30596910;28816505;27861832;10961763;3921490;16942468;6101155;19740120;16630053;1852778;6541301;7540279;3917598;29231763;9117375;7552308;32050782;23534887;11252140;8895232",
"title": "Comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks.",
"title_normalized": "comprehensive clinical phenotyping of nitroglycerin infusion induced cluster headache attacks"
} | [
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"fulfillexpeditecriteria": "1",
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"activesubstance": {
"activesubstancename": "NITROGLYCERIN"
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