article dict | reports listlengths 1 3.97k |
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{
"abstract": "OBJECTIVE\nA multicentre prospective non-randomised study of de novo acute myeloid leukaemia (AML) in patients aged ≥70 yr was designed to reduce toxicity and achieve acceptable complete remission (CR) rates.\n\n\nMETHODS\nThe outpatient treatment included induction with oral fludarabine, subcutaneous cytarabine and subcutaneous filgrastim (FAG). The patients received more induction cycles according to the response achieved. If there was no response to induction with FAG, the following induction cycle included oral idarubicin, subcutaneous cytarabine and subcutaneous filgrastim (IAG). Patients achieving CR received one intensification (FAG on response to previous FAG or alternatively IAG) and one consolidation cycle (IAG).\n\n\nRESULTS\nThirty patients were enrolled from April 2004 to June 2007. The median age was 73 yr (range 70-77). Fifteen patients (50%) achieved CR. The 2-yr DFS was 29% (95% CI, 5-47%), and the 2-yr OS was 23% (95% CI, 12-35%). Twenty-five of 69 cycles (36%) were managed on a completely outpatient basis. The median hospital stay per cycle was 10 d (95% CI, 3-25).\n\n\nCONCLUSIONS\nThis study demonstrates the tolerability and efficacy of a semi-intensive treatment in elderly de novo patients with AML managed on an outpatient basis, without substantial toxicity.",
"affiliations": "Haematology Department, ICO-Hospital Germans Trias i Pujol, Badalona, Spain.;Haematology Department, ICO-Hospital Germans Trias i Pujol, Badalona, Spain.;Haematology Department, Hospital Taulí, Sabadell, Spain.;Haematology Department, Jose Carreras Leukaemia Research Institute, Universitat Autonòma of Barcelona, Barcelona, Spain.;Haematology Department, ICO-Hospital Duran y Reynals, Barcelona, Spain.;Haematology Department, ICO-Hospital Josep Trueta, Girona, Spain.;Haematology Department, Hospital Althaia, Manresa, Spain.;Haematology Department, Jose Carreras Leukaemia Research Institute, Universitat Autonòma of Barcelona, Barcelona, Spain.;Haematology Department, ICO-Hospital Germans Trias i Pujol, Badalona, Spain.",
"authors": "Vives|Susana|S|;Oriol|Albert|A|;Piernas|Sònia|S|;Brunet|Salut|S|;Clapés|Victòria|V|;Guardia|Ramon|R|;Subirà|Maricel|M|;Sierra|Jordi|J|;Ribera|Josep-Maria|JM|;|||",
"chemical_list": "D003561:Cytarabine; D014740:Vidarabine; C024352:fludarabine; D015255:Idarubicin",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12538",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "95(6)",
"journal": "European journal of haematology",
"keywords": "AML; elderly patients; intermediate dose cytarabine; outpatient management",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow; D003561:Cytarabine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015255:Idarubicin; D015470:Leukemia, Myeloid, Acute; D008297:Male; D016019:Survival Analysis; D016896:Treatment Outcome; D014740:Vidarabine",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "576-82",
"pmc": null,
"pmid": "25692738",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Feasibility and efficacy of outpatient therapy with intermediate dose cytarabine, fludarabine and idarubicin for patients with acute myeloid leukaemia aged 70 or older.",
"title_normalized": "feasibility and efficacy of outpatient therapy with intermediate dose cytarabine fludarabine and idarubicin for patients with acute myeloid leukaemia aged 70 or older"
} | [
{
"companynumb": "ES-PFIZER INC-2019521320",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Kaposi sarcoma (KS) may rarely occur in transplant recipients through primary human herpesvirus-8 (HHV-8) infection from a seropositive donor. This report describes a patient who developed hepatic KS after receiving a split liver transplant from an HHV-8-positive donor. The recipient was treated with liposomal doxorubicin after reduction in immunosuppression led to acute cellular rejection. This treatment achieved regression of KS while preserving allograft function, demonstrating a successful therapeutic strategy for this malignancy.",
"affiliations": "Departments of Surgery, Yale School of Medicine, New Haven, Connecticut.;Departments of Surgery, Yale School of Medicine, New Haven, Connecticut.;Departments of Medicine, Yale School of Medicine, New Haven, Connecticut.;Departments of Medicine, Yale School of Medicine, New Haven, Connecticut.;Departments of Pathology, Yale School of Medicine, New Haven, Connecticut.;Departments of Medicine, Yale School of Medicine, New Haven, Connecticut.;Departments of Surgery, Yale School of Medicine, New Haven, Connecticut.;Departments of Surgery, Yale School of Medicine, New Haven, Connecticut.",
"authors": "Fu|Whitney|W|http://orcid.org/0000-0002-6935-9121;Merola|Jonathan|J|http://orcid.org/0000-0002-9283-1893;Malinis|Maricar|M|;Lacy|Jill|J|;Barbieri|Andrea|A|;Liapakis|Annmarie H|AH|;Mulligan|David C|DC|;Yoo|Peter S|PS|",
"chemical_list": "C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12966",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "human herpesvirus-8; liver transplant; post-transplant Kaposi Sarcoma",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D064591:Allografts; D004317:Doxorubicin; D005260:Female; D006566:Herpesviridae Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D012514:Sarcoma, Kaposi; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12966",
"pmc": null,
"pmid": "30014622",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of primary donor-derived human herpesvirus-8 infection and hepatic Kaposi Sarcoma in an adult liver transplant recipient.",
"title_normalized": "successful treatment of primary donor derived human herpesvirus 8 infection and hepatic kaposi sarcoma in an adult liver transplant recipient"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2018US-190364",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Recent studies have demonstrated feasibility and substantial benefit of direct-acting antivirals (DAAs) administration during or after first-line immune-chemotherapy (I-CT) in patients with hepatitis C virus (HCV)-positive diffuse large B-cell lymphomas (DLBCL). However, data on DAAs used during or after salvage treatments are still lacking. In this study we assessed clinical and virological outcome in 11 patients with relapsed (n = 7) or refractory (n = 4) HCV-positive DLBCL. DAAs were given either concurrently (n = 3) or subsequent (n = 8) to salvage I-CT. Most patients (10 of 11) received sofosbuvir-based regimens. All patients completed their planned courses of DAAs and achieved sustained virological response. DAAs were well tolerated, with no grade ≥2 adverse events. At a median follow-up of 3.6 years four patients died (4-year OS: 76%). In conclusion, we provide evidence that DAAs in HCV-positive relapsed/refractory DLBCL are extremely safe and effective, suggesting that they should be used if HCV eradication was not instituted before.",
"affiliations": "Department of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi -ASST Sette Laghi, University of Insubria, Varese, Italy.;Department of Molecular Medicine, University of Pavia, Pavia, Italy.;Department of Medicine, Section of Hematology, University of Verona, Verona, Italy.;Unit of Hematology-Oncology, Centre Hospitalier de Versailles, Le Chesnay, France.;Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.;Hematology Unit, Department of Onco-Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy.;Department of Oncology and Hematology, AOU \"Luigi Vanvitelli\", Naples, Italy.;Department of Hematology, Azienda Ospedaliera Senese, University of Siena, Siena, Italy.;Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.;Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.;Department of Infectious and Tropical Diseases, University Hospital Ospedale di Circolo e Fondazione Macchi - ASST Sette Laghi, University of Insubria, Varese, Italy.;Department of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi -ASST Sette Laghi, University of Insubria, Varese, Italy.;Department of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi -ASST Sette Laghi, University of Insubria, Varese, Italy.;Department of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi -ASST Sette Laghi, University of Insubria, Varese, Italy.;Department of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.;Department of Hematology, University Hospital Ospedale di Circolo e Fondazione Macchi -ASST Sette Laghi, University of Insubria, Varese, Italy.;Department of Molecular Medicine, University of Pavia, Pavia, Italy.",
"authors": "Merli|Michele|M|0000-0002-0905-5927;Defrancesco|Irene|I|;Visco|Carlo|C|;Besson|Caroline|C|;Di Rocco|Alice|A|;Arcari|Annalisa|A|;Sica|Antonello|A|;Cencini|Emanuele|E|;Tisi|Maria Chiara|MC|;Frigeni|Marco|M|;Grossi|Paolo|P|;Bianchi|Benedetta|B|;Mora|Barbara|B|;Bertù|Lorenza|L|;Bruno|Raffaele|R|;Passamonti|Francesco|F|0000-0001-8068-5289;Arcaini|Luca|L|0000-0002-9504-991X",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2020.1755859",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "61(9)",
"journal": "Leukemia & lymphoma",
"keywords": "Diffuse large B-cell lymphoma (DLBCL); direct-acting antivirals (DAA); hepatitis C virus (HCV); salvage therapy",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000998:Antiviral Agents; D016174:Hepacivirus; D006526:Hepatitis C; D019698:Hepatitis C, Chronic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2122-2128",
"pmc": null,
"pmid": "32343165",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Direct-acting antivirals in relapsed or refractory hepatitis C virus-associated diffuse large B-cell lymphoma.",
"title_normalized": "direct acting antivirals in relapsed or refractory hepatitis c virus associated diffuse large b cell lymphoma"
} | [
{
"companynumb": "IT-NOVARTISPH-NVSC2021IT074580",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": "4",
... |
{
"abstract": "Glanzmann thrombasthenia is a rare platelet disorder characterized by an abnormal integrin receptor on the surface of platelets that results in the failure of platelets to aggregate. Currently, curative therapy is allogeneic hematopoietic stem cell transplantation (HSCT). The authors report 2 patients with Glanzmann thrombasthenia who successfully underwent allogeneic HSCT from unrelated donors, including one using umbilical cord blood stem cells. Although both patients had evidence of engraftment, hematopoietic recovery, and normalization of platelet aggregation, they also experienced several post-transplant complications. Allogeneic HSCT carries a significant risk of morbidity and mortality that should be considered before proceeding with the transplant.",
"affiliations": "Division of Pediatric Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA.;Division of Pediatric Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA.;Division of Pediatric Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA.;Division of Pediatric Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA.",
"authors": "Friend|Brian D|BD|;Roach|Gavin D|GD|;Kempert|Pamela H|PH|;Moore|Theodore B|TB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001646",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D011379:Prognosis; D013915:Thrombasthenia; D014184:Transplantation, Homologous",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e521-e526",
"pmc": null,
"pmid": "31693514",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Successful Use of Hematopoietic Stem Cell Transplantation for 2 Pediatric Cases of Glanzmann Thrombasthenia and Review of the Literature.",
"title_normalized": "successful use of hematopoietic stem cell transplantation for 2 pediatric cases of glanzmann thrombasthenia and review of the literature"
} | [
{
"companynumb": "US-ASPEN-GLO2021US000493",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Treatment of Pseudomonas aeruginosa remains challenging, despite the availability ceftolozane-tazobactam. We report a treatment failure with ceftolozane-tazobactam salvage therapy for pneumonia complicated by lung abscess. Drug resistance, dose selection, and source control are possible contributing factors. Ceftolozane-tazobactam susceptibility testing should precede therapy and consideration should be given to dosing selection.",
"affiliations": "Department of Pharmacy Johnson City Medical Center Johnson City TN USA.;Department of Pharmacy Practice Bill Gatton College of Pharmacy East Tennessee State University Johnson City TN USA.;Department of Pharmacy Johnson City Medical Center Johnson City TN USA.;Division of Infectious Diseases Quillen College of Medicine East Tennessee State University Johnson City TN USA.;Division of Infectious Diseases Quillen College of Medicine East Tennessee State University Johnson City TN USA.",
"authors": "Lewis|Paul O|PO|0000-0002-2626-7390;Cluck|David B|DB|;Tharp|Jennifer L|JL|;Krolikowski|Matthew A|MA|;Patel|Paras D|PD|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1612",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1612CCR31612Case ReportCase ReportsFailure of ceftolozane‐tazobactam salvage therapy in complicated pneumonia with lung abscess LEWIS et al.Lewis Paul O. http://orcid.org/0000-0002-2626-7390plewis16@gmail.com \n1\nCluck David B. \n2\nTharp Jennifer L. \n1\nKrolikowski Matthew A. \n3\nPatel Paras D. \n3\n\n1 \nDepartment of Pharmacy\nJohnson City Medical Center\nJohnson City\nTN\nUSA\n\n2 \nDepartment of Pharmacy Practice\nBill Gatton College of Pharmacy\nEast Tennessee State University\nJohnson City\nTN\nUSA\n\n3 \nDivision of Infectious Diseases\nQuillen College of Medicine\nEast Tennessee State University\nJohnson City\nTN\nUSA\n* Correspondence\n\nPaul O. Lewis, Department of Pharmacy, Johnson City Medical Center, Johnson City, TN, USA.\n\nEmail: plewis16@gmail.com\n28 5 2018 7 2018 6 7 10.1002/ccr3.2018.6.issue-71308 1312 22 12 2017 30 4 2018 04 5 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nTreatment of Pseudomonas aeruginosa remains challenging, despite the availability ceftolozane‐tazobactam. We report a treatment failure with ceftolozane‐tazobactam salvage therapy for pneumonia complicated by lung abscess. Drug resistance, dose selection, and source control are possible contributing factors. Ceftolozane‐tazobactam susceptibility testing should precede therapy and consideration should be given to dosing selection.\n\nceftolozane‐tazobactampneumoniaPseudomonas aeruginosaresistancetreatment failure source-schema-version-number2.0component-idccr31612cover-dateJuly 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.1.1 mode:remove_FC converted:02.07.2018\n\n\nLewis \nPO \n, \nCluck \nDB \n, \nTharp \nJL \n, \nKrolikowski \nMA \n, \nPatel \nPD \n. Failure of ceftolozane‐tazobactam salvage therapy in complicated pneumonia with lung abscess . Clin Case Rep . 2018 ;6 :1308 –1312 . https://doi.org/10.1002/ccr3.1612\n==== Body\n1 INTRODUCTION\nCeftolozane‐tazobactam is a new oxyimino‐cephalosporin/beta‐lactamase inhibitor combination currently approved by the United States (US) Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections and complicated intraabdominal infections at a dose of 1.5 g intravenous (IV) every 8 hours.1 This agent has gained notable attention for enhanced activity against resistant Gram‐negative organisms, specifically Pseudomonas aeruginosa.2\nPseudomonas aeruginosa is problematic due to numerous resistance mechanisms against beta‐lactams, including loss of porin channels, efflux pumps, and beta‐lactamase production (see Table 1).2 Ceftolozane contains structural differences that allow it to remain active against these mechanisms and is currently the most active beta‐lactam directed against P. aeruginosa.3\n\n\nTable 1 Notable resistance mechanisms produced by Pseudomonas aeruginosa\n2, 11, 13, 16, 17, 18, 19\n\n\n\tMero\tImi\tCfp\tAzt\tPT\tCT\t\nBeta‐lactamases\t\nClass A carbapenemase (KPC)\tR\tR\tR\tR\tR\tR\t\nClass B (MBL, NDM, VIM, IMP)\tR\tR\tR\t\tR\tR\t\nClass C (AmpC)a\n\tr\tr\tr\tR\tR\tr\t\nClass D (OXA‐type ESBL)\t\t\tR\tR\tr\t\t\nClass D (OXA‐type carbapenemase)\tR\tR\tR\tR\tR\tR\t\nEfflux pumps\t\nMexAB‐OprM\tR\t\tR\tR\tR\t\t\nMexCD‐OprJ\tR\t\tR\t\tR\t\t\nMexEF‐OprN\tR\tR\tR\tR\tR\t\t\nMexXY‐OprM\tR\t\tR\tR\tR\t\t\nOther mechanisms\t\nLoss of OprD (porins)\tr\tR\t\t\t\t\t\nAzt, aztreonam; Cfp, cefepime; CT, ceftolozane‐tazobactam; Imi, imipenem; Mer, meropenem; PT, piperacillin‐tazobactam; r, partial resistance; R, complete resistance.\n\na Includes Pseudomonas‐derived cephalosporinases (PDC) variants.\n\nJohn Wiley & Sons, LtdWhile not FDA approved, a phase I trial demonstrated ceftolozane‐tazobactam achieved higher epithelial lung concentrations than piperacillin‐tazobactam in 51 healthy adults.4 A phase III trial registered with the National Institute of Health (NCT018539) for the treatment of ventilator‐associated pneumonia was terminated early to redirect all efforts to a larger trial within the clinical development program (NCT02070757) and is currently enrolling patients with ventilated nosocomial pneumonia.5, 6 Notably, these trials are evaluating a higher dose of 3 g IV every 8 hours. Several case reports have also described successful use of ceftolozane‐tazobactam in pneumonia, secondary to multi‐drug resistant P. aeruginosa (MDRPA).7, 8, 9, 10\n\n\nFailures have been observed with ceftolozane‐tazobactam when used off‐label. Caston and colleagues studied 6 patients with pneumonia, 2 resulting in deaths and one resulting in a clinical cure but microbiological persistence at 30 days.8 These patients were confounded by septic shock and multiple medical comorbidities, including one with a lung transplantation. Munita and colleagues studied 18 patients with pneumonia, 7 of whom were considered treatment failures.9 We report our experience and lessons learned with a treatment failure in a patient treated for pneumonia complicated by lung abscess.\n\n2 CASE PRESENTATION\nWe present the case of a 53‐year‐old female who transferred from an outside facility requiring a higher level of care, due to worsening pneumonia with possible abscess and the need for cardiothoracic surgery (CTS) consultation. Past medical history included previous breast cancer post‐lumpectomy and radiotherapy, remote history of vulvar and rectal cancer post wide‐debulking, chronic obstructive pulmonary disease, and ventilator‐dependent respiratory failure with tracheostomy. Home medications included albuterol/ipratropium nebulizer, alprazolam, amlodipine, aripiprazole, budesonide/formoterol metered dose inhaler, citalopram, tamoxifen, tiotropium inhaler, trazodone, and oxycodone. She reported an allergy to nonsteroidal anti‐inflammatory drugs. The patient initially presented to another facility complaining of fever, diarrhea, shortness of breath, and increasing oxygen demands. On examination, the patient was not in acute distress. All systems were negative except for diminished lung sounds with rhonchi bilaterally. A chest X‐ray demonstrated left upper lobe pneumonia. Blood cultures were drawn, and a sample of tracheostomy secretions was sent for culture and sensitivities. She was initiated on vancomycin and piperacillin‐tazobactam for treatment of healthcare‐associated pneumonia. The patient reported a history of Clostridium difficile colitis and was started on oral vancomycin and IV metronidazole. On day 2, a bronchoscopy was performed with washings sent for culture. Both respiratory cultures grew MDRPA while blood cultures remained negative. The susceptibility profile is outlined in Table 2. Piperacillin‐tazobactam was switched to meropenem at 2 g IV every 8 hours, and inhaled tobramycin was added. A repeat bronchoscopy was performed on day 12 due to mucus plugging and lack of clinical response. This culture grew persistent MDRPA, necessitating the addition of IV tobramycin on day 16. Inhaled tobramycin was switched to inhaled colistin on day 20. On day 23, tobramycin IV and metronidazole were discontinued and the meropenem dose was decreased.\n\nTable 2 Summary of the patient cultures and sensitivitiesa\n\n\nDay\tDay 1\tDay 2\tDay 12\tDay 24\tDay 32\tDay 36\t\nSite\tTracheostomy\tBronchoscopy\tBronchoscopy\tPleural Fluid\tPleural Fluid\tBronchoscopy\t\nOrganism\t\nPseudomonas aeruginosa\n\t\nPseudomonas aeruginosa\n\t\nPseudomonas aeruginosa\n\t\nPseudomonas aeruginosa\n\t\nPseudomonas aeruginosa\n\t\nAcinetobacter baumanii\n\t\nIsolate no.\t1\t1\t2\t1\t2\t1\t2\t1\t1\t\nCefepime\t16 I\t16 I\t≥64 R\t8 S\t≥64 R\t≥64 R\t16 I\t≥64 R\t≥64 R\t\nGentamicin\t4 I\t4 I\t4 I\t≤1 S\t4 I\t4 I\t2 S\t8 I\t8 I\t\nLevofloxacin\t≥8 R\t≥8 R\t≥8 R\t≥8 R\t≥8 R\t≥8 R\t≥8 R\t4 I\t4 I\t\nImipenem\t\t\t\t\t\t\t\t≥16 R\t≥16 R\t\nMeropenem\t≥16 R\t≥16 R\t≥16 R\t≥16 R\t≥16 R\t≥16 R\t≥16 R\t≥16 R\t\t\nPip/tazo\t32 S\t32 S\t\t32S\t\t\t\t\t\t\nTobramycin\t≤1 S\t≤1 S\t≤1 S\t≤1 S\t≤1 S\t≤1 S\t≤1 S\t≤1 S\t≤1 S\t\nAmikacin\t\t\t\t\t\t\t\t128 R\t128 R\t\nCef/tazo\t\t\t\t\t\t\t\t12 NS\t\t\nColistin\t\t\t\t\t\t\t\t0.094 S\t0.094 S\t\nCef/tazo, ceftolozane‐tazobactam; I, intermediate; NS, nonsusceptible; Pip/tazo, piperacillin‐tazobactam; R, resistant; S, susceptible.\n\na All tested susceptibilities are provided. If not listed, susceptibilities were either not performed or not reported.\n\nJohn Wiley & Sons, LtdOn day 24, a 12‐French chest tube was successfully placed into the left upper lobe abscess. Approximately 30 mL of purulent material was aspirated and sent for culture. Growth from this drainage continued to demonstrate MDRPA. One day after chest tube insertion, a computed tomography (CT) scan of the chest demonstrated significantly diminished fluid component of the left upper lobe abscess with drain positioned in the air‐containing component; residual left upper lobe and left lingular pneumonia and pulmonary emphysema was also noted. The patient failed to improve and on day 28 ceftolozane‐tazobactam was initiated at 1.5 g IV every 8 hours. A repeat chest CT scan on day 30 showed a decrease in the left upper gas‐fluid collection, but persistent dense pneumonia of the left upper lung and a new smaller infiltrate in the left lower lobe.\n\nTwo days after the repeat chest CT, the patient was transferred to our facility for worsening pneumonia, requiring a higher level of care and CTS consultation. Abnormal clinical examination findings included diffusely diminished lung sounds, rales in the left lower lobe, a left pigtail chest tube drain, tachycardia with heart rate of 120 beats per minute, and tachypnea with a respiratory rate of 22 breaths per minute. The patient's chest tube was intact with a small amount of thick, white drainage, which was sent for culture, along with 2 sets of blood cultures. Ceftolozane‐tazobactam 1.5 g IV every 8 hours was continued, and meropenem was stopped. The patient was initiated on tobramycin 280 mg (7 mg/kg) IV every 24 hours. CTS diagnosed the condition as a pulmonary abscess with bronchopulmonary fistula (BPF). The patient was deemed a poor surgical candidate, and continued medical management and drainage via chest tube was recommended. Repeat cultures from the pleural fluid drainage continued to grow MDRPA, while blood cultures remained negative. Susceptibility testing for ceftolozane‐tazobactam was requested and performed using an investigational elipsometer (E)‐strip. On day 36 overall (day 5 post‐transfer), a repeat bronchoscopy was performed. Culture of the washings grew Acinetobacter baumaunii. Additionally, the results from the ceftolozane‐tazobactam E‐strip for Pseudomonas finalized, demonstrating an MIC of 12 mg/L (nonsusceptible). Chest CT on day 37 demonstrated mild interval increase in the air‐fluid collection size, drain in place, persistent extensive left upper lobe pneumonia, and mild improvement in the lingula and left lung base. With no improvement and the growth of Acinetobacter, ceftolozane‐tazobactam was discontinued on day 39, after 12 days total. Meropenem at 1.5 g (pediatric dosing of 40 mg/kg) IV every 8 hours and colistin 100 mg (2.5 mg/kg) IV every 12 hours were started. After 14 days of meropenem and colistin without improvement, all therapy was stopped and the patient was transitioned to comfort care and ultimately expired.\n\n3 DISCUSSION\nThis case describes treatment failure with ceftolozane‐tazobactam for pneumonia with pulmonary abscess. Several contributing factors warrant further discussion. In our case, the reported MIC to ceftolozane‐tazobactam was 12 mg/L. The prescribing information for ceftolozane‐tazobactam defines susceptible as ≤ 4 mg/L for P. aeruginosa.1 Susceptibilities prior to starting treatment were not available. This raises an unanswerable question whether resistance was present at baseline or had developed during therapy.\n\nFraile‐Ribot and colleagues reported the emergence of ceftolozane‐tazobactam resistance during the treatment of surgical site infection with ceftazidime.11 Polymerase chain reaction sequencing performed on the initial culture and the resistant culture demonstrated that resistance was due to an amino acid residue insertion at D149 on blaOXA‐2 beta‐lactamase, now designated OXA‐539.11 This report is concerning for multiple reasons. In vivo resistance to novel cephalosporins is possible even without previous exposure.11 An extended spectrum beta‐lactamase emerged from a narrow spectrum beta‐lactamase (OXA‐2).11 Furthermore, this gene is highly transmissible, associated with higher virulence factor (exoU cytotoxin), and has already been detected in 14 different countries.12 While our patient was exposed to multiple beta‐lactams prior to treatment with ceftolozane‐tazobactam, the patient had not been exposed to any cephalosporins. Haidar and colleagues have also described ceftolozane‐tazobactam failures in a single center retrospective analysis.13 Notably, 18 of 21 cases in their analysis were respiratory tract infections.13 The failure rate in the study approached 30% with the majority of these cases being attributed to pneumonia.13 Moreover, the authors describe emergence of resistance while on therapy, citing ampC overexpression and/or point mutations as possible mechanisms contributing to the aforementioned failures.13 This is the first study to utilize whole genome sequencing to characterize resistance.13\n\n\nThe current FDA labeling only includes 1.5 g IV every 8 hours, while the proposed dose for pneumonia is 3 g IV every 8 hours.1, 6 Haidar and colleagues observed that dose was not associated with clinical failure or 90‐day mortality.13 In fact, only the approved dose of 1.5 g was found to result in success in some cases. Munita and colleagues were also challenged by this debate as they reported variations in their dosing.9 Ultimately, our decision was made to continue 1.5 g every 8 hours, given the patient's weight of 40 kg and poor nutritional status. Protein binding is 16%‐21%, and volume of distribution is 13.5 L following a single dose of 1.5 g in healthy adults. The prescribing information does not include pharmacokinetic data in patients with low body weight.1\n\n\nSource control may have contributed to treatment failure. It remains a critical step in managing a wide variety of infectious processes. The course was complicated by the presence of an abscess and BPF, making the decision for more aggressive surgical intervention difficult. Infectious Diseases Society of America community‐acquired pneumonia guidelines state a thoracentesis should be performed whenever possible in patients with empyema and pleural effusion as these often represent causes for nonresponse.14 The chest tube allowed for continuous drainage. Furthermore, once the underlying lung disease improves, BPFs usually resolve without surgery.15 Ultimately, risk‐benefit analysis did not favor a more invasive surgical intervention.\n\nIn conclusion, ceftolozane‐tazobactam, preceded by piperacillin‐tazobactam, meropenem, tobramycin, and colistin, for the treatment of pneumonia in our patient was not successful. The patient's history was complicated by multiple medical comorbidities. Resistance to this agent was reported during treatment. Despite the success reported in other cases, caution is still warranted when using this agent for off‐label indications, especially when source control cannot be obtained. Consideration must also be given to which dose to use, the lower FDA‐approved dose or the higher dose, currently in clinical trials. Furthermore, P. aeruginosa should have susceptibilities performed to ceftolozane‐tazobactam, when available, prior to initiating therapy and upon re‐isolation.\n\nAUTHORSHIP\nPOL: wrote the introduction and case description. DBC, MAK, and JLT: wrote the discussion and added details of the case. PDP: was involved with the clinical care of the patient and edited the manuscript.\n\nCONFLICT OF INTEREST\nNo authors have any conflicts of interest to report. All authors contributed substantially to the concepts, writing, editing, and approval of this manuscript.\n==== Refs\nREFERENCES\n1 \nZERBAXA (ceftolozane‐tazobactam) [package insert] . Whitehouse Station, NJ : Merck & Co., Inc. ; 2015 .\n2 \n\nCluck \nD \n, \nLewis \nP \n, \nStayer \nB \n, \nSpivey \nJ \n, \nMoorman \nJ \n. Ceftolozane‐tazobactam: a new‐generation cephalosporin . Am J Health Syst Pharm . 2015 ;72 :2135 ‐2146 .26637512 \n3 \n\nFarrell \nDJ \n, \nSader \nHS \n, \nFlamm \nRK \n, \nJones \nRN \n. Ceftolozane/tazobactam activity tested against gram‐negative bacterial isolates from hospitalized patients with pneumonia in US and European medical centres (2012) . Int J Antimicrob Agents . 2014 ;43 :533 ‐539 .24856078 \n4 \n\nChandorkar \nG \n, \nHuntington \nJA \n, \nGotfried \nMH \n, et al. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects . J Antimicrob Chemother . 2012 ;67 :2463 ‐2469 .22773741 \n5 \nClinicalTrials.gov \n. Study of intravenous ceftolozane/tazobactam compared to piperacillin/tazobactam in ventilator‐associated pneumonia . https://clinicaltrials.gov/ct2/show/NCT01853982. Accessed August 27, 2017.\n6 \nClinicalTrials.gov \n. Safety and efficacy study of ceftolozane/tazobactam to treat ventilated nosocomial pneumonia (ASPECT‐NP) . https://clinicaltrials.gov/ct2/show/ NCT02070757. Accessed August 27, 2017.\n7 \n\nGelfand \nMS \n, \nCleveland \nKO \n. Ceftolozane/tazobactam therapy of respiratory infections due to multidrug‐resistant Pseudomonas aeruginosa\n . Clin Infect Dis . 2015 ;61 :853 ‐855 .26021991 \n8 \n\nCastón \nJJ \n, \nDe la Torre \nÁ \n, \nRuiz‐Camps \nI \n, et al. Salvage therapy with ceftolozane‐tazobactam for multidrug‐resistant Pseudomonas aeruginosa infections . Antimicrob Agents Chemother . 2017 ;61 :e02136‐16 .27956431 \n9 \n\nMunita \nJM \n, \nAitken \nSL \n, \nMiller \nWR \n, et al. Multicenter evaluation of ceftolozane/tazobactam for serious infections caused by carbapenem‐resistant Pseudomonas aeruginosa\n . Clin Infect Dis . 2017 ;65 :158 ‐161 .28329350 \n10 \n\nSoliman \nR \n, \nLynch \nS \n, \nMeader \nE \n, \nPike \nR \n, \nTurton \nJF \n, \nHill \nRLR \n, \nWoodford \nN \n, \nLivermore \nDM \n, et al. Successful ceftolozane/tazobactam treatment of chronic pulmonary infection with pan‐resistant Pseudomonas aeruginosa\n . JMM Case Rep . 2015 ;2 : https://doi.org/10.1099/jmmcr.0.000025.\n11 \n\nFraile‐Ribot \nPA \n, \nMulet \nX \n, \nCabot \nG \n, et al. In vivo emergence of resistance to novel cephalosporin‐β‐lactamase inhibitor combinations through the duplication of the amino acid D149 from OXA‐2 β‐lactamase (OXA‐539) in ST235 Pseudomonas aeruginosa\n . Antimicrob Agents Chemother . 2017 ;61 :e01117‐17 .28674059 \n12 \n\nOliver \nA \n, \nMulet \nX \n, \nLópez‐Causapé \nC \n, \nJuan \nC \n. The increasing threat of Pseudomonas aeruginosa high‐risk clones . Drug Resist Updat . 2015 ;21–22 :41 ‐59 .\n13 \n\nHaidar \nG \n, \nPhilips \nNJ \n, \nShields \nRK \n, et al. Ceftolozane‐tazobactam for the treatment of multidrug‐resistant Pseudomonas aeruginosa infections: clinical effectiveness and evolution of resistance . Clin Infect Dis . 2017 ;65 :110 ‐120 .29017262 \n14 \n\nMandell \nLA \n, \nWunderlink \nRG \n, \nAnzueto \nA \n, et al. Infectious diseases Society of America/American Thoracic Society consensus guidelines on the management of community‐acquired pneumonia in adults . Clin Infect Dis . 2007 ;44 :S27 ‐S72 .17278083 \n15 \n\nPierson \nDJ \n, \nHorton \nCA \n, \nBates \nPW \n. Persistent bronchopleural air leak during mechanical ventilation. A review of 39 cases . Chest . 1986 ;90 :321 ‐323 .3743142 \n16 \n\nKazmierczak \nKM \n, \nRabine \nS \n, \nHackel \nM \n, et al. Multiyear, multinational survey of the incidence and global distribution of metallo‐β‐lactamase‐producing enterobacteriaceae and Pseudomonas aeruginosa\n . Antimicrob Agents Chemother . 2015 ;60 :1067 ‐1078 .26643349 \n17 \n\nAlatoom \nA \n, \nElsayed \nH \n, \nLawlor \nK \n, et al. Comparison of antimicrobial activity between ceftolozane‐tazobactam and ceftazidime‐avibactam against multidrug‐resistant isolates of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa\n . Int J Infect Dis . 2017 ;62 :39 ‐43 .28610832 \n18 \n\nBerrazeg \nM \n, \nJeannot \nK \n, \nNtsogo Enguéné \nVY \n, et al. Mutations in β‐lactamase AmpC increase resistance of Pseudomonas aeruginosa isolates to antipseudomonal cephalosporins . Antimicrob Agents Chemother . 2015 ;59 :6248 ‐6255 .26248364 \n19 \n\nRodríguez‐Martínez \nJM \n, \nPoirel \nL \n, \nNordmann \nP \n. Molecular epidemiology and mechanisms of carbapenem resistance in Pseudomonas aeruginosa\n . Antimicrob Agents Chemother . 2009 ;53 :4783 ‐4788 .19738025\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "6(7)",
"journal": "Clinical case reports",
"keywords": "Pseudomonas aeruginosa; ceftolozane‐tazobactam; pneumonia; resistance; treatment failure",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1308-1312",
"pmc": null,
"pmid": "29988582",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports",
"references": "26643349;28674059;28610832;22773741;26304792;3743142;17278083;26021991;29017262;26637512;27956431;24856078;28329350;19738025;26248364",
"title": "Failure of ceftolozane-tazobactam salvage therapy in complicated pneumonia with lung abscess.",
"title_normalized": "failure of ceftolozane tazobactam salvage therapy in complicated pneumonia with lung abscess"
} | [
{
"companynumb": "US-009507513-1806USA005386",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTOLOZANE SULFATE\\TAZOBACTAM SODIUM"
},
"... |
{
"abstract": "We intended to evaluate the influence of sex mismatch between donor and recipient, which is still under much debate, on survival and comorbidities after cardiac transplantation. From November 2003 to December 2013, a total of 258 patients were transplanted in our center. From these, 200 receptors were male (77.5%) and constituted our study population, further divided into those who received the heart from a female donor (Group A) - 44 patients (22%) and those who received it from a male donor (Group B) - 156 (78%). Median follow-up was 4.2 ± 3.0 years (1-10 years). The two groups were quite comparable with each other, except for body mass index, systolic pulmonary artery pressure, and transpulmonary gradient, which were significantly lower in Group A. A low donor/recipient weigh ratio (<0.8) was avoided whenever possible. Hospital mortality was not different in the two groups. During follow-up, global survival was similar, as was survival free from acute cellular rejection and cardiac allograft vasculopathy. However, patients in Group A had decreased survival free from serious infections and malignant tumors. Allocation of female donors to male receptors can be done safely, at least in receptors without pulmonary hypertension and when an adequate donor/recipient weigh ratio is ensured.",
"affiliations": "Center of Cardiothoracic Surgery, University Hospital and Medical School, Coimbra, Portugal.",
"authors": "Correia|Pedro|P|;Prieto|David|D|;Batista|Manuel|M|;Antunes|Manuel J|MJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/tri.12432",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "27(12)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "gender mismatch; heart transplantation; survival",
"medline_ta": "Transpl Int",
"mesh_terms": "D001794:Blood Pressure; D015992:Body Mass Index; D001835:Body Weight; D002423:Cause of Death; D018572:Disease-Free Survival; D005260:Female; D016027:Heart Transplantation; D017052:Hospital Mortality; D006801:Humans; D006976:Hypertension, Pulmonary; D007239:Infections; D053208:Kaplan-Meier Estimate; D008297:Male; D009369:Neoplasms; D011183:Postoperative Complications; D011651:Pulmonary Artery; D012727:Sex Characteristics; D014019:Tissue Donors; D014652:Vascular Diseases",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "1303-10",
"pmc": null,
"pmid": "25159913",
"pubdate": "2014-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Gender mismatch between donor and recipient is a factor of morbidity but does not condition survival after cardiac transplantation.",
"title_normalized": "gender mismatch between donor and recipient is a factor of morbidity but does not condition survival after cardiac transplantation"
} | [
{
"companynumb": "PT-ROCHE-1771133",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Secondary cutaneous dissemination from an orbital diffuse large B cell lymphoma has not been described before. The authors report an unusual case of anaplastic variant of diffuse large B cell lymphoma which primarily presented in the orbit and during the course of disease had subcutaneous dissemination.",
"affiliations": "a Department of Obit , Oculoplasty and Ocular Oncology, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology , Anna Nagar, Madurai, Tamilnadu , India and.;a Department of Obit , Oculoplasty and Ocular Oncology, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology , Anna Nagar, Madurai, Tamilnadu , India and.;a Department of Obit , Oculoplasty and Ocular Oncology, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology , Anna Nagar, Madurai, Tamilnadu , India and.;a Department of Obit , Oculoplasty and Ocular Oncology, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology , Anna Nagar, Madurai, Tamilnadu , India and.;a Department of Obit , Oculoplasty and Ocular Oncology, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology , Anna Nagar, Madurai, Tamilnadu , India and.",
"authors": "Bains|Sukhdeep|S|;Vidhya|N|N|;Kim|Usha|U|;Shanti|R|R|;Devanand|J|J|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.3109/01676830.2015.1078364",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6830",
"issue": "34(6)",
"journal": "Orbit (Amsterdam, Netherlands)",
"keywords": "Diffuse large B cell lymphoma; orbital; secondary; subcutaneous",
"medline_ta": "Orbit",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009918:Orbital Neoplasms; D011239:Prednisolone; D012878:Skin Neoplasms; D014057:Tomography, X-Ray Computed; D014750:Vincristine",
"nlm_unique_id": "8301221",
"other_id": null,
"pages": "338-9",
"pmc": null,
"pmid": "26452055",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subcutaneous Dissemination from an Orbital Diffuse Large B Cell Lymphoma.",
"title_normalized": "subcutaneous dissemination from an orbital diffuse large b cell lymphoma"
} | [
{
"companynumb": "IN-WATSON-2016-11588",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nTo investigate the efficacy and toxicity of bortezomib in combination with dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma(MM).\n\n\nMETHODS\nSixteen patients(9 males, 7 females, mean age 57. 5 yrs) with refractory or relapsed MM were treated with bortezomib (1. 3 mg/m(2) ) by intravenous bolus twice a week for 2 weeks, or 3. 5 mg once a week in a 21-day cycle, followed by an intravenous injection of dexamethasone 30 - 40 mg. The patients had received one to four courses at least. Response to bortezomib was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT) before initiation of each bortezomib chemotherapy course. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3. 0.\n\n\nRESULTS\nThe median follow-up duration from the beginning of bortezomib treatment was 6 months. Clinical response was observed in 14 patients (87.5%), including near complete response in 6, partial response in 5, minimal response in 3 and no response in 2. The most common adverse events were gastrointestinal symptoms (nausea and vomiting in 12, constipation in 3, severe diarrhea in 3 patients), thrombocytopenia (8 patients) and fatigue(3 patients). The adverse events were subsided on routine supportive care.\n\n\nCONCLUSIONS\nBortezomib in combination with dexamethasone is an effective therapy with a high response rate and manageable toxicities for patients with relapsed or refractory myeloma.",
"affiliations": "Department of Hematology, Changzheng Hospital, the Second Military Medical University, Shanghai 200003, China.",
"authors": "Yuan|Zhen-gang|ZG|;Hou|Jian|J|;Zhou|Fan|F|;Fu|Wei-jun|WJ|;Chen|Yu-bao|YB|;Xi|Hao|H|;Yang|Sheng-ling|SL|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-2727",
"issue": "27(10)",
"journal": "Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi",
"keywords": null,
"medline_ta": "Zhonghua Xue Ye Xue Za Zhi",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012008:Recurrence",
"nlm_unique_id": "8212398",
"other_id": null,
"pages": "653-5",
"pmc": null,
"pmid": "17343194",
"pubdate": "2006-10",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma.",
"title_normalized": "bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma"
} | [
{
"companynumb": "CN-TAKEDA-2016MPI007750",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "Generally, it is very rare for clinically significant hypermagnesemia to develop in an individual with normal renal functions as the renal handling of serum magnesium is a very potent process and it has the capacity, under conditions of hypermagnesemia, to completely block Mg (magnesium) reabsorption from the thick ascending limb of Henle. Therefore, hypermagnesemia usually arises in the setting of renal failure.\nWe present a very rare case of a 40-year-old African American obese female with prior normal renal functions, who presented post-cardiac arrest following accidental overdose of Epsom salt. The patient was initially given supportive therapy and was later considered for the dialysis despite normal renal functions, as serum Mg levels kept on creeping up and clinical status kept on deteriorating continuously.\nSeemingly harmless magnesium containing (over-the-counter) (OTC) can potentially be lethal, and such consequences must always be taken into account when using such medications for a prolonged period of time.",
"affiliations": "Department of Cardiac MRI, Division of Cardiovascular Medicine, Allegheny General Hospital, Pittsburgh, USA.;Department of Internal Medicine, Allegheny General Hospital, Pittsburgh, USA.;Department of Internal Medicine, Marshfield Clinic, Marshfield, USA.",
"authors": "Shoaib Khan|Muhammad|M|;Zahid|Sohaib|S|;Ishaq|Muhammad|M|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.22088/cjim.9.4.413",
"fulltext": "\n==== Front\nCaspian J Intern MedCaspian J Intern MedCJIMCaspian Journal of Internal Medicine2008-61642008-6172Babol University of Medical Sciences Babol, Iran 10.22088/cjim.9.4.413Case ReportFatal Hypermagnesemia: an acute ingestion of Epsom Salt in a patient with normal renal function Shoaib Khan Muhammad MD1*Zahid Sohaib MD2Ishaq Muhammad MD3\n1 Department of Cardiac MRI, Division of Cardiovascular Medicine, Allegheny General Hospital, Pittsburgh, USA.\n2 Department of Internal Medicine, Allegheny General Hospital, Pittsburgh, USA.\n3 Department of Internal Medicine, Marshfield Clinic, Marshfield, USA.* Correspondence: Muhammad Shoaib Khan, Department of Cardiac MRI, Allegheny General Hospital , 320 E North Ave, Pittsburgh, PA 15212, USA. E-mail: fMShoaibKhanAimc@gmail.com, Tel: 001 4123598705, Fax: 001 4123596358Autumn 2018 9 4 413 415 25 12 2017 11 2 2018 1 5 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nGenerally, it is very rare for clinically significant hypermagnesemia to develop in an individual with normal renal functions as the renal handling of serum magnesium is a very potent process and it has the capacity, under conditions of hypermagnesemia, to completely block Mg (magnesium) reabsorption from the thick ascending limb of Henle. Therefore, hypermagnesemia usually arises in the setting of renal failure.\n\nCase presentation:\nWe present a very rare case of a 40-year-old African American obese female with prior normal renal functions, who presented post-cardiac arrest following accidental overdose of Epsom salt. The patient was initially given supportive therapy and was later considered for the dialysis despite normal renal functions, as serum Mg levels kept on creeping up and clinical status kept on deteriorating continuously.\n\nConclusions:\nSeemingly harmless magnesium containing (over-the-counter) (OTC) can potentially be lethal, and such consequences must always be taken into account when using such medications for a prolonged period of time\n\nKey Words\npsom saltMagnesiumHypermagnesemiaNormal Renal Functions\n==== Body\nThe active ingredient in Epsom salt is magnesium sulfate (MgSO4). Mg is the second most abundant intracellular cation and has essential physiological roles in the body (1). Mg has widespread therapeutic uses such as in the management of torsades de pointes, asthma exacerbation and eclampsia. However, life threatening consequences can occur if the serum Mg levels rise to toxic range. Its homeostasis is dependent on its gastrointestinal absorption and renal excretion (2). As its diffusion across the gut is mainly a passive process, therefore, kidneys play more important role in the regulation of serum magnesium by altering its reabsorption process and with normal renal functions clinically significant hypermagnesemia usually does not develop. Here we present a case of fatal hypermagnesemia following accidental overdose with Epsom salt in a patient with normal renal functions, which brings into attention the fact that a seemingly harmless magnesium containing OTC medication, can potentially be lethal.\n\nCase Presentation\nA 40-year-old obese African American female was brought in an unconscious state to the emergency department (ED) of Allegheny General Hospital, USA, in August 2017. Patient was received at her home in a cardiac arrest state by the emergency medical services (EMS) which prompted them to do CPR (cardiopulmonary resuscitation) on her. \n\nWith 35 minutes of CPR, spontaneous circulation was restored and then she was transferred to the hospital. On presentation, she was hypotensive, intubated, nonresponsive to noxious stimuli and had minimally reactive pupils. On further inquiry, it was found out that the patient had been ingesting Epsom salt for quite some time, apparently, to lose weight (and might have had over-ambitiously taken a large dose that day). Patient did not have any history of drug abuse or any findings suggestive of physical trauma. Differential diagnosis of acute coronary syndrome) (ACS), stroke and toxic ingestion of magnesium sulfate was contemplated. Initial blood work up revealed hypermagnesemia (9.7 mg/dL), lactic acidosis (AG metabolic acidosis), mild elevation of liver enzymes and negative urinary drug screen. 12 Lead ECG ruled out possibility of ACS, and a normal sinus rhythm with a prolonged QT (non-diagnostic for ischemia) was noted. The patient was then transferred to the ED of our hospital.\n\nHer glasgow coma scale (GCS)at the time of presentation was 3 and ECG revealed normal sinus rhythm with first degree atrioventricular (AV) block (PR interval=220 milliseconds), QRS interval of 120 milliseconds and nonspecific intraventricular block. Brain CT scan was unremarkable for any acute intracranial process and it effectively ruled out the possibility of stroke. Despite high blood magnesium level, nephrology and poison control team initially recommended only supportive therapy without any need for dialysis as serum creatinine (0.9 mg/dL) was normal. Her urinary output was consistently normal (between 1350-1600 milliliters per day) throughout. Later, the decision was taken to dialyze the patient despite normal renal functions (creatinine=1.1 mg/dL, BUN= 17 mg/dL) because of the severity of the signs and symptoms and continuous increase of serum magnesium level in the presence of ongoing supportive therapy. The patient was then transferred to the medical intensive care unit (MICU) and it turned out that dialysis effectively lowered the serum Mg level. However, she still remained encephalopathic. Neurological assessment demonstrated bilaterally reactive pupils and extensor posturing on painful stimuli. Brain magnetic resonance imaging (MRI)findings were consistent with hypoxic-ischemic injury, possibly because of prolonged cardiac arrest, and electroencephalography (EEG) recording was also suggestive of severe cortical injury with a minimal response to pain. Meaningful recovery of the brain functions was deemed unlikely based on the clinical status of the patient, the findings of MRI and that of EEG. The family was informed about the poor prognosis of the patient and the decision was made to provide comfort measures only. Unfortunately, patient expired on the 6th post-admission day. \n\nDiscussion\nTo the best of our knowledge, only a handful of hypermagnesemia related fatal cases resulting from overdose of Epsom salt have been reported before (3, 4, 5), especially in someone with intact renal functions. Epsom salt has traditionally been considered and used for reasons including but not limited to cosmetic and therapeutic. \n\nThe active ingredient in Epsom salt is MgSO4 . Mg is the second most abundant intracellular cation and the fourth most abundant cation in the body, which plays key roles in many functions of the body (1). Mg is an important cofactor for numerous enzymes and is crucial for the synthesis of nucleic acids and proteins. Mg homeostasis relies mainly on gastrointestinal absorption and renal excretion, and the kidney is the major organ involved in Mg regulation (2). \n\nNormally, the thick ascending limb of Henle’s loop has the capacity to completely block Mg reabsorption under conditions of hypermagnesemia which makes renal Mg excretion very efficient (6). Therefore, hypermagnesemia usually arises in the setting of renal failure (2). When it comes to gastrointestinal regulation of magnesium homeostasis, it is important to note that the upper small gut is the major gastrointestinal site for Mg absorption and passive diffusion is the principle regulatory mechanism (7). For that reason, massive oral Mg ingestion may result in hypermagnesemia if the absorbed amount of Mg goes beyond the renal excretory capacity (2), as it seems to be the reason in our patient.\n\nMagnesium has long been used as a therapeutic agent for a variety of conditions and its use as a cathartic agent was its earliest therapeutic application and is being used for this purpose till date (1). It is also considered in severe asthma exacerbation where nebulized MgSO4 is considered as an addition to that with inhaled ß2-agonists (8). Its use as intravenous magnesium sulphate is recommended as the first line of therapy for torsades de pointes (9). It is also used as a prophylactic agent against the development of eclampsia in patients with severe pre-eclampsia and to prevent seizures in eclampsia patients. Nonetheless, increased serum level of magnesium can have serious consequences. Mild hypermagnesemia usually produces nonspecific signs and symptoms and may include nausea, vomiting, flushing, warmth, hypotension and lightheadedness. Magnesium concentrations of 6-12 mg/dL result in characteristic EKG changes, including prolongation of the PR interval, increased duration of QRS complex, prolonged QT interval and delayed intraventricular conduction block (10). Serum levels greater than 12 mg/dL may result in absent deep tendon reflexes, respiratory depression, paralysis, complete heart block, and at levels greater than 20 mg/dL cardiac arrest in asystole may ensue (2). Supportive therapy is the mainstay of the management of hypermagnesemia, involving respiratory support, diuresis, calcium infusion and dialysis. Calcium antagonizes the toxic effects of magnesium in addition to making up for the concomitant hypocalcemia in magnesium toxicity and, therefore, patients with severe magnesium intoxication should be given calcium gluconate. Administration of glucose and insulin also helps to promote magnesium entry into cells. Dialysis may be necessary for hypermagnesemic patients with renal dysfunction or for patients with normal renal function who have a massive overdose (11) and/or have severe signs and symptoms, as in our patient, where the decision to dialyze her was taken in the mileu of rising serum magnesium level and grave clinical status despite normal renal functions. Serum magnesium levels should be closely monitored even in patients with normal renal functions till they come back to the baseline and the precipitating factor is removed. Otherwise, higher magnesium levels may rapidly prove lethal should any complication related to the vital organs arise, as happened with this patient, where prolonged cardiac arrest resulted in irreversible diffuse injury to the brain and eventually patient died despite restoring the serum magnesium levels back to the baseline.\n\nIn conclusion fatal hypermagnesemia may ensue following acute (or chronic) overdose with Epsom salt even in people with normal renal functions. This brings into attention (yet another time) the fact that a seemingly harmless magnesium containing OTC, such as a laxative or antacid can potentially be lethal and, therefore, such consequences must not be disregarded while prescribing or using such medications for a prolonged period of time. Supportive therapy remains the mainstay of treatment of hypermagnesemia and there is no need to do urgent dialysis if the renal functions are normal, and it only needs to be considered in the setting of renal failure or deteriorating clinical status of the patient.\n\nAcknowledgments\nWe wish to thank Syed Ziad Ali (MBBS) for editing the article.\n\nConflict of Interest:\nThere was no conflict of interest.\n==== Refs\nReferences\n1 Swaminathan R Magnesium metabolism and its disorders Clin Biochem Rev 2003 24 47 66 18568054 \n2 Kontani M Hara A Ohta S Ikeda T Hypermagnesemia induced by massive cathartic ingestion in an elderly woman without pre-existing renal dysfunction Intern Med 2005 44 448 52 15942092 \n3 Tofil NM Bennerand KW Winkler MK Fatal hypermagnesemia caused by an Epsom salt enema: a case illustration South Med J 2005 98 253 6 15759964 \n4 Birrer RB Shallash AJ Totten V Hypermagnesemia-induced fatality following epsom salt gargles J Emerg Med 2002 22 185 8 11858925 \n5 Vissers RJ Purssell R Iatrogenic magnesium overdose: two case reports J Emerg Med 1996 14 187 91 8740750 \n6 Jeffrey R Schelling Fatal hypermagnesemia. Clin Nephrol 2000 53 61 5 10661484 \n7 Weisinger JR Bellorín-Font E Magnesium and Phosphorus Lancet 1998 352 391 6 9717944 \n8 Blitz M Blitz S Hughes R Aerosolized magnesium sulfate for acute asthma: a systematic review Chest 2005 128 337 44 16002955 \n9 Tzivoni D Banai S Schuger C Treatment of torsade de pointes with magnesium sulfate Circulation 1988 77 392 7 3338130 \n10 Jhang WK Lee YJ Kim YA Park SJ Park YS Severe hypermagnesemia presenting with abnormal electrocardiographic findings similar to those of hyperkalemia in a child undergoing peritoneal dialysis Korean J Pediatr 2013 56 308 11 23908672 \n11 Onishi S Yoshino S Cathartic-induced fatal hypermagnesemia in the elderly Intern Med 2006 45 207 10 16543690\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2008-6164",
"issue": "9(4)",
"journal": "Caspian journal of internal medicine",
"keywords": "Hypermagnesemia; Magnesium; Normal Renal Functions; psom salt",
"medline_ta": "Caspian J Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101523876",
"other_id": null,
"pages": "413-415",
"pmc": null,
"pmid": "30510660",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "10661484;3338130;23908672;15942092;8740750;16002955;9717944;11858925;18568054;16543690;15759964",
"title": "Fatal Hypermagnesemia: an acute ingestion of Epsom Salt in a patient with normal renal function.",
"title_normalized": "fatal hypermagnesemia an acute ingestion of epsom salt in a patient with normal renal function"
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"abstract": "BACKGROUND\nActivated PI3K/AKT/mTOR pathway frequently occurs in metastatic or recurrent cervical carcinomas. However, the clinical benefits of matched therapy, a therapeutic approach targeting a specific mutational abnormality, have not yet been established.\n\n\nMETHODS\nWe analyzed the outcomes of patients with metastatic or recurrent cervical carcinomas who had a test for PIK3CA mutation and/or PTEN loss/mutation, and received ≥1 phase I therapeutic regimen between January 2006 and June 2013.\n\n\nRESULTS\nPatients with adenocarcinoma had fewer PIK3CA mutations (14%), and survived longer (median, 14.2 months) than those with squamous cell carcinoma (48% and 7.2 months; p = 0.016, and 0.001, respectively). Matched therapy targeting the activated PI3K/AKT/mTOR pathway led to a favorable rate of SD ≥ 6 months/CR/PR (53%) and significantly longer progression-free survival (median, 6.0 months) than non-matched therapy (11% and 1.5 months; p = 0.08 and 0.026; respectively). In patients with squamous cell carcinoma of the cervix, the presence of PIK3CA mutations was associated with a significantly longer overall survival (median, 9.4 months) than the absence of PIK3CA mutations (median, 4.2 months; p = 0.019).\n\n\nCONCLUSIONS\nMatched therapy targeting the activated PI3K/AKT/mTOR pathway provided meaningful clinical benefits. Thus, further evaluation of PI3K/AKT/mTOR pathway targeted therapy is warranted, especially in metastatic or recurrent squamous cell carcinoma.",
"affiliations": "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;UC San Diego Moores Cancer Center, La Jolla, California.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Hou|Ming-Mo|MM|;Liu|Xiaochun|X|;Wheler|Jennifer|J|;Naing|Aung|A|;Hong|David|D|;Coleman|Robert L|RL|;Tsimberidou|Apostolia|A|;Janku|Filip|F|;Zinner|Ralph|R|;Lu|Karen|K|;Kurzrock|Razelle|R|;Fu|Siqing|S|",
"chemical_list": "D000081082:Phosphoinositide-3 Kinase Inhibitors; C546842:MTOR protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human",
"country": "United States",
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"doi": "10.18632/oncotarget.2584",
"fulltext": "\n==== Front\nOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 25426553Clinical Research PaperTargeted PI3K/AKT/mTOR therapy for metastatic carcinomas of the cervix: A phase I clinical experience Hou Ming-Mo 14Liu Xiaochun 1Wheler Jennifer 1Naing Aung 1Hong David 1Coleman Robert L. 2Tsimberidou Apostolia 1Janku Filip 1Zinner Ralph 1Lu Karen 2Kurzrock Razelle 3Fu Siqing 11 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas2 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas3 UC San Diego Moores Cancer Center, La Jolla, California4 Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, TaiwanCorrespondence to: Siqing Fu, siqingfu@mdanderson.org11 2014 29 10 2014 5 22 11168 11179 21 7 2014 9 10 2014 Copyright: © 2014 Hou et al.2014This 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 creditedBackground\nActivated PI3K/AKT/mTOR pathway frequently occurs in metastatic or recurrent cervical carcinomas. However, the clinical benefits of matched therapy, a therapeutic approach targeting a specific mutational abnormality, have not yet been established.\n\nMethods\nWe analyzed the outcomes of patients with metastatic or recurrent cervical carcinomas who had a test for PIK3CA mutation and/or PTEN loss/mutation, and received ≥1 phase I therapeutic regimen between January 2006 and June 2013.\n\nResults\nPatients with adenocarcinoma had fewer PIK3CA mutations (14%), and survived longer (median, 14.2 months) than those with squamous cell carcinoma (48% and 7.2 months; p = 0.016, and 0.001, respectively). Matched therapy targeting the activated PI3K/AKT/mTOR pathway led to a favorable rate of SD ≥ 6 months/CR/PR (53%) and significantly longer progression-free survival (median, 6.0 months) than non-matched therapy (11% and 1.5 months; p = 0.08 and 0.026; respectively). In patients with squamous cell carcinoma of the cervix, the presence of PIK3CA mutations was associated with a significantly longer overall survival (median, 9.4 months) than the absence of PIK3CA mutations (median, 4.2 months; p = 0.019).\n\nConclusions\nMatched therapy targeting the activated PI3K/AKT/mTOR pathway provided meaningful clinical benefits. Thus, further evaluation of PI3K/AKT/mTOR pathway targeted therapy is warranted, especially in metastatic or recurrent squamous cell carcinoma.\n\nCervical CancerPhase I TrialMatched TherapyPIK3CA mutationPTEN loss\n==== Body\nINTRODUCTION\nCancer of the uterine cervix is one of the most common gynecologic malignancies and causes of death worldwide [1]. In the United States, more than 12,000 women were diagnosed with cervical cancer in 2013, and more than 4,000 patients died from this disease [2]. Squamous cell carcinoma and adenocarcinoma account for about 95% of all cervical cancers [3]. Most patients who are diagnosed with early-stage disease have a high rate of long-term survival after they have undergone curative surgical resection and/or chemoradiotherapy [4, 5]. Patients with recurrent or metastatic cervical cancers who are not amenable to radical local excision or curative chemoradiotherapy, have a poor prognosis [6, 7]. Palliative systemic therapies such as platinum-based doublets plus an anti-angiogenic agent as the standard of care for first-line treatment yield modest survival gains of 3.7 months [8–10]. Subsequent conventional chemotherapeutic regimens result in increased toxicity with limited clinical benefit [11]. The overall poor prognosis of these patients warrants the urgency for the development of novel therapeutic regimens [12, 13].\n\nThere are three classes of phosphoinositide 3-kinase (PI3K) isoforms [14]. Class I PI3Ks are heterodimeric lipid kinases composed of the p110 catalytic subunit and the p85 regulatory subunit. Three major p110 isoforms have been described: p110α (PIK3CA), p110β (PIK3CB), and p110δ (PIK3CD) [15, 16]. PI3K and PTEN counterpoise each other on conversion between phosphatidyl-inositol-4-5-bisphosphate (PIP2) and phosphatidyl-inositol-3, 4, 5-trisphosphate (PIP3) [17, 18]. Upon activation through either PIK3CA mutation or PTEN loss/mutation, PI3K phosphorylates PIP2 to PIP3, which facilitates recruitment and activation of AKT to initiate a cascade of downstream signaling events including the mTOR complex, a major downstream pathway [16]. Therefore, a regimen including a PI3K inhibitor and/or an mTOR inhibitor can be utilized to target PIK3CA mutation and/or PTEN loss/mutation-mediated activated PI3K/AKT/mTOR pathway [19]. This strategy is defined as matched therapy: a therapeutic regimen including an agent (either as a single agent or as a part of a combination regimen) that is known to directly inhibit a specific mutation, and/or to inhibit its key downstream pathways, such as treatment with a PI3K inhibitor, an mTOR inhibitor, or these agent-based regimens for a cancer patient carrying a PIK3CA mutation and/or PTEN loss/mutation [20].\n\nOur previous study and others have documented that the activated PI3K/AKT/mTOR pathway is frequently identified in patients with metastatic or recurrent cervical cancers [21–25]. We hypothesized that cervix cancer patients with aberrations in this pathway would achieve clinical benefit (defined as objective response and prolonged stable disease) when treated with PI3K/AKT/mTOR pathway targeted agents. In this article, we further our previous study by limiting patients who only have either squamous cell carcinoma or adenocarcinoma of the cervix in order to reach definitive conclusions, which will be applied to facilitate future drug development by choosing appropriate therapeutic regimens for appropriate cancer patients. Herein we document a clear observation of antitumor responses with acceptable toxicity from PI3K/AKT/mTOR matched therapy, representing an important new therapeutic strategy for a patient population possessing limited treatment options.\n\nPATIENTS AND METHODS\nPatient selection\nConsecutive patients with metastatic or recurrent cervical carcinoma (either squamous cell carcinoma or adenocarcinoma) who were referred to the Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program) at MD Anderson between January 1, 2006, and June 30, 2013, had a test for PIK3CA mutation and/or PTEN loss/mutation in a Clinical Laboratory Improvement Amendments-certified molecular diagnostic laboratory, and received treatment in at least one phase I clinical trial, were evaluated. Follow-up was defined as the time of the initial office visit after the patient was referred to the phase I clinic until death or February 28, 2014. This study was conducted in accordance with MD Anderson's Institutional Review Board guidelines.\n\nData collection\nTwo individuals independently reviewed patients' electronic medical records at MD Anderson and crosschecked the collected data. Clinical information that was collected included race, prior treatment history (e.g., surgery, radiation therapy, and chemotherapy), date of birth, Eastern Cooperative Oncology Group performance status at the initial phase I clinic visit, mutation profiling of the tumor specimen including PIK3CA mutation and/or PTEN loss/mutation status, phase I clinical trial therapies, and clinical outcomes: severe adverse event (SAEs), progression-free survival (PFS), overall survival (OS), and objective responses including complete remission (CR), partial response (PR), and stable disease for 6 months or longer (SD ≥ 6months).\n\nSAEs were defined as toxic effects that were grade 3 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 or v4.0 (http://ctep.cancer.gov/reporting/ctc.html) [26]. Clinical objective responses were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.0 or 1.1 per individual study protocols [27, 28]. PFS was defined as the interval from the date of initial treatment to the first objective documentation of disease progression, the time of death if it occurred, or the last date of contact on February 28, 2014, at which time the patients' data were censored. OS was estimated from the date of the initial phase I clinical trial therapy to death or the last date of contact on February 28, 2014, at which time the patients' data were censored.\n\nEnrollment of an eligible patient into a specific phase I trial depended on the availability of the phase I trial at the time of presentation and the preference of the treating physician according to good clinical practice. If a phase I trial was unsuccessful, another available phase I trial was introduced as long as a patient was eligible and willing to participate.\n\nStatistical analyses\nCategorical data were described using contingency tables. Continuously scaled measures were summarized with descriptive statistical measures (i.e., the median with the range), whereas PFS and OS rates were estimated using the Kaplan-Meier method. Patients who were still alive at the time of data analysis were censored at that time. Fisher's exact test was used to assess the associations between categorical variables and mutation status. Statistical inferences were based on two-sided tests at a significance level of p < 0.05. Statistical analyses were carried out using SPSS Statistics version 22 (IBM Inc., Armonk, NY).\n\nRESULTS\nStudy population\nFifty-five consecutive patients with metastatic or recurrent adenocarcinoma (n = 24) or squamous cell carcinoma (n = 31) who had a test for PIK3CA mutation and/or PTEN loss/mutation and underwent treatment in at least one phase I clinical trial in the Phase I Clinical Trials Program were included in this study. Patient characteristics and molecular profiling are listed in Table 1. All patients had received at least one prior systemic chemotherapeutic regimen for metastatic or recurrent disease (median 2 regimens, range 1 to 4) and underwent molecular marker studies in a Clinical Laboratory Improvement Amendments-certified molecular diagnostic laboratory.\n\nTable 1 Patient characteristics and molecular profiles\nPatient characteristics\tAdenocarcinoma\tSquamous cell carcinoma\tTotal patients\t\n\t(n = 24)\t(n = 31)\t(n = 55)\t\nAge, years\t\n Median (range)\t51 (27–67)\t42 (25–69)\t46 (25–69)\t\nRace\t\n White\t17\t19\t36\t\n African American\t2\t5\t7\t\n Hispanic\t3\t6\t9\t\n Others\t2\t1\t3\t\nPrior therapies\t\n Surgery\t15\t12\t27\t\n Radiotherapy\t23\t28\t51\t\n Chemotherapy\t24\t31\t55\t\n Antiangiogenic\t3\t6\t9\t\n Median regimen\t2\t2\t2\t\n (range)\t(1–4)\t(1–4)\t(1–4)\t\nEastern cooperative oncology group performance status\t\n0\t8\t7\t15\t\n1\t14\t17\t31\t\n2\t2\t7\t9\t\nMolecular profiles\tAberrant/tested (%)\t\nPIK3CA\t3/22 (14)\t14/29 (48)\t17/51 (33)\t\nPTEN\t4/16 (25)\t3/24 (13)\t7/40 (18)\t\nTP53\t3/7 (43)\t1/12 (8)\t4/19 (21)\t\nHER2\t1/9 (11)\t1/14 (7)\t2/23 (9)\t\nCKIT\t0/11 (0)\t2/18 (11)\t2/29 (7)\t\nCMET\t0/11 (0)\t2/18 (11)\t2/29 (7)\t\nKRAS\t3/19 (16)\t0/26 (0)\t3/45 (7)\t\nALK1\t0/7 (0)\t1/13 (8)\t1/20 (5)\t\nEGFR\t1/16 (6)\t0/22 (0)\t1/38 (3)\t\nBRAF\t0/18 (0)\t0/25 (0)\t0/43 (0)\t\nNRAS\t0/13 (0)\t0/18 (0)\t0/31 (0)\t\nAKT1\t0/8 (0)\t0/14 (0)\t0/22 (0)\t\nTwenty-two patients were found to harbor PIK3CA mutations and/or PTEN loss: 17 (33%) of 51 tested patients with PIK3CA aberrations (E545K = 8, E542K = 4, H1047L = 1, H1047R = 1, E545K and D549H = 1, E542K and M1043I = 1, amplification = 1); 7 (18%) of 40 tested patients with PTEN loss (n = 6) and/or mutation (R173C = 1); and 2 patients have both of PIK3CA mutation (E545K) and PTEN loss. Further analyses revealed that patients with squamous cell carcinomas were significantly younger and more likely to carry PIK3CA mutations than those with adenocarcinomas (p = 0.034 per independent samples t-test for age and p = 0.016 per Fisher's exact test for PIK3CA mutations, respectively). Approximately 20% (n = 11/55) and 36% (n = 4/11) of the referred patients received subsequent second- and third-line phase I trial therapies.\n\nSevere adverse events\nAll patients were included for analyses of SAEs; a total of 450 cycles of therapy were administered according to 38 phase I clinical trials [21]. During their first phase I trial therapy, approximately 20% of patients (n = 11/55) experienced 19 episodes of SAEs: neutropenia and thrombocytopenia (n = 5 each, 9%); hyponatremia (n = 2, 4%); and hypokalemia, hypomagnesaemia, hypophosphatemia, mucositis, fatigue, bowel perforation, and bacterial infection (n = 1 each, 2%). During the second phase I trial therapy, only 1 (9%) of 11 patients had an SAE (fatigue). Subsequently, no patient experienced an SAE before all 4 patients progressed within the initial 8 weeks of their phase I trial therapy. In patients who received PI3K/AKT/mTOR pathway targeted therapeutic regimens, no apparent difference was observed between patients with PI3KCA mutation and/or PTEN loss/mutation and those without.\n\nAntitumor activity\nThe waterfall plot shown in Figure 1 demonstrates the best tumor response to their first-line phase I clinical trial therapy. Of 55 patients who received their first-line phase I trial therapy (see Tables 2 and 3), 35% achieved SD ≥ 6 months/CR/PR (CR = 2, PR = 8, and SD ≥ 6 months = 9), and the median PFS in this group was 3.6 months (95% confidence interval [CI], 2.3–5; Figure 2A). Of 15 patients with PIK3CA mutations and/or PTEN loss/mutations who received matched therapy, 53% achieved SD ≥ 6 months/CR/PR (CR = 1, PR = 5 and SD ≥ 6 months = 2), and the median PFS in this group was 6.0 months (95% CI, 3.2–8.8). These results compared favorably with nine patients who did not receive matched therapy targeting activated PI3K/AKT/mTOR pathway: 11.1% achieved PR (PR = 1; p = 0.08), and the median PFS in this group was 1.5 months (95% CI, 1.2–1.8; p = 0.026; Figure 3A); as well as with seven patients without PIK3CA mutation and PTEN loss/mutations who received therapies targeting activated PI3K/AKT/mTOR pathway: 14% achieved PR (PR = 1, p = 0.16) and the median PFS in this group was 1.5 months (95% CI, 0.4 – 10.6; p = 0.06).\n\nFigure 1 The waterfall plot shows the best tumor response to their initial phase I clinical trial therapy (n = 55)\nTable 2 Clinical outcomes in patients with advanced squamous cell carcinoma of the cervix\nAge\tPIK3CA mutation\tPTEN loss or mutation\tBest tumor response\tPFS (months)\tOS (months)\tMatched therapy\tTreatment\t\n35\tE542K\tND\t−44%\t9.7\t10.1\tY\tBevacizumab and Temsirolimus plus Doxil\t\n37\tE542K\tN\t−37%\t10.3\t10.3\tY\tA PI3K Inhibitor\t\n37\tE542K\tN\t−2%\t4.2\t6.4\tY\tEverolimus and Pazopanib\t\n42\tE542K\tN\t21%\t0.9\t2.5\tN\tErlotinib and Praletrexate\t\n59\tE542K / M1043I\tN\t50%\t1.7\t7.8\tN\tErlotinib and Praletrexate\t\n35\tE545K\tY\t0%\t4.4\t10.8\tY\tBevacizumab and Temsirolimus plus Doxil\t\n56\tE545K\tP\t8%\t6.4\t13.6\tY\tSirolimus and Docetaxol\t\n48\tE545K\tND\t−68%\t32.6\t40.3\tY\tBevacizumab and Temsirolimus\t\n40\tE545K\tND\t7%\t1.2\t4.1\tY\tBevacizumab and Temsirolimus plus Doxil\t\n38\tE545K\tN\t−1%\t6.7\t7.0\tY\tBevacizumab and Temsirolimus plus Doxil\t\n46\tE545K\tN\t10%\t5.4\t9.3\tN\tLenalidomide and Bevacizumab\t\n48\tE545K\tN\t10%\t3.5\t9.4\tN\tHAI Abraxane and IV Gemcitabine plus Bevacizumab\t\n62\tE545K / D549H\tND\t21%\t0.7\t2.1\tY\tBevacizumab and Temsirolimus plus Doxil\t\n61\tH1047R\tN\t21%\t1.3\t1.3\tY\tA PI3K Inhibitor\t\n28\tN\tY\t−42%\t6.0\t6.0\tY\tBevacizumab and Temsirolimus plus Doxil\t\n49\tN\tY\t−15%\t2.6\t3.5\tN\tBendamustine and Bevacizumab\t\n62\tN\tP\t21%\t2.4\t2.5\tN\tHAI Abraxane\t\n36\tN\tP\t82%\t1.5\t7.7\tN\tBevacizumab and Temsirolimus plus Doxil\t\n39\tN\tP\t21%\t1.1\t1.3\tN\tA MEK Inhibitor and Docetaxol\t\n41\tN\tP\t21%\t0.4\t1.1\tN\tBevacizumab and Temsirolimus plus Carboplatin\t\n34\tN\tND\t−43%\t6.8\t9.1\tN\tBevacizumab and Temsirolimus\t\n25\tN\tND\t14%\t4.2\t7.7\t?\tA PI3K Inhibitor and Carboplatin plus Paclitaxel\t\n37\tN\tND\t−27%\t1.4\t10.9\t?\tBevacizumab and Temsirolimus plus Doxil\t\n43\tN\tN\t10%\t7.9\t12.4\tN\tErlotinib and Praletrexate\t\n58\tN\tN\t16%\t4.1\t4.6\tN\tErlotinib and Praletrexate\t\n29\tN\tN\t21%\t2.7\t4.2\tN\tBendamustine and Bevacizumab\t\n69\tN\tN\t21%\t1.2\t1.7\tN\tErlotinib and Praletrexate\t\n45\tN\tN\t21%\t0.9\t1.8\tN\tHAI Oxaliplatin and PO Capecitabine\t\n63\tN\tN\t21%\t0.5\t0.7\tN\tEverolimus and Denosumab\t\n48\tND\tP\t−21%\t6.9\t12.4\t?\tBevacizumab and Temsirolimus plus Doxil\t\n37\tND\tN\t26%\t2.3\t7.2\tN\tTrientine and Carboplatin\t\nI, insufficient; N, no; ND, not done; OS, overall survival; P, partial loss; PFS, progression-free survival; Y, yes; +, censored; and ?, unknown.\n\nTable 3 Clinical outcomes in patients with advanced adenocarcinoma of the cervix\nAge\tPIK3CA mutation\tPTEN loss or mutation\tBest tumor response\tPFS (months)\tOS (months)\tMatched therapy\tTreatment\t\n55\tAmplification\tP\t−100%\t29.3 +\t29.3 +\tY\tEverolimus and Anastrozole\t\n61\tE545K\tY\t−52%\t18.7\t19.4\tY\tBevacizumab and Temsirolimus\t\n51\tH1047L\tN\t21%\t1.7\t4.3\tY\tSirolimus and Metformin\t\n63\tN\tY\t−24%\t1.7\t7.9\tY\tBevacizumab and Temsirolimus plus Doxil\t\n41\tN\tY\t−11%\t28.5 +\t28.5 +\tN\tAn Aurora Kinase Inhibitor\t\n50\tN\tR173C\t−6%\t7.7\t11.3\tN\tPazopanib and Pemetrexate\t\n44\tN\tP\t−21%\t9.8\t15.7\tN\tA MEK Inhibitor and Docetaxol\t\n62\tN\tP\t20%\t2.1\t19.7\tN\tA Proteasome Inhibitor\t\n43\tN\tP\t−13%\t40.4 +\t40.4 +\tN\tA c-Met Inhibitor\t\n51\tN\tND\t−21%\t6.0\t6.4\t?\tBevacizumab and Temsirolimus\t\n58\tN\tND\t0%\t5.7\t7.9\t?\tBevacizumab and Temsirolimus plus Doxil\t\n27\tN\tND\t−29%\t3.7\t21.7\t?\tBevacizumab and Cetuximab plus Erlotinib\t\n46\tN\tND\t−16%\t2.9\t3.5\t?\tBevacizumab and Temsirolimus plus Doxil\t\n58\tN\tND\t430%\t2.5\t20.8\t?\tTemsirolimus and Topotecan plus Bortezomib\t\n63\tN\tND\t21%\t2.1\t2.4\tN\tAzacitidine and Oxaliplatin\t\n44\tN\tN\t−100%\t18.9\t28.7 +\tN\tAn Aurora Kinase Inhibitor and Docetaxol\t\n37\tN\tN\t−64%\t10.6\t35.6\tN\tA PI3K Inhibitor and Carboplatin plus Paclitaxel\t\n59\tN\tN\t0%\t3.7\t5 +\tN\tBevacizumab and VEGF Inhibition\t\n57\tN\tN\t−23%\t3.2\t14.2\tN\tBevacizumab and Temsirolimus\t\n49\tN\tN\t−5%\t2.9\t4.6\tN\tAn Aurora Kinase Inhibitor\t\n41\tN\tN\t23%\t2.8\t8.2\tN\tBevacizumab and Temsirolimus plus Paclitaxel\t\n60\tN\tN\t21%\t0.7\t2.1\tN\tBevacizumab and Temsirolimus plus Sorafenib\t\n67\tND\tI\t21%\t3.6\t10.7 +\t?\tEverolimus and Anastrozole\t\n40\tND\tI\t21%\t1.1\t13.3\t?\tBevacizumab and Temsirolimus plus Doxil\t\nI, insufficient; N, no; ND, not done; OS, overall survival; P, partial loss; PFS, progression-free survival; Y, yes; +, censored; and ?, unknown.\n\nFigure 2 Kaplan-Meier plots for survivals\nIn Figure 2A, a median OS of 9.1 months (95% CI, 7.1–11.1, in green) and a median PFS of 3.6 months (95% CI, 2.3–5.0, in blue) were observed in patients with metastatic or recurrent cervical carcinomas (n = 55). In Figure 2B, patients with adenocarcinoma (in green) showed a median OS of 14.2 months (n = 24; 95% CI, 7.8–20.6), significantly longer those with squamous cell carcinoma (in blue), 7.2 months (n = 31; 95% CI, 5.3–9.1; p = 0.001).\n\nFigure 3 Kaplan-Meier plots for survivals\nIn Figure 3A, match therapy (in green) was associated with a median PFS of 6.0 months (n = 15; 95% CI, 3.2–8.8), significantly greater than non-matched therapy (in blue) with 1.5 months (n = 9; 95% CI, 1.2–1.8; p = 0.026). In Figure 3B, matched therapy (in green) was associated with a median OS of 10.1 months (n = 15; 95% CI, 5.9–14.3), compared to non-matched therapy (in blue) with 7.7 months (n = 9; 95% CI, 1.6–13.8; p = 0.427).\n\nOf 11 patients who received their second phase I clinical trial therapy, 27% achieved SD ≥ 6 months/CR/PR (PR = 1 and SD ≥ 6 months = 2), and the median PFS in this group was 4.2 months (95% CI, 3.0–5.4). Of 4 patients who received their third phase I clinical trial therapy, no patient achieved SD ≥ 6 months/CR/PR.\n\nOverall survivals\nAll patients were included in survival analyses. The median OS was 9.1 months (95% CI, 7.1–11.1 months; Figure 2A). Patients with metastatic or recurrent adenocarcinomas had a significantly greater median OS of 14.2 months (95% CI, 7.8–20.6) than those with squamous cell carcinomas (OS = 7.2 months; 95% CI, 5.3–9.1; p = 0.001), as shown in Figure 2B. Patients with PIK3CA mutation and/or PTEN loss/mutation who received matched therapy, achieved a median OS of 10.1 months (95% CI, 5.9–14.3), compared with those who did not (7.7 months; 95% CI, 1.6–13.8; p = 0.43; Figure 3B). Furthermore, patients with metastatic or recurrent squamous cell carcinomas who carried PIK3CA mutations (n = 14) achieved a median OS of 9.4 months (95% CI, 8.1–10.7), significantly longer than the median OS of those who did not carry PIK3CA mutations (n = 15; 4.2 months, 95% CI, 2.2–6.2; p = 0.019), as shown in Figure 4A. Patients with metastatic or recurrent adenocarcinomas who carried PIK3CA mutations (n = 3) achieved a median OS of 19.4 months (95% CI, 0 – 43.6), similar to those who did not carry PIK3CA mutations (n = 19; 14.2 months, 95% CI, 4.0–24.4; p = 0.75), as shown in Figure 4B. Patients with metastatic or recurrent PTEN-loss/mutation squamous cell carcinomas (n = 3) and adenocarcinomas (n = 4) achieved a median OS of 6 months (95% CI, 2–10) and 11.3 months (95% CI, 0–22.6), respectively, similar to the median OS of those with metastatic or recurrent PTEN-intact squamous cell carcinoma (n = 21; 7 months, 95% CI, 3.1–10.9; p = 0.76) and adenocarcinoma (n = 16; 15.7 months, 95% CI, 7.1–24.3; p = 0.79), respectively (see Figure 5A and 5B).\n\nFigure 4 Kaplan-Meier plots for survivals\nIn Figure 4A for in patients with squamous cell carcinoma, PI3KCA mutations (in green) were associated with a median OS of 9.4 months (n = 14; 95% CI, 8.1–10.7), significantly longer than wild-type PI3KCA (in blue) with 4.2 months (n = 15; 95% CI, 2.2–6.2; p = 0.019). In Figure 4B for patients with adenocarcinoma, PI3KCA mutations (in green) were associated with a median OS of 19.4 months (n = 3; 95% CI, 0–43.6), compared to wild-type PI3KCA (in blue) with 14.2 months (n = 19; 95% CI, 4–24.4; p = 0.754).\n\nFigure 5 Kaplan-Meier plots for survivals\nIn Figure 5A for in patients with squamous cell carcinoma, PTEN aberrations (in green) were associated with a median OS of 6 months (n=3; 95% CI, 2–10), similar to PTEN intact (in blue) with 7 months (n = 21; 95% CI, 3.1–10.9; p = 0.762). In Figure 5B for patients with adenocarcinoma, PTEN aberrations (in green) were associated with a median OS of 11.3 months (n = 4; 95% CI, 0–22.6), similar to PTEN intact (in blue) with 15.7 months (n = 16; 95% CI, 7.1–24.3; p = 0.791).\n\nDISCUSSION\nIn this study, we identified that patients with previously treated, locally advanced or metastatic cervical cancer harboring mutations in the PI3K/AKT/mTOR pathway achieved meaningful clinical benefit from a number of novel therapeutics administered in a phase I cancer center. Of particular interest were the objective responses, prolonged stable disease and PFS among these patients treated with PI3K/AKT/mTOR pathway targeted agents matching the somatic aberrations in this pathway. We conclude from these observations that targeted therapy among these patients with pathway potentiation is a viable strategy for further development.\n\nPatients with metastatic or recurrent carcinoma of the cervix have limited therapeutic treatment options, particularly those in whom combination chemotherapy (without or with anti-angiogenesis agents) have been administered [11, 29, 30]. The Gynecologic Oncology Group (now NRG Oncology) developed phase II queues to explore chemotherapeutic (GOG 127 series, GOG 128 series) and biological agents (GOG 227 series) in this setting. Reflecting the poor anticipated outcomes in these patient cohorts, the statistical decision rules were powered to evaluate “inactive” therapy at ≤ 15% for chemotherapy and ≤ 10% response and/or ≤ 10% non-progression at 6 months, respectively. This provides context upon which to examine the findings in this study.\n\nSeveral observations are of note. In general, patients with metastatic or recurrent squamous cell carcinoma of the cervix were significantly younger, and had a higher prevalence of PIK3CA mutations. However, they displayed lower antitumor activity to currently available phase I clinical trials at MD Anderson associated with significantly shorter OS than patients with metastatic or recurrent adenocarcinoma of the cervix. Second, matched therapy targeting the activated PI3K/AKT/mTOR pathway in patients with metastatic or recurrent squamous cell carcinoma of the cervix led to a favorably higher rate of SD ≥ 6 months/CR/PR as well as significantly longer PFS and OS than non-matched therapy. However, in patients with metastatic or recurrent adenocarcinoma of the cervix, there was no significant difference in OS associated with matched therapy in spite of a higher rate of SD ≥ 6 months/CR/PR and significantly longer PFS, which might be owing to at least three potential factors: lower prevalence of the activated PI3K/AKT/mTOR pathway, intrinsic sensitivity to novel phase I trial therapy available at MD Anderson phase I service, and the presence of PIK3CA mutation and/or PTEN loss/mutation that cannot stratify for aggressiveness of disease. Third, PIK3CA mutation, but not PTEN loss/mutation, was associated with significantly longer OS, indicating the differential effects of these genetic aberrations on sensitivity to matched therapy, as well as matched patients and the preferential choices of the treating physicians in the Phase I Clinical Trials Program, MD Anderson for assigning patients to matched therapy.\n\nOf 136 patients with PIK3CA-mutation and/or PTEN-loss/mutation advanced solid tumors seen in our phase I clinic, 25% achieved SD ≥ 6 months/CR/PR (95%CI, 0.18–0.33) after receiving matched therapy targeting the activated PI3K/AKT/mTOR pathway, and a median PFS of 2.5 months (95% CI, 1.8–3.2) [31]. These outcomes were significantly lower than those reported in the current study of patients with PIK3CA-mutation and/or PTEN-loss/mutation metastatic or recurrent carcinoma receiving matched therapy. Several confounding factors might have contributed to these differences. Almost half of the patients with metastatic or recurrent cervical carcinoma, especially those with squamous cell carcinoma, presented with PIK3CA mutation and/or PTEN loss/mutation, and this proportion was significantly higher in patients with advanced solid tumors (48% versus 22%, p = 0.002), suggesting that the activated PI3K/AKT/mTOR pathway is a driving mechanism for the survival of cervical carcinoma cells. Another factor is that concurrent mutations or specific molecular profiles might be more important than a single gene mutation. PIK3CA mutation was more prevalent in patients with KRAS mutation than in patients with wild-type KRAS [31], whereas in this report, a low frequency of KRAS mutation was found in metastatic or recurrent cervical carcinomas, and in squamous cell carcinomas specifically, no KRAS mutation was identified in any of the 26 tested patients (Table 1). Since PIK3CA mutation and/or PTEN loss/mutation with simultaneous KRAS mutation were associated with significantly lower antitumor activity and shorter PFS than PIK3CA mutation and/or PTEN loss/mutation without simultaneous KRAS mutation, two or more coexisting mutations constitute different classes of mutation profiles that predict responses to various biologically targeting agents and/or their combinations and render matched therapy more complicated than expected. When developing efficacious regimens to target the activated PI3K/AKT/mTOR pathway, metastatic or recurrent squamous cell carcinomas of the cervix might be an appropriate clinical model to be tested in early-phase clinical trials because of their high prevalence of PIK3CA mutation and/or PTEN loss/mutation as previously reported [15, 32–35] and their lack of simultaneous KRAS mutation, in agreement with the hypothesis that coexisting KRAS mutation become resistant to regimens targeting the activated PI3K/AKT/mTOR pathway.\n\nWhen considering the clinical relevance of our findings, several limitations should be kept in mind. First, matched therapy includes not only phase I clinical trials of a single agent targeting the activated PI3K/AKT/mTOR pathway, but also phase I clinical trials of an agent targeting this pathway in combination with other biologically targeted agents or conventional chemotherapeutic agents. The importance of using an agent to target the activated PI3K/AKT/mTOR pathway might be overestimated since tumor control might be induced by simultaneous inhibition of other key targets and/or processes by the combination regimens. Second, patients with poor clinical outcomes may have been selectively excluded from being referred to a phase I trial because of rapid tumor progression, poor performance status, insufficient organ function, severe comorbidity, economic issues, and inaccessibility of treatment. Third, molecular studies of mutation profiles were usually conducted on archival tumor specimens whenever available, regardless of whether the specimens had been treated in a phase I clinical trial. Finally, we had a limited sample size available for subgroup analyses, which confounded the ability to validate statistical significance in category assessment. Therefore, conclusions from this retrospective study should be considered preliminary evidence to generate hypotheses, which require further validation in larger prospective studies.\n\nIn conclusion, our results showed that almost half of the patients with metastatic or recurrent squamous cell carcinoma of the cervix had PIK3CA mutation and/or PTEN loss/mutation without coexisting KRAS mutation, providing an appropriate patient population to the test efficacy of a regimen including a single agent targeting the PI3K/AKT/mTOR pathway or a combination regimen with either another biologically targeted agent and/or conventional chemotherapeutic agent. Matched therapy targeting a specific mutation has provided apparent clinical benefits for cancer patients. Complicated mutation profiles might be more important and useful than a single gene mutation in predicting antitumor activity and clinical efficacy to a specific regimen [36–40]. Therefore, future development and evaluation of novel regimens targeting the activated PI3K/AKT/mTOR pathway for the purpose of translating high antitumor activity to prolonged survival benefit is warranted in larger prospective clinical trials for the treatment cervical carcinoma, especially squamous cell carcinoma.\n\nThe authors thank Ellen Chiu in the Department of Investigational Cancer Therapeutics at MD Anderson for conducting database searches and Markeda Wade in the Department of Scientific Publications at MD Anderson for editing the manuscript.\n\nFUNDING\n\nRLC is supported by the Ann Rife Cox Chair in gynecology.\n\nPotential conflicts of interest\n\nThe authors have no potential conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1 Forouzanfar MH Foreman KJ Delossantos AM Lozano R Lopez AD Murray CJ Naghavi M Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis Lancet 2011 378 1461 1484 21924486 \n2 Siegel R Ma J Zou Z Jemal A Cancer statistics, 2014 CA: a cancer journal for clinicians 2014 64 9 29 24399786 \n3 Grisaru D Covens A Chapman B Shaw P Colgan T Murphy J DePetrillo D Lickrish G Laframboise S Rosen B Does histology influence prognosis in patients with early-stage cervical carcinoma? 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Expert Rev Anticancer Ther 2010 10 451 460 20214525 \n5 Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials J Clin Oncol 2008 26 5802 5812 19001332 \n6 Long HJ 3rd Bundy BN Grendys EC Jr Benda JA McMeekin DS Sorosky J Miller DS Eaton LA Fiorica JV Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study J Clin Oncol 2005 23 4626 4633 15911865 \n7 Monk BJ Sill MW McMeekin DS Cohn DE Ramondetta LM Boardman CH Benda J Cella D Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study J Clin Oncol 2009 27 4649 4655 19720909 \n8 Barbera L Thomas G Management of early and locally advanced cervical cancer Semin Oncol 2009 36 155 169 19332250 \n9 Tewari KS Monk BJ Recent achievements and future developments in advanced and recurrent cervical cancer: trials of the Gynecologic Oncology Group Semin Oncol 2009 36 170 180 19332251 \n10 Tewari KS Sill MW Long HJ 3rd Penson RT Huang H Ramondetta LM Landrum LM Oaknin A Reid TJ Leitao MM Michael HE Monk BJ Improved survival with bevacizumab in advanced cervical cancer N Engl J Med 2014 370 734 743 24552320 \n11 Movva S Rodriguez L Arias-Pulido H Verschraegen C Novel chemotherapy approaches for cervical cancer Cancer 2009 115 3166 3180 19452541 \n12 Zagouri F Sergentanis TN Chrysikos D Filipits M Bartsch R Molecularly targeted therapies in cervical cancer. A systematic review Gynecol Oncol 126 291 303 22504292 \n13 Duenas-Gonzalez A Cetina L Coronel J Cervantes-Madrid D Emerging drugs for cervical cancer Expert Opin Emerg Drugs 17 203 218 22530838 \n14 Wee S Lengauer C Wiederschain D Class IA phosphoinositide 3-kinase isoforms and human tumorigenesis: implications for cancer drug discovery and development Current opinion in oncology 2008 20 77 82 18043260 \n15 Ma YY Wei SJ Lin YC Lung JC Chang TC Whang-Peng J Liu JM Yang DM Yang WK Shen CY PIK3CA as an oncogene in cervical cancer Oncogene 2000 19 2739 2744 10851074 \n16 German S Aslam HM Saleem S Raees A Anum T Alvi AA Haseeb A Carcinogenesis of PIK3CA Hereditary cancer in clinical practice 2013 11 5 23768168 \n17 Zhang S Yu D PI(3)king apart PTEN's role in cancer Clinical cancer research : an official journal of the American Association for Cancer Research 2010 16 4325 4330 20622047 \n18 Carnero A Blanco-Aparicio C Renner O Link W Leal JF The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications Current cancer drug targets 2008 8 187 198 18473732 \n19 Kim KW Myers CJ Jung DK Lu B NVP-BEZ-235 enhances radiosensitization via blockade of the PI3K/mTOR pathway in cisplatin-resistant non-small cell lung carcinoma Genes & cancer 2014 5 293 302 25221647 \n20 Tsimberidou AM Iskander NG Hong DS Wheler JJ Falchook GS Fu S Piha-Paul S Naing A Janku F Luthra R Ye Y Wen S Berry D Kurzrock R Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative Clin Cancer Res 2012 18 6373 6383 22966018 \n21 Hou MM Wheler J Hong D Naing A Tsimberidou A Janku F Zinner R Piha-Paul S Falchook G Kurzrock R Fu S Phase I Clinical Experience of Patients with Cervical Cancer Anticancer Res 2014 \n22 Bertelsen BI Steine SJ Sandvei R Molven A Laerum OD Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation International journal of cancer Journal international du cancer 2006 118 1877 1883 16287065 \n23 Cui B Zheng B Zhang X Stendahl U Andersson S Wallin KL Mutation of PIK3CA: possible risk factor for cervical carcinogenesis in older women International journal of oncology 2009 34 409 416 19148475 \n24 McIntyre JB Wu JS Craighead PS Phan T Kobel M Lees-Miller SP Ghatage P Magliocco AM Doll CM PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy Gynecologic oncology 2013 128 409 414 23266353 \n25 Henken FE Banerjee NS Snijders PJ Meijer CJ De-Castro Arce J Rosl F Broker TR Chow LT Steenbergen RD PIK3CA-mediated PI3-kinase signalling is essential for HPV-induced transformation in vitro Molecular cancer 2011 10 71 21663621 \n26 Cancer Therapy Evaluation Program NCI [16 April 2013];Common Terminology Criteria for Adverse events (CTCAE) http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm \n27 Therasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L Verweij J Van Glabbeke M van Oosterom AT Christian MC Gwyther SG New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst 2000 92 205 216 10655437 \n28 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L Kaplan R Lacombe D Verweij J New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 19097774 \n29 Tao X Hu W Ramirez PT Kavanagh JJ Chemotherapy for recurrent and metastatic cervical cancer Gynecol Oncol 2008 110 S67 71 18533239 \n30 Hirte HW Strychowsky JE Oliver T Fung-Kee-Fung M Elit L Oza AM Chemotherapy for recurrent, metastatic, or persistent cervical cancer: a systematic review Int J Gynecol Cancer 2007 17 1194 1204 17540006 \n31 Janku F Hong DS Fu S Piha-Paul SA Naing A Falchook GS Tsimberidou AM Stepanek VM Moulder SL Lee JJ Luthra R Zinner RG Broaddus RR Wheler JJ Kurzrock R Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors Cell Rep 2014 6 377 387 24440717 \n32 Lu D Qian J Yin X Xiao Q Wang C Zeng Y Expression of PTEN and survivin in cervical cancer: promising biological markers for early diagnosis and prognostic evaluation Br J Biomed Sci 2013 69 143 146 23310986 \n33 Bourmenskaya O Shubina E Trofimov D Rebrikov D Sabdulaeva E Nepsha O Bozhenko V Rogovskaya S Sukhikh G Host gene expression profiling of cervical smear is eligible for cancer risk evaluation J Clin Pathol 2013 66 282 285 23268324 \n34 Vazquez-Ulloa E Lizano M Aviles-Salas A Alfaro-Moreno E Contreras-Paredes A Abnormal distribution of hDlg and PTEN in premalignant lesions and invasive cervical cancer Gynecol Oncol 2011 122 663 668 21664656 \n35 Eijsink JJ Noordhuis MG ten Hoor KA Kok M Hollema H de Bock GH Nijman HW Schuuring E Wisman GB van der Zee AG The epidermal growth factor receptor pathway in relation to pelvic lymph node metastasis and survival in early-stage cervical cancer Hum Pathol 2010 41 1735 1741 21078436 \n36 McIntyre JB Wu JS Craighead PS Phan T Kobel M Lees-Miller SP Ghatage P Magliocco AM Doll CM PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy Gynecol Oncol 2012 128 409 414 23266353 \n37 Janku F Wheler JJ Naing A Falchook GS Hong DS Stepanek VM Fu S Piha-Paul SA Lee JJ Luthra R Tsimberidou AM Kurzrock R PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials Cancer Res 2013 73 276 284 23066039 \n38 Janku F Wheler JJ Westin SN Moulder SL Naing A Tsimberidou AM Fu S Falchook GS Hong DS Garrido-Laguna I Luthra R Lee JJ Lu KH Kurzrock R PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2012 30 777 782 22271473 \n39 Janku F Tsimberidou AM Garrido-Laguna I Wang X Luthra R Hong DS Naing A Falchook GS Moroney JW Piha-Paul SA Wheler JJ Moulder SL Fu S Kurzrock R PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors Molecular cancer therapeutics 2011 10 558 565 21216929 \n40 Edgar KA Crocker L Cheng E Wagle MC Wongchenko M Yan Y Wilson TR Dompe N Neve RM Belvin M Sampath D Friedman LS Wallin JJ Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition Genes & cancer 2014 5 113 126 25053989\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "5(22)",
"journal": "Oncotarget",
"keywords": null,
"medline_ta": "Oncotarget",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "11168-79",
"pmc": null,
"pmid": "25426553",
"pubdate": "2014-11-30",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23266353;18473732;23768168;17540006;19332251;20214525;22966018;23066039;15911865;19332250;10655437;19148475;24552320;16287065;21216929;24440717;19720909;23268324;19452541;21663621;21078436;19097774;23310986;19001332;18043260;10851074;18533239;21924486;22504292;24778042;11753977;22271473;24399786;22530838;21664656;20622047;25221647;25053989",
"title": "Targeted PI3K/AKT/mTOR therapy for metastatic carcinomas of the cervix: A phase I clinical experience.",
"title_normalized": "targeted pi3k akt mtor therapy for metastatic carcinomas of the cervix a phase i clinical experience"
} | [
{
"companynumb": "US-JNJFOC-20160827682",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo evaluate the effects of a commonly used combined hormonal oral contraceptive (OC) on carbohydrate metabolism in obese as compared with lean women.\n\n\nMETHODS\n6-month prospective study.\n\n\nMETHODS\nClinical research center at an academic medical center.\n\n\nMETHODS\nPremenopausal nondiabetic women with body mass index <25 kg/m(2) (n = 15) or >30 kg/m(2) (n = 14).\n\n\nMETHODS\nEthinyl estradiol (35 μg) and norgestimate (0.18/0.215/0.25 mg) for 6 cycles.\n\n\nMETHODS\nInsulin sensitivity by frequent sampling intravenous glucose tolerance test; other indices of insulin sensitivity (homeostatic model assessment of insulin sensitivity index [ISI HOMA], the Matsuda index); fasting lipid panel.\n\n\nRESULTS\nInsulin sensitivity changed from 6.62 ± 3.69 min(-1)/mIU/L (baseline) to 8.23 ± 3.30 min(-1)/mIU/L (6 months) in lean women, and from 4.36 ± 2.32 to 3.82 ± 2.32 min(-1)/mIU/L in obese women. Divergent effects on insulin sensitivity were also observed with ISI HOMA and the Matsuda index. Low-density lipoprotein increased by approximately 20 mg/dL in both the lean and obese groups.\n\n\nCONCLUSIONS\nLean and obese women exhibit differential changes in insulin sensitivity when given 6 months of a commonly used oral contraceptive. The mechanisms of these differences and whether these divergent effects persist in the long term require further investigation.",
"affiliations": "Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA. kicheang@vcu.edu",
"authors": "Cheang|Kai I|KI|;Essah|Paulina A|PA|;Sharma|Susmeeta|S|;Wickham|Edmond P|EP|;Nestler|John E|JE|",
"chemical_list": "D001786:Blood Glucose; D003277:Contraceptives, Oral, Combined; D003278:Contraceptives, Oral, Hormonal; D004338:Drug Combinations; D007328:Insulin; D008077:Lipoproteins, LDL; C109079:norgestimate, ethinyl estradiol drug combination; D009644:Norgestrel; D004997:Ethinyl Estradiol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.fertnstert.2011.05.039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0015-0282",
"issue": "96(2)",
"journal": "Fertility and sterility",
"keywords": null,
"medline_ta": "Fertil Steril",
"mesh_terms": "D000046:Academic Medical Centers; D000328:Adult; D000704:Analysis of Variance; D001786:Blood Glucose; D001794:Blood Pressure; D015992:Body Mass Index; D003277:Contraceptives, Oral, Combined; D003278:Contraceptives, Oral, Hormonal; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004997:Ethinyl Estradiol; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin; D007333:Insulin Resistance; D008077:Lipoproteins, LDL; D009644:Norgestrel; D009765:Obesity; D011446:Prospective Studies; D013851:Thinness; D013997:Time Factors; D014768:Virginia; D055815:Young Adult",
"nlm_unique_id": "0372772",
"other_id": null,
"pages": "353-359.e1",
"pmc": null,
"pmid": "21676394",
"pubdate": "2011-08",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "7593446;12519844;10999803;443421;17443615;86774;10480510;16157765;3899825;16532609;3546379;1324556;9773262;15504932;16723306;2892414;5413954;15181063;17426085;7856434;10449692;1605286;3640682;16684901;9010389;4162055;15070917;16011472;3102539;3933351;2146499;15576394;2351014",
"title": "Divergent effects of a combined hormonal oral contraceptive on insulin sensitivity in lean versus obese women.",
"title_normalized": "divergent effects of a combined hormonal oral contraceptive on insulin sensitivity in lean versus obese women"
} | [
{
"companynumb": "US-JNJFOC-20120406901",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETHINYL ESTRADIOL\\NORGESTIMATE"
},
"drugaddition... |
{
"abstract": "Using immune-checkpoint inhibitors (ICIs) to manage cancer is associated with various immune-related adverse events. Central and/or peripheral neurological disorders are rare and potentially serious. We analyzed the characteristics of non-small-cell lung cancer (NSCLC) patients who developed immune-related encephalitis under anti-programmed-death protein-1 or its ligand (PD-1/PD-L1).\n\n\n\nClinical, biological and radiological characteristics of ICI-treated NSCLC patients with immune-related encephalitis, from 6 centers, were evaluated retrospectively.\n\n\n\nThe 6 centers included 9 patients: all men, all smokers, median (range) age 67 (48-77) years, 78% adenocarcinomas, first- or second-line ICI for 5 and 4 patients, respectively. Two patients had non-active cerebral metastases at ICI onset. A median of 5 (1-22) ICI infusions preceded neurological symptoms, the most frequent being confusion (78%), fever (45%) and cerebellar ataxia (33%). CSF analyses revealed a median white blood cell count of 22/mm3 (1-210/mm3), with hyperlymphocytosis in 8 patients and high protein levels in all. All bacteriological and virological analyses were negative. Cerebral MRI was considered normal for 5 patients; 4 patients had FLAIR hypersignals consistent with brain parenchyma inflammation. Three patients required intensive care. All patients received corticosteroids (different doses), a median of 8.5 (6-18) days post-onset. Corticosteroids achieved rapid symptom regression without sequelae in 8 patients. The last patient, with the longest time until corticosteroid introduction, died. ICIs were never restarted in any patient.\n\n\n\nImmune encephalitis, a rare but serious complication of anti-PD-1/PD-L1 therapy, carries a good prognosis when managed with early corticosteroids.",
"affiliations": "Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, 40, avenue de Verdun, 94010 Créteil, France. Electronic address: mateosanchisborja@gmail.com.;Service de Pneumologie, Centre Hospitalier Universitaire de Rennes, Rennes, France.;Service de Pneumologie, Centre Hospitalier de Cornouailles, Quimper, France.;Service de Pneumologie, Centre Hospitalier Universitaire d'Angers, Angers, France.;Service de Pneumologie, Centre Hospitalier de Villefranche-sur-Soane, Villefranche-sur-Soane, France.;Service de Pneumologie, Centre Hospitalier Universitaire de Clermont Ferrand, Clermont Ferrand, France.;Service de Pneumologie, Centre Hospitalier Universitaire de Brest, Brest, France.;Service d'Oncologie, Centre Anti-Cancéreux François-Baclesse, Caen, France.;Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, 40, avenue de Verdun, 94010 Créteil, France.;Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, 40, avenue de Verdun, 94010 Créteil, France.;Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, 40, avenue de Verdun, 94010 Créteil, France.",
"authors": "Sanchis-Borja|Mateo|M|;Ricordel|Charles|C|;Chiappa|Anne Marie|AM|;Hureaux|José|J|;Odier|Luc|L|;Jeannin|Gaelle|G|;Descourt|Renaud|R|;Gervais|Radj|R|;Monnet|Isabelle|I|;Auliac|Jean-Bernard|JB|;Chouaïd|Christos|C|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2020.03.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "143()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Encephalitis; Immunotherapy; Lung cancer; Management",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D004660:Encephalitis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "36-39",
"pmc": null,
"pmid": "32200139",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Encephalitis related to immunotherapy for lung cancer: Analysis of a multicenter cohort.",
"title_normalized": "encephalitis related to immunotherapy for lung cancer analysis of a multicenter cohort"
} | [
{
"companynumb": "FR-009507513-2004FRA004463",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We aimed to perform an analysis of individual case safety reports retrieved after the Standardized MedDRA Query \"Pregnancy and neonatal topics\" for which Direct-Acting Oral Anticoagulants (DOACs) were claimed as suspected/interacting drugs. Additionally, to investigate if exists a disproportion of cases reporting \"Pregnancy and neonatal topics\" adverse events rather than other adverse events for DOACs in comparison with all other drugs registered in VigiBase or warfarin. VigiBase, the World Health Organization (WHO)'s global database of individual case safety reports was used as data source. Forty-two cases of abortion were detected of which 18 (42.8%) had alternative causes for its occurrence. Fourteen cases reported congenital anomaly (8 cases) or low birth weight baby/fetal growth restriction (6 cases) of which 62.5% and 33.3% had at least one confounder, respectively. In the disproportionality analyses, a potential safety signal for spontaneous abortion emerged for rivaroxaban (Reporting Odds Ratio, ROR 2.70; 95% CI 1.79-4.07) and apixaban (ROR 6.76; 95% CI 2.99-15.25). However, when the same analyses were performed using only cases without alternative causes, no statistically significant associations for rivaroxaban when compared to all other drugs (ROR 1.05; 95% CI 0.54-2.02) or warfarin (ROR 0.79; 95% CI 0.47-1.32) were found. For apixaban, we found a statistically significant ROR for induced abortion when compared to all other drugs or warfarin. For the majority of cases claiming DOACs-induced teratogenic effects, spontaneous or induced abortion there was at least one alternative cause explaining the occurrence of the adverse events. For rivaroxaban, when cases without confounders were considered, no safety signals emerged. However, for apixaban, we found a potential safety signal suggesting an increased probability of reporting spontaneous/induced abortion rather than other events when compared to all other drugs or warfarin.",
"affiliations": "Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, København Ø, Denmark. maurizio.sessa@sund.ku.dk.;Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania \"L. Vanvitelli\", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy.;Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, København Ø, Denmark.;Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania \"L. Vanvitelli\", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy.;Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania \"L. Vanvitelli\", Via Santa Maria di Costantinopoli 16, 80138, Naples, Italy.;Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, København Ø, Denmark.",
"authors": "Sessa|Maurizio|M|http://orcid.org/0000-0003-0874-4744;Mascolo|Annamaria|A|;Callréus|Torbjörn|T|;Capuano|Annalisa|A|;Rossi|Francesco|F|;Andersen|Morten|M|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1038/s41598-019-43715-4",
"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 4371510.1038/s41598-019-43715-4ArticleDirect-acting oral anticoagulants (DOACs) in pregnancy: new insight from VigiBase® http://orcid.org/0000-0003-0874-4744Sessa Maurizio maurizio.sessa@sund.ku.dk 12Mascolo Annamaria 2Callréus Torbjörn 1Capuano Annalisa 2Rossi Francesco 2Andersen Morten 11 0000 0001 0674 042Xgrid.5254.6Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 København Ø, Denmark 2 Campania Pharmacovigilance and Pharmacoepidemiology Regional Centre, Department of Experimental Medicine, University of Campania “L. Vanvitelli”, Via Santa Maria di Costantinopoli 16, 80138 Naples, Italy 10 5 2019 10 5 2019 2019 9 723615 1 2019 15 4 2019 © The Author(s) 2019Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.We aimed to perform an analysis of individual case safety reports retrieved after the Standardized MedDRA Query “Pregnancy and neonatal topics” for which Direct-Acting Oral Anticoagulants (DOACs) were claimed as suspected/interacting drugs. Additionally, to investigate if exists a disproportion of cases reporting “Pregnancy and neonatal topics” adverse events rather than other adverse events for DOACs in comparison with all other drugs registered in VigiBase or warfarin. VigiBase, the World Health Organization (WHO)’s global database of individual case safety reports was used as data source. Forty-two cases of abortion were detected of which 18 (42.8%) had alternative causes for its occurrence. Fourteen cases reported congenital anomaly (8 cases) or low birth weight baby/fetal growth restriction (6 cases) of which 62.5% and 33.3% had at least one confounder, respectively. In the disproportionality analyses, a potential safety signal for spontaneous abortion emerged for rivaroxaban (Reporting Odds Ratio, ROR 2.70; 95% CI 1.79–4.07) and apixaban (ROR 6.76; 95% CI 2.99–15.25). However, when the same analyses were performed using only cases without alternative causes, no statistically significant associations for rivaroxaban when compared to all other drugs (ROR 1.05; 95% CI 0.54–2.02) or warfarin (ROR 0.79; 95% CI 0.47–1.32) were found. For apixaban, we found a statistically significant ROR for induced abortion when compared to all other drugs or warfarin. For the majority of cases claiming DOACs-induced teratogenic effects, spontaneous or induced abortion there was at least one alternative cause explaining the occurrence of the adverse events. For rivaroxaban, when cases without confounders were considered, no safety signals emerged. However, for apixaban, we found a potential safety signal suggesting an increased probability of reporting spontaneous/induced abortion rather than other events when compared to all other drugs or warfarin.\n\nSubject terms\nInterventional cardiologyEpidemiologyhttps://doi.org/10.13039/501100009708Novo Nordisk Fonden (Novo Nordisk Foundation)NNF15SA0018404NNF15SA0018404Sessa Maurizio Andersen Morten issue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nCurrently, low molecular weight heparins represent the gold standard for the prophylaxis of venous thromboembolism during pregnancy. In selected clinical scenarios and timeframe of pregnancy, unfractionated heparin and low dose vitamin K antagonist may represent therapeutic alternatives. Direct-Acting Oral Anticoagulants (DOACs) are not recommended in pregnancy1,2. However, it was recently questioned in the scientific literature if DOACs may represent a valuable drug class in the therapeutic armamentarium of thrombosis’ prophylaxis in pregnancy3. From a clinical perspective, the main reasoning for discussing their use in pregnancy is based on the observation that DOACs may have intrinsic advantages for pregnant women when compared to vitamin K antagonists, such as the rapid withdrawal in case of premature delivery and a shortened antepartum interruption period, due to their shorter half-life3,4. Additionally, from a drug safety perspective, recent evidence suggests they may not have the same magnitude of embryotoxicity as the vitamin K antagonists5. In this regard, it should be highlighted that despite promising, clinical evidence on the benefit/risk associated with DOACs for the mother and fetus is scarce and needed1,2. To date, no clinical trials have been conducted for DOACs in pregnancy and current concerns are based on the observation that DOACs can cross the placenta/reach the fetus and have the potential to cause reproductive toxicity2. No study has been conducted on available cases of DOACs-induced teratogenesis in order to investigate the role of comorbidities, concurrent teratogenic drugs (whenever reported), temporal and biological plausibility of drug-event couples, i.e. the presence of confounders that could potentially explain the outcome and/or reduce the strength of the individual causality between the drug and the adverse event6. Moreover, a disproportionality to quantify if, for DOACs, the probability of reporting teratogenic event rather than any other event is higher compared to the probability for all other drugs or for other oral anticoagulants drugs currently used in pregnancy is lacking. Considering aforementioned gaps in knowledge, we aimed to perform a case series of all individual case safety reports enlisting adverse events included in the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) “Pregnancy and neonatal topics” for which Direct-Acting Oral Anticoagulants (DOACs) were claimed as suspected/interacting drugs. Additionally, to investigate if exists a disproportion of cases reporting “Pregnancy and neonatal topics” adverse events rather than other adverse events for DOACs in comparison with all other drugs registered in VigiBase or warfarin.\n\nMethods\nData source\nIn this study, we used VigiBase as the data source. VigiBase is the largest database of individual case safety records in the world with more than 16 million individual case reports of suspected adverse drug reaction of medicine sent by 131 countries participating to the World Health Organization (WHO) Programme for International Drug Monitoring7. VigiBase virtually covers the global population with a high standard of coherence and quality of the data. VigiBase use standardized dictionaries to code adverse events (WHO Adverse Reactions Terminology/MedDRA, and WHO International Statistical Classification of Diseases) and medicinal products (WHODrug) to guarantee effective and accurate data management and analysis. For each individual case safety report, we retrieved demographic, clinical and administrative characteristics/information of the case, ongoing and past pharmacological treatment (including dosage regimen, route of administration, therapy start/end dates, the indication of use, dechallenge and rechallenge). Additionally, it is possible to retrieve information on comorbidities, adverse events (coded according to the medical dictionary for regulatory activities), the source of the reports and the professional qualification of the reporter, and adverse event’s outcomes.\n\nData extraction strategy\nThe Uppsala Monitoring Centre that developed and maintains VigiBase on behalf of the WHO was requested to extract all individual case reports recorded in the VigiBase from 01/01/1967 to 13/07/2017 (date format: DDMMYYYY) having DOACs as suspected/interacting drugs for which there was reported at least one adverse event included in the MedDRA SMQ “Pregnancy and neonatal topics”. With this research strategy, we obtained a dataset that included 764 individual case safety reports. From this preliminary dataset, we extracted our final dataset which was composed of individual case safety reports claiming DOACs-induced teratogenic events or abortion for which DOACs had a temporal and biological plausible correlation with the events (for the formal definition of temporal and biological plausibility please refer to section 2.3). The same procedure was performed also for individual case safety report having warfarin as suspected/interacting drug in order to perform symmetric disproportionality sensitivity analyses as described in section 2.4.\n\nTo perform disproportionality analyses, we also requested aggregated data for all drugs included in the anatomical therapeutic chemical classification (ATC) code B01A and for all other drugs. In particular, we requested the number of individual case safety reports having: (1) preferred terms enlisted in the MedDRA SMQ “Pregnancy and neonatal topics”; (2) all other preferred terms.\n\nConsidering the drug-event pairs under investigation, for disproportionality analyses, we used the female gender and the age of cases (the range between 14 and 40 years) as filters (Supplementary Figs 1–3), i.e. we restricted the disproportionality analyses to the population of cases of female gender in the fertile age. This restriction was performed because we believed it necessary in relation to pregnancy-related outcomes for a meaningful computation of the Reporting Odds Ratio (ROR), or rather the statistical measure used in the disproportionality analyses8. In such evaluations, the inclusion of adverse events occurred in male cases or in women that were not in fertile age may lead to bias. By using the aforementioned filters, we restricted two elements of the ROR, the “other adverse events for the drug of interest” and “other adverse events for all the other drugs”.\n\nA sensitivity analysis was performed by restricting our data source to the period 2009–2017.\n\nCase by case assessment\nFor each individual case safety report, a team composed of clinical pharmacologists and a cardiologist with long-time experience in the Pharmacovigilance field assessed the temporal and biological plausibility for each drug event couple as well as the role of comorbidities and concurrent drugs on the reported adverse events, including potential drug-drug interactions. The case-by-case assessment was composed of three steps.\n\nIn the first step, we evaluated the temporal and biological plausibility for all drug-event pairs by looking at the clinical and demographic characteristics of cases, the treatment period and the time to the event. In particular, we considered a drug as being used during pregnancy if, in the individual case report, it was codified as one of the following preferred terms: (1) drug exposure during pregnancy; (2) drug exposure in pregnancy; (3) exposure during pregnancy; (4) fetal exposure during pregnancy; (5) maternal exposure during pregnancy; (6) fetal exposure during pregnancy, first trimester; (7) drug exposure in utero; (8) maternal exposure during pregnancy, first trimester; (9) fetal exposure during pregnancy, first trimester and (10) drug exposure via mother. Additionally, we considered drugs as used in pregnancy if the route of administration was flagged as transplacental i.e. the fetus was exposed to DOACs through the mother. We considered a drug-event couple as temporal or biological implausible if the exposure period was incompatible with the reported event (i.e. 1-day exposure to oxytocin for inducing labor was not considered as biologically plausible for the occurrence of a congenital anomaly). Additionally, we excluded those cases for which the start date of DOACs was subsequent to the date of the adverse event.\n\nIn the second step, we assessed the role of comorbidities on adverse events of interest by using both medical judgment and documental approaches. In particular, for the medical judgment approach, the aforementioned team assessed each case in order to identify comorbidities potentially associated with the development of the adverse event. For the documental approach, we screened the scientific literature (MEDLINE) in order to assess if the aforementioned comorbidities were found associated with the occurrence of the reported adverse event.\n\nFinally, in the third step, for each drug, we assessed potential drug-drug interactions that could lead to a pregnancy-related outcome and the teratogenic profile. To identify potential drug-drug interactions, we preliminarily assessed, for each drug, if there was an overlapping period of exposure with any other drug enlisted in the individual case safety report. This procedure was performed by looking at the date of commencement and the date of discontinuation of drugs. For those drugs having an overlapping period of exposure, we assessed the presence of drug-drug interaction by using Micromedex® a software that provides instant access to drug-drug, drug-food, drug-ethanol, and drug-lab test reactions9. To assess the teratogenic profile of drugs, we used the new FDA Pregnancy Categories list10.\n\nCase series and disproportionality analyses\nAll cases retrieved by using the strategy described in section 2.3 were grouped and presented as a case series. For all adverse events listed in the case series that involved DOACs, we performed a disproportionality analysis by using the ROR that was calculated as following using the statistical notation: (Pr (adverse event of interest|drug of interest)/Pr (other adverse events|drug of interest))/(Pr (adverse event of interest|all other drugs or an active comparator)/Pr (other adverse events|all other drugs or an active comparator)) where Pr stands for the reporting probability8. According to the European Medicines Agency recommendations, the threshold for signal detection was defined as a ROR lower boundary 95% Confidence Interval ≥1 and a number of cases ≥311,12.\n\nAdditionally, we performed a case/non-case analysis i.e. a disproportionality analysis in which selected drugs are used as comparators. We used warfarin as the comparator as it has a spectrum of indication of use that overlaps with DOACs, is a well-known teratogen13 and, as DOACs, in the Summary of Product Characteristics (SmPC) is currently not recommended in pregnancy. For the case/non-case analysis, we used the threshold previously described for the disproportionality analysis.\n\nFor both disproportionality analyses, sensitivity analyses were performed by using only cases without reported confounders.\n\nData management was performed using SAS statistical software (version 9.4, SAS Institute Inc., Cary, North Carolina) and analysis was performed using R (version 3.2.2, R Development Core Team).\n\nData protection\nData contained in VigiBase are anonymized and it is not possible to access patients’ or reporters’ personal information. The data applicant adhered to all applicable legislation such as, but not limited to, EU and national legislation regarding the protection of personal data (e.g. the Data Protection Directive 95/46/EC and Regulation (EC) No 45/2001, as applicable). The person responsible for the data request, management, and analysis was Dr. Maurizio Sessa.\n\nResults\nIn the study period, 60 (7.8%) out of 764 cases fulfilled the data extraction criteria. Excluded cases along with the reasons for exclusion provided in Supplementary Table 1. We observed an incremental trend over years of cases reporting adverse event included in the MedDRA SMQ “Pregnancy and neonatal topics” (Fig. 1A). The majority of retrieved cases derived from Germany (N = 35; 58.3%), while a lower frequency of reports was observed for United Kingdom (N = 5; 8.3%), United States (N = 4; 6.7%), France (N = 3; 5.0%), Switzerland, Sweden, Austria, Hungary (for each N = 2; 3.3%), Norway, Portugal, Ireland, Turkey, and New Zealand (for each N = 1; 1.7%). In all, 46 (76.7%) out of 60 cases were reported through spontaneous reporting systems. Overall, 39 (65.0%) out of 60 cases were medically confirmed or rather reported by physicians, 15 (25.0%) were sent by other healthcare professionals, and only six (10.0%) reports were sent by consumers (Fig. 1B). DOACs were prescribed for more than 21.7% of cases for venous thromboembolism (13 out of 60 cases; 21.7%) or pulmonary embolism (12 out 60 cases; 20.0%) (Fig. 1C).Figure 1 (A) Trend over time of selected cases (year of reporting); (B) Source and reporter qualification; (C) Indication of use of direct-acting oral anticoagulants in selected cases.\n\n\n\nIndividual case safety report listing adverse event included in the MedDRA SMQ “Pregnancy and neonatal topics”\nThe characteristics of each case are provided in Supplementary Table 2. In 26 cases (43.3%) we identified an alternative cause for the adverse events. Forty-two cases of abortion were identified of which 18 (42.8%) had an alternative cause for its occurrence. Fourteen cases reported congenital anomaly (8 cases) or low birth weight baby/fetal growth restriction (6 cases) of which, 62.5% and 33.3% had an alternative cause, respectively. Detected alternative causes included maternal age (11 cases; 18.3%) and the co-exposure to drugs (18 cases; 30.0%) or comorbidities (3 cases; 5.0%) having a potential teratogenic effect (in each individual case safety report, more than one confounder can be present) (Table 1, Supplementary Table 2). In 14 (23.3%) cases, we detected major/moderate potential drug-drug interactions (Supplementary Table 2). Raw data from VigiBase are provided in Supplementary Table 3. The case series of individual case safety report having warfarin as the suspected/interacting drug is provided in Supplementary Table 4.Table 1 Adverse events included in the MedDRA Query “Pregnancy and neonatal topics” that were identified during the case-by-case assessment of individual case safety reports.\n\nDOAC\tNumber of cases without alternative causes for the adverse event\tNumber of cases with alternative causes for the adverse event\tTotal*\t\n\nApixaban\n\t\n\nInduced abortion\n\t\n5\n\t\n0\n\t\n5\n\t\nPregnancy termination\t1\t0\t1\t\nSpina bifida\t0\t1\t1\t\nDysmorphism\t0\t1\t1\t\nFace malformation NOS\t0\t1\t1\t\nUnspecified congenital anomaly of heart\t0\t1\t1\t\nCongenital hydronephrosis\t0\t1\t1\t\n\nSpontaneous abortion/miscarriage\n\t\n6\n\t\n0\n\t\n6\n\t\nFetal growth retardation\t0\t1\t1\t\nSkeletal dysplasia\t0\t1\t1\t\nMultiple epiphyseal dysplasia\t0\t1\t1\t\nFetal growth restriction\t0\t1\t1\t\nNeonatal respiratory distress syndrome\t0\t1\t1\t\nSkeletal malformation\t0\t1\t1\t\nCongenital musculoskeletal anomaly\t0\t1\t1\t\nPremature baby\t0\t1\t1\t\nChondrodystrophy\t0\t1\t1\t\nBrachydactyly\t0\t1\t1\t\nUterus evacuation\t1\t0\t1\t\nAbortion\t1\t0\t1\t\nAbortion early\t1\t0\t1\t\nLow birth weight baby\t1\t0\t1\t\n\nDabigatran\n\t\nMiscarriage\t0\t1\t1\t\nInduced abortion\t1\t0\t1\t\nEdoxaban\t\t\t\t\nSpontaneous abortion\t1\t0\t1\t\n\nRivaroxaban\n\t\n\nIntrauterine growth retardation/Low birth weight baby\n\t\n4\n\t\n1\n\t\n5\n\t\n\nSpontaneous abortion/miscarriage\n\t\n9\n\t\n14\n\t\n23\n\t\nAbortion\t1\t0\t1\t\nFetal heartbeat absent\t1\t0\t1\t\nCongenital limb anomaly\t1\t0\t1\t\nFetal death\t1\t0\t1\t\nFetal heart rate deceleration\t1\t0\t1\t\nMissed abortion\t0\t1\t1\t\nFacial dysmorphism\t1\t0\t1\t\nOligohydramnios\t0\t1\t1\t\nVentricular hypoplasia\t0\t1\t1\t\nAbortion (unspecified)\t0\t1\t1\t\nCongenital cerebral cyst\t1\t0\t1\t\nCongenital anomaly NOS\t0\t1\t1\t\nCongenital cardiac septal defect\t0\t1\t1\t\nHeart disease congenital\t0\t1\t1\t\nCongenital cardiovascular anomaly\t0\t1\t1\t\nAbortion early\t0\t1\t1\t\nPost-abortion bleeding\t0\t1\t1\t\nInduced abortion\t0\t1\t1\t\nPremature delivery\t1\t0\t1\t\n*In each Individual Case Safety Report, more than one adverse event could be reported.\n\n\n\nDisproportionality analyses\nIn the disproportionality analysis, when cases with and without alternative causes for the adverse event were considered, rivaroxaban (ROR 2.70; 95% CI 1.79–4.07) and apixaban (ROR 6.76; 95% CI 2.99–15.25) had an increased probability of reporting spontaneous abortion compared to other adverse events in comparison to all other drugs. However, when the analysis was restricted to cases without confounders, rivaroxaban did not show a statistically significant estimation (ROR 1.05; 95% CI 0.54–2.02). Similarly, when all cases were used, rivaroxaban did not show a statistically significant ROR for spontaneous abortion in comparison to warfarin (ROR 0.79; 95% CI 0.47–1.32). Similar results were observed when the analysis was restricted only to cases without reported alternative causes for spontaneous abortion (ROR 0.86 95% CI 0.37–1.99). For the association apixaban and spontaneous abortion, we observed no statistically significant ROR if compared to warfarin (ROR 1.97; 95% CI 0.82–4.72) and a statistically significant ROR compared to rivaroxaban (ROR 2.59; 95% CI 1.01–6.23). When only cases without confounders were considered, apixaban showed a statistically significant ROR for spontaneous abortion if compared to warfarin (ROR 5.55; 95% CI 2.11–14.63) or rivaroxaban (ROR 6.45; 95% CI 2.27–18.35). For induced abortion, we found an increased probability of reporting this adverse event as opposed to other adverse events for apixaban when compared to both all other drugs and warfarin. Estimations are provided in Fig. 2. Frequencies used to compute reporting odds ratio are provided in Table 2. The results of the sensitivity analysis performed by restricting our data source to the period 2009–2017 were consistent with those obtained in the main analysis and are provided in Fig. 3 and Supplementary Table 5.Figure 2 Disproportionality and case/non-case analyses.\n\nTable 2 Two by two tables used to compute reporting odds ratios and 95% confidence intervals.\n\n\tCases without alternative causes\tAll cases\t\n\nDrug\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\n\nRivaroxaban\n\t9\t1675\t23\t1661\t\n\nOther drugs\n\t9644\t1878495\t9644\t1878495\t\n\nDrug\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\n\nRivaroxaban\n\t9\t1675\t23\t1661\t\n\nWarfarin\n\t14\t2241\t39\t2216\t\n\nDrug\n\t\nIntrauterine growth retardation/Low birth weight baby\n\t\nOther adverse events\n\t\nIntrauterine growth retardation/Low birth weight baby\n\t\nOther adverse events\n\t\n\nRivaroxaban\n\t4\t1680\t5\t1679\t\n\nOther drugs\n\t2025\t1886114\t2025\t1886114\t\n\nDrug\n\t\nIntrauterine growth retardation/Low birth weight baby\n\t\nOther adverse events\n\t\nIntrauterine growth retardation/Low birth weight baby\n\t\nOther adverse events\n\t\n\nRivaroxaban\n\t4\t1680\t5\t1679\t\n\nWarfarin\n\t2*\t2253\t4\t2251\t\n\nDrug\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\n\nApixaban\n\t6\t173\t6\t173\t\n\nOther drugs\n\t9644\t1878495\t9644\t1878495\t\n\nDrug\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\n\nApixaban\n\t6\t173\t6\t173\t\n\nWarfarin\n\t14\t2241\t39\t2216\t\n\nDrug\n\t\nInduced abortion\n\t\nOther adverse events\n\t\nInduced abortion\n\t\nOther adverse events\n\t\n\nApixaban\n\t5\t174\t5\t174\t\n\nOther drugs\n\t2596\t1885543\t2596\t1885543\t\n\nDrug\n\t\nInduced abortion\n\t\nOther adverse events\n\t\nInduced abortion\n\t\nOther adverse events\n\t\n\nApixaban\n\t5\t174\t5\t174\t\n\nWarfarin\n\t2*\t2253\t11\t2244\t\n\nDrug\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\nSpontaneous abortion/miscarriage\n\t\nOther adverse events\n\t\n\nApixaban\n\t6\t173\t6\t173\t\n\nRivaroxaban\n\t9\t1675\t23\t1661\t\n*Not assessable because the number of cases was lower than three.\n\nFigure 3 Disproportionality and case/non-case analyses performed in the sensitivity analysis.\n\n\n\nDiscussion\nThis is the first study showing that for almost half of the cases describing DOACs-induced adverse events enlisted in the MedDRA SMQ “Pregnancy and neonatal topics” the effect is confounded by factors other than DOACs that could potentially explain the adverse event. Additionally, this study provides, for the first time, a quantitative measure of the ROR of the aforementioned adverse events for DOACs in comparison to all other drugs or warfarin. Despite our results have inherent limitations due to the data source, they can potentially open a new discussion in the scientific community in virtue of the recent recommendations of the European Society of Cardiology guidelines on anticoagulation during pregnancy1. The aforementioned guideline suggests that to date, no adequate well-controlled studies are available for DOACs. However, they mentioned that the largest case-series available in the scientific literature, the study conducted Beyer-Westendorf and colleagues5, seems to suggest a potential teratogenic effect of DOACs, and in particular for rivaroxaban1. Similar results were found by Lameijer et al.14. Our results do not confirm this, but in contrast, suggest that rivaroxaban is not associated with a disproportional reporting of spontaneous abortion. In this regard, it should be considered that we found an alternative cause for spontaneous abortion/miscarriage or induced abortion for most of the cases described in the article of Beyer-Westendorf and colleagues. Additionally, we found that when cases with confounders were removed from the disproportionality analyses there was no statistically significant evidence to suggest an increased probability of reporting spontaneous abortion/miscarriage or induced abortion rather than other adverse events for rivaroxaban, either if compared to warfarin. It should be highlighted that those cases not having confounders, as also described by Beyer-Westendorf and colleagues, occurred during the first trimester of pregnancy. Overall, the risk of early pregnancy loss is 17–22% during the first trimester where miscarriage could occur spontaneously in absence of noxae15. Therefore, also in these cases, we may argue that the first trimester might represent a potential confounder for the occurrence of miscarriage. Another aspect for which our study may open new discussion points is the increased probability of reporting spontaneous or induced abortion for apixaban. A recent study has found that apixaban can easily cross the placenta and, at the steady state, fetal concentrations may range from 35 to 90% of the mother’s concentration having potential direct fetal effects16. Despite interesting, our results required further investigation. Considered the discrepancy between the results in the current study and those in Beyer-Westendorf and colleagues, it is our opinion that we do not have sufficient clinical evidence on the safety profile of DOACs in pregnancy and, therefore, no clear answer can be provided on their benefit-risk profile. Most of the available evidence was obtained from observational studies or extrapolation from non-pregnant cohorts mostly small-sized1 and lacking information on comorbidities and medicine co-exposure prior to or during pregnancy which may have a strong impact in confounding this drug-event association. As wisely recommended in the aforementioned clinical guidelines, recommendations might be provided only when adequate well-controlled studies will provide the necessary evidence potentially in the set of a common data model from an international collaboration.\n\nStrength and limitations\nThe use of VigiBase, a database that virtually covers the entire global population, with regard to adverse events report is considered a strength. Because clinical trials on drug safety of DOACs in pregnancy are unethical to perform, evidence on the role of DOACs-induced teratogenesis in humans can be obtained mainly from observational studies or case series of individual case safety reports. In this context, considering the rarity of both exposure and adverse events, spontaneous reporting systems may represent the only data source able to provide new clinical evidence into the role of DOACs-induced teratogenesis. Although not recommended in pregnancy, women in treatment with DOACs might not be aware of pregnancy at a time when organogenesis has already started and the fetus could be unknowingly exposed during the early embryonic period. Therefore, if adverse events occur, whenever they are reported to regulatory agencies, they could be potentially tracked through individual case safety reports. However, our study’s results should be considered in virtue of a set of limitations. The supplied data come from a variety of sources for which the likelihood of a causal relationship may not be the same in all reports. On the other hand, the aforementioned data source is also a limitation. By using data from the spontaneous reporting system, we cannot rule out the effect biases such as differential reporting, underreporting, lack of denominator and irregular information quality. Therefore, interpretations of adverse reaction data, and particularly those based on comparisons between medicinal products, may be misleading. Any use of this information must consider these factors. Additionally, we cannot exclude the existence of differential reporting of aforementioned drug-event pairs given the labeling difference among DOACs and warfarin. For both disproportionality and case/non-case analyses, we restricted our study outcomes to selected adverse events because only for these adverse events, for at least one DOAC (in particular rivaroxaban and apixaban), were reported at least three individual case safety reports in VigiBase (with and/or without alternative causes). It cannot be ruled out that in the disproportionality and case/non-case analyses the exclusion rate due to alternative causes was similar between DOACs and all other drugs. Finally, it should be highlighted that for three cases involving warfarin (1 spontaneous abortion and 2 induced abortions) adverse events occurred in the setting of an ectopic pregnancy.\n\nConclusion\nThis is the first study showing that for most of the cases describing DOACs-induced adverse events enlisted in the MedDRA SMQ “Pregnancy and neonatal topics” the association is confounded by factors other than DOACs. When cases with alternative causes are removed, on a global scale this study found no evidence from spontaneous reporting systems for an increased probability of reporting spontaneous abortion rather than other adverse events for rivaroxaban when it was compared to all other drugs included in VigiBase or warfarin. For apixaban, we observed an increased probability of reporting the aforementioned event or induced abortion when compared to all other drugs, warfarin or rivaroxaban. The current study results do not allow drawing any conclusions that can be directly implemented into clinical practice.\n\nSupplementary information\n\nSupplementary material\n\n \n\n\nPublisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1038/s41598-019-43715-4.\n\nAcknowledgements\nWe kindly thank the Uppsala Monitoring Center for their technical support and validation, in particular, Mr. Raghu Damarla and Dr. Pia Caduff. We declare that the information/position reported in this article not represent the opinion of the World Health Organization or the Uppsala Monitoring Center. Dr. Maurizio Sessa, Prof. Morten Andersen and Dr. Torbjörn Callréus belong to the Pharmacovigilance Research Group at the Department of Drug Design and Pharmacology, University of Copenhagen, receiving funding by the Novo Nordisk Foundation (NNF15SA0018404).\n\nAuthor Contributions\nProf. Morten Andersen, Dr. Maurizio Sessa, and Dr. Annamaria Mascolo analyzed data, wrote the paper and performed the case-by-case assessment. Prof. Annalisa Capuano and Prof. Francesco Rossi interpreted the results and wrote the papers. All authors commented on and approved the manuscript.\n\nData Availability\nAll relevant data were included in the manuscript.\n\nCompeting Interests\nDr. Maurizio Sessa, Dr. Annamaria Mascolo, Dr. Torbjörn Callréus,Prof. Annalisa Capuano, and Prof. Francesco Rossi declare no competing interest that are directly relevant to the contents of this work. Prof. Morten Andersen has participated in research projects funded by AstraZeneca, H. Lundbeck & Mertz, Novartis, Pfizer and Janssen, with grants paid to the institutions where he has been employed, and has personally received fees from Medicademy, the Danish Pharmaceutical Industry Association, for leading and teaching pharmacoepidemiology courses.\n==== Refs\nReferences\n1. Regitz-Zagrosek V ESC Guidelines for the management of cardiovascular diseases during pregnancy Eur. Heart J. 2018 39 3165 3241 10.1093/eurheartj/ehy340 30165544 \n2. Bates SM American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy Blood Adv. 2018 2 3317 3359 10.1182/bloodadvances.2018024802 30482767 \n3. Godin R Tanguay M-C The Anticoagulation Conundrum of Mechanical Heart Valves in Pregnancy: Should DOACs Be Considered? Journal of the American College of Cardiology 2017 70 3073 3074 10.1016/j.jacc.2017.09.1138 \n4. Steinberg ZL Krieger EV Reply: The Anticoagulation Conundrum of Mechanical Heart Valves in Pregnancy: Should DOACs Be Considered? Journal of the American College of Cardiology 2017 70 3074 3075 10.1016/j.jacc.2017.09.1139 29241499 \n5. Beyer-Westendorf J Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting Thromb. Haemost. 2016 116 651 658 10.1160/TH16-04-0305 27384740 \n6. Mascolo Annamaria Scavone Cristina Sessa Maurizio di Mauro Gabriella Cimmaruta Daniela Orlando Valentina Rossi Francesco Sportiello Liberata Capuano Annalisa Can causality assessment fulfill the new European definition of adverse drug reaction? A review of methods used in spontaneous reporting Pharmacological Research 2017 123 122 129 10.1016/j.phrs.2017.07.005 28694146 \n7. Olsson S The role of the WHO programme on International Drug Monitoring in coordinating worldwide drug safety efforts Drug Saf. 1998 19 1 10 10.2165/00002018-199819010-00001 9673854 \n8. Sessa M Pillars and Pitfalls of the New Pharmacovigilance Legislation: Consequences for the Identification of Adverse Drug Reactions Deriving From Abuse, Misuse, Overdose, Occupational Exposure, and Medication Errors Front. Pharmacol. 2018 9 611 10.3389/fphar.2018.00611 29946258 \n9. Patel RI Beckett RD Evaluation of resources for analyzing drug interactions J. Med. Libr. Assoc. 2016 104 290 295 10.3163/1536-5050.104.4.007 27822150 \n10. Pernia S DeMaagd G The New Pregnancy and Lactation Labeling Rule Pharm. Ther. 2016 41 713 715 \n11. Candore G Comparison of statistical signal detection methods within and across spontaneous reporting databases Drug Saf. 2015 38 577 587 10.1007/s40264-015-0289-5 25899605 \n12. Wisniewski AFZ Good Signal Detection Practices: Evidence from IMI PROTECT Drug Saf. 2016 39 469 490 10.1007/s40264-016-0405-1 26951233 \n13. Finkelstein Y Motherisk rounds. Warfarin embryopathy following low-dose maternal exposure J. Obstet. Gynaecol. Can. 2005 27 702 706 10.1016/S1701-2163(16)30550-3 16100627 \n14. Lameijer H Aalberts JJJ van Veldhuisen DJ Meijer K Pieper PG Efficacy and safety of direct oral anticoagulants during pregnancy; a systematic literature review Thromb. Res. 2018 169 123 127 10.1016/j.thromres.2018.07.022 30036784 \n15. Garcia-Enguidanos A Calle ME Valero J Luna S Dominguez-Rojas V Risk factors in miscarriage: a review Eur. J. Obstet. Gynecol. Reprod. Biol. 2002 102 111 119 10.1016/S0301-2115(01)00613-3 11950476 \n16. Bapat P Examining the transplacental passage of apixaban using the dually perfused human placenta J. Thromb. Haemost. 2016 14 1436 1441 10.1111/jth.13353 27149680\n\n",
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"title": "Direct-acting oral anticoagulants (DOACs) in pregnancy: new insight from VigiBase®.",
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"abstract": "Although more common with tacrolimus, it is known that calcineurin inhibitors may induce the development of electrolyte disorders such as hyponatremia and hyperkalemia by causing a hyporeninemic hypoaldosteronism-like syndrome. We present a 32-year-old female renal transplant patient who admitted to clinic with hyponatremia and hyperkalemia. Normal anion gap metabolic acidosis and renal tubular dysfunction were detected and after other reasons were excluded, it was considered as electrolyte disorder due to tacrolimus. No response was detected after tacrolimus conversion to everolimus and considering tubular dysfunction due to aldosterone resistance, we initiated fludrocortisone therapy and electrolyte disorders rapidly improved. Fludrocortisone therapy should be considered when hyponatremia and/or hyperkalemia due to tacrolimus are detected in renal transplant patients.",
"affiliations": "Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.;Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.;Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.;Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.;Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.;Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.;Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.;Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.;Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey.",
"authors": "Çağlayan|Feyza Bayraktar|FB|;Koç|Yener|Y|;Baştürk|Taner|T|;Hasbal|Barış|B|;Sakacı|Tamer|T|;Ahbap|Elbis|E|;İslam|Mahmut|M|;Nazif|Perin|P|;Ünsal|Abdulkadir|A|",
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"fulltext": "\n==== Front\nSisli Etfal Hastan Tip Bul\nSisli Etfal Hastan Tip Bul\nThe Medical Bulletin of Sisli Etfal Hospital\n1302-7123 1308-5123 Kare Publishing Turkey \n\nMBSEH-52-310\n10.14744/SEMB.2017.75436\nCase Report\nAldosterone Resistance Due to Tacrolimus: A Case Report\nÇağlayan Feyza Bayraktar Koç Yener Baştürk Taner Hasbal Barış Sakacı Tamer Ahbap Elbis İslam Mahmut Nazif Perin Ünsal Abdulkadir Department of Nephrology, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey\nAddress for correspondence: Feyza Bayraktar Çağlayan, MD. Şişli Hamidiye Etfal Eğitim ve Araştırma Hastanesi, Nefroloji Kliniği, İstanbul, Turkey Phone: +90 212 373 50 00 E-mail:feyzabayraktars@hotmail.com\n2018 \n21 3 2018 \n52 4 310 312\n30 6 2017 03 9 2017 Copyright: © 2018 by The Medical Bulletin of Sisli Etfal Hospital2018This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).Although more common with tacrolimus, it is known that calcineurin inhibitors may induce the development of electrolyte disorders such as hyponatremia and hyperkalemia by causing a hyporeninemic hypoaldosteronism-like syndrome. We present a 32-year-old female renal transplant patient who admitted to clinic with hyponatremia and hyperkalemia. Normal anion gap metabolic acidosis and renal tubular dysfunction were detected and after other reasons were excluded, it was considered as electrolyte disorder due to tacrolimus. No response was detected after tacrolimus conversion to everolimus and considering tubular dysfunction due to aldosterone resistance, we initiated fludrocortisone therapy and electrolyte disorders rapidly improved. Fludrocortisone therapy should be considered when hyponatremia and/or hyperkalemia due to tacrolimus are detected in renal transplant patients.\n\nHyponatremiarenal transplantationtacrolimus\n==== Body\nNowadays, calcineurin inhibitors are indispensable treatment for patients after solid organ transplantation. Although it is more frequently seen with tacrolimus, it has long been known that inhibitors of the calcineurin inhibitors can lead to electrolyte disturbances such as hyponatremia and hyperkalemia.[1] With these drugs, it has been demonstrated that an entity resembling a hyporeninemic hypoaldosteronism syndrome coursing with a decrease in the aldosterone release and mineralocorticoid (MC) receptor expression may develop.[2] In our article, a case of tacrolimus-induced aldosterone resistance that responded to MC replacement but could not be treated with conversion to an mTOR inhibitor everolimus which belongs to another immunosuppressive drug group is presented.\n\nCase Report\nA 32-year-old female patient who had been followed up with sessions of peritoneal dialysis performed due to end-stage renal disease developed after amyloidosis due to familial Mediterranean fever and had a cadaveric renal transplantation in May 2016 applied to the transplantation polyclinic with complaints of nausea and fatigue on the 149th day after transplantation. Her biochemical test results were as follows: Creatinine 1 mg/dL, urea 34 mg/dL, sodium 122 mmol/L, and potassium 5.5 mmol/L. Other laboratory test results are given in Table 1. Her treatment protocol consisted of tacrolimus (6 mg/d), mycophenolate mofetil (2 g/d), and prednisolone (5 mg/d) as immunosuppressive drugs, metoprolol (100 mg/d) and doxazosin mesylate (8 mg/d) for the treatment of hypertension, trimethoprim-sulfamethoxazole for prophylaxis, magnesium preparation for hypomagnesemia, and calcium and Vitamin D preparations for osteopenia. To exclude any treatment with pseudohyponatremia agents, her current treatment and tests were analyzed. He had not recently received diuretic therapy and intravenous fluid replacement. His blood glucose levels were within normal limits. Albumin and triglyceride values were normal. The level of tacrolimus was within normal limits (7 ng/mL), and no pathology was observed in thyroid and liver tests. Clinically, signs of hypovolemia were present, and 24-h urine output was 3.5–4 l/day. Serum osmolarity was 260 mosm/L, and 24-h urine sodium excretion was 340 mosm, while urine output was 3.8 lt, so the test results were compatible with salt-losing nephropathies. In the blood gas - anion deficit was 10 mmol/L and urinary anion deficit was calculated as 7 mmol/L. The results were consistent with normal anion gap metabolic acidosis and renal tubular dysfunction.\n\nTable 1 Laboratory data of the patient\n\nUrea (mg/dl)\t34\tTriglyceride (mg/dl)\t170\t\nCreatinine (mg/dl)\t1\tTotal cholesterol (mg/dl)\t206\t\nUric acid (mg/dl)\t4.1\tAlbumin (g/dl)\t3.9\t\nGlucose (mg/dl)\t76\tTotal protein (g/dl)\t6.3\t\nSodium (mmol/l)\t122\tCK (U/L)\t21\t\nPotassium (mmol/l)\t5.5\tLDH (U/L)\t221\t\nChloride (mmol/l)\t92\tWBC (103/µL)\t9860\t\nCalcium (mg/dl)\t9.28\tHb (g/dL)\t11.6\t\nPhosphorus (mg/dl)\t3.4\tHct %\t35.1\t\nMagnesium (mg/dl)\t1.54\tMCV (fL)\t74.2\t\nALT (U/L)\t22\tPlatelet (103/µL)\t317000\t\nAST (U/L)\t22\t24-h urinary Na (mosm/L)\t340\t\nGGT (U/L)\t77\tTSH (µIU/ml)\t2.8\t\nALP (U/L)\t109\tAldosterone (ng/dL) (while seated)\t28\t\nCK: Creatinine kinase; LDH: Lactate dehidrogenase; WBC: White blood cell; MCV: Mean corpuscular volume; TSH: Thyroid stimulating hormone; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma glutamyl transferase; ALP: Alkaline phosphatase.\n\nThe level of aldosterone (28 ng/dL when sitting) was found to be normal, and during her post-operative follow-up, hyponatremia was not observed, and the serum sodium value, including post-operative period, was over 130 mmol/L. Initially, she received 0.9% NaCl as an intravenous infusion. Parenteral fluid therapy was terminated when serum sodium level reached normal limits within 48 h. Sodium level in 24-h urine was 354 mosm/L and serum osmolarity was 284 mosm/L. During the follow-up, the sodium level gradually decreased to 120 mmol /L within 4 days. Then, tacrolimus-induced nephropathy was thought, and we switched to treatment with everolimus. During the maintenance treatment with everolimus, the patient’s clinical symptoms (malaise and nausea) and serum sodium levels did not improve, so fludrocortisone treatment at daily doses of 0.1 mg was initiated. At the 48th h of the treatment, serum sodium level increased to 140 mmol/L and K+ level regressed to 3.8 mmol/L. In 24-h, urine Na decreased to 125 mmol/L/day. The patient tolerated fludrocortisone treatment (hypertension, gastric irritation, etc., were not seen), its dose was reduced to 0.05 mg/day after observation of minimal peripheral edema at the end of the 1st week. The patient whose peripheral edema regressed and blood pressure dropped within normal limits was discharged with fludrocortisone treatment. Serum Na level was found to be 138 mmol/L and K level 4.6 mmol/L at 9 months of her post-operative follow-up. She is still under our routine and regular surveillance.\n\nDiscussion\nHyponatremia after transplantation may develop for many reasons including renal tubular sodium loss relative hypervolemia (dilutional hyponatremia), post-operative early-onset polyuria all due to inhibitory effect of calcineurin, and replacement of urinary loss with hypotonic fluids.[3]\n\nThese etiological factors were excluded due to the absence of polyuria, hypervolemia, and history of parenteral fluid therapy. Hyperglycemia, hypothyroidism, diuretic, or any drug use that may cause hyponatremia in the normal patient population were not present in our patient. Clinical signs of volume depletion and increased Na level in 24-h urine in the patient’s clinic suggested the presence of salt-losing nephropathy.\n\nThe first studies on various potential effects of calcineurin inhibitors given after renal transplantation on ion exchange, for example, hyperkalemia and salt-losing nephropathy by affecting Na/K-ATPase and Na-K-2Cl cotransporters were performed in 90 s.[4, 5] In the year 2002, an in vitro study showed that these drugs caused aldosterone resistance by inhibiting the transcriptional activity of human MK receptor more frequently with tacrolimus.[6] In another study published as an extension to this study, it was reported that hyponatremia and hyperkalemia after immunosuppressive treatment were related to aldosterone resistance with an incidence rate as high as 75%.[7]\n\nIn this study conducted in patients with renal transplantation, it was shown that MC receptors in lymphocytes of patients with cyclosporine was decreased significantly compared to the normal healthy population and the reason why findings of hypoaldosteronism were observed in these patients while maintaining aldosterone level was explained.[7] In our patient, hyperkalemia accompanied by severe hyponatremia despite metabolic acidosis with normal anion gap was explained with aldosterone resistance.\n\nIn another study conducted with 125 renal transplant patients, hyponatremia and hyperkalemia had been more frequently encountered in patients using tacrolimus than in those on cyclosporine treatment. Similar to our study, nine patients with hyponatremia had been treated with fludrocortisone which was tolerated well with resultant normalization of serum sodium levels. In their study, hyponatremia developed 14–79 days after transplantation, while in our case, it developed 149 days after transplantation, similar to a case report published in 2015.[8] In all of the similar studies, tacrolimus levels were found to be normal in patients with hyponatremia as in our case. In another recent study, although serum sodium levels improved within 48 h as a result of conversion from tacrolimus to everolimus,[7] in our case, hyponatremia did not improve despite a 4-week follow-up period and the need for replacement with 0.9% NaCl solution continued. After starting fludrocortisone, serum sodium level returned to normal after 48 h and no subsequent hyponatremia was observed. In addition, some studies have shown that fludrocortisone treatment is beneficial in renal transplant patients with calcineurin nephrotoxicity.[1, 9]\n\nAlthough calcineurin inhibitors may produce renal toxicity, they are the cornerstone of treatment in the renal transplantation population. Although a case report regarding a patient with tacrolimus-associated hyponatremia.[8] That responded to conversion to everolimus, it may not be appropriate to remove tacrolimus from the treatment protocol, particularly in the immunologically high-risk patient group. Fludrocortisone treatment can be preferred for this purpose due to its easy availability, rapid dose titration, and low side effect profile. However, despite the cessation of tacrolimus in our patient, hyponatremia could not improve, suggesting that this effect may be irreversible or may be accompanied by different mechanisms. There is a continuing need for further studies in this area.\n\nConclusion\nIn patients with renal transplantation, renal tubular dysfunction may occur despite normal tacrolimus levels and this condition should be kept in mind when hyponatremia develops. Fludrocortisone is effective and useful in the treatment of aldosterone-resistant salt-losing nephropathy. When hyponatremia is detected in the renal transplant patient, and tacrolimus-induced hyponatremia is considered after exclusion of other etiologies, fludrocortisone should be kept in mind as an effective treatment alternative.\n\nDisclosures\nInformed consent: Written informed consent was obtained from the patient for the publication of the case report.\n\nPeer-review: Externally peer-reviewed.\n\nConflict of Interest: None declared.\n\nAuthorship contributions: Concept – Y.K.; Design – F.B.Ç.; Supervision – Y.K., T.B.; Materials – F.B.Ç., P.N.; Data collection &/or processing – F.B.Ç., B.H.; Literature search – P.N., M.İ.; Writing –F.B.Ç.; Critical review – T.S., E.A., A.Ü.\n==== Refs\n1 Higgins R Ramaiyan K Dasgupta T Kanji H Fletcher S Lam F Hyponatraemia and hyperkalaemia are more frequent in renal transplant recipients treated with tacrolimus than with cyclosporin. Further evidence for differences between cyclosporin and tacrolimus nephrotoxicities Nephrol Dial Transplant 2004 19 444 50 14736972 \n2 Heering PJ Kurschat C Vo DT Klein-Vehne N Fehsel K Ivens K Aldosterone resistance in kidney transplantation is in partinduced by a down-regulation of mineralocorticoid receptorexpression Clin Transplant 2004 18 186 92 15016134 \n3 Bagchi S Husain Zaidi S Prasad Mathur R Severe symptomatic hyponatremia--an uncommon presentationof tacrolimus nephrotoxicity Nephrol Dial Transplant 2011 26 2042 4 21454354 \n4 Tumlin JA Sands JM Nephron segment-specific inhibition of Na+/K(+)-ATPase activity by cyclosporin A Kidney Int 1993 43 246 51 8381891 \n5 Ferrer-Martínez A Felipe A Barceló P Casado FJ Ballarín J Pastor-Anglada M Effects of cyclosporine A on Na,K-ATPase expression in the renal epithelial cell line NBL-1 Kidney Int 1996 50 1483 9 8914013 \n6 Deppe CE Heering PJ Viengchareun S Grabensee B Farman N Lombès M Cyclosporine a and FK506 inhibit transcriptional activity of the human mineralocorticoid receptor: a cell-based model to investigate partial aldosterone resistance in kidney transplantation Endocrinology 2002 143 1932 41 11956176 \n7 Heering PJ Klein-Vehne N Fehsel K Decreased mineralocorticoid receptor expression in blood cellsof kidney transplant recipients undergoing immunosuppressivetreatment: cost efficient determination by quantitative PCR J Clin Pathol 2004 57 33 6 14693832 \n8 Sayin B Tacrolimus-Induced Salt Losing Nephropathy Resolved AfterConversion to Everolimus Transplant Direct 2015 1 e37 27500237 \n9 Rabb HA Niles JL Cosimi AB Tolkoff-Rubin NE Severe hyponatremia associated with combined pancreatic and renal transplantation Transplantation 1989 48 157 9 2665224\n\n",
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"issue": "52(4)",
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"keywords": "Hyponatremia; renal transplantation; tacrolimus",
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"title": "Aldosterone Resistance Due to Tacrolimus: A Case Report.",
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"abstract": "We present a 7 yr old boy afflicted with super-refractory seizure that responded poorly to antiepileptic drugs and sustained a long course of hospitalization and complications of high doses of medications as well as longstanding stay in hospital. The differential diagnoses were, fever-induced refractory epileptic encephalopathy (FIRES), and infectious and autoimmune encephalitis. However, work-ups had not revealed any evidence of any specific diagnosis, so we assumed that he was afflicted by viral infectious encephalitis as he had, fever, vomiting, and prodromal symptoms of infectious (most probably viral) disease prior to onset of the seizure attacks.",
"affiliations": "Pediatric Neurology Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.;Pediatric Intensive Care Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.;Radiology Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.;Pediatric Neurology Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.;Pediatrics Department, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran.;Pediatric Neurology Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.;Pediatric Intensive Care Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Tavasoli|Alireza|A|;Gharib|Behdad|B|;Alizadeh|Houman|H|;Farshadmoghaddam|Hossein|H|;Memarian|Sara|S|;Ashrafi|Mahmoodreza|M|;Sharifzade|Meisam|M|",
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"fulltext": "\n==== Front\nIran J Child NeurolIran J Child NeurolIJCNIranian Journal of Child Neurology1735-46682008-0700Shahid Beheshti University of Medical Sciences Tehran, Iran ijcn-10-080Case ReportBrain on FIRES: Super Refractory Seizure in a 7 yr Old Boy Tavasoli Alireza MD 1GHARIB Behdad MD 2ALIZADEH Houman MD 3FARSHADMOGHADDAM Hossein MD 1MEMARIAN Sara MD 4ASHRAFI Mahmoodreza MD 1SHARIFZADE Meisam MD 21 Pediatric Neurology Department, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran2 Pediatric Intensive Care Department, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran3 Radiology Department, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran 4 Pediatrics Department, Children’s Medical Center, Tehran University of Medical Science, Tehran, IranCorresponding Author: Tavasoli AR. MD, Garib st, Pediatric Center, Tehran,Iran, Email:a_tavasoli@sina.tums.ac.irAutumn 2016 10 4 80 85 28 1 2016 10 7 2016 8 8 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a 7 yr old boy afflicted with super-refractory seizure that responded poorly to antiepileptic drugs and sustained a long course of hospitalization and complications of high doses of medications as well as longstanding stay in hospital. The differential diagnoses were, fever-induced refractory epileptic encephalopathy (FIRES), and infectious and autoimmune encephalitis. However, work-ups had not revealed any evidence of any specific diagnosis, so we assumed that he was afflicted by viral infectious encephalitis as he had, fever, vomiting, and prodromal symptoms of infectious (most probably viral) disease prior to onset of the seizure attacks.\n\nKey Words\nRefractory seizureInfectious encephalitisLateralized seizureAutoimmune encephalitis\n==== Body\nCase presentation\nA 7 yr old boy was referred to our hospital (Children’s Medical Center, Tehran, Iran) with the history of ‘fever’, ‘pharyngitis’, and ‘reduced level of consciousness’ (LOC). Five days prior to the initiation of the impaired level of consciousness and lethargy, he had had fever, sore throat, headache, lymphadenopathy of back of the neck, skin exanthema, pharyngitis and post nasal drip and was administered, benzathin penicillin and cefuroxime. \n\nThe day prior to hospitalization, he felt lethargic and generalized weakness, and developed status epilepticus with mixed type seizure (partial seizure presented by corner of lip twitching and eye blinking and myoclonic jerks of left upper and lower limbs) and as the seizure was not controlled with phenytoin, phenobarbital and midazolam continuous infusion, doctors of another hospital decided to induce barbiturate coma with pentobarbital. He was also prescribed the following medications: vancomycin, meropenem, acyclovir, azithromycin, ribavirin, oseltamivir and dexamethasone, with the impression of infectious encephalitis, however no germ was recognized in the blood and cerebrospinal fluid cultures, and three lumbar punctures performed later in the evolution of the illness were normal. His past medical history was unremarkable except for having contact with travelers to Haj (a Muslims’ pilgrimage ceremony, where Muslims gather around from all over the world in Saudi Arabia, and occasionally cases of meningitis, and new species of influenza have been reported among the travelers).\n\nWe received the patient on the third day of LOC with Glasgow coma scale (GCS) of 6 without spontaneous respiration and attached to the mechanical ventilator. On physical examination, his weight was 23 kg, no deep tendon reflex was detected, oculocephalic reflex was normal, Babinski reflex was unresponsive, heart and pulmonary auscultation were normal, the pupils were midsized and non-reactive to light and liver border located 4 centimeters below the costal border, pulse rate= 140 beats per min, and blood pressure= 104/72 cm Hg.\n\nThe blood work results were as follows; white blood cells: 1900/μl, neutrophils: 55% (absolute neutrophil count=1045), lymphocyte= 45%, hemoglobin=10.9 gr/deciliter, platelet= 104000/ μl, blood urea nitrogen (BUN)= 11 mg/ deciliter, creatinine= 0.7 mg/ deciliter, lactate dehydrogenase (LDH)= 1047 IU/l (normal range up to 746), AST= 60 U/l (up to 37), ALT= 28 U/l (up to 41), C-reactive protein (CRP)= 7.3 milligram/liter (normal range up to 6), erythrocyte sediment rate= 13 mm/h (normal range up to 10), calcium= 7.7 mg/ deciliter (normal range 8.8-10.2), sodium= 133 mill equivalent/l, potassium= 4 milliequivalent/l and normal serum ammonia and coagulation profile.\n\nThe complementary blood and cerebrospinal laboratory test were negative for autoimmune disease (antithyroid peroxidase and anti-double-stranded DNA antibodies), metabolic disease, thyroid diseases, immunodeficiency disorders, and PCR of cat scratch disease, CMV, HSV, HHV 5 and 6, Corona virus, influenza, Ebstein- Barrand JC virus. Later in the course of the disease, the complete panel of CSF for autoimmune encephalitis was also performed, which was negative. The patient’s first diagnosis was super refractory seizure caused by infectious encephalitis and hospitalized for 77 days. \n\nOn the 1st day of admission, we started with midazolam and phenobarbital. As the convulsions continued, the neurologist consultant recommended administering repeated loading dose and increasing gradually the maintenance dose to the maximum level of, phenytoin, phenobarbital and sodium valproate. Propofol (load and maintenance) was started, and midazolam infusion increased to 10 mcg/kg/min, but without success in controlling seizure. The seizures started with simultaneous loss of consciousness and seemed to be very sensitive to tactile stimulus from the beginning, and were mostly localized on left side. Because of hypotension caused by side effects of antiepileptic drugs, norepinephrine 0.05 microgram/kg/min started and echocardiography performed and revealed that the ejection fraction of heart was 50-60%. Brain computerized tomography (CT scan) was performed and revealed; faint low attenuated areas in the right Lentiform nucleus at the level of midbrain (Figure 1).\n\nFig 1 Faint low attenuated areas in the left lentiform nucleus at the level of midbrain are seen\n\nOn the 2nd day, mannitol infusion and other measures for cerebral edema (seen on brain computerized tomography) were administered. On the 3rd day, he had myoclonic seizures in the left hand, and sodium valproate continuous infusion, topiramate (25 mg/twice a day per gavage) was started and considered the possibility of autoimmune encephalitis, high dose of methyl prednisolone (500 mg intravenous/d for 5 d) was also administered but did not affect the course of seizures. Because of hypotension, pentobarbital discontinued.\n\nOn the 4th day, as the super refractory seizure was not controlled, midazolam discontinued, and pyridoxine (100 mg intravenous daily), chloral hydrate (15 cc/4 h via enteral route from the 1% solution), topiramate (increased to 50 mg twice a day), thiopental, intravenous immunoglobulin (IVIG), and levetiracetam started. The probable diagnoses were considered autoimmune encephalitis or infectious-related epileptic encephalopathy.\n\nCerebro-spinal fluid (CSF) analysis was normal and was also negative for autoimmune encephalitis. On the 5th day, sodium valproate continuous infusion changed to the intermittent dose (160 mg/ 3 times a day) and diazepam load and continuous infusion started. \n\nOn the 6th day, he developed cerebral salt wasting. On the 7th day, ketamine infusion (14 mg/h) started and continued with gradual increments, still without any success in controlling seizures.\n\nAfter 2-3 weeks, the seizure attacks were reduced, and with gradual tapering of the drugs, dyskinesia phenomenology compatible with “Dystonic tremor” and chorea appeared. Therefore, we prescribed, baclofen, artan, madopar (levodopa and benserazide) and tetrabenazine, which were partially effective. The dyskinesia continued even during comatose condition. Moreover, the initiation of these movements was also very sensitive to touch and sound. An electroencephalogram (EEG) revealed ‘’generalized multifocal paroxysmal epileptic discharge’’ and because of status dystonicus type of dyskinesia, madopar, clonidine and tetrabenazine were continued which seemed to be effective partially. \n\nThe focal convulsion continued with presentation of, ‘’jaw lock, drooling, lateral gaze, dystonia, corner of lip twitching and blinking’’. On the 40th day of hospitalization; chorea and dystonia continued but the pattern of dyskinesia started changing gradually to a movement disorder, as they stopped during sleeping state. Therefore, trihexyphenidyl was added to the medication list. Magnetic resonance imaging (MRI) in FLAIR sequence on the 50th day of admission revealed “abnormal right parietal cortico-subcortical high signal’ (Figure 2).\n\nFig 2 Magnetic resonance imaging (MRI) in FLAIR sequence showing ‘abnormal right parietal corticosubcortical high signal’\n\nDuring his long stay he sustained the problems of prolonged hospitalization such as nosocomial blood stream infection, gastric content pulmonary aspiration, drug induced neutropenia, tracheal tube dislocation and intubation and extubation procedures, tracheostomy, and low blood pressure as the side effect of antiepileptic medications, managed accordingly. He also afflicted by left wrist flexion deformity and spasm, that continued after discharge. \n\nThe long list of antiepileptic medications prescribed (gradually increased and tapered off or continued, according to the useful effects and side effects) were as follows:\n\nPhenytoin (day 1 to 38), phenobarbital (day 1 to ‘discharged with’), pentobarbital (day 1 to 3), sodium valproate (day 1 to ‘discharged with’), midazolam (day 2 to 5, as continuous infusion and intermittent doses), propofol (day 2 to 3), topiramate (day 3 to ‘discharged with’), high dose methylprednisolone (day 3 to 9), IVIG (day 4 to 7), clonazepam (day 4 to 39), pyridoxine (day 4 to ‘discharged with’), levetiracetam (day 4 to ‘discharged with’), thiopental (day 4 to 7),chloral hydrate (day 4 to 10), diazepam (day 4 to 35 as continuous infusion and intermittent doses), vigabatrin (day 5 to 63), ketamine infusion (day 8 to 15), and carbamazepin (day 28 to 52). \n\nAround the 45th – 50th day of hospitalization the seizure activity reduced significantly, and on the day 77, the patient discharged with; phenobarbital tablet (30mg in morning, 60 mg in night), pyridoxine tablet (60 mg daily), topiramate tablet (25 mg in morning, 50 mg in night), epilim syrup (200 mg/5cc, 5cc * 3 times a day), levetiracetam (500 mg 3 times a day), trihexyphenidyl (2 mg 3 times a day), risperidone tablet (0.5 mg 2 times a day), and carnitine syrup.\n\nOn the follow-up visits, he had not had any seizure activity for about 4 months after discharge. The seizure activity started for the first time after discharge, triggered by staying awake till morning and playing computer games, in sleep state, and it was in figure of left upper and lower limb jerk, and left hemifacial twitching, which extended to both lower limb jerk. This episode lasted shortly and a similar episode occurred one month later (5 month after discharge), and since the latter episode, he has had several episodes (2-3 times per month) and all of the seizures were associated with loss of consciousness (predominantly partial type with staring) without loss of muscle tone, and lateralized on the left side. \n\nOne year after discharge, he still has seizure activity with the frequency of about 1-2 times weekly which lasts 1-2 min, as mentioned above. He also has minimal cognitive dysfunction, slurred speech and flexion deformity of left hand. His weight is 37 kg now and is receiving the following list of medications: topiramate 50 mg/twice a day, levetiracetam 500mg/twice a day, phenobarbital 50 mg/ twice a day, valproate sodium 400 mg/twice a day, pregabaline 25 mg/three times a day (for neuropathic pain of the left hand), thiamine 100 mg and pyridoxine 40 mg twice a week.\n\nDiscussion\n“When status epilepticus continues or recurs in spite of 24 hours of general anesthesia, it is defined as superrefractory status epilepticus” (8). Encephalopathies or another central nervous (CNS) infection should be considered when the patient has a group of symptoms of recent febrile illness with behavior, cognition, consciousness and personality changes or new focal neurological signs (6). The differential diagnosis of encephalopathy in children includes a wide range of etiologies such as metabolic, genetic, traumatic, infectious, para-infectious, toxic and malignancies (4). Inflammation caused by etiologies such as direct invasion of brain parenchyma, antibodies directed against components of CNS, has an important role in status epilepticus (SE) (2).\n\nFIRES is an infection-related epileptic encephalopathy with undefined etiology. It has many names like, Devastating epileptic encephalopathy in school-aged children (DESC), Acute encephalitis with refractory repetitive partial seizures (AERRPS), Idiopathic catastrophic epileptic encephalopathy, and New onset refractory status epilepticus (NORSE). Severe refractory status epilepticus due to presumed encephalitis. Genetic susceptibility and inflammation have been proposed as the etiologies (3). In FIRES, children develop seizure that rapidly turns into SE. This situation occurs a few days to one week after a non-specific febrile infection. \n\nThe chronic phase continues after the acute phase characterized by pharmaco-resistent epilepsy. Seizures are usually generalized with focal onset. Weeks or months after the initiation of the illness, seizures decrease or stop, and intractable epilepsy starts a few weeks to 3 months after the end of SE (2). The prognosis of FIRES is poor (3).\n\nAll patients afflicted by FIRES have an infection one week before the beginning of the symptoms which is mostly respiratory tract infection (5).\n\nAutoimmune encephalitis is a group of disorders associated with antibodies against the surface proteins of neuronal cells and synaptic receptors. They have a wide range of symptoms including seizure, behavioral changes, psychosis, catatonia, autonomic dysregulation and abnormal movements (10). Some patients afflicted by autonomic encephalitis may progress to a more generalized encephalopathy with movement disorder (4). Nonspecific viral infections may lead to breaking immune tolerance and increase the possibility of the antibodies to enter CNS by increasing the permeability of the blood-brain barrier. Occasionally a tumor that produces the target neuronal antigen likely contributes in triggering the immune response. However in many of autoimmune encephalitis disorders the blood brain barrier seems to be intact and the autoantibodies may be synthetized inside the CNS (10).\n\nPerhaps HSV is the most frequent cause of sporadic encephalitis, and have a tendency to affect the temporal lobe (1).\n\nIn herpes encephalitis negative result of polymerase chain reaction for HSV, does not rule out the infection and treatment with acyclovir should be completed for 21 days (9). A cerebro-spinal fluid sample without abnormal cells has been described for varicella zoster virus, Epstein- Barr virus and cytomegalovirus and is more prevalent in immune-deficient patients (6). \n\nSystemic infection with influenza virus can cause seizure provoked by fever and systemic illness, extrapyramidal syndromes, Guillain-Barre syndrome, encephalitis and transverse myelitis. H1N1 can lead to encephalopathy and focal findings and there has been no evidence supporting the benefits of antiviral treatment for neurologic course of the disease. A rare type of acute encephalopathy/ encephalitis associated with influenza, can begin with a fulminant neurologic disease and may be accompanied with any influenza viral serotype. This disease may be associated with a genetic disorder in releasing pro- inflammatory cytokines and hypercytokinemia (1).\n\nHuman herpes virus type 6 which is a common viral illness in childhood may invade CNS at the time of primary infection and rarely cause a clinical neurologic disease but long-term latent infection may occur, and in case of immunosuppression, acute limbic encephalitis, probably due to reactivation of the virus can occur (1). \n\nThe patient’s problem presented first with an infectious disease (upper respiratory tract infection) and fever that proceeded to vomiting, decreased level of consciousness and refractory seizure with lateralized features. He responded poorly to antiepileptic drugs and sustained a long course of hospitalization and complications of high doses of medications and longstanding stay in hospital. The neurologist consultant even tried ketamine, which has had promising effects in controlling refractory status epilepticus, when midazolam, propofol and phenobarbital, failed to control seizures (7). The differential diagnosis were as follows: Fever-induced refractory epileptic encephalopathy (FIRES), infectious and autoimmune encephalitis, however work-ups had not revealed any evidence of any specific diagnosis, at last we assume that he was afflicted by viral infectious encephalitis as he had, fever, vomiting, and prodromal symptoms of infectious (most probably viral) disease, prior to onset of the seizure attacks. Autoimmune encephalitis was considered because of the refractory course and abnormal movements occurred in the course of the illness and ruled out as the antibodies’panel of cerebro-spinal fluid (CSF) was negative and no response seen to high dose of methylprednisolone and intravenous immunoglobulin administration. \n\n\nIn Conclusion, we did not find abnormal results in CSF analysis and viral PCR work-ups, but as mentioned above occasionally this may happen and clinically we assume viral encephalitis as the first differential diagnosis of our patient. \n\nAuthors’ Contribution\nAR Tavasoli: Drafting. \n\nB.Gharib: Drafting, Designing, final approval of the work, Interpretation.\n\nH. Alizadeh: Interpretation\n\nH. Farshad moghaddam: Drafting.\n\nS. Memarian: Drafting, Final approval of the work Mahmoodreza Ashrafi: Designing of the work\n\nM. Sharifzade: Drafting, Final approval of the work\n\nAll authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\n\n\nConflict of interest: Non- declared\n==== Refs\nReferences\n1 William H Theodore, Epilepsy and Viral Infections 2014 Vol. 14 No. 1 Supplement Epilepsy Currents 35 42 \n2 Rima Nabbout AnnamariaVezzani Olivier Dulac Catherine Chiron Acute encephalopathy with inflammation-mediated status epilepticus Lancet Neurol 2011 10 99 108 21163447 \n3 Uri Kramer Ching-Shiang Chi Kuang-Lin Lin Nicola Specchio Mustafa Sahin Heather Olson Rima Nabbout Gerhard Kluger Jainn-Jim Lin Andreas van Baalen Febrile infection–related epilepsy syndrome (FIRES): Pathogenesis, treatment, and outcome, A multicenter study on 77 children Epilepsia 2011 52 11 1956 1965 21883180 \n4 Yael Hacohen Sukhvir Wright Patrick Waters Shakti Agrawal Lucinda Carr Helen Cross et al Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens J Neurol Neurosurg Psychiatry 2012 0 1 8 \n5 Pedro J Serrano-Castro Pablo Quiroga-Subirana Manuel Payan-Ortiz Javier Fernandez-Perez The expanding spectrum of febrile infection-related epilepsy syndrome (FIRES) Seizure 2013 22 153 155 23237766 \n6 R Kneen BD Michael E Menson B Mehta A Easton C Hemingway PE Klapper A Vincent M Lim E Carrol T Solomon, On behalf of the National Encephalitis Guidelines Development and Stakeholder Groups Management of suspected viral encephalitis in children e Association of British Neurologists and British Paediatric Allergy Immunology and Infection Group National Guidelines J Infect 2012 64 449 477 22120594 \n7 Raoul Sutter Stephan Rüegg Refractory Status Epilepticus: Epidemiology, Clinical Aspects and Management of a Persistent Epileptic Storm Epileptologie 2012 29 186 193 \n8 Simon Shorvon Super-refractory status epilepticus: An approach to therapy in this difficult clinical situation Epilepsia 2011 52 Suppl. 8 53 56 \n9 Mustafa AM Salih Heba Y El Khashab Hamdy H Hassan Amal Y Kentab Sara S Al Subaei Radwan M Zeidan Mohammed N Al-Nasser Saleh A Othman A Study on Herpes Simplex Encephalitis in 18 Children, Including 3 Relapses Open Pediatr Med J 2009 3 48 57 \n10 Thais Armangue Josep O Robert M. Kliegman Bonita F Stanton Joseph W. St. Geme III Nina F. Schor Richard E. Behrman Autoimmune Encephalitis Dalmau 2016 20th Edition Philadelphia United States of America: Saunders 2905 2910\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1735-4668",
"issue": "10(4)",
"journal": "Iranian journal of child neurology",
"keywords": "Autoimmune encephalitis; Infectious encephalitis; Lateralized seizure; Refractory seizure",
"medline_ta": "Iran J Child Neurol",
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"pages": "80-85",
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"pmid": "27843471",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "21967364;23175854;23237766;21883180;22120594;21163447;24955074",
"title": "Brain on FIRES: Super Refractory Seizure in a 7 yr Old Boy.",
"title_normalized": "brain on fires super refractory seizure in a 7 yr old boy"
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"abstract": "Plaque induced gingival enlargement is most commonly seen and when encountered simultaneously with erosive lichen planus poses a challenge to the treating dentist. Prognosis of one condition may influence the prognosis of another condition. The presented case highlights the significance of proper diagnosis and the management of simultaneously occurring gingival lesions. A 49-year-old hypertensive female presented with painful enlarged bleeding and suppurating gums with burning sensation on eating food along with long-term usage of antihypertensive drug amlodipine known for its gingival enlargement effect. All these multiple factors led to diagnostic dilemma. Effective management of the gingival enlargement was done by using electrocautery to rehabilitate the functions and esthetics of the patient. Gingival condition was also complicated by the presence of coexisting lichen planus which was predominantly erosive for which topical corticosteroid, antifungal, and antimicrobial agents were prescribed. Eight-month follow-up did not show recurrence of gingival enlargement. Electrocautery is an effective tool for the gingivectomy in severe inflammatory type of gingival enlargement because of rapid postoperative hemostasis. For the management of erosive lichen planus, long-term use of topical corticosteroids is an effective approach. Maintenance of oral hygiene and regular follow-ups are essential for these conditions.",
"affiliations": "Department of Periodontology, Centre for Dental Education & Research, AIIMS, New Delhi 110029, India.;Department of Oral Pathology and Microbiology, Centre for Dental Education & Research, AIIMS, New Delhi 110029, India.;Department of Pedodontics and Preventive Dentistry, Centre for Dental Education & Research, AIIMS, New Delhi 110029, India.;Department of Pedodontics and Preventive Dentistry, Centre for Dental Education & Research, AIIMS, New Delhi 110029, India.",
"authors": "Sharma|Ambika|A|;Aggarwal|Chakshu|C|;Mathur|Vijay P|VP|;Sardana|Divesh|D|",
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"country": "Egypt",
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"doi": "10.1155/2015/538538",
"fulltext": "\n==== Front\nCase Rep DentCase Rep DentCRIDCase Reports in Dentistry2090-64472090-6455Hindawi Publishing Corporation 10.1155/2015/538538Case ReportSevere Gingival Enlargement with Coexisting Erosive Lichen Planus in Severe Chronic Periodontitis Patient Sharma Ambika \n1\nAggarwal Chakshu \n2\n\n*\nMathur Vijay P. \n3\nSardana Divesh \n3\n1Department of Periodontology, Centre for Dental Education & Research, AIIMS, New Delhi 110029, India2Department of Oral Pathology and Microbiology, Centre for Dental Education & Research, AIIMS, New Delhi 110029, India3Department of Pedodontics and Preventive Dentistry, Centre for Dental Education & Research, AIIMS, New Delhi 110029, India*Chakshu Aggarwal: drchakshu@hotmail.comAcademic Editor: Tommaso Lombardi\n\n2015 9 3 2015 2015 5385381 10 2014 10 12 2014 23 2 2015 Copyright © 2015 Ambika Sharma et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Plaque induced gingival enlargement is most commonly seen and when encountered simultaneously with erosive lichen planus poses a challenge to the treating dentist. Prognosis of one condition may influence the prognosis of another condition. The presented case highlights the significance of proper diagnosis and the management of simultaneously occurring gingival lesions. A 49-year-old hypertensive female presented with painful enlarged bleeding and suppurating gums with burning sensation on eating food along with long-term usage of antihypertensive drug amlodipine known for its gingival enlargement effect. All these multiple factors led to diagnostic dilemma. Effective management of the gingival enlargement was done by using electrocautery to rehabilitate the functions and esthetics of the patient. Gingival condition was also complicated by the presence of coexisting lichen planus which was predominantly erosive for which topical corticosteroid, antifungal, and antimicrobial agents were prescribed. Eight-month follow-up did not show recurrence of gingival enlargement. Electrocautery is an effective tool for the gingivectomy in severe inflammatory type of gingival enlargement because of rapid postoperative hemostasis. For the management of erosive lichen planus, long-term use of topical corticosteroids is an effective approach. Maintenance of oral hygiene and regular follow-ups are essential for these conditions.\n==== Body\n1. Introduction\nGingival enlargement, previously known as gingival hyperplasia or gingival hypertrophy, is an increase in the size of gingiva. It is a common feature of gingival diseases. There are several causes of gingival enlargement which can be grouped into five categories: inflammatory, drug induced, in association with systemic diseases or conditions, neoplastic, and false enlargement [1]. Chronic plaque accumulation can also lead to chronic inflammatory gingival enlargement.\n\nOral lichen planus (OLP), the mucosal counterpart of cutaneous lichen planus, presents frequently in the fourth decade of life and affects women more than men in a ratio of 1.4 : 1 [2]. OLP can be seen clinically as reticular, papular, plaque-like, erosive, atrophic, or bullous types. Atrophic lesions account for 5% to 44% of OLP manifestations, while the erosive and/or ulcerative ones vary between 9% and 46% of cases [3]. Most of the subjects with erosive forms of lichen planus (LP) present with symptoms of pain and burning sensation in the affected area.\n\nGingival manifestation of multiple diseases/conditions may lead to difficulty in diagnosis as well as in management as seen in this reported case where multiple conditions like chronic periodontitis, gingival enlargement, erosive lichen planus, history of long-term use of drug Amlodipine known for causing drug induced gingival enlargement [4], and history of menopause were present.\n\nAn understanding of the cause and underlying pathologic changes is essential for the treatment of gingival enlargement. In the present case, patient had severe chronic inflammatory gingival enlargement with coexisting lichen planus which was predominantly erosive manifested as desquamative gingivitis with underlying severe chronic periodontitis. This case was treated effectively in the following phases: (1) through phase 1 therapy including supra- and subgingival scaling along with prescription of 0.2% chlorhexidine mouth rinse for two weeks and patient motivation and education, (2) substitution of the drug Amlodipine with drug Telmisartan, (3) surgical excision of the residual gingival overgrowth with the help of electrocautery under local anesthesia, and (4) maintenance and supportive therapy.\n\nElectrocautery was used at 50 Hz frequencies at electrosection and electrocoagulation modes. For the management of erosive lichen planus, topical corticosteroids including Kenacort oral paste (0.1% triamcinolone acetonide) and mouth rinse comprising 0.5 mg betamethasone were prescribed. Antifungal agent in the form of candid mouth-paint (1% w/v clotrimazole) was also prescribed to prevent opportunistic candida infection.\n\n2. Case History\nA 49-year-old female patient presented with chief complaint of swollen gums in upper front region. She first noticed a small painless growth from gingiva about a year back. The size of the growth did not increase much during the first six months; however, there was a rapid increase in the later six months. She also had multiple mobile teeth, halitosis, sticky discharge, and unprovoked bleeding from the gums during the last few months. The patient also had history of burning sensation while eating food and difficulty in mastication, speech, and brushing teeth. She did not have previous diagnosis and treatment for this burning sensation. Medical history of hypertension was present for which she was prescribed antihypertensive drug, Tab. Amlodipine (long-acting dihydropyridine) 5 mg/day, to be administered systemically once a day orally for the last 12 years.\n\nOn the day of reporting to the hospital, she was conscious, cooperative, and with no visible gross problems. However, the lips were incompetent and enlarged gingiva was protruding between the lips. Apart from this, no extraoral swelling or cutaneous lesions were observed.\n\nIntraoral examination revealed diffuse gingival enlargement which was massive in size in maxillary anterior region extending from right second premolar to left second premolar. Enlargement of the gingiva was in the horizontal as well as in the vertical direction protruding below the incisal edges of the anterior teeth on palatal aspect. Diffuse moderate gingival enlargement was also present on other regions of the upper arch and on the lower arch (Figure 1(a) shows incompetent lips due to gingival swelling; Figures 1(b) and 1(c) show the extent of intraoral gingival swelling). This was soft and edematous on palpation with high tendency to bleed even on gentle touch. Generalized diffuse desquamative gingivitis along with creamy striae on the periphery of desquamative gingival lesions was noted. Bilateral white lesions with striae at borders were noted on buccal mucosa and dorsum of tongue which were denuded of papilla (Figure 2(a) shows desquamative gingivitis; Figures 2(b) and 2(c) show plaque type lichen planus on buccal mucosa and tongue). Periodontal probing revealed presence of true periodontal pockets with attachment loss of more than 3 mm in most of the teeth in maxillary arch. Attachment loss of more than 5 mm along with pathological migration was noted in maxillary central and lateral incisors. Grade 2 mobility was noticed in both maxillary central incisors and grade 1 mobility in the mandibular incisors. Spontaneous bleeding and purulent discharge were present from gingival sulcus of most of the teeth. Based on these clinical findings, provisional diagnosis of severe chronic periodontitis was concluded with presentation of severe inflammatory gingival enlargement and lichen planus (LP) which was predominantly erosive in nature. These were coexisting conditions at the same time. Role of drug induced gingival enlargement was also suspected in the present case, as the patient was taking Tab. Amlodipine to control hypertension for the last 12 years, which is known to cause fibrotic gingival enlargement.\n\nOrthopantomograph revealed generalized horizontal pattern of bone loss. Routine blood investigations, including complete blood count, blood sugar test, bleeding time, and clotting time, were performed, which were found to be in normal range. Two incisional biopsies, one from palatal gingiva and another from left buccal mucosa, were obtained under local anaesthesia for the histopathological examination. Histopathological evaluation of gingival region biopsy revealed localized band-like dense inflammatory infiltrate with numerous capillary structures lined by plump endothelial cells, moderately scattered inflammatory cells in connective tissue with loss of surface epithelium compatible with erosive type of lichen planus, and pyogenic granuloma (Figure 3(a)). Histopathological evaluation of buccal mucosal lesion showed thickening of parakeratinized stratified squamous epithelium, degenerating basal cells with vacuolization, and dense lymphocytic infiltrate at epithelium connective tissue junction. Saw tooth rete ridge pattern and subepithelial histological clefts were also seen (Figure 3(b)). Confirmatory diagnosis of LP was rendered (which was plaque type in clinical presentation).\n\nBefore starting dental treatment, patient was referred to her treating physician for the substitution of drug Amlodipine, due to its known etiological role with another antihypertensive drug. Tab. Amlodipine was then substituted with Tab. Telmisartan 40 mg. Patient was motivated and educated for oral hygiene maintenance by instructing proper brushing technique. Treatment was started with nonsurgical phase 1 therapy which included gross scaling and root planning with ultrasonic scalers. 10 mL of 0.2% chlorhexidine gluconate mouthwash (which provides 20 mg of effective dose against plaque formation) was prescribed twice daily for two weeks. Only mild reduction was noted in signs and symptoms of gingival inflammation after 14 days of oral prophylaxis. Because of persisting inflammatory nature of the lesion, its massive size, and high bleeding tendency, excision of the enlarged gingival tissue was planned with the help of electrocautery. Debulking incisions were given for the gingivectomy at 50 Hz frequencies with needle electrode. Patient was prescribed nonsteroidal anti-inflammatory analgesic Tab. Flexon (ibuprofen 400 mg and paracetamol 500 mg) twice a day for three days, and to prevent postoperative infection, broad spectrum antibiotic effective against most of the pathogenic oral Gram-positive and Gram-negative bacteria, Cap. amoxicillin 500 mg 6 hourly for one week, was also prescribed. At 7-day follow-up visit (Figure 4(a)), no postoperative complication was encountered and healing was found to be uneventful. After 15 days, complete oral prophylaxis was done and oral hygiene instructions were reinforced. Consultation from dermatology and oral medicine department was taken by us for the first time for their expert opinion regarding treatment of erosive lichen planus. Patient was then prescribed topical corticosteroids, Kenacort oral paste (0.1% triamcinolone acetonide), and mouth rinse comprising 0.5 mg betamethasone along with antifungal agent candid mouth-paint (1% w/v clotrimazole) twice a day for one month. Patient was recalled after every week for the first month and then every month (Figure 4(b) after one month) for follow-ups and oral prophylaxis. No recurrence of gingival enlargement was seen after 8-month follow-up (Figure 4(c)) but with mild erythematous lesions. Patient was able to perform her routine functions normally. Patient is still under the treatment for erosive lichen planus with regular follow-ups.\n\n3. Discussion\nThe gingival enlargement in the reported case was of the inflammatory type. The exact role of Amlodipine was not predictable in the present case which is known to cause fibrotic gingival enlargement. Clinical manifestation of drug induced gingival enlargement frequently appears within 1 to 3 months after initiation of treatment with the associated medication [5]. But in the reported case, patient was taking Amlodipine for the last 12 years and noticed the enlargement since the last year only. Moreover, clinical and histological picture mimic inflammatory lesion instead of fibrotic drug induced gingival enlargement. In this case, chronic plaque accumulation which led to chronic periodontitis appeared to be the etiological agent for the inflammatory type of gingival enlargement. Hormonal changes due to menopause appeared to contribute further to the inflammation of the gingival tissue [6]. Concomitant presence of oral lichen planus which is also a chronic inflammatory disease has increased the inflammatory component. Impeded maintenance of oral hygiene practice because of bleeding tendency and increased size of gingiva led to the formation of vicious cycle for increased plaque accumulation and thus further increase in gingival inflammation. Commonly involved sites for OLP are the buccal mucosa, tongue, and the gingiva although other sites may be affected. The erosive form primarily manifests in the buccal mucosa and lingual dorsum, and it, along with the atrophic form, appears with most of the symptoms [7].\n\nThe diagnosis of OLP is based on the clinical appearance of the lesions and is subsequently confirmed by histopathological study [8]. In this case, diagnosis of LP was made by us for the first time by its clinical and histological evaluation. The presence of erosive lichen planus on the gingival mucosa is characterized by the presence of diffuse erythematous areas that may or may not be interspersed with desquamative and ulcerated foci. The whitish lesions may occur following the shape of the gingival outline. Characteristic hyperkeratotic radiating striae found at the periphery of the erosive regions also aid in diagnosis as observed in the present case. The clinical appearance known as desquamative gingivitis is not pathognomonic of oral erosive lichen planus and may represent the gingival manifestation of many other diseases such as pemphigus vulgaris, cicatricial pemphigoid, epidermolysis bullosa acquisita, lupus erythematosus, and linear IgA disease.\n\nSeveral antigen-specific and nonspecific inflammatory mechanisms have been put forward to explain the pathogenesis of OLP. It is considered as T-cell-mediated autoimmune disease in which the autocytotoxic CD8+ T cells trigger apoptosis of the basal cells of the oral epithelium [9]. The migrated CD8+ cells are activated directly by antigen binding to major histocompatibility complex (MHC-1) on keratinocyte or through activated CD4+ lymphocytes. The matrix metalloproteinase (MMP) is principally involved in tissue matrix protein degradation. MMP-9, which cleaves collagen 4 along with its activators, is upregulated in OLP lesional T cells, resulting in increased basement membrane disruption [10].\n\nThere is controversy regarding malignant potential of OLP. Some studies indicate an increased risk of squamous cell carcinoma in patients with OLP lesions [11, 12]. A review of previously published studies concluded that the risk of developing squamous cell carcinoma in patients with OLP is approximately ten times higher than that in the unaffected general population [13].\n\nIt has been commonly associated with the erosive and atrophic forms [3, 14]. Most cases of reported malignant transformation are rather poorly documented. Some of these cases may not have been true lichen planus, but rather they may have actually been dysplastic leukoplakia with secondary lichenoid inflammatory infiltrate which mimicked lichen planus [5].\n\nIn contrast, other studies rule out the connection between OLP and oral cancer [15, 16]. Despite the controversy, clinician should perform biopsy and close follow-up in these patients.\n\nHormonal dysfunction, candidosis, lichenoid lesions, and the vulvovaginal-gingival syndrome must also be included in the differential diagnosis of oral erosive lichen planus [17–19]. Difficulties in the establishment of diagnosis of gingival lichen planus may arise if gingivitis and periodontitis are superimposed on the lesions [8]. As in the present case, periodontitis with severe gingival enlargement and superimposed erosive lichen planus were present simultaneously and led to diagnostic dilemma.\n\nTreatment is aimed primarily at reducing the length and severity of symptomatic outbreaks. The most widely accepted treatment for OLP is topical corticosteroid because they are directly applied over the affected area and have less chance of systemic complications. These are the single most useful group of drugs having the ability to modulate inflammation and immune response. Alternative treatments like retinoid, cyclosporine, tacrolimus, surgery, and carbon dioxide (CO2) laser may also be used. Recently, low level laser therapy (LLLT) has been used for treating erosive OLP with minimal side effects [20–22]. Treatment choice may vary from patient to patient depending on their symptomatic history, severity of lesions, and systemic condition of the patient. Excellent oral hygiene is also required to reduce the severity of the symptoms, but it can be difficult for patients to achieve high levels of hygiene during periods of active disease. Currently, there is no definitive cure for OLP. Unlike cutaneous lichen planus, which in most cases progresses by short-term outbreaks that almost always respond well to treatment or even regress after a few months, OLP is characterized by its chronicity, persistence with periods of exacerbation and quiescence, and resistance to therapy.\n\nIn the present case, topical corticosteroids, antifungal agents, and antimicrobial mouth rinse were prescribed. Kenacort oral paste (0.1% triamcinolone acetonide) and mouth rinse prepared by dissolving Tab. Betnesol 0.5 mg (betamethasone) in 10 mL of water were prescribed after consultation with oral diagnostician. Since prolonged use of corticosteroids can cause opportunistic infection like oral candidiasis or thrush, antifungal agent as Candid gel (clotrimazole 1% w/v) was also prescribed to the patient for twice daily application. Patient was motivated and educated for maintaining good oral hygiene.\n\nFor patients with gingival overgrowth, the modification of tissue topography by surgical recontouring or gingivectomy may be undertaken to create a maintainable oral environment [17]. In the present case, treatment was largely limited to the maintenance of an improved level of oral hygiene by doing oral prophylaxis at every recall visit and surgical removal of the overgrowth tissues. Since the lesion was predominantly inflammatory in nature, electrocautery was used for the gingivectomy procedure. Electrocautery permits an adequate contouring of the tissue and controls hemorrhage [23, 24]. Patient was relieved symptomatically for OLP but not cured completely but was able to perform the routine functions and is aesthetically and psychologically satisfied.\n\n4. Conclusion\nProper diagnosis and management are essential when multiple diseases or conditions manifest in the oral cavity as seen in the present case. Electrocautery is effective means of gingivectomy in severely inflamed, massive sized gingival enlargement with marked tendency for bleeding.\n\nTopical steroids are safer and effective means for the palliative treatment of erosive lichen planus. Routine follow-up with maintenance of good oral hygiene is also an important part of management of gingival lesions.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 (a) shows incompetent lips due to gingival overgrowth. (b) and (c) show intraoral gingival enlargement with erythematous lesion, spontaneous bleeding sites, calculus, and purulent discharge.\n\nFigure 2 (a) shows generalized erythema and fragility with very fine white striae at the tips of interdental papillae. (b) shows dense white striae (plaque type LP) bordering erythematous lesions on buccal mucosa. (c) shows white plaque type patch with loss of papilla and melanin pigmentation on the dorsum of tongue.\n\nFigure 3 (a) shows localized band-like inflammatory cell infiltrate in the connective tissue and ulcerated surface epithelium with thin endothelium-lined capillary structures and inflammatory cells. (b) shows thickening of surface epithelium with basal cells vacuolization, dense lymphocytic infiltrate at epithelium connective tissue junction with serrated rete ridge pattern.\n\nFigure 4 (a) shows follow-up after 1 week with initial healing. (b) shows healing after one month. (c) shows gingival status on 8-month follow-up.\n==== Refs\n1 Newman M. G. Takie H. Klokkevold P. R. Carranza F. A. Gingival enlargement Carranza’s Clinical Periodontology 2007 10th Saunders p. 373 \n2 Sugerman P. B. Savage N. W. Walsh L. J. The pathogenesis of oral lichen planus Critical Reviews in Oral Biology and Medicine 2002 13 4 350 365 10.1177/154411130201300405 2-s2.0-0036929027 12191961 \n3 Scully C. Beyli M. Ferreiro M. C. Update on oral lichen planus: etiopathogenesis and management Critical Reviews in Oral Biology and Medicine 1998 9 1 86 122 10.1177/10454411980090010501 2-s2.0-7844242240 9488249 \n4 Seymour R. A. Ellis J. S. Thomason J. M. Monkman S. Idle J. R. Amlodipine-induced gingival overgrowth Journal of Clinical Periodontology 1994 21 4 281 283 10.1111/j.1600-051x.1994.tb00318.x 2-s2.0-0028411662 8195445 \n5 Meraw S. J. Sheridan P. J. Medically induced gingival hyperlasia Mayo Clinic Proceedings 1996 73 1196 1199 \n6 Haas A. N. Rosing C. K. Oppermann R. V. Albandar J. M. Susin C. Association among menopause, hormone replacement therapy, and periodontal attachment loss in Southern Brazilian women Journal of Periodontology 2009 80 9 1380 1387 10.1902/jop.2009.090082 2-s2.0-69949185490 19722786 \n7 Eisen D. Carrozzo M. Sebastian J.-V. B. Thongprasom K. Number V Oral lichen planus: clinical features and management Oral Diseases 2005 11 6 338 349 10.1111/j.1601-0825.2005.01142.x 2-s2.0-28444474150 16269024 \n8 Rubira I. R. Gobetti J. P. Gingival lichen planus: a diagnostic problem The Journal of the Michigan Dental Association 1994 76 2 44 48 2-s2.0-0028376899 \n9 Eversole L. R. Immunopathogenesis of oral lichen planus and recurrent aphthous stomatitis Seminars in Cutaneous Medicine and Surgery 1997 16 4 284 294 10.1016/S1085-5629(97)80018-1 2-s2.0-0031444254 9421220 \n10 Zhou X. J. Sugerman P. B. Savage N. W. Walsh L. J. Matrix metalloproteinases and their inhibitors in oral lichen planus Journal of Cutaneous Pathology 2001 28 2 72 82 10.1034/j.1600-0560.2001.280203.x 2-s2.0-0035182799 11168755 \n11 Barnard N. A. Scully C. Eveson J. W. Cunningham S. Porter S. R. Oral cancer development in patients with oral lichen planus Journal of Oral Pathology and Medicine 1993 22 9 421 424 10.1111/j.1600-0714.1993.tb00134.x 2-s2.0-0027674727 8301608 \n12 Silverman S. Jr. Oral lichen planus: a potentially premalignant lesion Journal of Oral and Maxillofacial Surgery 2000 58 11 1286 1288 10.1053/joms.2000.16630 2-s2.0-0033760401 11078141 \n13 Drangsholt M. Truelove E. L. Morton T. H. Jr. Epstein J. B. A man with a 30-year history of oral lesions Journal of Evidence-Based Dental Practice 2001 1 2 123 135 10.1016/S1532-3382(01)70023-1 2-s2.0-0035691687 \n14 Silverman S. Jr. Bahl S. Oral lichen planus update: clinical characteristics, treatment responses, and malignant transformation The American Journal of Dentistry 1997 10 6 259 263 2-s2.0-0031324412 9590911 \n15 Eisenberg E. Krutchkoff D. J. Lichenoid lesions of oral mucosa: diagnostic criteria and their importance in the alleged relationship to oral cancer Oral Surgery Oral Medicine and Oral Pathology 1992 73 6 699 704 10.1016/0030-4220(92)90013-g 2-s2.0-0026684862 \n16 Ramer M. A. Altchek A. Deligdisch L. Phelps R. Montazem A. Buonocore P. M. Lichen planus and the vulvovaginal-gingival syndrome Journal of Periodontology 2003 74 9 1385 1393 2-s2.0-0242320401 10.1902/jop.2003.74.9.1385 14584875 \n17 Pihlstrom B. L. Prevention and treatment of Dilantin-associated gingival enlargement Compendium 1990 6 14, supplement S506 S510 2-s2.0-0007950016 \n18 Neville B. W. Damm D. D. Allen C. M. Bouquot J. E. Oral & Maxillofacial Pathology 1995 Philadelphia, Pa, USA W.B. Saunders \n19 Yih W.-Y. Maier T. Kratochvil F. J. Zieper M. B. Analysis of desquamative gingivitis using direct immunofluorescence in conjunction with histology Journal of Periodontology 1998 69 6 678 685 10.1902/jop.1998.69.6.678 2-s2.0-0032085636 9660337 \n20 Passeron T. Zakaria W. Ostovari N. Mantoux F. Lacour J. P. H. Ortonne J. P. Treatment of erosive oral lichen planus by the 308 nm excimer laser Lasers in Surgery and Medicine 2004 34 3 p. 205 10.1002/lsm.20016 2-s2.0-1842534217 \n21 Trehan M. Taylor C. R. Low-dose excimer 308-nm laser for the treatment of oral lichen planus Archives of Dermatology 2004 140 4 415 420 10.1001/archderm.140.4.415 2-s2.0-1842736577 15096369 \n22 Köllner K. Wimmershoff M. Landthaler M. Hohenleutner U. Treatment of oral lichen planus with the 308-nm UVB excimer laser - Early preliminary results in eight patients Lasers in Surgery and Medicine 2003 33 3 158 160 10.1002/lsm.10202 2-s2.0-0141962539 12949944 \n23 Glickman I. Imber L. R. Comparison of gingival resection with electrosurgery and periodontal knives: a biometric and histologic study Journal of Periodontology 1970 41 3 142 148 10.1902/jop.1970.41.3.142 2-s2.0-0014753209 5265934 \n24 Oringer M. J. Electrosurgery for definitive conservative modern periodontal therapy Dental Clinics of North America 1969 13 1 53 73 2-s2.0-0014446847 5249438\n\n",
"fulltext_license": "CC BY",
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"issue": "2015()",
"journal": "Case reports in dentistry",
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"medline_ta": "Case Rep Dent",
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"pmid": "25838949",
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"references": "9590911;12191961;9488249;19722786;9868421;15022246;11078141;9660337;11168755;5265934;1437039;2097044;7932660;16269024;8195445;8301608;12949944;15096369;9421220;14584875;5249438",
"title": "Severe gingival enlargement with coexisting erosive lichen planus in severe chronic periodontitis patient.",
"title_normalized": "severe gingival enlargement with coexisting erosive lichen planus in severe chronic periodontitis patient"
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"abstract": "Anakinra is a selective IL-1 inhibitor, which has been used in the context of secondary haemophagocytic lymphohistiocytosis. Although usually given in the s.c. form, previous anecdotal reports have emphasized its utility when given i.v. Our aim is to report our experience on the beneficial effects of anakinra i.v. in patients with SARS-CoV-2 and evidence of hyperinflammation.\nWe report four patients with severe COVID-19 infection requiring intensive care admission and ventilatory support.\nAll four patients showed evidence of deterioration, with hyperferritinaemia and increasing oxygen requirements and with superadded bacterial infections. Upon commencement of anakinra i.v., there was subsequent improvement in the patients clinically, with reduction in ventilatory support and inotropic support, and biochemically, with rapid improvement in inflammatory markers.\nAnakinra is safe to use i.v. in patients with COVID-19 and evidence of superadded bacterial infection. Although its utility has not been confirmed in a randomized trial, current research in the COVID-19 pandemic aims to establish the utility of immunosuppression, including IL-1 blockade, on the outcomes of patients with moderate to severe disease. Our case series supports its use in patients with severe, life-threatening COVID-19 and evidence of hyperinflammation.",
"affiliations": "Department for Rheumatology and Connective Tissue Diseases, University College London.;Department of Intensive Care, Royal Free Hospital London NHS Foundation Trust.;UK National Amyloidosis Centre, University College London.;Department of Rheumatology.;Department of Rheumatology.;Department of Infectious Diseases, Royal Free Hospital London NHS Foundation Trust, London, UK.",
"authors": "Clark|Kristina E N|KEN|0000-0002-5926-3900;Collas|Oliver|O|;Lachmann|Helen|H|;Singh|Animesh|A|;Buckley|Jim|J|;Bhagani|Sanjay|S|",
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"doi": "10.1093/rap/rkaa040",
"fulltext": "\n==== Front\nRheumatol Adv Pract\nRheumatol Adv Pract\nrheumap\nRheumatology Advances in Practice\n2514-1775\nOxford University Press\n\n10.1093/rap/rkaa040\nrkaa040\nConcise Report\nAcademicSubjects/MED00010\nSafety of intravenous anakinra in COVID-19 with evidence of hyperinflammation, a case series\nhttp://orcid.org/0000-0002-5926-3900\nClark Kristina E N r1\nCollas Oliver r2\nLachmann Helen r3\nSingh Animesh r4\nBuckley Jim r4\nBhagani Sanjay r5\nr1 Department for Rheumatology and Connective Tissue Diseases, University College London\nr2 Department of Intensive Care, Royal Free Hospital London NHS Foundation Trust\nr3 UK National Amyloidosis Centre, University College London\nr4 Department of Rheumatology\nr5 Department of Infectious Diseases, Royal Free Hospital London NHS Foundation Trust, London, UK\nCorrespondence to: Kristina E. N. Clark, Department for Rheumatology and Connective Tissue Diseases, University College London, Royal Free Hospital London NHS Foundation Trust Campus, Rowland Hill Street, London NW3 2PF, UK. E-mail: kristina.clark@ucl.ac.uk\n2020\n04 8 2020\n04 8 2020\n4 2 rkaa0405 6 2020\n7 7 2020\n© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.\n2020\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nObjectives\n\nAnakinra is a selective IL-1 inhibitor, which has been used in the context of secondary haemophagocytic lymphohistiocytosis. Although usually given in the s.c. form, previous anecdotal reports have emphasized its utility when given i.v. Our aim is to report our experience on the beneficial effects of anakinra i.v. in patients with SARS-CoV-2 and evidence of hyperinflammation.\n\nMethods\n\nWe report four patients with severe COVID-19 infection requiring intensive care admission and ventilatory support.\n\nResults\n\nAll four patients showed evidence of deterioration, with hyperferritinaemia and increasing oxygen requirements and with superadded bacterial infections. Upon commencement of anakinra i.v., there was subsequent improvement in the patients clinically, with reduction in ventilatory support and inotropic support, and biochemically, with rapid improvement in inflammatory markers.\n\nConclusion\n\nAnakinra is safe to use i.v. in patients with COVID-19 and evidence of superadded bacterial infection. Although its utility has not been confirmed in a randomized trial, current research in the COVID-19 pandemic aims to establish the utility of immunosuppression, including IL-1 blockade, on the outcomes of patients with moderate to severe disease. Our case series supports its use in patients with severe, life-threatening COVID-19 and evidence of hyperinflammation.\n\nCOVID-19\nhaemophagocytic lymphohistiocytosis\nanakinra\nhyperinflammation\n==== Body\nKey messages\n\nAnakinra is safe in severe COVID-19 infections with evidence of superadded bacterial infection.\n\nAnakinra i.v. results in clinical and biochemical improvement in severe COVID-19 requiring ventilatory support.\n\nAnakinra should be considered in the arsenal of treatment options for COVID-19.\n\nIntroduction\n\nAnakinra is a recombinant IL-1 receptor antagonist originally marketed for use in RA. It has increasingly found off-label use in patients with haemophagocytic lymphohistiocytosis (HLH). Efficacy data come predominantly from case series [1, 2], where it achieves disease remission, normalization of laboratory abnormalities and resolution of pyrexia from cytokine storm [3, 4], even in the context of sepsis. Traditionally given s.c., the i.v. form is safe at doses ≤10 mg/kg [5]. Despite the limited evidence, consensus guidelines support its use in the treatment algorithm of cytokine storm [6].\n\nCOVID-19 typically presents with fever, dry cough and dyspnoea, although the array of symptoms is wide. The mean time lag from symptom onset to dyspnoea is 5–8 days, and to ARDS it is 8–14 days [7, 8]. ARDS affects 8–19% of patients [3], and these patients have increased risk of cytokine storm and progressive multi-organ damage. Severe COVID-19 is more common in older patients and in those with certain co-morbidities, including obesity, diabetes and cardiovascular disease [9].\n\nSevere COVID-19 is characterized by prominent alveolar damage, with focal reactive hyperplasia of pneumocytes, patchy inflammatory cellular infiltration and intravascular thrombosis. Key pathological cells include CD4+ and CD8+ T cells and macrophages. The cytokine profile is similar to HLH, with increased IL-6, IL-1β, IL-10, GM-CSF, IFN-γ, macrophage inflammatory protein 1-α, monocyte chemoattractant protein-1 and TNF-α [3, 10, 11].\n\nSARS-CoV2 evades a number of immune system recognition points that usually initiate virus-mediated immunity. The activation of innate immune cells by infected macrophages results in the expression of pro-inflammatory IL-1, IL-6 and TNF-α production through the nuclear factor-κB pathway. The concentrations of these cytokines continue to increase via a process of auto-amplification, and recruit adaptive immune cells [12].\n\nAberrant CD4+ T-cell activation releases IFN-γ and GM-CSF. The GM-CSF results in increased CD14+CD16+ inflammatory monocyte subsets, a subset rarely seen at significant levels in health [13]. This subset of monocytes expresses increased levels of IL-6, which are likely to be responsible for the acceleration and progression of a systemic ihinflammatory response.\n\nIL-1 and related pro-inflammatory pathways intertwined with aberrant T-cell responses play a crucial role in disease severity [14]. Elevated ferritin and IL-6 concentrations are correlates with mortality [15]. We define hyperinflammation by this systemic inflammatory response, which has strong similarities to that seen in cytokine release syndrome. One current treatment strategy is to control hyperinflammation with targeted immunosuppression.\n\nWe describe a cohort of patients with severe SARS-CoV-2 infection admitted to the intensive care unit (ICU) during the pandemic, with elevated ferritins between 4000–30 000 µg/l. All four patients were diagnosed with COVID-19 and required ventilatory support. These patients all showed evidence of hyperinflammation with raised inflammatory markers and CRP and were given anakinra i.v., with safe and successful use, suggesting the potential benefit of IL-1 blockade in this subgroup of patients with confirmed COVID-19.\n\nCase series\n\nCase 1\n\nA 30-year-old man presented with a background of end-stage renal failure secondary to birth asphyxia and with a donation after brainstem death renal transplant (baseline creatinine 290 µmol/l), maintained on sirolimus and tacrolimus. This was the patient’s second transplant, the first being complicated by graft rejection, microangiopathic haemolytic anaemia and requiring graft nephrectomy in 2013. The current transplant had taken place >1 year before the current presentation, of which he had had one episode of BK viral nephropathy treated with CSs. He had been stable after this, with no significant infections. He presented with a 14-day history of feeling unwell with fevers, and a 5-day history of a cough, sore throat and difficulty breathing.\n\nInitial oxygen saturation was 80% on room air, which improved to 100% on 35% oxygen via a venturi face mask. His blood pressure was 127/73 mmHg, heart rate 95 beats/min, temperature 38°C and respiratory rate 21 breaths/min. Chest X-ray (CXR) showed bilateral patchy consolidation, and nasopharyngeal swab (NPS) confirmed SARS-CoV-2. Blood tests revealed ferritin of 24617 µg/l, creatinine 519 µmol/l and CRP 92 mg/l.\n\nOxygen was titrated to keep his saturations >94%, and he was initiated on co-amoxiclav. After 2 days, with increasing oxygen requirements and progressive CXR consolidation, he was transferred to the ICU, where he was commenced on continuous positive airway pressure. The sirolimus was stopped, but he remained on tacrolimus. Ferritin at the time was 23 788 µg/l, CRP 73 mg/l and procalcitonin 17.27 μg/l (normal range <0.5 μg/l). Microscopy from blood cultures and urine cultures was negative, and CMV and EBV viraemias remained very low level. Given the increasing oxygen requirement and persistent inflammatory state, anakinra 200 mg i.v. was initiated (Table 1). A marked improvement in ferritin was seen within 2 days; CRP steadily decreased (Fig. 1), creatinine improved, and his respiratory effort stabilized. After 3 days of continuous positive airway pressure, he was weaned off and stepped down to the ward. Anakinra i.v. was stopped on day 10, when the ferritin was 4969 µg/l. He was discharged on day 12 with a creatinine of 371 µmol/l and CRP 7 mg/l and remained on tacrolimus.\n\nFig. 1 Graphs showing serum ferritin and CRP concentrations after initiation of anakinra for all four cases\n\n(A) Ferritin concentration (in micrograms per litre). (B) CRP concentration (in milligrams per litre).\n\nTable 1 Table to highlight different medications used during the care of each case\n\n\tCase 1\tCase 2\tCase 3\tCase 4\t\nBefore admission\tSirolimus 3 mg\tTacrolimus 5 mg BD\tRituximab 500 mg\tPrednisolone 10 mg\t\nMMF 500 mg BD\t\nTacrolimus 2/1 mg\tPrednisolone 5 mg OD\t\nAnakinra dose\t200 mg OD\t200 mg OD\t200 mg BD\t200 mg OD\t\nAntibiotics and antifungals\tCeftriaxone\tCeftriaxone\tCeftriaxone\tCeftriaxone\t\n\t\tTeicoplanin\tMeropenem\tGentamicin\t\n\t\t\tAmbisome\tTemocillin\t\n\t\t\t\tTeicoplanin\t\n\t\t\t\tMeropenem\t\n\t\t\t\tCaspofungin\t\nBD: twice a day; OD: once a day.\n\nCase 2\n\nA 48-year-old man was admitted 11 days after having a donation after brainstem death renal transplant for end-stage renal failure secondary to IgA nephropathy. The transplant itself was uneventful. His other past medical history consisted of transfusion dependent beta-thalassaemia intermedia (baseline ferritin was 2236 μg/l) and splenectomy. He was discharged on tacrolimus, MMF and prednisolone.\n\nHe was re-admitted 6 days later with a 2-day history of dry cough, dyspnoea and self-recorded pyrexia of 38°C. Examination revealed coarse crepitations predominantly on the right, saturation of 97% in room air, respiratory rate 18 breaths/min and blood pressure 161/84 mmHg. Blood tests showed a ferritin of 4054 μg/l, CRP 84 mg/l and procalcitonin of 1.71 μg/l. CXR showed consolidation in the right mid and lower zones, and NPS confirmed SARS-CoV-2. Ceftriaxone was initiated.\n\nOn day 2, his oxygen requirement increased, with worsening bilateral mid zone air space shadowing. He was commenced on continuous positive airway pressure 5 days after admission and underwent endotracheal intubation on day 7. Given the clinical deterioration and rising CRP (170 mg/l), he was commenced on anakinra 200 mg i.v. once a day (Table 1). After initiation of anakinra, inotropes were weaned within 24 h, and significant improvement in his blood parameters was noted (ferritin 2687 µg/l and CRP 26 mg/l).\n\nHis ICU admission was complicated by an Enterococcus faecium bacteraemia on day 9 of admission, for which he completed 7 days of teicoplanin. Anakinra was reduced and stopped after 21 days. After a successful tracheostomy wean, he was discharged on day 45.\n\nCase 3\n\nA 68-year-old woman with a background of non-Hodgkin’s lymphoma was re-admitted 2 weeks after being discharged with COVID-19. She had known follicular lymphoma stage 4A diagnosed in May 2018. She was treated with rituximab, last receiving a dose 3 months before her first admission. At the time of her first admission, she presented with a few weeks’ history of fever, myalgia and a sore throat. She had been given co-amoxiclav and azithromycin in the community, 1 week before admission. Her shortness of breath on exertion was worsening, and she was found to have a saturation of 89%. NPS confirmed SARS-CoV-2, and her CXR was consistent with the diagnosis. She was managed on the ward with oxygen and i.v. antibiotics and was discharged 3 weeks later, having had a CT pulmonary angiogram, confirming no pulmonary emboli, and a PET scan, which showed no advancement of her non-Hodgkin’s lymphoma.\n\nShe was re-admitted 21 days later with profound hypoxia, requiring intubation on arrival in hospital. A CT pulmonary angiogram at the time showed extensive bilateral pulmonary emboli, with evidence of right heart strain. There were severe COVID-related changes, with widespread ground glass opacification throughout both lung fields. On admission, ferritin was 29 784 µg/l, CRP 78 mg/l and procalcitonin 2.04 μg/l. She was anaemic (haemoglobin 100 g/l), but not cytopenic, with platelets of 199 × 109/l and a neurophilia of 15.9 × 109/l. NPS and EDTA blood samples were positive for SARS-CoV-2.\n\nShe was admitted to the ICU, initiated on tazocin i.v. and underwent thrombolysis for her pulmonary emboli. The following day, ferritin rose to 40 069 µg/l, CRP was 109 mg/l, and procalcitonin increased to 9.85 μg/l. Anakinra i.v. was initiated (Table 1). She was initially started on 100 mg four times a day, but owing to pressures on the nursing staff this was changed to 200 mg twice a day. Within 24 h of commencing anakinra i.v., the ferritin improved to 20 479 μg/l (Fig. 1), and 3 days later continued to fall to 5118 μg/l. A BioFire film was positive for Streptococcus pneumonia. Her ICU stay was complicated by worsening consolidation on her CXRs, necessitating a prolonged course of meropenem. She commenced ambisome on day μg/l2 of admission, which was continued after a positive galactomannan test on her sputum and strongly positive βD-glucan (341.5 pg/ml), 2 weeks into her admission. It took 24 days from admission for the SARS-CoV-2 viraemia to disappear on both EDTA blood and NPS. She remains in the ICU and is currently weaning off the ventilator, with a tracheostomy in situ and on minimal inotropic support.\n\nCase 4\n\nA 49-year-old woman presented with a 2-week history of non-productive cough and fever, with 1 week of diarrhoea. She had end-stage renal failure secondary to lupus nephritis, requiring haemodialysis. Her past medical history included APS with thromboses and ischaemic heart disease. Her medication included warfarin and prednisolone.\n\nInitial blood tests showed an elevated CRP (339 mg/l) and ferritin (2890 µg/l), with bilateral patchy consolidation on CXR. She was admitted on oxygen 2 l/min via nasal cannula. Ceftriaxone and gentamicin were initiated, and SARS-CoV-2 was confirmed via NPS.\n\nOn day 6 her oxygen requirements increased, with worsening patchy consolidation bilaterally on CXR. She underwent endotracheal intubation in the ICU, and her antibiotics were changed to temocillin, teicoplanin and gentamicin.\n\nOn day 10, blood tests showed worsening thrombocytopenia and transaminitis with rising ferritin: platelets 91 × 109/l, ferritin 7636 μg/l, with a peak in her procalcitonin of 198 μg/l. An assumed diagnosis of HLH was made, and she commenced anakinra 200 mg i.v. (Table 1). She required increasing inotropic support, and her thrombocytopaenia deteriorated, with associated increasing ferritin over the following days.\n\nOn day 17, blood tests revealed ferritin 30 086 μg/l. A CT chest revealed small bilateral lower lobe pulmonary emboli and extensive consolidation throughout both lungs. The clinical deterioration suggested worsening HLH; therefore, anakinra was increased sequentially to 300 mg twice a day, and antibiotics were switched to meropenem and caspofungin.\n\nTwo days later there was notable improvement in ferritin and CRP, and the transaminases started to normalize. The patient remains intubated and ventilated, with reducing inotropic support.\n\nDiscussion\n\nWe present four cases of immunosuppressed patients, who received beneficial effects from the use of anakinra i.v. to treat severe COVID-19 with hyperinflammation and concomitant bacterial infections.\n\nCareful consideration of the immunosuppressive treatment needs to factor in the ability to clear the virus without allowing for hyperinflammation. Anakinra has previously been used in the context of virally induced inflammatory conditions, such as multicentric Castleman’s disease, which is a reactive lymphoproliferative disorder typically described in HIV-positive patients, with a close association with HHV-8 [12].\n\nCavalli et al. [16] described the use of anakinra in patients with ARDS attributable to COVID-19 who also had hyperinflammation. They used anakinra at 5 mg/kg i.v. twice a day (high-dose group) for 21 days. A subgroup of patients received 100 mg s.c. twice a day (low-dose group) for 7 days. Standard care included 400 mg HCQ, along with lopinavir and ritonavir. At 21 days, survival was 90% in the high-dose group and 56% in the standard treatment group (P = 0.009).\n\nTheir lower threshold for diagnosis of hyperinflammation (CRP >100 mg/l or ferritin 900 ng/ml) and differing standard practice reflect a cohort of patients not necessarily classified as severe in the UK. A ferritin <500 ng/ml has a high negative predictive value for HLH [6], whereas >10 000 mg/l is diagnostic of HLH in children [17]. The use of oral HCQ might skew the mortality data, with a potential for increased cardiac complications [18]. An observational study on the use of HCQ in COVID-19 did not report any difference in mortality [19], and it is not included in UK treatment algorithms. Furthermore, concomitant bacterial infections were excluded.\n\nAnakinra has received increasing use in the context of cytokine storm syndromes/HLH [4]. Although licensed s.c., concerns over unreliable absorption in the critically ill patient and the requirement of multiple injections, along with the support of its safety at higher doses in the context of sepsis, have all favoured i.v. administration. Support for our use of higher dose anakinra i.v. is also gained from the recent lack of benefit for the s.c. form in the context of COVID-19 [16].\n\nThe administration of anakinra i.v. leads to a maximal plasma concentration 24–29 times higher when compared with s.c. administration. It also has a shorter terminal half-life in the i.v. format (2.64 h, compared with 5.24 h s.c.) [20, 21], with the caveat that the s.c. half-life increases with greater adipose tissue. The i.v. form therefore enables a higher and faster maximal plasma concentration of anakinra; a trait that is desirable during cytokine storm syndromes.\n\nThere is currently not sufficient evidence to suggest that the majority of patients with severe COVID-19 develop HLH, because the other diagnostic parameters not including ferritin (hypertriglyceridaemia, low fibrinogen and cytopenias) are not correlated with severe disease [22]. None of our cases developed organomegaly, and only case 4 showed evidence of thrombocoytopenia, but the other blood count lineages did not fall. Therefore, we believe we are treating hyperinflammation and not HLH in our four cases.\n\nThe timing of treatment with anakinra is one of the challenges in managing patients with COVID-19 and of any clinical trial design. Although antiviral therapy is likely to be beneficial in the early phase of the disease, cytokine modulation and immunosuppressive therapy are most likely to have an impact at later stages [11]. A number of trials are attempting to answer this question. A recent large adaptive-platform trial (Recovery trial) showed a significant benefit on mortality of low-dose dexamethasone, with the biggest reduction in risk of mortality being observed in patients requiring invasive mechanical ventilation [23]. This affirms the concept of the need for immune modulation in critically unwell patients requiring ventilatory and organ support. Further trials in the UK include REMAP-CAP (https://www.remapcap.org/), an adaptive-platform trial to assess the use of antibiotics, antivirals and immunomodulators in COVID-19. It offers the opportunity to explore targeted immune modulation therapy, which will include IFN-β1a, IL-1 receptor antagonists (anakinra), tocilizumab and sarilumab (both anti-IL-6), all against placebo.\n\nCOVACTA (https://clinicaltrials.gov/ct2/show/NCT04320615) randomized severe SARS-CoV-2 pneumonitis patients to tocilizumab (a monoclonal antibody targeting the IL-6 receptor). CAN-COVID (https://clinicaltrials.gov/ct2/show/NCT04362813) randomizes canikunimab (a monoclonal antibody that targets the IL-1β cytokine specifically) to patients with severe COVID-19, not requiring mechanical ventilation.\n\nThe results of these trials will be extremely informative to direct treatment strategy for COVID-19 infections in the future. Whether single treatment, combination therapy or early intervention is optimal remains to be elucidated.\n\nOur case series supports the hypothesis of IL-1 blockade as an important disease-modifying treatment in those patients with severe, late-stage COVID-19, with evidence of cytokine storm. We show that the i.v. form is safe at high doses, even in patients with concomitant bacterial infections. We believe that administering anakinra i.v. at the height of the cytokine storm has profound beneficial effects, both clinically and biochemically, on patients with severe COVID-19 infection.\n\nFunding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.\n\nDisclosure statement: The authors have declared no conflicts of interest.\n==== Refs\nReferences\n\n1 Shakoory B Carcillo JA Chatham WW et al Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med 2016;44 :275–81.26584195\n2 Meyer NJ Reilly JP Anderson BJ et al Mortality benefit of recombinant human interleukin-1 receptor antagonist for sepsis varies by initial interleukin-1 receptor antagonist plasma concentration. Crit Care Med 2018;46 :21–8.28991823\n3 Chen G Wu D Guo W et al Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020;130 :2620–9.32217835\n4 Mehta P Cron RQ Hartwell J Manson JJ Tattersall RS. Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol 2020;2 :e358–67.32373790\n5 Granowitz EV Porat R Mier JW et al Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine 1992;4 :353–60.1420996\n6 Halyabar O Chang MH Schoettler ML et al Calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Pediatr Rheumatol Online J 2019;17 :7.30764840\n7 Wang D Hu B Hu C et al Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323 :1061–9.32031570\n8 Cevik M Bamford CGG Ho A. COVID-19 pandemic—a focused review for clinicians. Clin Microbiol Infect 2020;26 :842–7.32344166\n9 Zhou F Yu T Du R et al Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395 :1054–62.32171076\n10 Huang C Wang Y Li X et al Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395 :497–506.31986264\n11 Zhang C Wu Z Li JW Zhao H Wang GQ. The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents 2020;55 :105954.32234467\n12 Felsenstein S Herbert JA McNamara PS Hedrich CM. COVID-19: immunology and treatment options. Clin Immunol 2020;215 :108448.32353634\n13 Zhou Y Fu B Zheng X et al Pathogenic T-cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl Sci Rev 2020;7 :998–1002.\n14 Ong EZ Chan YFZ Leong WY et al A dynamic immune response shapes COVID-19 progression. Cell Host Microbe 2020;27 :879–82.e2.32359396\n15 Ruan Q Yang K Wang W Jiang L Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46 :846–8.32125452\n16 Cavalli G De Luca G Campochiaro C et al Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020;2 :e325–31.32501454\n17 Allen CE Yu X Kozinetz CA McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50 :1227–35.18085676\n18 Mercuro NJ Yen CF Shim DJ et al Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020:e201834. doi: 10.1001/jamacardio.2020.1834. Online ahead of print.\n19 Geleris J Sun Y Platt J et al Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 2020;382 :2411–8.32379955\n20 Yang B-B Gozzi P Sullivan JT. Pharmacokinetics of anakinra in subjects of heavier vs. lighter body weights. Clin Transl Sci 2019;12 :371–8.30884170\n21 Yang B-B Baughman S Sullivan JT. Pharmacokinetics of anakinra in subjects with different levels of renal function. Clin Pharmacol Ther 2003;74 :85–94.12844139\n22 Leverenz DL Tarrant TK. Is the HScore useful in COVID-19? Lancet 2020;395 :e83.32423585\n23 RECOVERY Collaborative Group, Horby P, Lim WS et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report N Engl J Med 2020; doi:10.1056/NEJMoa2021436.\n\n",
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"issue": "4(2)",
"journal": "Rheumatology advances in practice",
"keywords": "COVID-19; anakinra; haemophagocytic lymphohistiocytosis; hyperinflammation",
"medline_ta": "Rheumatol Adv Pract",
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"title": "Safety of intravenous anakinra in COVID-19 with evidence of hyperinflammation, a case series.",
"title_normalized": "safety of intravenous anakinra in covid 19 with evidence of hyperinflammation a case series"
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"abstract": "OBJECTIVE\nThe aim of this study is to identify the prognostic factors of distant metastasis (DM) after induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) for locoregionally advanced head and neck cancer (HNC).\n\n\nMETHODS\nA total of 321 patients with HNC who underwent IC followed by CRT treated between January 2005 and December 2010 were analyzed retrospectively. IC consisted of three courses of docetaxel (70 mg/m(2)) and cisplatin (75 mg/m(2)) every three weeks, followed by radiotherapy of 66-70 Gy/2 Gy per fraction/5 fractions per week concurrent with weekly cisplatin (40 mg/m(2)). Tumor/nodal stage, primary site, tumor differentiation, lower neck node involvement (level IV, VB, and supraclavicular regions), number of concurrent chemotherapy cycles, overall duration of radiotherapy, and response to IC were assessed as potential prognostic factors influencing DM and survival outcome.\n\n\nRESULTS\nThe five-year loco-regional recurrence and DM rates were 23.6% and 18.2%. N stage, overall duration of radiotherapy, lower neck node involvement, and response to IC were significant factors for DM. With a median follow-up period of 52 months (range, 4 to 83 months), the 5-year progression-free, DM-free, and overall survival rates were 41.2%, 50.7%, and 55.1%, respectively. Lower neck node involvement (p=0.008) and poor response to IC (p < 0.001) showed an association with significantly inferior DM-free survival.\n\n\nCONCLUSIONS\nEven with the addition of IC, the DM rate and survival outcome were poor when metastatic lower neck lymph nodes were present or when patients failed to respond after receiving IC.",
"affiliations": "Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.;Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.;Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.;Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.;Department of Radiation Oncology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea.;Departments of Otorhinolaryngology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.;Departments of Otorhinolaryngology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.;Departments of Hemato-oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.;Departments of Hemato-oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.;Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.",
"authors": "Kim|Dong Hyun|DH|;Kim|Won Taek|WT|;Lee|Joo Hye|JH|;Ki|Yong Kan|YK|;Nam|Ji Ho|JH|;Lee|Byung Joo|BJ|;Lee|Jin Choon|JC|;Choi|Young Jin|YJ|;Seol|Young Mi|YM|;Kim|Dong Won|DW|",
"chemical_list": null,
"country": "Korea (South)",
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"doi": "10.4143/crt.2013.212",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 10.4143/crt.2013.212crt-2013-212Original ArticleAnalysis of the Prognostic Factors for Distant Metastasis after Induction Chemotherapy Followed by Concurrent Chemoradiotherapy for Head and Neck Cancer Kim Dong Hyun MD1Kim Won Taek MD1Lee Joo Hye MD1Ki Yong Kan MD1Nam Ji Ho MD2Lee Byung Joo MD3Lee Jin Choon MD3Choi Young Jin MD4Seol Young Mi MD4Kim Dong Won MD11 Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea2 Department of Radiation Oncology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea3 Departments of Otorhinolaryngology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea4 Departments of Hemato-oncology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, KoreaCorrespondence: Wontaek Kim, MD Department of Radiation Oncology, Pusan National University Hospital, Pusan National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan 602-739, Korea Tel: 82-51-240-7383 Fax: 82-51-248-5747 E-mail: rokwt@hanmail.net1 2015 25 8 2014 47 1 46 54 24 10 2013 10 12 2013 Copyright © 2015 by the Korean Cancer Association2015This 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\nThe aim of this study is to identify the prognostic factors of distant metastasis (DM) after induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) for locoregionally advanced head and neck cancer (HNC).\n\nMaterials and Methods\nA total of 321 patients with HNC who underwent IC followed by CRT treated between January 2005 and December 2010 were analyzed retrospectively. IC consisted of three courses of docetaxel (70 mg/m2) and cisplatin (75 mg/m2) every three weeks, followed by radiotherapy of 66-70 Gy/2 Gy per fraction/5 fractions per week concurrent with weekly cisplatin (40 mg/m2). Tumor/nodal stage, primary site, tumor differentiation, lower neck node involvement (level IV, VB, and supraclavicular regions), number of concurrent chemotherapy cycles, overall duration of radiotherapy, and response to IC were assessed as potential prognostic factors influencing DM and survival outcome.\n\nResults\nThe five-year loco-regional recurrence and DM rates were 23.6% and 18.2%. N stage, overall duration of radiotherapy, lower neck node involvement, and response to IC were significant factors for DM. With a median follow-up period of 52 months (range, 4 to 83 months), the 5-year progression-free, DM-free, and overall survival rates were 41.2%, 50.7%, and 55.1%, respectively. Lower neck node involvement (p=0.008) and poor response to IC (p < 0.001) showed an association with significantly inferior DM-free survival.\n\nConclusion\nEven with the addition of IC, the DM rate and survival outcome were poor when metastatic lower neck lymph nodes were present or when patients failed to respond after receiving IC.\n\nHead and neck neoplasmsChemoradiotherapyInduction chemotherapyNeoplasm metastasisPrognosis\n==== Body\nIntroduction\nApproximately 60% of patients with head and neck cancer (HNC) present with locoregionally advanced stage III and IV disease [1]. Multiple clinical trials have confirmed the locoregional control and overall survival (OS) benefit of concurrent chemoradiotherapy (CRT), and CRT is now considered the standard management paradigm for locoregionally advanced HNC [2]. The concept of induction chemotherapy (IC) followed by CRT has several theoretical advantages, including reduced risk of distant metastasis (DM), induction of tumor shrinkage to allow more effective and less toxic local therapy, and prediction of tumor responsiveness [3].\n\nStudies over the past two decades have reported DM rates between 4.0% and 26.0% in patients treated for squamous cell carcinoma of the head and neck [4,5]. Preliminary results from a randomized trial (DeCIDE) showed that the incidence of DM at three years was 10% with IC followed by CRT and 19% with CRT alone (p=0.025) [6]. As DM develops, the chance of cure is very low, and the survival decreases dramatically. Some reports have demonstrated an association of locoregional control and risk factors including primary site, nodal stage, tumor differentiation, and lower neck involvement (level IV, VB, and supraclavicular regions) with DM in patients treated with radiotherapy alone or CRT [7,8].\n\nPrevious studies analyzed the prognostic factors for survival outcome after treatment with IC followed by CRT [9,10]. However, none of these studies determined the prognostic factors for DM in HNC patients treated with IC and CRT. The incidence and related risk factors of DM in patients treated with IC followed by CRT should be precisely assessed. The objective of this study was to re-evaluate prognostic factors known as risk factors for DM in patients treated with CRT for HNC, and to determine whether or not these factors still have an effect on DM and survival after addition of IC to CRT.\n\nMaterials and Methods\n1. Patients\nOf 355 patients treated with IC and CRT for HNC in two institutions between January 2005 and December 2010, data for 321 consecutive patients were reviewed in this retrospective study. Fourteen patients who presented with disease progression after receiving a second course of IC, 12 patients who underwent salvage neck dissection prior to CRT, and eight patients who refused further therapy were excluded from this study. All patients were diagnosed with previously untreated, biopsy-proven squamous cell carcinoma. DM was undetected from computed tomography (CT) or positron emission tomography (PET)-CT scans at the time of their initial diagnosis. Five patients showed N3 stages, but none of them were included in the analysis due to incomplete treatment. All patients showed a performance status of 0 to 1. Patients with primary tumors of the nasopharynx, paranasal sinus, or salivary gland were excluded from this study.\n\nClinically significant lymph nodes in the cervical region were distinguished according to the criteria described by van den Brekel et al. [11] (i.e., shortest axis of ≥ 11 mm in the jugulodigastric regions, or ≥ 10 mm in other cervical regions). In addition, conglomerate lymph nodes of borderline size on CT, or any positive results for neck lymph nodes from PET scans, were considered metastatic lesions. The TNM stages of the patients were re-evaluated from their medical records and images at the time of data analysis. Patients were staged according to the 2009 classification of the American Joint Committee on Cancer Staging (AJCC) [12]. The study protocol was approved by the institutional review board (IRB).\n\n2. Treatment\nIC consisted of three courses of docetaxel (70 mg/m2 as 1-hour infusion) and cisplatin (75 mg/m2 as 2-hour infusion) every three weeks. Three weeks after completion of the second course of IC, response to IC was evaluated using CT scan. If disease progression was noted, the third course of IC was cancelled and surgical treatment was considered. Neck dissection was performed prior to CRT in some cases where multiple necrotic lymph nodes showing a stable response after IC were presented. Radiotherapy was recommended for patients determined as unresectable or who refused surgery.\n\nAfter completion of IC, CRT was initiated within four weeks. Conventional fractionated radiation therapy with a daily dose of 2 Gy and a total dose of 66-70 Gy was planned for all patients. Concurrent with radiation therapy, administration of six courses of chemotherapy using weekly cisplatin (40 mg/m2 as 1-hour infusion) was planned for patients.\n\nThree-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) was performed on a 6 MV linear accelerator (Clinac 21EX, Varian Medical Systems, Palo Alto, CA). The gross tumor volume (GTV) was defined as the pre-IC gross disease volume (primary and node) shown on imaging studies. The clinical target volume (CTV) encompassed the GTV plus a margin of 0.5-1.0 cm for the potential microscopic extension of the disease, and an additional margin of 0.3 cm was considered to compensate for setup uncertainty. Segmentation of nodal CTV into two parts (CTV2 and CTV3) was performed according to estimation of the risk. Standard doses were 66-70 Gy for CTV1 (the area of primary tumor and metastatic nodes), 60 Gy for CTV2 (CTV1 plus the next echelon nodal area or ipsilateral cervical nodal chains), and 50 Gy for CTV3 (contralateral lymph nodal area or uninvolved lower neck nodal region).\n\n3. Response assessment and follow-up\nResponse to treatment was documented using the World Health Organization (WHO) response grading system [13]. The response was evaluated between six and 12 weeks after completion of CRT by physical examination and radiological images (CT, magnetic resonance imaging [MRI], and PET-CT). A biopsy was recommended if there was clinical evidence of residual tumor. A complete response (CR) of the primary site was defined by the disappearance of disease evidence on physical examination, radiological images, or pathological reports. In case of neck nodes, CR included all lymph nodes less than 1.0 cm in greatest axial dimension without contrast enhancement on CT scans and with negative results on PET scans. Patients with less than a CR were recommended to go ahead with additional surgery or close observation. Patients were observed by all members of the multidisciplinary team after completion of therapy. Careful clinical examination including imaging studies (CT, ultrasonography and PET, or MRI) was performed at 1-3 month intervals over the first year, every 3-6 months in the second and third years after treatment, and every 6-12 months thereafter.\n\n4. Statistical analyses\nSurvival times were calculated from the initial date of IC. The Kaplan-Meier method was used for progression-free survival (PFS), distant metastasis-free survival (DMFS), and OS. Except for the OS calculations, a patient was considered censored at death if the event had not occurred. A logistic regression model was used for multivariate analysis of risk factors related to DM. As stated in the Introduction, previous studies reported an association of five variables; tumor stage, nodal stage, primary site, tumor differentiation, and lower neck node involvement with development of DM in patients treated with radiotherapy alone or CRT [7,8]. Therefore, these tumor-related factors were assessed as potential prognostic factors having an effect on DM, PFS, DMFS, and OS. Treatment related factors, including number of concurrent chemotherapy cycles and overall duration of radiotherapy were also evaluated as variables. Response to IC was included in the potential prognostic factors in order to evaluate its predictive role for disease control and survival outcome. We performed multivariate analysis with a logistic regression model and used a binomial distribution statistical model to determine the 95% confidence interval of the probability of development of DM. Multivariate analyses of survival outcome were performed using a Cox’s regression model. PASW software (PASW ver. 18.0, SPSS Inc., Chicago, IL) was used for the statistical analyses. p < 0.05 was used to indicate statistical significance.\n\nResults\n1. Patient characteristics\nThe median age of patients was 60 years (range, 27 to 79 years), and 275 patients (85.7%) were men. Three hundred five patients (95.0%) were treated with IMRT, and 16 patients (5.0%) received 3D-CRT. The median dose (for CTV1) of radiation therapy was 70 Gy (range, 56 to 70 Gy), delivered in a median of 35 fractions (range, 28 to 35 fractions) over 45-73 days (median, 51 days). The tumor characteristics are described in Table 1.\n\n2. Compliance with treatment\nThree hundred eleven patients (96.9%) received the prescribed total radiotherapy dose (range, 66 to 70 Gy). In the majority of patients (304 patients, 94.7%), the overall treatment time for radiotherapy was ≤ 8 weeks. Seventeen patients (5.3%) required more than eight weeks to complete treatment because of a variety of treatment-induced toxicities. All patients received three cycles of IC. The dose of docetaxel in the third cycle was reduced by 25% in 21 patients who presented with grade III neutropenia. Two hundred thirty-six patients (73.5%) completed all six cycles of concurrent chemotherapy; however, 23 patients (7.2%) received less than five cycles of weekly cisplatin.\n\n3. Disease control\nAccording to results for response to IC, 59 patients showed a CR (18.4%), 208 showed a partial response (PR; 64.8%), and 54 showed an stable disease (SD; 16.8%). Responses after CRT were as follows: CR at the primary site was seen in 227 patients (70.7%); 201 patients (62.6%) had CR of the metastatic lymph nodes in the neck; 96 patients (29.9%) had PR at the primary site or lymph node; treatment failure occurred in 59 of 211 patients (28.0%) who presented with complete remission at the three-month post-treatment assessment; local recurrence was noted in 41 patients, isolated regional recurrence in 13 patients, and locoregional recurrence in nine patients; DM was detected in 24 patients who had achieved CR after CRT—in 18 of these patients, development of DM was preceded by occurrence of locoregional failure; and DM manifested in 36 patients with persistent locoregional disease following treatment. Detailed data regarding the patterns of failure are shown in Fig. 1. The 5-year locoregional recurrence and distant metastasis rates were 23.6% and 18.2%, respectively. At the time of the last follow-up, DM was reported in 60 of 321 patients (18.7%). The sites of metastases were distributed as follows: lung, 28 cases (8.7%); liver, 15 cases (4.7%); bone, 12 cases (3.7%); and multiple sites (lung and bone), five cases (1.6%). Results of multivariate analysis of risk factors related to DM are shown in Table 2. Significantly high risk of DM was observed in patients with N2c stage, lower neck node involvement, prolonged overall duration of radiotherapy, and poor response to IC.\n\n4. Survival outcome\nThe median follow-up period for all patients and survivors was 52 months (range, 4 to 83 months) and 68 months (range, 33 to 90 months), respectively. At the time of analysis, 132 patients (41.1%) had died. The causes of death were as follows: cancer progression in 103 patients, other causes in 24 patients, treatment-related toxicity in three patients, and undetermined in two patients. The PFS, DMFS, and OS at five years were 41.2%, 50.7%, and 55.1%, respectively. Various factors related to survival outcomes were evaluated by multivariate analysis, and the results are shown in Tables 3 and 4, respectively.\n\nIn multivariate analysis, the significant factors affecting DMFS and PFS were lower neck node involvement (p=0.008 and p= 0.021, respectively) and response to IC (p < 0.001 and p < 0.001, respectively). The DMFS rate at five years according to lower neck lymph node (positive vs. negative) was 34.3% versus 55.2% (Fig. 2) and response to IC (CR, PR, and SD) was 68.9%, 47.3%, and 0% (Fig. 3), respectively. However, OS was not affected by any of these prognostic factors.\n\nDiscussion\nThe patterns of failure have changed in patients with squamous cell HNC [14,15]. Although CRT programs have provided improved results in locoregional control compared with radiotherapy alone, the failure rate at distant organs remains high. Thus, systemic control of micrometastases has emerged as an important treatment goal. Addition of IC to CRT protocols resulted in a modest reduction in the incidence of DM. In particular, taxane-based IC followed by cisplatin-based CRT is receiving much attention as a new therapeutic approach for treatment of advanced HNC and for organ preservation. The cancer treatment team in our hospital developed a protocol using docetaxel in combination with cisplatin as the IC regimen prior to CRT (weekly cisplatin). 5-Fluorouracil (5-FU) was omitted from the IC regimen because it may induce mucosal toxicity and cumulative myelosuppression. In a previous study, this regimen showed a comparable overall response rate (82.9%) and feasibility with docetaxel, cisplatin, and 5-FU based induction regimen [16]. In our study, of 321 eligible patients, 236 patients (73.5%) completed the full schedules of this program, and overall response rate to IC was 83.2%. In the docetaxel, cisplatin, and 5-fluorouracil (TPF) induction arm of a TAX 324 study, 27% patients did not complete the full schedule, and the overall response rate after IC was 72% [17].\n\nThis study demonstrated that lower neck node involvement and response to IC have an effect on the risk of DM and survival outcome despite the addition of aggressive systemic treatment. The 5-year DM rate in our study was 18.2%, slightly higher compared with results from some recent clinical studies on this topic. From the results of some trials, the DM rate varied between 7% and 17% in HNC patients treated with IC followed by CRT [7]. However, in these previous studies, 15-20% of patients were N0 stage. Considering that only 5.3% of patients presented with N0 stage and two-thirds of patients presented with N2b or N2c stage in this study, our results appear to be quite acceptable. Of 60 patients who presented with DM at last follow-up, 36 patients showed persistent locoregional disease after completion of treatment and locoregional recurrence was preceded DM in 18 patients. This means, of course, that locoregional control is also an important predictive factor related to development of DM, except lower neck node involvement or response to IC.\n\nAlvi and Johnson [18] reported an average time from development of DM to death of only five months. As a consequence, identification of groups of patients who are at high risk of developing DM is very important. Risk factors for DM are a matter of debate. Some reports have shown that the risk of DM is greater for nasopharyngeal and hypopharyngeal cancer [5,19]. Conversely, according to other authors [18,20], the site of the tumor had no significant influence on development of DM. In addition, there is disagreement as to the influence of the histologic grade and local extension of the tumor in the appearance of DM [4,5,18]. In our study, tumor related factors (N stage and lower neck node involvement) and treatment related factors (overall duration of radiotherapy and response to IC) showed association with development of DM.\n\nThe 5-year rate of distant metastases in patients with lymph nodes confined to the upper neck was reported as 15%, compared with 28% in oropharyngeal cancer patients with lymph nodes in the mid and/or lower jugular chains (p=0.01) treated with radiotherapy alone [21]. The influence of node location on survival periods was analyzed in previous studies. Patients with lower neck node involvement had a worse prognosis because of their tendency for vascular dissemination. The adverse effect of lower neck node involvement was reported by Kalnins et al. [22] in their study of 450 patients who underwent radical neck dissection for oral cavity carcinoma. They clearly demonstrated an inferior survival rate when metastatic adenopathy was found in the lower neck (5-year OS: upper 38%, mid 19%, and lower 14%). Our results showed a marked association of lower neck node involvement with an increased probability of developing DM. Although IC was added prior to CRT to overcome DM, patients with lower neck node involvement still showed a higher rate of DM.\n\nIn this study, the PFS, DMFS, and OS at five years were 41.2%, 50.7%, and 55.1%, respectively. These results compare favorably with the outcomes of some trials testing the role of IC. The TAX 323 study reported a 2-year OS rate of 43% in patients treated with induction TPF and radiotherapy [23]. The TAX 324 trial reported a 3-year OS of 62% after TPF followed by radiotherapy concurrent with weekly carboplatin [17]. However, the patient characteristics in our study showed a more advanced stage (in particular, nodal stage ≥ N2, 75.1% vs. 63.0%) than those of patients in the TAX 324 study. Despite these adverse factors, our study presented 5-year OS rates consistent with the survival outcomes of the TAX 324 study. In addition, the locoregional failure rate (23.6%; median follow-up, 52 months) was comparable with that of the TAX 324 study (30%; median follow-up, 42 months).\n\nIn the risk factor analysis of the TAX 324 trial, WHO performance status of 1, non-oropharynx site, T3/4 stage, N3 status, and prolonged radiation treatment time showed association with significantly inferior OS [9]. In the current study, lower neck node involvement and response to IC were significant prognostic factors for survival outcome (DMFS and PFS), although they did not show significant association with OS. In univariate analysis, non-oropharyngeal primary sites showed less favorable PFS than orophaynx; however, this was not significant in multivariate analysis. We assume that the failure of systemic control in patients with lower neck node involvement induces poor survival outcome. Investigation of alternative therapeutic approaches may be needed for treatment of patients with metastatic lower neck nodes. A new adjuvant chemotherapy program after completion of CRT or an innovative combination of IC regimen in patients with metastatic lower neck node should be developed in the near future.\n\nClinical data from only two treatment centers and the retrospective nature of the study design could constitute other pitfalls. However, to the best of our knowledge, this study is the first analysis of DM-related risk factors in patients treated with IC followed by CRT. Considering the purpose of IC, these results are helpful for determining the appropriate treatment strategy for patients with lower neck node involvement and failure to respond after IC.\n\nConclusion\nEven with the addition of IC to control DM, the DM rate and survival outcome were poor when metastatic lower neck lymph nodes were present or when patients failed to respond after receiving IC. Investigation of alternative therapeutic approaches may be needed for treatment of patients with metastatic lower neck nodes or who failed to respond after IC.\n\nConflict of interest relevant to this article was not reported.\n\nFig. 1. Patterns of failure.\n\nFig. 2. Distant metastasis-free survival according to lower neck lymph node (LN) involvement.\n\nFig. 3. Distant metastasis-free survival according to response to IC. IC, induction chemotherapy; CR, complete response; PR, partial response; SD, stable disease.\n\nTable 1. Tumor characteristics\n\nCharacteristic\tNo. (%)\t\nSubsite of the primary tumor\t\n Oropharynx\t104 (32.4)\t\n Oral cavity\t48 (15.0)\t\n Larynx\t75 (23.4)\t\n Hypopharynx\t94 (29.2)\t\nT stage\t\n 1\t42 (13.1)\t\n 2\t155 (48.3)\t\n 3\t64 (19.9)\t\n 4\t60 (18.7)\t\nN stage\t\n 0\t17 (5.3)\t\n 1\t63 (19.6)\t\n 2a\t50 (15.6)\t\n 2b\t124 (38.6)\t\n 2c\t67 (20.9)\t\nHistological differentiation\t\n Well\t42 (13.1)\t\n Moderate\t191 (59.5)\t\n Poor\t88 (27.4)\t\nLower neck LNa)\t\n Negative\t218 (67.9)\t\n Positive\t103 (32.1)\t\nLN, lymph node.\n\na) Lower neck: level IV, VB and supraclavicular regions.\n\nTable 2. Multivariate analysis of risk factors for distant metastasis\n\nCharacteristics\tOR (95% CI)\t\nPrimary site\t\n Oropharynx\t1.0\t\n Oral cavity\t0.987 (0.896-1.042)\t\n Larynx\t0.742 (0.582-1.169)\t\n Hypopharynx\t1.191 (0.879-1.483)\t\nT stage\t\n 1\t1.0\t\n 2\t0.843 (0.581-1.371)\t\n 3\t1.713 (0.822-3.421)\t\n 4\t1.519 (0.811-3.799)\t\nN stage\t\n 0\t1.0\t\n 1\t1.088 (0.696-1.441)\t\n 2a\t1.318 (0.577-1.421)\t\n 2b\t1.389 (0.776-2.889)\t\n 2c\t1.479 (1.171-3.286)\t\nLower neck LN\t\n Negative\t1.0\t\n Positive\t3.881 (1.682-6.379)\t\nTumor differentiation\t\n Well\t1.0\t\n Moderate\t1.092 (0.562-1.991)\t\n Poor\t1.371 (0.779-2.377)\t\nNo. of concurrent chemotherapy cycles\t\n 5-7\t1.0\t\n <5\t1.229 (0.562-4.669)\t\nOverall duration of radiotherapy (wk)\t\n 7-8\t1.0\t\n >8\t2.189 (1.214-7.442)\t\nResponse to induction chemotherapy\t\n CR\t1.0\t\n PR\t1.871 (1.171-4.331)\t\n SD\t8.826 (6.668-16.974)\t\nOR, odds ratio; CI, confidence interval; LN, lymph node; CR, complete response; PR, partial response; SD, stable disease.\n\nTable 3. Multivariate analysis correlating prognostic factors with 5-year distant metastasis-free survival (DMFS)\n\n\t5-Year DMFS rate (%)\tHR (95% CI)\tp-value\t\nPrimary site\t\n Oropharynx\t60.7\t1.0\t\t\n Oral cavity\t55.5\t1.077 (0.640-1.525)\t0.362\t\n Larynx\t52.1\t1.213 (0.767-1.428)\t0.441\t\n Hypopharynx\t45.2\t1.426 (0.861-1.927)\t0.218\t\nT stage\t\t\t\t\n 1\t64.7\t1.0\t\t\n 2\t66.7\t0.889 (0.452-1.778)\t0.768\t\n 3\t52.1\t1.339 (0.779-1.880)\t0.231\t\n 4\t40.3\t1.752 (0.901-2.771)\t0.11\t\nN stage\t\n 0\t60.7\t1.0\t\t\n 1\t58.6\t1.125 (0.551-1.339)\t0.568\t\n 2a\t52.7\t1.334 (0.769-1.552)\t0.325\t\n 2b\t52.6\t1.326 (0.662-1.625)\t0.376\t\n 2c\t43.8\t1.666 (0.979-3.225)\t0.072\t\nLower neck LN\t\t\t\t\n Negative\t55.2\t1.0\t\t\n Positive\t34.3\t2.375 (1.247-6.286)\t0.008\t\nTumor differentiation\t\n Well\t54.7\t1.0\t\t\n Moderate\t57.7\t0.902 (0.723-1.559)\t0.225\t\n Poor\t46.8\t1.445 (0.802-2.888)\t0.107\t\nNo. of concurrent chemotherapy cycles\t\n 5-7\t50.9\t1.0\t\t\n <5\t48.6\t1.076 (0.611-2.429)\t0.689\t\nOverall duration of radiotherapy (wk)\t\n 7-8\t50.5\t1.0\t\t\n >8\t46.1\t1.177 (0.672-1.819)\t0.443\t\nResponse to induction chemotherapy\t\n CR\t68.9\t1.0\t\t\n PR\t47.3\t2.116 (1.337-5.256)\t0.001\t\n SD\t0\t9.77 (3.289-18.925)\t< 0.001\t\nHR, hazard ratio; CI, confidence interval; LN, lymph node; CR, complete response; PR, partial response; SD, stable disease.\n\nTable 4. Multivariate analysis correlating prognostic factors with 5-year progression-free survival (PFS)\n\n\t5-Year PFS rate (%)\tHR (95% CI)\tp-value\t\nPrimary site\t\n Oropharynx\t53.2\t1.0\t\t\n Oral cavity\t44.5\t1.331 (0.757-1.780)\t0.452\t\n Larynx\t43.1\t1.409 (0.809-1.960)\t0.411\t\n Hypopharynx\t38.1\t1.557 (0.852-2.004)\t0.278\t\nT stage\t\n 1\t56.2\t1.0\t\t\n 2\t55.1\t1.019 (0.479-1.811)\t0.661\t\n 3\t43.7\t1.588 (0.719-2.562)\t0.211\t\n 4\t36.9\t1.771 (0.863-3.224)\t0.139\t\nN stage\t\n 0\t52.2\t1.0\t\t\n 1\t53.7\t0.956 (0.791-1.211)\t0.760\t\n 2a\t46.6\t1.177 (0.766-1.690)\t0.442\t\n 2b\t41.1\t1.223 (0.825-1.776)\t0.309\t\n 2c\t36.6\t1.462 (0.963-3.625)\t0.077\t\nLower neck LN\t\n Negative\t45.9\t1.0\t\t\n Positive\t32.6\t2.106 (1.204-4.003)\t0.021\t\nTumor differentiation\t\n Well\t45.9\t1.0\t\t\n Moderate\t42.4\t1.012 (0.692-1.558)\t0.525\t\n Poor\t37.7\t1.265 (0.715-2.166)\t0.311\t\nNo. of concurrent chemotherapy cycles\t\n 5-7\t41.9\t1.0\t\t\n <5\t40.0\t1.119 (0.718-1.776)\t0.389\t\nOverall duration of radiotherapy (wk)\t\n 7-8\t42.5\t1.0\t\t\n >8\t36.0\t1.299 (0.879-1.778)\t0.271\t\nResponse to induction chemotherapy\t\n CR\t58.8\t1.0\t\t\n PR\t42.7\t1.712 (1.229-2.886)\t0.005\t\n SD\t0\t8.862 (3.908-15.223)\t<0.001\t\nHR, hazard ratio; CI, confidence interval; LN, lymph node; CR, complete response; PR, partial response; SD, stable disease.\n==== Refs\nReferences\n1 Lee JH Song JH Lee SN Kang JH Kim MS Sun DI Adjuvant postoperative radiotherapy with or without chemotherapy for locally advanced squamous cell carcinoma of the head and neck: the importance of patient selection for the postoperative chemoradiotherapy Cancer Res Treat 2013 45 31 9 23613668 \n2 Adelstein DJ Li Y Adams GL Wagner H Jr Kish JA Ensley JF An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neckcancer J Clin Oncol 2003 21 92 8 12506176 \n3 Haddad RI Shin DM Recent advances in head and neck cancer N Engl J Med 2008 359 1143 54 18784104 \n4 Leemans CR Tiwari R Nauta JJ van der Waal I Snow GB Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma Cancer 1993 71 452 6 8422638 \n5 Leon X Quer M Orus C del Prado Venegas M Lopez M Distant metastases in head and neck cancer patients who achieved loco-regional control Head Neck 2000 22 680 6 11002323 \n6 Cohen EE Karrisson T Kocherginsky M Huang CH Agulnik M Mittal BB DeCIDE: a phase III randomized trial of docetaxel (D), cisplatin (P), 5-fluorouracil (F) (TPF) induction chemotherapy (IC) in patients with N2/N3 locally advanced squamous cell carcinoma of the head and neck (SCCHN) J Clin Oncol 2012 30 S Abstr 5500 \n7 Garavello W Ciardo A Spreafico R Gaini RM Risk factors for distant metastases in head and neck squamous cell carcinoma Arch Otolaryngol Head Neck Surg 2006 132 762 6 16847186 \n8 Ellis ER Mendenhall WM Rao PV Parsons JT Spangler AE Million RR Does node location affect the incidence of distant metastases in head and neck squamous cell carcinoma? Int J Radiat Oncol Biol Phys 1989 17 293 7 2753756 \n9 Sher DJ Posner MR Tishler RB Sarlis NJ Haddad RI Holupka EJ Relationship between radiation treatment time and overall survival after induction chemotherapy for locally advanced head-and-neck carcinoma: a subset analysis of TAX 324 Int J Radiat Oncol Biol Phys 2011 81 e813 8 21300455 \n10 Bhide SA Ahmed M Barbachano Y Newbold K Harrington KJ Nutting CM Sequential induction chemotherapy followed by radical chemo-radiation in the treatment of locoregionally advanced head-and-neck cancer Br J Cancer 2008 99 57 62 18560402 \n11 van den Brekel MW Stel HV Castelijns JA Nauta JJ van der Waal I Valk J Cervical lymph node metastasis: assessment of radiologic criteria Radiology 1990 177 379 84 2217772 \n12 Edge SB Byrd DR Compton CC Fritz AG Greene FL Trotti A AJCC cancer staging manual 7th ed New York Springer 2009 \n13 Miller AB Hoogstraten B Staquet M Winkler A Reporting results of cancer treatment Cancer 1981 47 207 14 7459811 \n14 Vokes EE Kies MS Haraf DJ Stenson K List M Humerickhouse R Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer J Clin Oncol 2000 18 1652 61 10764425 \n15 Machtay M Rosenthal DI Hershock D Jones H Williamson S Greenberg MJ Organ preservation therapy using induction plus concurrent chemoradiation for advanced resectable oropharyngeal carcinoma: a University of Pennsylvania Phase II Trial J Clin Oncol 2002 20 3964 71 12351593 \n16 Shin HJ Chung JS Choi YJ Lee BJ Wang SG Kim DW Neoadjuvant docetaxel and cisplatin chemotherapy followed by local irradiation is highly active on locoregionally advanced squamous cell carcinoma of the head and neck J Laryngol Otol 2008 122 722 7 17925058 \n17 Posner MR Hershock DM Blajman CR Mickiewicz E Winquist E Gorbounova V Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer N Engl J Med 2007 357 1705 15 17960013 \n18 Alvi A Johnson JT Development of distant metastasis after treatment of advanced-stage head and neck cancer Head Neck 1997 19 500 5 9278758 \n19 Spector JG Sessions DG Haughey BH Chao KS Simpson J El Mofty S Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx Laryngoscope 2001 111 1079 87 11404625 \n20 Johnson JT Wagner RL Myers EN A long-term assessment of adjuvant chemotherapy on outcome of patients with extracapsular spread of cervical metastases from squamous carcinoma of the head and neck Cancer 1996 77 181 5 8630927 \n21 Garden AS Asper JA Morrison WH Schechter NR Glisson BS Kies MS Is concurrent chemoradiation the treatment of choice for all patients with Stage III or IV head and neck carcinoma? Cancer 2004 100 1171 8 15022283 \n22 Kalnins IK Leonard AG Sako K Razack MS Shedd DP Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity Am J Surg 1977 134 450 4 911028 \n23 Vermorken JB Remenar E van Herpen C Gorlia T Mesia R Degardin M Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer N Engl J Med 2007 357 1695 704 17960012\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "47(1)",
"journal": "Cancer research and treatment",
"keywords": "Chemoradiotherapy; Head and neck neoplasms; Induction chemotherapy; Neoplasm metastasis; Prognosis",
"medline_ta": "Cancer Res Treat",
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"pages": "46-54",
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"pmid": "25327492",
"pubdate": "2015-01",
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"references": "8630927;7459811;11002323;911028;17960012;21300455;12351593;11404625;18560402;16847186;12506176;18784104;10764425;9278758;2217772;17960013;8422638;2753756;23613668;15022283;17925058",
"title": "Analysis of the prognostic factors for distant metastasis after induction chemotherapy followed by concurrent chemoradiotherapy for head and neck cancer.",
"title_normalized": "analysis of the prognostic factors for distant metastasis after induction chemotherapy followed by concurrent chemoradiotherapy for head and neck cancer"
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"abstract": "Pulmonary artery aneurysms (PAA) can be complicated with pulmonary arterial hypertension (PAH), causing sudden death due to PA rupture and dissection. Because treatment with PAH-targeted drugs does not always prevent PAA progression, prophylactic surgical repair of the PAA seems a promising alternative. However, although it avoids rupture and dissection of the PAs, additional benefits have not been forthcoming. We therefore present two patients with co-existing PAH and a PAA who underwent surgical repair of the aneurysm. Following the surgery, their lung function and pulmonary hypertension improved. Optimal treatment of PAA remains uncertain, however, with no clear guidelines regarding the best therapeutic approach. This case series provides physicians with reasons to repair PAA surgically in patients with PAH.",
"affiliations": "1 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.;1 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.;2 Department of Cardiovascular Surgery, Okayama University Hospital, Okayama, Japan.;1 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.;1 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.",
"authors": "Akagi|Satoshi|S|https://orcid.org/0000-0002-9392-7117;Ejiri|Kentaro|K|;Kasahara|Shingo|S|;Nakamura|Kazufumi|K|;Ito|Hiroshi|H|",
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"doi": "10.1177/2045894019831217",
"fulltext": "\n==== Front\nPulm CircPulm CircPULsppulPulmonary Circulation2045-89322045-8940SAGE Publications Sage UK: London, England 3069848510.1177/204589401983121710.1177_2045894019831217Case ReportImprovement of lung function and pulmonary hypertension after pulmonary aneurysm repair: case series https://orcid.org/0000-0002-9392-7117Akagi Satoshi 1Ejiri Kentaro 1Kasahara Shingo 2Nakamura Kazufumi 1Ito Hiroshi 11 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan2 Department of Cardiovascular Surgery, Okayama University Hospital, Okayama, JapanSatoshi Akagi, Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, 2-5-1, Kita-ku, Shikata-cho, Okayama 700-8558, Japan. Email: akagi-s@cc.okayama-u.ac.jp15 2 2019 Jan-Mar 2019 9 1 204589401983121722 10 2018 18 1 2019 © The Author(s) 20192019SAGE Publications Ltd, or Pulmonary Vascular Research Institute, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Pulmonary artery aneurysms (PAA) can be complicated with pulmonary arterial hypertension (PAH), causing sudden death due to PA rupture and dissection. Because treatment with PAH-targeted drugs does not always prevent PAA progression, prophylactic surgical repair of the PAA seems a promising alternative. However, although it avoids rupture and dissection of the PAs, additional benefits have not been forthcoming. We therefore present two patients with co-existing PAH and a PAA who underwent surgical repair of the aneurysm. Following the surgery, their lung function and pulmonary hypertension improved. Optimal treatment of PAA remains uncertain, however, with no clear guidelines regarding the best therapeutic approach. This case series provides physicians with reasons to repair PAA surgically in patients with PAH.\n\nvital capacitypulmonary artery pressurelung perfusion and oxygenationcover-dateJanuary-March 2019\n==== Body\nIntroduction\nPulmonary artery aneurysms (PAA) are sometimes associated with pulmonary arterial hypertension (PAH).1 A PAA can be an independent risk factor for unexpected death due to aneurysm rupture or dissection in patients with PAH.2 Because it is known that PAAs progress in patients with PAH despite treatment for the pulmonary hypertension (PH),3 prophylactic surgical repair of a PAA could be a treatment option.4 The benefit of surgical repair of a PAA is that it precludes the possibility of its rupture and dissection. Any additional benefits of such surgical repair of a PAA in the presence of PAH have not been elucidated. We therefore present two patients, each with coexisting PAH and a PAA, who underwent surgical repair of the aneurysm and whose lung function and PH improved.\n\nCase report 1\nA 63-year-old woman had been diagnosed with idiopathic PAH at the age of 49 years. At that time, contrast-enhanced computed tomography (CT) showed a large PAA (diameter 67 mm). Right heart catheterization (RHC) showed a mean pulmonary artery pressure (mPAP) of 75 mmHg. She was started on beraprost with sequentially added bosentan at the age 51 years and sildenafil at 54 years. The bosentan was changed to ambrisentan at age 57 years and the sildenafil to riociguat at the age of 60 years. Although mPAP decreased to 44 mmHg, the PAA’s diameter had expanded to 129 mm (Fig. 1a), and her SpO2 was 95% with oxygen administration at 4 L/min. She had exertional breathlessness and was in World Health Organization (WHO) functional class (FC) II. We therefore decided to repair the PAA surgically. When she was aged 61 years, we reconstructed the right ventricular outflow tract and performed bilateral pulmonary artery plication (Fig. 1b). Seven months postoperatively, RHC showed a mPAP of 35 mmHg (with the patient on ambrisentan and riociguat). Lung perfusion scintigraphy showed that a preoperative perfusion ratio in her left upper and middle lung had increased postoperatively (Fig. 1c and d). In addition, the lung function test showed that her preoperative vital capacity of 1.7 L (71.4% of predicted value) had increased postoperatively to 2.4 L (93.7% of predicted value). Her SpO2 was 99% with oxygen administration at 1 L/min. Precise clinical, echocardiographic, and hemodynamic parameters, lung function test, and blood gas test of case 1 before and after surgery of PAA are shown in Table 1.\nFig. 1 Chest CT and lung perfusion scintigraphy. Top: Before repair of a PAA. Bottom: After repair of a PAA. (a, b) Contrast-enhanced CT of case 1. (c, d) Lung perfusion scintigraphy of case 1. (e, f) Contrast-enhanced CT of case 2. (g, h) Lung perfusion scintigraphy of case 2. CT, computed tomography; PAA, pulmonary artery aneurysm.\n\n\nTable 1. Clinical, echocardiographic, and hemodynamic parameters, lung function test, and blood gas test of patients before and after surgery of PAA.\n\n\tCase 1\tCase 2\t\nParameters\tPre\tPost\tPre\tPost\t\n\nClinical\n\t\n WHO FC\tII\tII\tIII\tII\t\n\nEchocardiographic\n\t\n TR\tTrivial\tTrivial\tMild\tMild\t\n TRPG (mmHg)\t68\t49\t55\t44\t\n TAPSE (mm)\t13\t13\t12\t14\t\n S’ (cm/s)\t9\t9\t8\t8\t\n RVFAC (%)\t35\t33\t32\t29\t\nHemodynamic\t\n PAP (s/d/m) (mmHg)\t62/35/44\t63/16/35\t56/17/35\t50/14/26\t\n RVSP/EDP (mmHg)\t62/2\t75/0\t57/8\t54/6\t\n RAP (mmHg)\t2\t0\t8\t6\t\n PAWP (mmHg)\t–\t0\t–\t14\t\n CO (L/min)\t2.3\t3.6\t5.7\t8.1\t\n CI (L/min/m2)\t1.6\t2.5\t3.9\t5.3\t\n PVR or TPR (Wood units)\t19*\t10\t6*\t2\t\n\nLung function test\n\t\n VC (L)\t1.7\t2.4\t1.6\t2.2\t\n %VC (%)\t71.4\t93.7\t57.8\t82.3\t\n FEV1.0 (L)\t1.03\t1.59\t0.95\t1.24\t\n FEV1.0% (%)\t66.0\t69.4\t60.0\t58.2\t\n Pattern\tMixed\tObstructive\tMixed\tObstructive\t\n\nBlood gas test\n\t\n Oxygen administration\t4 L\t–\t4 L\t2 L\t\n pH\t7.4\t–\t7.4\t7.4\t\n PaO2 (mmHg)\t94.7\t–\t72.2\t88.3\t\n PaCO2 (mmHg)\t33.9\t–\t45.9\t43.4\t\n* Values are TPR because PAWP was not measured due to large PAA.\n\nWHO FC, World Health Organization functional class; TR, tricuspid regurgitation; TRPG, tricuspid regurgitation pressure gradient; TAPSE, tricuspid annular plane systolic excursion; S’, tricuspid annular velocity; RVFAC, right ventricular fractional area change; PAP, pulmonary artery pressure; s/d/m, systolic/diastolic/mean; RVSP, right ventricular systolic pressure; RVEDP, right ventricular end diastolic pressure; RAP, right atrial pressure; PAWP, pulmonary artery wedge pressure; CO, cardiac output; CI, cardiac index; PVR, pulmonary vascular resistance; TPR, total pulmonary resistance; VC, vital capacity; FEV1.0, forced expiratory volume in 1 s.\n\n\n\nCase report 2\nA 61-year-old woman had been diagnosed at the age of 31 years with portopulmonary hypertension associated with a congenital portosystemic venous shunt. At age 50 years, CT demonstrated a large PAA (diameter 71 mm). RHC showed a mPAP of 52 mmHg. Bosentan was initiated; tadalafil was added sequentially at age 54 years. Bosentan was changed to ambrisentan at age 56 years. Although her mPAP had decreased to 41 mmHg, the aneurysm’s diameter had expanded to 133 mm (Fig. 1e), and her SpO2 was 95% with oxygen administration at 3 L/min. She underwent coil occlusion of a congenital portosystemic venous shunt and intravenous epoprostenol was added to the regimen. She had exertional breathlessness, cough, and general fatigue and was in WHO FC III. Because the mPAP had decreased to 35 mmHg, we decided repair the aneurysm surgically. At the age of 61 years, she underwent reconstruction of the right ventricular outflow tract and bilateral pulmonary artery plication (Fig. 1f). RHC performed nine months postoperatively showed a mPAP of 26 mmHg (with the patient on ambrisentan, tadarafil, and selexipag). Lung perfusion scintigraphy showed that a preoperative perfusion ratio in her left upper and middle lung had increased postoperatively (Fig. 1g and h). The lung function test revealed that her preoperative vital capacity of 1.6 L (57.8% of predicted value) increased postoperatively to 2.2 L (82.3% of predicted value). Also, her SpO2 was 99% with oxygen administration at 2 L/min. Precise clinical, echocardiographic, and hemodynamic parameters, lung function test, and blood gas test of case 2 before and after PAA surgery are shown in Table 1.\n\nDiscussion\nPAA is defined as the main pulmonary artery diameter measuring > 40 mm.5 Its prevalence was approximately 1 in 14,000 autopsies.6 Elevated PAP, high flow, connective tissue diseases, pulmonary valve stenosis, systematic vasculitis, infections, and trauma are the most probable causes of a PAA.1 Dissection or rupture of PAA is rare but life-threatening. Hence, prophylactic treatment for PAA is required—although there is no clear evidence that one or another treatment/therapeutic strategy for PAA is more effective than any other. Reduced hemodynamic stress on the pulmonary artery wall might help prevent the formation and progression of PAA because increased shear stress would injure a pulmonary artery wall.7 However, lowering the PAP by PAH-targeted drugs has not always prevented PAA progression.3,8 Aggressive surgical intervention has also been advocated for patients with PAH.\n\nTo date, although surgical repair of PAA precludes the possibility of impending dissection and rupture, there has been no evidence reported that the repair offers additional benefits. In our two patients, however, their vital capacity increased after repairing the PAA. We think that expansion of the left upper and middle lung, which had been compressed by the PAA in each patient, resulted in the improved lung function. In addition, repair of the PAA recanalized the left upper and middle pulmonary artery, which allowed increased pulmonary blood flow. Thus, these ventilation and perfusion recoveries in the left upper and middle lung could lead to improved oxygenation. Furthermore, expansion of the pulmonary vascular bed could result in reduced hemodynamic stress, thereby contributing to decreased PAP. Hence, we believe that there are additional benefits of surgical repair of PAA. They are improved lung function and PH in patients with PAH.\n\nKreibich et al. recommended the following indications for PAA surgery: (1) an absolute PAA diameter of ≥5.5 cm; (2) increase in the aneurysm’s diameter of ≥0.5 cm within six months; (3) compression of adjacent structures; (4) thrombus formation in the aneurysm sac; (5) appearance of clinical symptom; (6) evidence of valvular pathology or a shunt; (7) verification of PAH; (8) signs of rupture or dissection.1 More evidence is needed to know whether the benefit of therapeutic intervention exceeds the risk of the surgery. We think that appropriate indications for PAA surgery would provide the benefit of therapeutic intervention beyond risks of the surgery. Preoperative lung function test showed the reduced vital capacity and mixed pattern in both cases. Preoperative lung perfusion scintigraphy showed the reduced perfusion ratio in lung compressed by PAA in both cases. Cardiac output (CO) was also an important factor for indication for PAA surgery. There were some case reports and series of PAA surgery with or without PAH. In reports with patients without PAH who were received PAA surgery, CO was not described,9,10 but ejection fraction was preserved (EF = 51%).10 In reports of patients with PAH who received PAA surgery, CO was not described.11 In a report of a patient with PAH who did not receive PAA surgery, the patient had a low cardiac index (2.5 L/min/m2) and died although the patient was treated with PAH-specific drugs.12 Decreased CO was an independent risk factor of all all-cause mortality in PAH patients with PAA.2 In our cases, CO was relatively preserved before PAA surgery. In our opinion, these respiratory function, image findings, and preserved CO would be factors of indication for PAA surgery.\n\nThe diameter of PAA at diagnosis was > 55 mm in both cases. However, we chose not to operate on the patients then because PAP was high (Case 1: mPAP = 75 mmHg, Case 2: mPAP = 52 mmHg) and PH was not stable in both cases. Thereafter, we chose to operate patients because mPAP decreased, PH improved, and CO was relatively preserved, but hypoxia progressed.\n\nAs these two cases suggested, surgical repair of a PAA could achieve improved lung function and PH. Therefore, we believe that the presence of reduced vital capacity, reduced perfusion ratio in lung compressed by PAA, and severe oxygen desaturation indicate the need to consider surgical repair of a PAA.\n\nAcknowledgments\nWe thank Nancy Schatken, from Edanz Group (www.edanzediting.com/ac), for editing a draft of this manuscript. We thank Nobuhiro Tahara and Yoshihiro Fukumoto (Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine) and Machiko Asaka (Department of Cardiovascular Medicine, Saga University) for their contributions to the management of a patient (case 2).\n\nConflict of interest\nThe author(s) declare that there is no conflict of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Kreibich M Siepe M Kroll J et al. \nAneurysms of the pulmonary artery . Circulation \n2015 ; 131 : 310 –316 .25601950 \n2 Zylkowska J Kurzyna M Florczyk M et al. \nPulmonary artery dilatation correlates with the risk of unexpected death in chronic arterial or thromboembolic pulmonary hypertension . Chest \n2012 ; 142 : 1406 –1416 .22797193 \n3 Akagi S Nakamura K Sarashina T et al. \nProgression of pulmonary artery dilatation in patients with pulmonary hypertension coexisting with a pulmonary artery aneurysm . J Cardiol \n2018 ; 71 : 517 –522 .29246394 \n4 Hou R Ma GT Liu XR et al. \nSurgical treatment of pulmonary artery aneurysm: an institutional experience and literature review . Interact Cardiovasc Thorac Surg \n2016 ; 23 : 438 –442 .27226398 \n5 Duijnhouwer AL Navarese EP Van Dijk AP et al. \nAneurysm of the pulmonary artery, a systematic review and critical analysis of current literature . Congenit Heart Dis \n2016 ; 11 : 102 –109 .26555132 \n6 Deterling RA JrClagett OT \nAneurysm of the pulmonary artery; review of the literature and report of a case . Am Heart J \n1947 ; 34 : 471 –499 .20266464 \n7 Akagi S Matsubara H Nakamura K et al. \nModern treatment to reduce pulmonary arterial pressure in pulmonary arterial hypertension . J Cardiol \n2018 ; 72 : 466 –472 .29898864 \n8 Boerrigter B Mauritz GJ Marcus JT et al. \nProgressive dilatation of the main pulmonary artery is a characteristic of pulmonary arterial hypertension and is not related to changes in pressure . Chest \n2010 ; 138 : 1395 –1401 .20495109 \n9 Theodoropoulos P Ziganshin BA Tranquilli M et al. \nPulmonary artery aneurysms: four case reports and literature review . Int J Angiol \n2013 ; 22 : 143 –148 .24436601 \n10 Vistarini N Aubert S Gandjbakhch I et al. \nSurgical treatment of a pulmonary artery aneurysm . Eur J Cardiothorac Surg \n2007 ; 31 : 1139 –1141 .17420137 \n11 Reisenauer JS Said SM Schaff HV et al. \nOutcome of surgical repair of pulmonary artery aneurysms: a single-center experience with 38 patients . Ann Thorac Surg \n2017 ; 104 : 1605 –1610 .28648537 \n12 Degano B Prevot G Tetu L et al. \nFatal dissection of the pulmonary artery in pulmonary arterial hypertension . Eur Respir Rev \n2009 ; 18 : 181 –185 .20956141\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2045-8932",
"issue": "9(1)",
"journal": "Pulmonary circulation",
"keywords": "lung perfusion and oxygenation; pulmonary artery pressure; vital capacity",
"medline_ta": "Pulm Circ",
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"pmid": "30698485",
"pubdate": "2019",
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"references": "17420137;20266464;20495109;20956141;22797193;24436601;25601950;26555132;27226398;28648537;29246394;29898864",
"title": "Improvement of lung function and pulmonary hypertension after pulmonary aneurysm repair: case series.",
"title_normalized": "improvement of lung function and pulmonary hypertension after pulmonary aneurysm repair case series"
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"abstract": "Baclofen, a muscle relaxant prescribed for the alleviation of symptoms of spasticity acts primarily at the spinal level but with high doses, it penetrates the blood-brain barrier and can result in prominent central nervous depression. Baclofen toxicity has been associated with a variety of symptoms ranging from dizziness to deep coma. We report the clinical course, management, and outcome of a case of baclofen overdose who presented in deep coma with loss of brainstem reflexes and a burst suppression (BS) pattern on his electroencephalogram (EEG). In addition, we reviewed the presentation and outcomes of all reported cases of baclofen toxicity with a BS pattern on EEG to evaluate if those cases share a common clinical presentation and for the presence of signs and symptoms that would help the clinician to consider this diagnosis. There appears to be a common clinical picture associated with severe baclofen toxicity consisting of deep coma associated with loss of all brainstem reflexes including pupillary reactivity, frequent association with seizures/myoclonic jerks, and a BS pattern on EEG. The outcome is generally good, and serial EEGs are recommended to document a reversal of the abnormal electrographic features.",
"affiliations": "Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon.;Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon.",
"authors": "Farhat|Sahar|S|;El Halabi|Tarek|T|;Makki|Achraf|A|;Atweh|Samir F|SF|;Nasreddine|Wassim|W|;Beydoun|Ahmad|A|",
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"doi": "10.3389/fneur.2020.00404",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.00404\nNeurology\nCase Report\nComa With Absent Brainstem Reflexes and a Burst Suppression on EEG Secondary to Baclofen Toxicity\nFarhat Sahar † El Halabi Tarek † Makki Achraf Atweh Samir F. Nasreddine Wassim Beydoun Ahmad * Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon\nEdited by: Bryan G. Young, London Health Sciences Centre, Canada\n\nReviewed by: Peter W. Kaplan, Johns Hopkins University, United States; Ryan Matthew Martin, University of California, United States\n\n*Correspondence: Ahmad Beydoun ab29@aub.edu.lbThis article was submitted to Neurocritical and Neurohospitalist Care, a section of the journal Frontiers in Neurology\n\n†These authors have contributed equally to this work\n\n\n13 5 2020 \n2020 \n11 40406 1 2020 17 4 2020 Copyright © 2020 Farhat, El Halabi, Makki, Atweh, Nasreddine and Beydoun.2020Farhat, El Halabi, Makki, Atweh, Nasreddine and BeydounThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Baclofen, a muscle relaxant prescribed for the alleviation of symptoms of spasticity acts primarily at the spinal level but with high doses, it penetrates the blood-brain barrier and can result in prominent central nervous depression. Baclofen toxicity has been associated with a variety of symptoms ranging from dizziness to deep coma. We report the clinical course, management, and outcome of a case of baclofen overdose who presented in deep coma with loss of brainstem reflexes and a burst suppression (BS) pattern on his electroencephalogram (EEG). In addition, we reviewed the presentation and outcomes of all reported cases of baclofen toxicity with a BS pattern on EEG to evaluate if those cases share a common clinical presentation and for the presence of signs and symptoms that would help the clinician to consider this diagnosis. There appears to be a common clinical picture associated with severe baclofen toxicity consisting of deep coma associated with loss of all brainstem reflexes including pupillary reactivity, frequent association with seizures/myoclonic jerks, and a BS pattern on EEG. The outcome is generally good, and serial EEGs are recommended to document a reversal of the abnormal electrographic features.\n\ncomabaclofen toxicityburst suppressionbrainstem reflexesseizure\n==== Body\nIntroduction\nBaclofen, [β-(4-chlorophenyl) GABA] is a skeletal muscle relaxant frequently prescribed for the alleviation of symptoms of spasticity (1), which is associated with various neurologic conditions such as multiple sclerosis and spinal cord lesions. It is also used for the treatment of other conditions such as chronic back pain associated with muscle spasms, trigeminal neuralgia, cluster headaches, or intractable hiccups (2). As a structural analog to gamma-aminobutyric acid (GABA), it is believed to exert its mechanism of action by binding to the GABA-B receptors at the level of the spinal interneurons (1). In therapeutic doses, baclofen primarily acts at the spinal level (3) and is rarely associated with severe adverse effects although drowsiness may occur (4). However, at higher doses it penetrates the blood-brain barrier and can result in prominent central nervous depression (5, 6).\n\nBaclofen toxicity has been associated with a variety of symptoms ranging from dizziness to deep coma (7, 8). We report the clinical course, management, and outcome of a case of baclofen overdose who presented in deep coma with loss of brainstem reflexes and a burst suppression (BS) pattern on his electroencephalogram (EEG). In addition, we reviewed the presentation and outcomes of all reported cases of baclofen toxicity with a BS pattern on EEG to evaluate if those cases share a common clinical presentation and for the presence of signs and symptoms that would help the clinician consider this diagnosis.\n\nCase Report\nA 68-year old right-handed man was brought to the emergency department (ED) with an altered level of consciousness. His present medical illness started a few hours prior to presentation with somnolence followed by unresponsiveness associated with multifocal myoclonus.\n\nUpon admission, the patient required immediate intubation and ventilator support to protect his airway. On his initial examination, his blood pressure was 115/54 mm Hg, heart rate was regular at 54 beats/min and his temperature was 36.6°C. On neurological examination, the patient was in deep coma, with 4 mm fixed unreactive pupils, and absent corneal, oculocephalic, and gag reflexes. Funduscopic examination was normal, and neck was supple with no evidence of meningismus. There were no spontaneous movements with evidence of diffuse hypotonia and no response to noxious stimuli. The reflexes were diffusely reduced and the plantar responses were flexor bilaterally. The rest of his medical examination was normal with no external signs of a traumatic head injury. In the ED, the patient developed a generalized tonic-clonic seizure that was abolished with intravenous diazepam and was followed by a loading dose of valproate.\n\nA complete blood count and differential, electrolytes, liver function tests, renal function, and ammonia were unremarkable. Serum creatine kinase and venous lactic acid were elevated at 702 IU/L (reference range: 20–205 for males), and 2.27 mmol/L (reference range: 0.55–2.20), respectively. A urine toxicology screen was positive for benzodiazepines and opiates. A head computed tomography (CT) and a CT-angiogram were normal. Chest x-ray and electrocardiogram were normal. An epilepsy protocol magnetic resonance imaging (MRI) of the brain failed to reveal any abnormalities, specifically no restricted diffusion. A 90 min video/EEG recording in the ED showed a burst suppression pattern with bursts of mixed theta delta activity lasting 1–3 s alternating with severe diffuse suppression of the background amplitude lasting 4–5 s (Figure 1). There was no spontaneous variability in the record nor any reactivity to noxious or auditory stimuli.\n\nFigure 1 Burst suppression pattern upon presentation to the Emergency department.\n\nHis past medical history is relevant for a history of chronic low back pain associated with muscle spasms for which he was prescribed pregabalin, tramadol, and baclofen. Based on that history along with the BS pattern seen on EEG, all his home medications were held and blood for tramadol and baclofen serum levels were immediately drawn in the ED.\n\nThe patient was admitted to the intensive care unit where his mental status gradually improved over the subsequent 48 h. He was extubated on day 3 at which time he was following commands, although he remained intermittently agitated, and required treatment with quetiapine. His EEG on that day showed resolution of the BS pattern with mild generalized slowing of the background (Figure 2). The patient was discharged home with no neurological deficits on day 9. The serum levels drawn on the day of admission revealed an elevated tramadol level at 1,960 ng/mL (Reference range: 100–1,000 ng/mL), and a toxic baclofen level at 4.30 ug/ml (Reference range 0.08–0.6 ug/ml; toxic >1.1ug/ml).\n\nFigure 2 Resolution of the burst suppression pattern and normalization of the EEG after stopping baclofen.\n\nLiterature Review\nWe searched for all English-language reported cases of baclofen overdose via MEDLINE using the following key words: “baclofen,” “overdose,” “intoxication,” “EEG,” and “burst suppression.” Additional studies were obtained by checking the references. We reviewed all reported cases of accidental or intentional oral baclofen overdose to determine if a BS pattern was present on the EEG. The nine cases identified from the literature (including the one reported here) are listed in Table 1, along with some of the findings on neurological examination and pertinent clinical features.\n\nTable 1 Clinical characteristics of published cases of baclofen intoxication with a BS pattern on EEG.\n\nReferences\tAge (yrs)\tGender\tPresentation\tIntubated\tBrainstem reflexes\tPupillary reflexes\tReflexes\tSeizure\tMyo-clonus\tEEG pattern\tBaclofen level (ug/ml)\tStart of recovery\t\nPaulson (9)\t29\tF\tDeep coma\tYes\tAbsent\tAbsent\tNR\tNo\tYes\tBS\tND\tDay 3\t\nWeissenborn et al. (10)\t40\tF\tDeep coma\tYes\tAbsent\tAbsent\tAbsent\tYes\tNo\tBS\t1.2\tDay 4\t\nOstermann et al. (11)\t59\tM\tDeep coma\tYes\tAbsent\tAbsent\tHypo\tNo\tNo\tBS\tND\tDay 2\t\nSlaughter et al. (12)\t14\tF\tDeep coma\tYes\tAbsent\tAbsent\tAbsent\tYes\tNo\tBS\t0.6\tDay 4\t\nWall et al. (13)\t48\tM\tDeep coma\tYes\tNR\tAbsent\tNR\tYes\tNo\tBS\t1.2\tDay 2\t\nKumar et al. (14)\t35\tF\tDeep coma\tYes\tAbsent\tAbsent\tAbsent\tNo\tYes\tBS\tND\tDay 3\t\nSullivan et al. (15)\t40\tF\tDeep coma\tYes\tAbsent\tAbsent\tNR\tYes\tNo\tBS\tND\tDay 5\t\nCaron et al. (2)\t17\tF\tDeep coma\tYes\tAbsent\tAbsent\tAbsent\tYes\tNo\tBS\t0.8\tDay 5\t\nOur case\t68\tM\tDeep coma\tYes\tAbsent\tAbsent\tHypo\tYes\tYes\tBS\t4.3\tDay 3\t\nNR, Not reported; ND, Not done; Hypo, hyporeflexia; M, Males; F, Females.\n\nStart of recovery indicated the time when patient was extubated and started to follow commands.\n\nDiscussion\nThis case demonstrates that severe baclofen toxicity with a BS pattern on EEG is fully reversible with adequate supportive treatment. The baclofen overdose was documented with a serum level drawn shortly after presentation to the ED and was ~7 times the upper limit of the reference range and four times higher than the toxic level.\n\nA series of 37 patients reported that the common clinical presentations of baclofen overdose consisted of an encephalopathy in all patients, coma in 59%, seizures in 43%, as well as respiratory depression, hyporeflexia, and autonomic dysfunction (7). Of the 16 patients with seizures, 50% experienced generalized tonic-clonic seizures, 31% experienced myoclonus, and 19% experienced both seizure types. Other less frequent manifestations included hallucinosis, impaired memory, catatonia, acute mania, orofacial dyskinesia, and tremor (7). The severity of symptoms with baclofen toxicity were found to be dose-related with delirium, seizures, and coma only seen following ingestion of 200 mg or more of baclofen (8).\n\nBaclofen toxicity is also associated with a variety of EEG abnormalities including generalized slowing of the background activity, appearance of triphasic waves, generalized periodic sharp waves, or rhythmic generalized high-amplitude delta waves (16–19). A BS pattern, which consists of bursts of mixed activity alternating with severe suppression of the background amplitude has rarely been reported following baclofen intoxication. This pattern, which indicates a severe cerebral dysfunction and depressed function of the deep pontine areas (20) is mostly seen after diffuse hypoxic-ischemic injuries in which case it portends a very bad prognosis (21). It was also reported after severe traumatic brain injuries and following prolonged status epilepticus (10). When associated with a toxic etiology, this pattern can be reversible with the patient making a complete recovery. Intoxications leading to a BS pattern are rare and have mostly been described after barbiturates or gluthetimide overdoses (22). In our patient, although the level of tramadol was above the therapeutic range and could have contributed to his encephalopathy, intoxication with this drug was never reported to lead to a BS pattern. The electrographic features associated with tramadol intoxication mostly consisted of epileptiform and non-epileptiform abnormalities with no BS pattern reported (23–25). Similarly, the clinical features of pregabalin toxicity described in a few case reports consisted of patients presenting in a comatose state, severe neurological depression, encephalopathy, or psychosis associated with rhythmic epileptiform discharges or triphasic waves over the scalp EEG (9, 26, 27).\n\nThe first case of baclofen intoxication associated with a BS pattern on EEG was published in 1976 and described a 29 years old woman who ingested 900–970 mg in a suicide attempt (11). Since then, seven additional cases of accidental or intentional intoxication with baclofen associated with a BS pattern on EEG have been reported (Table 1). Upon review of those cases, which included adults and children, it is clear that the initial clinical presentation is very similar and consists of deep coma, absence of brainstem reflexes including pupillary reflexes, respiratory failure, and diffuse hypotonia with hyporeflexia or areflexia (Table 1). This initial clinical presentation can therefore suggest a catastrophic central nervous system (CNS) event, sometimes mimicking brain death (15, 28). A striking clinical feature of all reported cases (including our own) is the absence of pupillary reflexes which are usually preserved in metabolic encephalopathies and most drug toxicities, a finding that would favor a severe hypoxic, or traumatic injury, or a brainstem lesion (29). However, there was no consistent pattern regarding the pupillary size since out of 9 patients, 5 patients were reported to have midsize pupils, two had dilated pupils, one had small pupils, and the pupillary size in the last patient was not reported. A severe anoxic or traumatic injury as well as intoxication with certain drugs can lead to a BS pattern on EEG, a pattern that would not be seen following an ischemic event or a lesion to the brainstem.\n\nIn addition, there was a frequent association with generalized tonic-clonic seizures or multifocal myoclonic jerks as five of the nine patients presented with generalized tonic-clonic seizures, two with myoclonus, and one patient experienced both seizure types (Table 1). Although an analog of GABA, an inhibitory neurotransmitter, baclofen interacts with the GABA-B receptors that are located on pre and postsynaptic positions. It was therefore suggested that baclofen can act as a proconvulsant by hyperpolarizing presynaptic and postsynaptic inhibitory interneurons, which will shift the neuronal balance toward excitation and lower the seizure threshold (30).\n\nThe time span for recovery is overall consistent with the half-life reported for baclofen overdose. Although with chronic dosing the elimination half-life of baclofen was estimated at 3–4 h (31), it was reported to sometimes increase to more than 30 h following ingestion of toxic doses (32). In addition, experimental studies have shown that its elimination from the CNS is slower than its pharmacokinetic half-life (33). This can explain the persistence of CNS depression even when the plasma concentrations of baclofen levels return to within the therapeutic range (14, 32).\n\nSince there is no antidote for baclofen, the management of overdose is symptomatic and consists of supportive care with intravenous fluids, inotropes, and mechanical ventilation when necessary (15, 34). All reported patients who presented in deep coma and a BS pattern on EEG required intubation, were admitted to the intensive care unit (ICU) for a few days and recovered completely with adequate supportive care (Table 1). Although not an antagonist to baclofen, some have advocated the use of physostigmine in cases of baclofen toxicity based on the fact that this drug reversed the respiratory depression and somnolence due to opiates (35). However, its lack of efficacy as reported by others coupled with its adverse effects that include bradycardia and increased airway secretions would argue against its routine use (36).\n\nOthers have suggested the use of flumazenil, a benzodiazepine antagonist (37), but subsequent reports failed to support its use in cases of baclofen toxicity (38). Hemodialysis can be considered especially in patients with renal insufficiency, since it will result in a delayed clearance of baclofen (7, 39).\n\nConclusions\nSince baclofen is a commonly prescribed drug and is also used as recreational drug [38], it is important for clinicians to be aware of the signs and symptoms associated with an overdose, whether accidental or intentional. There appears to be a common clinical picture associated with severe baclofen toxicity consisting of deep coma associated with loss of all brainstem reflexes including pupillary reactivity, frequent association with seizures/myoclonic jerks, and a BS pattern on EEG. When hypoxic or traumatic injuries are ruled out, this clinical picture should strongly suggest the possibility of intoxication and a serum level of baclofen, when possible, should be drawn. A high level of suspicion is required since baclofen is not detected by routine urine drug screening. The outcome is generally good, and serial EEGs are recommended to document a reversal of the abnormal electrographic features.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.\n\nEthics Statement\nWritten informed consent was obtained from the participant for the publication of this case report.\n\nAuthor Contributions\nAB, AM, and SA contributed to the conception of the case. SF and TE collected the data and wrote the manuscript. AB and WN edited the manuscript. All the authors contributed to manuscript revision, read, and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Davidoff RA . Antispasticity drugs: mechanisms of action\n. Annal Neurol. (1985 ) 17 :107 –16\n. 10.1002/ana.410170202 2858176 \n2. Caron E Morgan R Wheless JW . An unusual cause of flaccid paralysis and coma: baclofen overdose\n. J Child Neurol. (2014 ) 29 :555 –9\n. 10.1177/0883073813479668 23481445 \n3. Koella W . Pharmacological aspects of spasticity with special reference to Lioresal\n. Postgrad Med J. (1972 ) 48 (Suppl. 5 ):13 –18\n.4271236 \n4. Jones RF Lance JW \nBaclofen (Lioresal) in the long-term management of spasticity\n. Med J Aust. (1976 ) 1 :654 –7\n.820953 \n5. Young RR Delwaide PJ \nSpasticity\n. N Engl J Med. (1981 ) 304 :28 –33\n. 10.1056/NEJM198101013040107 6448959 \n6. Nugent S Katz MD Little TE . Baclofen overdose with cardiac conduction abnormalities: case report and review of the literature\n. J Toxicol. (1986 ) 24 :321 –8\n. 10.3109/15563658608992596 3018274 \n7. Lee T-H Chen S-S Su S-L Yang S-S . Baclofen intoxication: report of four cases and review of the literature\n. Clin Neuropharmacol . (1992 ) 15 :56 –62\n. 10.1097/00002826-199202000-00008 1576599 \n8. Leung NY Whyte IM Isbister GK . Baclofen overdose: defining the spectrum of toxicity\n. Emerg Med Australas. (2006 ) 18 :77 –82\n. 10.1111/j.1742-6723.2006.00805.x 16454779 \n9. Paulson GW . Overdose of lioresal\n. Neurology. (1976 ) 26 :1105 –1105\n. 10.1212/WNL.26.11.1105 135933 \n10. Weissenborn K Wilkens H Hausmann E Degen P . Burst suppression EEG with baclofen overdose\n. Clin Neurol Neurosurg. (1991 ) 93 :77 –80\n. 10.1016/0303-8467(91)90015-H 1651198 \n11. Ostermann M Young B Sibbald WJ Nicolle M . Coma mimicking brain death following baclofen overdose\n. Intensive Care Med. (2000 ) 26 :1144 –6\n. 10.1007/s001340051330 11030173 \n12. Slaughter AF Roddy SM Holshouser BA Abd-Allah SA . Magnetic resonance spectroscopy and electroencephalography in baclofen coma\n. Pediatr Neurol. (2006 ) 34 :151 –5\n. 10.1016/j.pediatrneurol.2005.07.014 16458831 \n13. Wall GC Wasiak A Hicklin GA . An initially unsuspected case of baclofen overdose\n. Am J Crit Care. (2006 ) 15 :611 –3\n. 10.4037/ajcc2006.15.6.611 17053268 \n14. Kumar G Sahaya K Goyal MK Sivaraman M Sahota PK . Electroencephalographic abnormalities in baclofen-induced encephalopathy\n. J Clin Neurosci. (2010 ) 17 :1594 –6\n. 10.1016/j.jocn.2010.04.038 20833050 \n15. Sullivan R Hodgman MJ Kao L Tormoehlen LM . Baclofen overdose mimicking brain death\n. Clin Toxicol. (2012 ) 50 :141 –4\n. 10.3109/15563650.2011.654209 22292975 \n16. Abarbanel J Herishanu Y Frisher S . Encephalopathy associated with baclofen\n. Annal Neurol. (1985 ) 17 :617 –8\n. 10.1002/ana.410170618 4026235 \n17. Wainapel SF Lee L Riley TL . Reversible electroencephalogram changes associated with administration of baclofen in a quadriplegic patient: case report\n. Spinal Cord. (1986 ) 24 :123 . 10.1038/sc.1986.16 3714292 \n18. Hormes JT Benarroch EE Rodriguez M Klass DW . Periodic sharp waves in baclofen-induced encephalopathy\n. Arch Neurol. (1988 ) 45 :814 –5. 12\n. Triplett JD, Lawn ND, Dunne JW. Baclofen neurotoxicity: a metabolic encephalopathy susceptible to exacerbation by benzodiazepine therapy. J Clin Neurophysiol. (2019 ) 36 :209 –12\n. 10.1097/WNP.0000000000000565 3390037 \n19. Sutter R Kaplan PW \nElectroencephalographic patterns in coma: when things slow down\n. Epileptologie. (2012 ) 29 :201 –9\n.\n20. Kuroiwa Y Celesia GG . Clinical significance of periodic EEG patterns\n. Arch Neurol. (1980 ) 37 :15 –20\n. 10.1001/archneur.1980.00500500045005 6766064 \n21. Bauer G Trinka E . Nonconvulsive status epilepticus and coma\n. Epilepsia. (2010 ) 51 :177 –90\n. 10.1111/j.1528-1167.2009.02297.x 19744116 \n22. Jovanović-Cupić V Martinović Ž Nešić N . Seizures associated with intoxication and abuse of tramadol\n. Clin Toxicol. (2006 ) 44 :143 –6\n. 10.1080/1556365050014418 16615669 \n23. Pedramfar P Haghighi AB \nTramadol Induced Seizure: Report of 106 Patients . Tehran (2010 ).\n24. Aghabiklooei A Erfani SS \nElectroencephalogram and brain CT-Scan changes in tramadol associated seizures\n. Int J Clin Med Res. \n6 :23 –27\n. (2018 )\n25. Olaizola I Ellger T Young P Bösebeck F Evers S Kellinghaus C . Pregabalin-associated acute psychosis and epileptiform EEG-changes\n. Seizure. (2006 ) 15 :208 –10\n. 10.1016/j.seizure.2006.02.004 16530431 \n26. Wood DM Berry DJ Glover G Eastwood J Dargan PI . Significant pregabalin toxicity managed with supportive care alone\n. J Med Toxicol. (2010 ) 6 :435 –7\n. 10.1007/s13181-010-0052-3 20373065 \n27. Lee S . Pregabalin intoxication-induced encephalopathy with triphasic waves\n. Epilepsy Behav. (2012 ) 25 :170 –3\n. 10.1016/j.yebeh.2012.08.002 23032125 \n28. Posner JB Plum F Saper CB Schiff N \nPlum and Posner's Diagnosis of Stupor and Coma\n. Durham, NC : OUP (2007 ). 10.1093/med/9780195321319.001.0001 \n29. Mott DD Bragdon AC Lewis DV Wilson WA . Baclofen has a proepileptic effect in the rat dentate gyrus\n. J Pharmacol Exp Ther. (1989 ) 249 :721 –5\n.2543809 \n30. Anderson P Noher H Swahn C . Pharmacokinetics in baclofen overdose\n. J Toxicol. (1984 ) 22 :11 –20\n. 10.3109/00099308409035078 6492227 \n31. Gerkin R Curry SC Vance MV Sankowski PW Meinhart RD . First-order elimination kinetics following baclofen overdose\n. Ann Emerg Med. (1986 ) 15 :843 –6\n. 10.1016/S0196-0644(86)80388-2 3729110 \n32. Faigle J Keberle H . The chemistry and kinetics of Lioresal\n. Postgrad Med J. (1972 ) 48 (Suppl. 5 ):9 –13\n.4668367 \n33. Haubenstock A Hruby K Jäger U Lenz K . Baclofen (LioresalR) intoxication report of 4 cases and review of the literature\n. J Toxicol. (1983 ) 20 :59 –68\n. 10.3109/15563658308990050 6887300 \n34. Müller-Schwefe G Penn RD . Physostigmine in the treatment of intrathecal baclofen overdose: report of three cases\n. J Neurosurg. (1989 ) 71 :273 –5\n. 10.3171/jns.1989.71.2.0273 2746350 \n35. Saltuari L Baumgartner H Kofler M Schmutzhard E Russegger L Aichner F . Failure of physostigmine in treatment of acute severe intrathecal baclofen intoxication\n. N Engl J Med. (1990 ) 322 :1533 –4\n. 10.1056/NEJM199005243222117 2336084 \n36. Saissy J Vitris M Demaziere J Seck M Marcoux L Gaye M . Flumazenil counteracts intrathecal baclofen-induced central nervous system depression in tetanus\n. Anesthesiology. (1992 ) 76 :1051 –3\n. 10.1097/00000542-199206000-00027 1599091 \n37. Byrnes S Watson G Hardy P . Flumazenil: an unreliable antagonist in baclofen overdose\n. Anaesthesia. (1996 ) 51 :481 –2\n. 10.1111/j.1365-2044.1996.tb07796.x 8694164 \n38. Wu V-C Lin S-L Lin S-M Fang C-C . Treatment of baclofen overdose by haemodialysis: a pharmacokinetic study\n. Nephrol Dial Transplant. (2005 ) 20 :441 –3\n. 10.1093/ndt/gfh297 15615812 \n39. Perry HE Wright RO Shannon MW Woolf AD . Baclofen overdose: drug experimentation in a group of adolescents\n. Pediatrics. (1998 ) 101 :1045 –8\n. 10.1542/peds.101.6.1045 9606233\n\n",
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"keywords": "baclofen toxicity; brainstem reflexes; burst suppression; coma; seizure",
"medline_ta": "Front Neurol",
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"title": "Coma With Absent Brainstem Reflexes and a Burst Suppression on EEG Secondary to Baclofen Toxicity.",
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"abstract": "OBJECTIVE\nImmune-mediated necrotizing myopathy (IMNM) is characterized by the predominant presence of necrotic muscle fibres in muscle biopsy and variable response to immunosuppressive treatment. The aims of this study were to analyse the temporal trend of IMNM incidence in our centre over the past 10 years and to explore the role of statins as possible causative agents.\n\n\nMETHODS\nA retrospective evaluation of muscle biopsy results, clinical and laboratory data, including antibody associations of all patients with idiopathic inflammatory myopathy newly diagnosed between 2004 and June 2014, was performed. Available sera were tested for the presence of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) autoantibodies.\n\n\nRESULTS\nOf 357 biopsied patients, 233 fulfilled criteria for inflammatory/immune-mediated myopathy, including 27 (11.6%) classified as IMNM. There were no patients with IMNM diagnosed between 2004 and 2007; subsequently, two to three cases of IMNM per year were seen during the period 2008-11, with a substantial increase to 18 cases (66.6% of all IMNM biopsies) in 2012-14. Thirteen of 27 patients (48%) had a history of statin use, 11 (85%) of whom had positive anti-HMGCR antibodies. There was no IMNM patient without a history of statin use who was anti-HMGCR antibody positive.\n\n\nCONCLUSIONS\nOur data show an increasing incidence of IMNM, which is mainly accounted for by anti-HMGCR-positive IMNM associated with the use of statins.",
"affiliations": "Clinical Department, Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague.;Clinical Department, Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague.;Clinical Department, Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague.;Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.;Department of Pharmacy and Pharmacology, University of Bath and.;Department of Pharmacy and Pharmacology, University of Bath and Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath, UK.;Clinical Department, Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University in Prague, vencovsky@revma.cz.",
"authors": "Klein|Martin|M|;Mann|Heřman|H|;Pleštilová|Lenka|L|;Zámečník|Josef|J|;Betteridge|Zoe|Z|;McHugh|Neil|N|;Vencovský|Jiří|J|",
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"doi": "10.1093/rheumatology/kev229",
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"issue": "54(11)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibodies; muscle biopsy; myositis; necrotizing myopathy",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D000368:Aged; D001323:Autoantibodies; D001706:Biopsy; D018153:Czech Republic; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015994:Incidence; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal; D009135:Muscular Diseases; D009220:Myositis; D009336:Necrosis; D012189:Retrospective Studies",
"nlm_unique_id": "100883501",
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"pubdate": "2015-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Increasing incidence of immune-mediated necrotizing myopathy: single-centre experience.",
"title_normalized": "increasing incidence of immune mediated necrotizing myopathy single centre experience"
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"abstract": "BACKGROUND\nAs a common morphological change of aging heart, sigmoid ventricular septum is frequently found during routine preoperative evaluation, but often disregarded because of its little clinical importance. However, in this report, we describe a 70-year old patient with sigmoid ventricular septum who developed severe hemodynamic deterioration during liver transplantation because of its unique morphology of heart.\n\n\nMETHODS\nDuring the course of reperfusion of the graft, patient's hemodynamics were closely monitored using transesophageal echocardiography.\n\n\nRESULTS\nImmediately after graft reperfusion, epinephrine was given as a treatment of choice for postreperfusion syndrome. Surprisingly, however, hemodynamic derangement persisted and became even worse. Intraoperative transesophageal echocardiography revealed left ventricular outflow tract obstruction resulting from systolic anterior motion of the mitral valve leaflet. Therefore, the patient was treated with phenylephrine and fluid bolus under the guidance of transesophageal echocardiography.\n\n\nCONCLUSIONS\nAs more elderly recipient present for liver transplantation surgery nowadays, left ventricular outflow tract obstruction should always be considered as a possible cause for hemodynamic instability during reperfusion period. In addition, transesophageal echocardiography is a useful tool for both diagnosis of hemodynamic derangement and guidance for appropriate management during liver transplantation surgery.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.",
"authors": "Moon|Young-Jin|YJ|;Park|Ji Hyun|JH|;Oh|JongEun|J|;Lee|Sooho|S|;Hwang|Gyu-Sam|GS|",
"chemical_list": "D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D004837:Epinephrine",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2755994810.1097/MD.0000000000004394043943300Research ArticleClinical Case ReportHarmful effect of epinephrine on postreperfusion syndrome in an elderly liver transplantation recipient with sigmoid ventricular septum A case reportMoon Young-Jin MDPark Ji Hyun MDOh JongEun MDLee Sooho MDHwang Gyu-Sam MD∗Xu. Lili Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.∗ Correspondence: Gyu-Sam Hwang, Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, Korea (e-mail: kshwang@amc.seoul.kr).8 2016 26 8 2016 95 34 e439429 1 2016 11 6 2016 5 7 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0Supplemental Digital Content is available in the text\n\nAbstract\nIntroduction:\nAs a common morphological change of aging heart, sigmoid ventricular septum is frequently found during routine preoperative evaluation, but often disregarded because of its little clinical importance. However, in this report, we describe a 70-year old patient with sigmoid ventricular septum who developed severe hemodynamic deterioration during liver transplantation because of its unique morphology of heart.\n\nMethods:\nDuring the course of reperfusion of the graft, patient's hemodynamics were closely monitored using transesophageal echocardiography.\n\nResults:\nImmediately after graft reperfusion, epinephrine was given as a treatment of choice for postreperfusion syndrome. Surprisingly, however, hemodynamic derangement persisted and became even worse. Intraoperative transesophageal echocardiography revealed left ventricular outflow tract obstruction resulting from systolic anterior motion of the mitral valve leaflet. Therefore, the patient was treated with phenylephrine and fluid bolus under the guidance of transesophageal echocardiography.\n\nConclusion:\nAs more elderly recipient present for liver transplantation surgery nowadays, left ventricular outflow tract obstruction should always be considered as a possible cause for hemodynamic instability during reperfusion period. In addition, transesophageal echocardiography is a useful tool for both diagnosis of hemodynamic derangement and guidance for appropriate management during liver transplantation surgery.\n\nKeywords\nepinephrineleft ventricular outflow tract obstructionliver transplantationpostreperfusion syndromesigmoid septumsystolic anterior motion of mitral valve leaflettransesophageal echocardiographyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nA sigmoid ventricular septum (SVS) is a morphological change of the heart characterized by angulation between the ascending aorta and the basal ventricular septum.[1,2] This morphological change has been considered a normal aging process involving elongation or tortuosity of the ascending aorta.[1,3] Because an SVS is frequently observed on echocardiography and has no clinical implications in most subjects, not much attention may have been paid to this feature in daily clinical practice.[4] However, in certain clinical circumstances, an SVS has been reported to cause left ventricular outflow tract (LVOT) obstruction, which may result in a severe hemodynamic derangement.[3,5,6]\n\nBecause of an increasing survival rate and larger number of elderly liver transplantation (LT) recipients, anesthesiologists may face an increasing incidence of SVSs in LT surgery.[7] During the reperfusion period from LT surgery, characteristic hemodynamic changes, known as postreperfusion syndrome (PRS), often occur.[8] Nevertheless, this potential risk from an SVS has been largely overlooked to date because severe hemodynamic perturbation has not been reported in LT patients with cardiac morphological changes. Herein, we describe a 70-year-old patient whose pretransplant echocardiography was reported as normal, although an SVS was seen during the examination. Severe hemodynamic instability occurred after administration of a small dose of epinephrine, the drug of choice for the treatment of PRS, because of a LVOT obstruction with systolic anterior motion (SAM) of the mitral valve leaflets after reperfusion of the graft.\n\n2 Clinical presentation\nWe obtained the written informed consent from the patient for publication of this case report and accompanying images. A 70-year-old male patient diagnosed with hepatitis C virus-related liver cirrhosis was scheduled for living donor LT. His past medical history was unremarkable. The preoperative electrocardiogram showed normal sinus rhythm without ST- or T-wave abnormalities. His chest radiograph showed a normal heart size with mild pleural effusion because of a large amount of cirrhotic ascites. Routine preoperative transthoracic echocardiography (TTE) showed a hyperdynamic left ventricle with normal systolic function and an ejection fraction of 65%. The end-diastolic thickness of both the interventricular septum and posterior wall was 9 mm, which was in the normal range. The mitral valve had a normal morphology with trivial regurgitation. Continuous-wave Doppler of the LVOT showed a peak systolic flow velocity of 1.25 m/s, which corresponded to a pressure gradient of 6 mm Hg. The overall conclusion was a normal echocardiogram by a cardiologist and did not mention the presence of SVS (Fig. 1). Upon arrival in the operating room, the patient's blood pressure was 103/60 with heart rate of 60 bpm. After applying standard monitoring, general anesthesia was induced with 200 mg thiopental sodium, 5 mg midazolam, and 100 mcg fentanyl. Neuromuscular blockage was achieved with 10 mg vecuronium, and anesthesia was maintained with a continuous infusion of fentanyl and 1 vol% sevoflurane in a 50% air/oxygen mixture. After endotracheal intubation, the radial and femoral arteries were cannulated for continuous blood pressure monitoring. Blood pressure waveforms were digitized and recorded during entire period of LT surgery. Two central venous cannulations for a pulmonary artery catheter and a large-bore catheter were placed in the right internal jugular vein. Transesophageal echocardiography (TEE) was placed to guide the intraoperative management.\n\nFigure 1 Preoperative TTE and intraoperative TEE of the study patient are shown. The apical 4-chamber view of the TTE appears normal (A) but the parasternal long-axis view of the TTE demonstrated an SVS (asterisk). The end-diastolic thickness of the SVS was 18 mm, and the angle between the basal septum and ascending aorta was 93° (B). In end-systole, the leaflet tethering distance was measured as 32 mm, and the left ventricular outflow tract diameter was measured as 16 mm (C). The mid-esophageal long-axis view of TEE showed a mitral-aortic angle (the angle formed by the intersection of the mitral annulus and aortic annulus) of 102° and C-sept distance (distance from the mitral coaptation point to the septum) of 20 mm (D). Ao = aorta, LA = left atrium, LV = left ventricle, RA = right atrium, RV = right ventricle, SVS = sigmoid ventricular septum, TEE = transesophageal echocardiography, TTE = transthoracic echocardiography.\n\nAfter 7 hours of uneventful preanhepatic and anhepatic phases, graft reperfusion was performed with unclamping of the hepatic and portal veins. Shortly after, PRS occurred with a decreased blood pressure as low as 49/27 mm Hg. Mixed venous oxygen saturation (SvO2) did not decrease, and TEE showed normal contractility of both ventricles without a LVOT obstruction in the mid-esophageal 5-chamber view (Fig. 2A, Video 1A). Because the decreased blood pressure persisted, 10 mcg epinephrine, the treatment of choice for PRS, was injected twice intravenously. However, the patient's blood pressure did not increase, and the SvO2 decreased. We were about to provide an incremental dose of epinephrine, as usually done, because we believed that the initial amount was not sufficient to overcome PRS. Surprisingly however, the TEE indicated a hypovolemic and hyperdynamic left ventricle along with SAM of the mitral valve leaflets that led to an obstruction of the LVOT (Fig. 2B, Video 1B). A moderate degree of mitral valve regurgitation was also found in the color Doppler mode (Fig. 2C, Video 1C). Therefore, 100 mcg phenylephrine was injected along with an intravenous fluid bolus to increase the intraventricular volume and afterload. Soon after, the blood pressure and SvO2 were rapidly restored to within the normal range. The LVOT obstruction with SAM of the mitral valve leaflets and mitral valve regurgitation resolved simultaneously.\n\nFigure 2 A mid-esophageal 5-chamber view of transesophageal echocardiography during the reperfusion period in the study patient is shown. Shortly after reperfusion, air bubbles rushed into the right atrium from the inferior vena cava (A). After administration of 20 mcg of epinephrine, a dynamic left ventricular outflow tract obstruction occurred with systolic anterior motion of the mitral valve leaflets (white arrow) (B). In the color Doppler mode, high-velocity turbulent flow through the left ventricular outflow tract and a mitral regurgitation jet were observed (C). LA = left atrium, LV = left ventricle, RA = right atrium, RV = right ventricle.\n\nAfter the patient's vital signs were stabilized, we reviewed the preoperative TTE and intraoperative TEE. These scans showed that the thickened end-diastolic basal interventricular septum had protruded into the LVOT, which was not mentioned in the preoperative TTE (Fig. 1). The patient had a prominent “knuckle” of the end-diastolic basal interventricular septum (18 mm) (Fig. 2B), and the LVOT was angulated. The angle measured between the basal portion of interventricular septum and the ascending aorta was 93°, which was far less than the normal range (145 ± 7°). With the features mentioned above, the diagnosis of an SVS could be established. During the neohepatic phase, no further adverse events occurred. The patient was transferred to the intensive care unit and extubated on postoperative day 1. Three days later, a follow-up TTE was performed showing no change in the SVS without any obstruction. The patient recovered and was discharged on postoperative day 26.\n\n3 Discussion\nOur present case clearly showed that anesthetic management of a patient with an SVS during LT surgery can be complicated by the potential risk of an LVOT obstruction, especially during the reperfusion period. Although dynamic LVOT obstruction has been reported in patients with an SVS,[3,5,6,9,10] our present report is the first to document this phenomenon during LT.\n\nBecause of unique hemodynamic and cardiac morphological characteristics, elderly patients with end-stage liver disease are highly susceptible for developing LVOT obstruction. After reperfusion of the graft, LT recipients often encounter severe hemodynamic instability, the so-called PRS. This instability can present as a decrease in systemic vascular resistance (SVR) and relative hypovolemia or sometimes can be accompanied by decreased contractility of both ventricles. In these situations, the treatment of choice is epinephrine, a nonselective adrenergic agonist that can be effective in both circumstances. However, as in our present case, further hemodynamic instability develops with epinephrine treatment in patients with an SVS. Strong inotropic and chronotropic effects by epinephrine in conjunction with low SVR and relative hypovolemia because of PRS can exacerbate a dynamic LVOT obstruction.[8,11] Thus, an early differential diagnosis of prolonged PRS is important, and patient management should be differentiated according to this diagnosis.\n\nIn our present case, TEE played a crucial role in both the early recognition and management of a dynamic LVOT obstruction caused by SAM of the mitral valve leaflets. Because TEE was continuously monitored during the reperfusion period in our patient, the dynamic LVOT obstruction could be recognized instantly. Also, appropriate management could be initiated with phenylephrine and fluid loading rather than treatment with additional epinephrine that may have resulted in fatal consequences. Unlike numeric data obtained from the blood pressure waveform, TEE permits an instant and direct assessment of both structural and dynamic functions of the heart.[12,13] Moreover, TEE has been reported to be relatively safe, as it showed low incidence of hemorrhagic complication despite the presence of esophageal varices.[14,15] Therefore, TEE should always be considered for patients with prolonged PRS, especially for patients with a high risk of developing an LVOT obstruction.[16,17]\n\nAlthough the underlying mechanism for a dynamic LVOT obstruction in an SVS case has not been well-established, it is believed that this mechanism is similar to that for hypertrophic cardiomyopathy.[9] The angulation of the LVOT alters flow vectors in the left ventricular cavity, and protrusion of the basal septum causes flow acceleration around the narrowed LVOT. The “drag effect” and “Venturi effect,” respectively, are thought to involve SAM of the mitral valve leaflets in patients with an SVS developing a dynamic LVOT obstruction.[6,9] A recent review by Hymel and Townsley[16] summarized several characteristic echocardiographic features for predicting SAM of the mitral valve leaflets. These include a basal interventricular septal thickness >15 mm, a C-sept distance (distance from the mitral coaptation point to the septum) <25 mm, a mitral-aortic angle (angle formed by the intersection of the mitral annulus and aortic annulus) <120°, and an abnormal mitral leaflet length. Another study by Tano et al[3] showed that a short end-systolic leaflet tethering distance (the distance between the tip of the posterior papillary muscle and the contralateral anterior part of the mitral annulus) in the resting state was a major determinant for developing an LVOT obstruction with SAM of the mitral valve leaflets in patients with an SVS during a dobutamine provocation test (29.9 ± 4.2 vs 35.2 ± 4.6 mm). Our present case satisfied most of these provocative conditions. Our present patient had an 18-mm end-diastolic basal interventricular thickness, a 20-mm C-sept distance, and a 32-mm leaflet tethering distance. The angle measured between the basal septum and ascending aorta was 93° and the mitral-aortic angle was 102° (Fig. 1).\n\nThere has been previous case report of an SVS with a LVOT obstruction during surgery.[10] In that patient, a low SVR caused by spinal anesthesia provoked a dynamic LVOT obstruction. In other previous case reports, dynamic LVOT obstructions were provoked in certain hemodynamic settings such as a dobutamine stress test, exercise test, or administration of a phosphodiesterase 3 inhibitor.[3,6] These settings are all associated with increased contractility and a decreased SVR. During LT surgery, recipients undergo a similar but usually more aggravated hemodynamic derangement during graft reperfusion. For this reason, anesthesiologists should keep in mind that a dynamic LVOT obstruction may occur during LT surgery even in patients with a less severe form of SVS. Moreover, whenever refractory hemodynamic instability occurs in circumstances with increasing contractility and decreasing SVR, an undiagnosed SVS should always be suspected as a hidden cause.\n\nIn summary, we here report the first case of a dynamic LVOT obstruction arising at the graft reperfusion period of LT surgery in a patient with an SVS. Dynamic LVOT obstruction should always be considered as a possible cause for hemodynamic instability during the reperfusion period, especially in elderly patients with an SVS. In addition, TEE is a very useful tool for both the diagnosis of hemodynamic derangements and the guidance for appropriate management during LT surgery. The routine use of TEE is therefore highly recommended.\n\nAcknowledgments\nThe authors thank Dr. Won-Jung Shin for her kind advises to this manuscript.\n\nSupplementary Material\nSupplemental Digital Content\n Abbreviations: LT = liver transplantation, LVOT = left ventricular outflow tract, PRS = postreperfusion syndrome, SAM = systolic anterior motion, SvO2 = mixed venous oxygen saturation, SVR = systemic vascular resistance, SVS = sigmoid ventricular septum, TEE = transesophageal echocardiography, TTE = transthoracic echocardiography.\n\nDisclosure: The part of this article was presented in 2014 American Society of Anesthesiologists annual meeting as a medically challenging case.\n\nAuthor contributions: Y-JM and G-SH were responsible for the conception of the case report and writing the manuscript. JHP and SL were involved in recording echocardiographic images and videos. J-EO was involved in anesthetic management of the patient.\n\nThe authors have no conflicts of interest to disclose.\n\nSupplemental Digital Content is available for this article.\n==== Refs\nReferences\n1 Dalldorf FG Willis PWt \nAngled aorta (“sigmoid septum”) as a cause of hypertrophic subaortic stenosis . Hum Pathol \n1985 ; 16 :457 –462 .4039296 \n2 Goor D Lillehei CW Edwards JE \nThe “sigmoid septum”. Variation in the contour of the left ventricular outt . Am J Roentgenol Radium Ther Nucl Med \n1969 ; 107 :366 –376 .\n3 Tano A Kasamaki Y Okumura Y \nMajor determinants and possible mechanism of dobutamine-induced left ventricular outflow tract obstruction in patients with a sigmoid ventricular septum . J Cardiol \n2013 ; 61 :428 –435 .23499172 \n4 Funabashi N Umazume T Takaoka H \nSigmoid shaped interventricular septum exhibit normal myocardial characteristics and has a relationship with aging, ascending aortic sclerosis and its tilt to left ventricle . Int J Cardiol \n2013 ; 168 :4484 –4488 .23915525 \n5 Sato Y Matsumoto N Kunimasa T \nSigmoid-shaped ventricular septum causing mid-ventricular obstruction: report of 2 cases . Int J Cardiol \n2009 ; 132 :e97 –101 .18063148 \n6 Umazume T Funabashi N Inoue T \nAdverse effects of cilostazol on left ventricular function in a patient with a sigmoid shaped interventricular septum . Int J Cardiol \n2013 ; 165 :551 –555 .22995418 \n7 Levy MF Somasundar PS Jennings LW \nThe elderly liver transplant recipient: a call for caution . Ann Surg \n2001 ; 233 :107 –113 .11141232 \n8 Cywinski JB Argalious M Marks TN \nDynamic left ventricular outflow tract obstruction in an orthotopic liver transplant recipient . Liver Transpl \n2005 ; 11 :692 –695 .15915494 \n9 Ranasinghe I Yeoh T Yiannikas J \nNegative ionotropic agents for the treatment of left ventricular outflow tract obstruction due to sigmoid septum and concentric left ventricular hypertrophy . Heart Lung Circ \n2011 ; 20 :579 –586 .21684204 \n10 Yokoya T Moromikawa J Uehara K \nSigmoid shaped ventricular septum causing hemodynamic deterioration during lumbar anesthesia: a case report . J Cardiol \n2002 ; 40 :167 –172 .12420671 \n11 Hensley N Dietrich J Nyhan D \nHypertrophic cardiomyopathy: a review . Anesth Analg \n2015 ; 120 :554 –569 .25695573 \n12 Oxorn D Edelist G Smith MS \nAn introduction to transoesophageal echocardiography: II. Clinical applications . Can J Anaesth \n1996 ; 43 :278 –294 .8829866 \n13 Rochon AG L’Allier PL Denault AY \nAlways consider left ventricular outflow tract obstruction in hemodynamically unstable patients . Can J Anaesth \n2009 ; 56 :962 –968 .19847589 \n14 Markin NW Sharma A Grant W \nThe safety of transesophageal echocardiography in patients undergoing orthotopic liver transplantation . J Cardiothorac Vasc Anesth \n2015 ; 29 :588 –593 .25622974 \n15 Burger-Klepp U Karatosic R Thum M \nTransesophageal echocardiography during orthotopic liver transplantation in patients with esophagoastric varices . Transplantation \n2012 ; 94 :192 –196 .22728290 \n16 Hymel BJ Townsley MM \nEchocardiographic assessment of systolic anterior motion of the mitral valve . Anesth Analg \n2014 ; 118 :1197 –1201 .24842174 \n17 Robertson A \nIntraoperative management of liver transplantation in patients with hypertrophic cardiomyopathy: a review . Transplant Proc \n2010 ; 42 :1721 –1723 .20620509\n\n",
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"mesh_terms": "D000368:Aged; D004452:Echocardiography; D004837:Epinephrine; D005440:Fluid Therapy; D006346:Heart Septum; D006352:Heart Ventricles; D006439:Hemodynamics; D006801:Humans; D007431:Intraoperative Complications; D016031:Liver Transplantation; D008297:Male; D010656:Phenylephrine; D015424:Reperfusion; D013577:Syndrome; D014662:Vasoconstrictor Agents; D014694:Ventricular Outflow Obstruction",
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"title": "Harmful effect of epinephrine on postreperfusion syndrome in an elderly liver transplantation recipient with sigmoid ventricular septum: A case report.",
"title_normalized": "harmful effect of epinephrine on postreperfusion syndrome in an elderly liver transplantation recipient with sigmoid ventricular septum a case report"
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"abstract": "We present 2 patients with Moyamoya disease undergoing revascularization surgery who developed transient intraoperative central diabetes insipidus with spontaneous resolution in the immediate postoperative period. We speculate that patients with Moyamoya disease may be predisposed to a transient acute-on-chronic insult to the arginine vasopressin-producing portion of their hypothalamus mediated by anesthetic agents. We describe our management, discuss pertinent literature, and offer possible mechanisms of this transient insult. We hope to improve patient safety by raising awareness of this potentially catastrophic complication.",
"affiliations": "From the *Department of Anesthesiology and Perioperative Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California; and †Medical Student, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California.",
"authors": "Hong|Joe C|JC|;Ramos|Emilio|E|;Copeland|Curtis C|CC|;Ziv|Keren|K|",
"chemical_list": "D001127:Arginine Vasopressin",
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"mesh_terms": "D061605:Administration, Intravenous; D001127:Arginine Vasopressin; D020790:Diabetes Insipidus, Neurogenic; D005260:Female; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease; D016896:Treatment Outcome; D014656:Vascular Surgical Procedures",
"nlm_unique_id": "101637720",
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"title": "Transient Intraoperative Central Diabetes Insipidus in Moyamoya Patients Undergoing Revascularization Surgery: A Mere Coincidence?",
"title_normalized": "transient intraoperative central diabetes insipidus in moyamoya patients undergoing revascularization surgery a mere coincidence"
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"abstract": "Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital.\n\n\n\nChildren 24-83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects. The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken.\n\n\n\nAmong 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose. Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects.\n\n\n\nEnteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital.\n\n\n\nNCT01660672 . NCT01982812 .",
"affiliations": "Department of Neurology, University of Rochester, 265 Crittenden Blvd, Rochester, NY, 14642, USA. gretchen_birbeck@urmc.rochester.edu.;Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.;University of California San Diego, Center for Research in Paediatric and Developmental Pharmacology, La Jolla, CA, USA.;Malawi-Liverpool-Wellcome Trust Research Programme, Blantyre, Malawi.;Bio-Signal Group Co., Acton, MA, USA.;Department of Paediatrics, Queen Elizabeth Central Hospital, Blantyre, Malawi.;Malawi-Liverpool-Wellcome Trust Research Programme, Blantyre, Malawi.;Department of Neurology, Children's National Medical Center, Washington, DC, USA.;Department of Epidemiology & Biostatistics, Michigan State University, East Lansing, MI, USA.;Blantyre Malaria Project, Blantyre, Malawi.;Blantyre Malaria Project, Blantyre, Malawi.",
"authors": "Birbeck|Gretchen L|GL|0000-0002-0735-3461;Herman|Susan T|ST|;Capparelli|Edmund V|EV|;Dzinjalamala|Fraction K|FK|;Abdel Baki|Samah G|SG|;Mallewa|Macpherson|M|;Toto|Neema M|NM|;Postels|Douglas G|DG|;Gardiner|Joseph C|JC|;Taylor|Terrie E|TE|;Seydel|Karl B|KB|",
"chemical_list": "D000927:Anticonvulsants; D001569:Benzodiazepines; D000077287:Levetiracetam; D010634:Phenobarbital",
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"fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 176610.1186/s12887-019-1766-2Research ArticleA clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria http://orcid.org/0000-0002-0735-3461Birbeck Gretchen L. 517-273-4265gretchen_birbeck@urmc.rochester.edu 12Herman Susan T. sherman2@bidmc.harvard.edu 3Capparelli Edmund V. ecapparelli@ucsd.edu 4Dzinjalamala Fraction K. fkdz72@yahoo.com 5Abdel Baki Samah G. samahabdulbaki@gmail.com 6Mallewa Macpherson mmallewa@mlw.medcol.mw 7Toto Neema M. ntoto@mlw.mw 5Postels Douglas G. dpostels@childrensnational.org 8Gardiner Joseph C. jgardiner@epi.msu.edu 9Taylor Terrie E. taylort@msu.edu 210Seydel Karl B. seydel@msu.edu 2101 0000 0004 1936 9174grid.16416.34Department of Neurology, University of Rochester, 265 Crittenden Blvd, Rochester, NY 14642 USA 2 Blantyre Malaria Project, Blantyre, Malawi 3 0000 0001 0664 3531grid.427785.bDepartment of Neurology, Barrow Neurological Institute, Phoenix, AZ USA 4 0000 0001 2107 4242grid.266100.3University of California San Diego, Center for Research in Paediatric and Developmental Pharmacology, La Jolla, CA USA 5 grid.419393.5Malawi-Liverpool-Wellcome Trust Research Programme, Blantyre, Malawi 6 Bio-Signal Group Co., Acton, MA USA 7 0000 0004 0598 3456grid.415487.bDepartment of Paediatrics, Queen Elizabeth Central Hospital, Blantyre, Malawi 8 0000 0004 0482 1586grid.239560.bDepartment of Neurology, Children’s National Medical Center, Washington, DC USA 9 0000 0001 2150 1785grid.17088.36Department of Epidemiology & Biostatistics, Michigan State University, East Lansing, MI USA 10 0000 0001 2150 1785grid.17088.36Department of Osteopathic Medical Specialties, Michigan State University, East Lansing, MI USA 1 11 2019 1 11 2019 2019 19 39914 11 2018 9 10 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\nAcute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital.\n\nMethods\nChildren 24–83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects.\n\nThe RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken.\n\nResults\nAmong 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose.\n\nComparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects.\n\nConclusion\nEnteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital.\n\nTrial registration\nNCT01660672.\n\nNCT01982812.\n\nKeywords\nAcute symptomatic seizuresTropicshttp://dx.doi.org/10.13039/100000065National Institute of Neurological Disorders and StrokeR01NS074409Birbeck Gretchen L. issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nCerebral malaria (CM) primarily affects African children [1]. Between 15 and 25% of CM children die and a third of survivors suffer neurologic sequelae [2–4]. Seizures, a common complication, are also a risk factor for post-CM brain injury [2, 5]. CM-associated seizures are prolonged, repetitive, focal, and refractory with subclinical seizures occurring in 18–47% [2, 6, 7]. Seizure management is challenging because phenobarbital and benzodiazepines remain the primary treatments, respiratory suppression is a common complication of both medications, and ventilatory support is generally unavailable [8]. Management of CM-associated seizures in most malarial regions entails some degree of tolerance for ongoing seizure activity due to the risk of respiratory compromise and death with aggressive use of phenobarbital. Whether levetiracetam is effective in this environment for acute symptomatic seizures has been identified by the World Health Organization as a top research priority [9].\n\nEven a short course of parenteral LVT is cost prohibitive in low income settings, but a 3-day supply of LVT oral solution for a 10 kg child is <$15. Pharmacokinetic (PK) studies of enteral LVT (eLVT) in healthy subjects indicate excellent bioavailability with rapid absorption, [10] but aspiration risks in comatose children are unknown. Pharmacokinetics are linear in children from 20 to 60 mg/kg/day. LVT is < 10% protein-bound, 66% of the dose is renally excreted unchanged, and 24% undergoes enzymatic hydrolysis. Metabolites are inactive and renally excreted. LVT clearance is reduced with impaired renal function [10].\n\nWe undertook a series of studies to evaluate the safety, PK properties and efficacy of eLVT for acute CM seizure management in children including (1) PK evaluations in a dose-escalation study to identify a potentially effective dose for CM seizures, (2) safety assessments, and (3) an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital. Given the ubiquitous nature of subclinical seizures in CM, efficacy was based upon ‘minutes with seizure’ using continuous electroencephalogram (cEEG) monitoring. Duration of coma and neurologic sequelae at discharge were secondary outcomes. Children with seizures, either clinically or electrographically, after the allocated treatment crossed over or received the alternate agent.\n\nMethods\nStudy design\nDose-escalation study\nA dose-escalation study titrating eLVT to seizure freedom based upon cEEG and limited by toxicity with pre-specified stopping rules.\n\nRandomized controlled trial\nUsing the dose of eLVT identified as effective in the Dose-Escalation Study, we conducted an open label, RCT of eLVT compared to phenobarbital for acute seizure control. PK data were obtained throughout. See study protocol, Additional file 1.\n\nPatient population\nStudies were conducted on the Paediatric Research Ward (PRW) of Queen Elizabeth Central Hospital in Blantyre, Malawi [2, 11, 12]. All aspects of this study received ethical review in Malawi and the US.\n\nInclusion criteria\nPRW admission; age 24–83 months; Blantyre Coma Score (BCS) ≤2 [13]; P. falciparum infection [14]; no other known coma etiology; seizures within past 24 h; guardian written consent.\n\nExclusion criteria\nSerum creatinine (SCr) > 2 mg/dL; use of enzyme-inducing medication in past 14 days; contraindication for nasogastric tube (NGT) and/or administration of enteral medications. For the RCT, additional exclusions were treatment with > 2 doses of short-acting antiseizure drug (ASD) in the past 12 h or a long-acting ASD in the past 3 days.\n\nRandomization\nPatients were block randomized with randomly selected block sizes of 4 and 6. Treatment was allocated based on a pre-defined randomly generated list with assignment available through the OpenClinica database or sequentially numbered, sealed opaque envelopes prepared by the Biomedical Research Informatics Core at Michigan State University. Acquisition of treatment assignment required the enrolling clinician to provide the name and demographic details for the consented subject. Ward clinicians enrolled participants and commenced treatment based upon allocation.\n\nProcedures\nDose-escalation study\nFour dose strata of eLVT with a maximum of 8 subjects per strata were prespecified. The initial dose was 40 mg/kg load, then 30 mg/kg Q12 hours for 72 h. Stopping was indicated if mortality plus grade 3 or 4 suspected adverse drug reactions (SADR) exceeded the ward baseline mortality rate of 16%. LVT serum levels were measured at time (t) = 0, 1.5, 4, 12, 24, 36, 40, and 84 h. LVT oral solution (100 mg/ml) was administered via NGT until the child was able to take LVT orally.\n\nRCT\nChildren allocated to eLVT received the optimal dose identified in the Dose-Escalation Study for 72 h. PK data were assessed at t = 0, 7, 24 h and 4–40 h after the last dose. If clinical or electrographic seizures recurred/continued after the initial eLVT dose, an LVT level at time of failure was captured, escalation to the next dosing strata occurred, and the more frequent PK assessments were conducted (t = 0, 1.5, 4, 12, 24, 36, 40, and 84 h). Benzodiazepines (maximum 2 doses/24 h) were given as needed for breakthrough seizures to allow time for eLVT absorption.\n\nThe dose escalation study was designed to identify the dose which would be effective for most patients but did not delineate what dose of eLVT might benefit a child with refractory seizures/status epilepticus. Escalating therapy for any selected antiepileptic is the commonest approach to treating refractory seizures. Thus, given the established safety profile of eLVT in other populations, data from other populations indicating that higher doses can be beneficial for refractory seizures, our ability to rapidly cross over to PB if higher dose LVT was ineffective and the value of having additional insights into the clinical and pharmacokinetic effects of escalating eLVT in this population, dose escalation of eLVT was undertaken for those children who failed standard dose.\n\nIn RCT year 1, children randomized to ‘usual care’ received phenobarbital 20 mg/kg load, then 5 mg/kg Q12 hours for 72 h. In RCT year 2, the Study Monitoring Committee (SMC) recommended that children randomized to ‘usual care’ receive phenobarbital only if they experienced post enrollment seizures (clinical or electrographic) unresponsive to diazepam or paraldehyde. Children who continued to have seizures after receiving the allocated treatment were given the alternative therapy for rescue.\n\nPK studies\nHigh performance liquid chromatography (HPLC) method determined LVT levels [15]. PK data were analyzed using a mixed-effects population approach using the computer program NONMEM (ver. 7.2 Icon, Dublin) and the First Order Conditional Estimation (FOCE) method. Size was incorporated into the model using a standard allometric approach [16]. Due to the limited study sample size, an exploratory analysis of potential covariates was limited to age, liver function tests and SCr. Reduction in the PK model objective function of at least 7.88 (p < 0.005) was required for inclusion into the final PK model. A 1000 replicate bootstrap analysis of the final model was performed using Wings v 7.4 to determine the parameter confidence interval. Monte Carlo simulations (15,000 virtual subjects) of the final model and dosing were performed to determine the frequency of achieving trough concentrations 6–20 g/mL.\n\nSince a key concern of eLVT administration in this population was adequate absorption, LVT concentrations collected early in the dose interval (< 4 h after the prior dose) were compared to their (individual) predicted values. The early measured LVT concentrations that were less than 30% of predicted were defined as having slow absorption. Individual subject steady-state trough concentrations, area under the plasma concentration time curve (AUC), apparent clearance (CL/F) and half-life (t1/2) were generated using a post hoc empiric Bayesian approach. In this analysis, doses defined as having slow absorption were modelled with an absorption lag time.\n\nElectroencephalography\nAll enrolled subjects underwent cEEG using a microEEG™ system (Bio-Signal Group Corp), with 21 scalp EEG electrodes placed according to the International 10–20 system. Electrographic seizures were defined based upon standard criteria [17]. Additionally, data was ascertained regarding seizure focality, electrographic seizure duration, the presence and duration of any clinical correlate and the presence and nature of any periodic EEG patterns including lateralized periodic discharges (LPDs) and lateralized rhythmic delta activity (LRDA).\n\nSafety assessments\nHematologic, hepatic and renal laboratory assessments were made at baseline, 24 h and 7 days post LVT initiation. An electrocardiogram (ECG) was obtained at baseline and 3 h. See Additional file 2 for Graded Toxicity Criteria. Coma duration was determined and examination at discharge identified neurologic sequelae.\n\nConcomitant interventions\nAll treatments routinely used in the acute care of children with CM as delineated in Malawi National Guidelines and consistent with WHO recommendations were provided [14].\n\nOutcomes\nDose-escalation\nThe primary outcome was the dose of eLVT for seizure freedom in at least 75% of participants. Secondary outcomes were frequency of vomiting, aspiration, NGT complications, aggression/irritability, coma duration, death and pre-specified adverse events (AE).\n\nRCT\nPrimary outcome was minutes with seizure in the 72 h after treatment allocation based on cEEG data transmitted to interpreter blinded to allocation. Secondary outcomes included efficacy failure requiring cross over, coma duration, neurologic sequelae at discharge based upon a detailed neurologic assessment completed by a clinician who was not blinded to treatment received, death, and safety assessments. ‘Treatment failure’ was defined as any additional seizures, including electrographic, subclinical seizures, after administration of the treatment.\n\nStatistical analysis\nDose escalation study\nUp to 8 study participants were to be administered one of four pre-specified doses of LVT. EFFICACY ANALYSIS: Beginning with the initial LVT loading dose (40 mg/kg load, then 30 mg/kg Q12 hours), the target response was seizure freedom in 75% of participants in that stratum for 24 h. We estimated the probability p of target response by the proportion of study participants meeting the target response. If the estimate of p was less than 0.75, the next higher dose would be used in the next group of children and p is re-estimated [18]. Dose escalation would be stopped if the lower limit of the CI exceeded 0.50; otherwise, escalation to the next dose level was indicated. In this scenario, an exact 90% CI for p based on 7 responses is (.529, .994) which met the imposed condition. Throughout the dose-escalation study we also monitored for toxicity and acute mortality. Toxicity Analysis: Let p denote the event probability of mortality plus grade 3 or 4 SADR in the LVT treatment group. The historic ward case fatality in CM is P0 (=.16). A non-inferiority test H0: p-p0 ≥ δ vs H1: p-p0 < δ was carried out where δ (> 0) was the acceptable margin of indifference between LVT and usual care. The conclusion from rejecting H0 in favor of H1 means that LVT is non-inferior to usual treatment.\n\nRCT\nTwo groups of 30 were planned to receive the LVT dose identified in the Dose-Escalation Study or usual care with phenobarbital (PB). Baseline characteristics between the LVT and PB groups were compared using chi-square tests for categorical variables. For normally distributed continuous variables we applied (independent) t-tests. The validity of normalcy was examined by graphical techniques, using histograms and QQ-plots. Where normalcy was untenable, the log-transformation was applied to mitigate skewness, and if sufficient, t-tests were used. If not, we used the nonparametric Mann-Whitney-Wilcoxon test for independent samples. Additional details are supplied in Additional file 3.\n\nPrimary Endpoint: Minutes with seizure during the first 72 h after treatment. Secondary Endpoints: (1) treatment failure requiring alternate therapy, (2) time to coma resolution, (3) neurologic sequelae at discharge, (4) acute mortality.\n\nLVT was expected to have a positive effect on outcomes, thus treatment effect was seen in a relative risk ω < 1 for an undesirable event such as mortality or presence of neurologic sequelae at discharge, while ω > 1 for a desirable event such as seizure freedom for 24 h after treatment initiation. The null hypothesis was H0:ω = 1 We estimated that with usual care ~ 25% of study participants would be seizure free for 24 h after initiation, whereas with LVT > 60% of study participants would have this outcome, that is ω > 2.4. With 30 participants in each arm, the power to detect this difference is over 79% [19]. If approximately 50% of study participants receiving usual care had neurologic sequelae at discharge, whereas with LVT approximately 17% of study participants were affected, that is ω ≈ .34, the power to detect this difference is ~ 79%.\n\nPK study\nIn healthy subjects, the %CV is 30% [20]. We used an assumed between subject variability of 50% to account for the expected increased variability in PK that could be encountered in the CM population. Assuming that the between-subject variability for CL/F (clearance/bioavailability) is approximately 50%, with 16–20 subjects the mean CL/F would have a 95% likelihood of being within 25% of the true population mean CL/F value.\n\nResults\nDose-escalation study\nFrom February 15–April 15, 2013, 40 children were screened, 11/40 met eligibility criteria and 7 were enrolled. The primary reason for exclusion was no P. falciparum infection. Two eligible children were enrolled in another research study whose enrollment alternated with the LVT study and 2/11 were screened when there was no cEEG bed available. The first seven children who received LVT 40 mg/kg load plus 30 mg/kg Q12 were seizure free, so no dose escalation was undertaken. Demographic and clinical characteristics are detailed in Table 1.\nTable 1 Demographic and Clinical Data from Dose-Escalation Study Population Receiving Enteral Levetiracetam 40 mg/kg load and 30 mg/kg Q12 hourly (n = 7)\n\nCharacteristic\t\t\nGender (n, % male)\t3/7, 43%\t\nAge in months\tMean 54.3; median 53; range 26–81\t\nRetinopathy positive (n, %)\t4/7, 57%\t\nAdmission hypoglycemia* (n, %)\t0/7, 0%\t\nAdmission lactate (mmol/L)\tMean 5.4; median 4.5; range 2.2–13.1\t\nAdmission hematocrit\n\n(% packed cell volume)\n\n\tMean 22.2; median 20.7; range 13.0–33.6\t\nParasitemia\n\n(parasite per μl)\n\n\tGeometric mean 73,700; median 70,000; range 25,920-374,460\t\nPlatelets (per μl)\tMean 123,000; median 80,000; range 47,000-259,000\t\nComa resolution time (hours)\tMean 35.2; median 32.8; range 6.5–78.0\t\n* Glucose < 2.2 mmol/L\n\n\n\nThe median (range) plasma LVT concentration at 1.5 h was 37.5 (16.7–46.0 μg/mL). Within 4 h of the loading dose, all children achieved at least one LVT concentration between 20 and 50 μg/mL. The median post-load trough was 9.5 μg/mL and after subsequent doses was 7.1 μg/mL. No trough accumulation was noted. No vomiting, aspiration, neurologic sequelae or deaths occurred; 5/7 experienced mildly elevated transaminases and electrolyte perturbations that were already evident at baseline. One child each had QTC prolongation prior to LVT, grade 3 elevation of transaminases and persistent anemia (grade 4)—none of these events were considered related to LVT. All AEs resolved without intervention.\n\nPK\nTherapeutic LVT concentrations were rapidly achieved with LVT levels > 20 μg/mL in 26/29 (90%) within 4 h of the loading dose. No child failed to achieve > 6 μg/mL after the loading dose. The LVT concentrations seen are shown in Fig. 1. Steady-state troughs were below 6 mg/mL in 6/29 (21%) and above 20 μg/mL in 6/29 (21%). Most of the AUC values were between 50 and 200% of the expected population average (Fig. 2). Of the 67 samples collected within 4 h of drug administration, 63 were > 30% of predicted, suggesting relatively normal absorption the vast majority of the time. Only 4 (8%) of the doses administered had altered absorption. In subjects with low initial concentrations, all had additional later samples with adequate concentrations suggesting that delayed rather than incomplete absorption was the issue.\nFig. 1 Measured relative to predicted levetiracetam concentrations among children with cerebral malaria receiving enteral LVT stratified by admission serum creatinine. LVT = levetiracetam. SCr = serum creatinine\n\n\nFig. 2 The frequency of observed levetiracetam concentrations 4 h after the first dose and predicted steady-state troughs and average concentrations. All 4 h post first dose and average steady state levels were above 6 μg/mL. LVT = levetiracetam\n\n\n\nThe population PK analysis utilized 131 LVT concentrations from 30 subjects and was well described by the one-compartment model. Despite the modest number of subjects and samples, CL/F and V/F were estimated with good precision and no bias was evident based on the bootstrap analysis. The estimates for other parameters and between subject variability also were without apparent bias but had lower precision with large standard errors and broad 95% confidence intervals. SCr was found to be a powerful covariate for LVT apparent clearance (objective function reduction of 28.16, p < 0.0001), Figs. 3 and 1. Across the range of admission SCr values observed in the study, 0.33 to 1.84 mg/dL, CL/F is predicted to change 10 fold. The final population PK model parameters and precision are summarized in Table 2. The population PK model predicts a typical eLVT apparent clearance (CL/F) of 0.091 L/h/kg for a 3.5 year old weighing 12 kg with a SCr = 0.58.\nFig. 3 Levetiracetam clearance, levels and half-live in relation to admission serum creatinine. LVT = levetiracetam. SCr = serum creatinine\n\n\nTable 2 Pharmacokinetic Parameters for Enteral Levetiracetam in Children with Cerebral Malaria (n = 7)\n\nParameter\tEstimate\tSE\nof Estimate\tMedian\tBS 2.5th\tBS 97.5th\t\nV (L/kg)\t0.711\t0.06\t0.696\t0.562\t0.825\t\nCL (L/h/kg0.75)\t0.169\t0.015\t0.171\t0.145\t0.206\t\nKA (hr−1)\t1.37\t0.286\t1.25\t0.553\t2.37\t\nLag time (h)\t1.96\t0.038\t1.54\t0.258\t3.97\t\nSCR factor\t−1.37\t0.343\t− 1.34\t−2.06\t−0.631\t\nBetween Subject Variability\t\n BSV-V\t25%\t5%\t22%\t5%\t39%\t\n BSV-CL\t43%\t6%\t42%\t28%\t56%\t\nV = volume of distribution; CL = total body clearance; KA = absorption rate constant; SCR = serum creatinine\n\n\n\nRCT\nThe RCT was conducted January–June in 2014 and 2015. See Fig. 4 for the Trial Profile. Eighty-nine children were screened, 44 enrolled and randomized. The groups did not differ clinically or demographically (Table 3).\nFig. 4 Randomized Control Trial Profile. * “Usual Care” group initially received phenobarbital at enrollment, but protocol revised in 2015 such that “Usual Care” group only received phenobarbital if seizures recurred after allocation\n\n\nTable 3 Baseline Characteristics of the Intent-to-Treat Population\n\n\tLevetiracetam (n = 23)\tUsual Care (n = 21) (Phenobarbital)\tP-value*\t\nAge (mean months, SD)\t41.4 (10.6)\t41.8 (16.7)\t0.50\t\nSex (n, % male)\t13 (57%)\t7 (33%)\t0.14\t\nParasite count (mean parasite/μL, SD)\t214,613 (412,786)\t259,729 (314,098)\t0.62\t\nMalaria retinopathy (n, % positive)\t16 (70%)\t12 (57%)\t0.35\t\nLactate (mean mmol/L, SD)\t5.4 (3.7)\t4.4 (3.3)\t0.43\t\nHemoglobin (mean gdL, SD)\t8.5 (3.5)*\t8.2 (1.5)\t0.41\t\nHematocrit (% packed cell volumte, SD)\t25.8 (11.1)*\t24.6 (5.0)\t0.63\t\nPlatelets (per μL, SD)\t163,450 (155,960)α\t134,430 (162,330)\t0.48\t\nAny rescue benzodiazepine or paraldehyde prior to enrollment¥\t8 (35%)\t6 (29%)\t0.76\t\n Two doses\t4 (17%)\t2 (10%)\t0.66\t\n* Binary variables compared by chi-square tests (exact). Continuous variables compared by t-tests, or non-parametric tests, as appropriate. See Additional file 3 for Evaluation of Normalcy. To mitigate skewness, log-transformation was applied to parasite count, lactate and platelets\n\nα One clotted sample\n\n¥ Diazepam or paraldhyde\n\n\n\nAll those allocated to LVT received the treatment. Among those allocated to phenobarbital in 2014, 13/13 received phenobarbital per protocol. In 2015, after the protocol was adapted to administer phenobarbital only to children with seizures who failed benzodiazepines, 2/8 received phenobarbital. Overall, in the phenobarbital group, 3/21 required the additional LVT, phenobarbital was stopped in 3/15 due to respiratory suppression and/or aspiration and five died. In the LVT group, 4/23 required dose escalation, 2/23 required phenobarbital and one died.\n\nIn the LVT group, 4/23 had breakthrough seizures, mean 165 min duration (SD 266; IQR 26–305; maximum 563). In the usual care group, 5/21 had breakthrough seizures after phenobarbital, mean 465 min (SD 639; IQR 42–734; maximum 1473). There were no differences in minutes with seizure, coma duration, need for alternate treatment, neurologic sequelae at discharge or death. See Table 4. Details regarding neurologic sequelae are provided in Additional file 4. As per our planned analysis, we compared minutes with seizure including all participants. Repeating this analysis but limiting the comparison to those who had any seizure was also not significant (p = 0.061). Similarly, the proportion of children with any seizures post enrollment was not different (4/23 vs. 5/21, p = 0.072). Despite limiting phenobarbital exposure to those with ongoing seizure in year 2, there was a higher safety failure rate in the usual care group (5/21) compared to LVT (0/23), p = 0.019.\nTable 4 Response to Seizure Treatment and Other Relevant Outcomes\n\n\tLevetiracetam (n = 23)\tUsual Care (n = 21) (Phenobarbital)\tP-value\t\nMinutes with seizure\t\t\tp = 0.54^\t\nmean (SD) ~\t165 (266)\t465 (639)\t\t\nIQR; maximum\t26–305; 563\t42–734; 1473\t\t\nStatus epilepticusŦ\t2\t4\tp = 0.58\t\nPeriodic EEG patterns∞\tLPDs (1)\n\nGPDs (1)\n\n\tBIRDS (1)\n\nLPDs (4)\n\nLRDA (2)\n\n\t–\t\nSeizure free (n, %)\t19 (83%)\t16 (76%)\tp = 0.72\n\nRR 1.08\n\n(95% CI 0.8–1.47)\n\n\t\nRequired dose escalation\t4/23 (17%)\tNot applicable\t–\t\nTreatment failure, crossed over\t2\t3\tp = 0.66\t\nSafety failure*\t0\t5\tp = 0.019#\n\nRR 0 (95% CI 0–0.59)\n\n\t\nComa durationϯ\n\n(mean hours, SD)\n\n\tn = 22\n\n35.4 (29.0)\n\n\tn = 16\n\n34.6 (27.8)\n\n\tp = 0.91\t\nDisposition\t\t\tp = 0.091\t\n-Alive, no sequelae\t19\t14\t\t\n-Sequelae\t3\t2\t\t\n-Died\t1\t5\t\t\n^ Comparison test based upon ranks using a non-parametric test\n\n~ Among only those with seizures\n\nŦ Evident both clinically and electrographically in all cases\n\n∞ LPD = lateralized periodic discharges; GPD = generalized periodic discharges; BIRDs = brief ictal rhythmic discharges; LRDA = lateralized rhythmic delta activity\n\n* Drug withdrawal due to SADR. 3/5 respiratory events and 2/5 with concerning decline in coma score after dosing\n\nϯ Among those who survived\n\n\n\nThirty children received LVT including four escalated to 60 mg/kg load, then 45 mg/kg Q12 hourly higher doses. LVT levels at seizure breakthrough ranged from 36.6–59.0 μg/mL. The LVT level was at least 20 μg/mL in 26/29 (90%) of children within 4 h of the loading dose. The steady state trough was below 6 in 6/29 and above 20 in 6/29 including 4/29 with AUC > 200% of the expected population average.\n\nWith one exception, all seizures captured through the continuous EEG monitoring were focal in onset with local propagation. Electrographic generalization was sometimes but not always seen. There was a single generalized onset seizure associated with brief ictal rhythmic discharges (BIRDs) in a PB allocated child.\n\nClinically evident seizures that appeared generalized in nature evolved from focal electrographically evident subclinical seizures that sometimes waxed and waned for several minutes prior to clinical manifestations being evident. Status epilepticus, meaning seizures lasting longer than 15 min, occurred in 2 LVT allocated children and 4 PB allocated children. In all instances of electrographic status epilepticus, the criteria for clinical status epilepticus were also met but the full extent and duration of ongoing seizures was not evident clinically.\n\nLateralized periodic discharges occurred in one LVT child and 2 PB children who also had seizures. In addition, 2 PB children who had seizures electrographically had periodic discharges and subsequently died. Generalized periodic discharges were seen in one LVT child. Lateralized rhythmic delta activity was seen in 2 PB children.\n\nAEs are detailed in Additional files 5 and 6. All comparisons for SAEs by allocation had p > 0.05 Most were attributed to CM. SADRs attributed to phenobarbital included respiratory suppression, aspiration and prolonged somnolence. Transient myoclonus occurred in one LVT child on awakening and resolved after LVT was stopped.\n\nThe Respiratory suppression/aspiration AEs that occurred in four children are detailed below.\nLVT 010: Admission BCs 0/5 but no seizures. Deep coma with shallow respiration and problems handling secretions led clinician caring for the child to elect to stop PB after two doses. After regaining consciousness, the child continued to require oxygen for 24 h and had exam findings consistent with an aspiration pneumonia.\n\nLVT012: Had received one dose of diazepam prior to randomization. Randomized to PB and within a few hours of admission, after the PB loading dose, developed seizures. No response to paraldehyde so LVT was added. PB was not continued due to physician concerns regarding respiratory suppression once seizures were controlled.\n\nLVT026: BCS 0/5 on admission. Received PB. EEG with lateralized periodic discharges but no seizures. EEG progressed with slowing and prolonged periods of attenuation for the 24 h after admission, but no respiratory concerns were documented. In the setting of an EEG showing prolonged periods of suppression, an abrupt respiratory arrest occurred and the child died despite bagging.\n\nLVT033: Admitted with BCS 1, hyperparasitemia, hyperlactatemia and seizures the morning of admission. Randomized to PB with no seizures on cEEG through first 24 h with EEG showing severe slowing on the left and suppression on the right. Due to tenuous respiratory status and decline in BCS to 0, phenobarbital was discontinued at 24 h. EEG continued to worsen with prolonged periods of suppression. Child had respiratory arrest and died at 48 h post enrollment, 24 h after last PB dose.\n\n\n\nPost hoc analysis of LVT elimination with elevated creatinine \nIn children with CM, eLVT was well-tolerated and rapidly absorbed. Children with admission SCr ≥ 0.9 had reduced LVT elimination and the highest LVT concentrations. In a post hoc comparison, children with admission SCr ≥ 0.9 had more severe AEs (p = 0.0002), all also having at least one grade 4–5 AE compared to 12% of those with SCr < 0.9 (p = 0.06) (Table 5).\nTable 5 Post hoc adverse events in LVT group with admission serum Cr < 0.9 vs. ≥0.9 μg/mL\n\n\tLVT Rx, Cr < 0.9\n(n = 25)\tLVT Rx Cr ≥ 0.9\n(n = 5)\t\np\n-value\n\t\nPB Rx, Cr ≥ 0.9\n\n(n = 6)\t\nAbnl electrolytes\t13 (52)\t3 (60)\tp = 0.57\t1 (17)\t\nAbnormal LFTs\t11 (44)\t3 (60)\tp = 0.28\t3 (50)\t\nAbnl Hematologic\t4 (16)\t3 (60)\tp = 0.07\t1 (17)\t\nAbnl other\t3 (12)\t2 (40)\tp = 0.18\t3 (50)\t\nNumber of AEs\t\t\tBy category\t\t\n0\t4 (16)\t0\t\t1 (17)\t\n1\t10 (40)\t1 (20)\t\t2 (34)\t\n2\t6 (24)\t1 (20)\tp = 0.17\t1 (17)\t\n3\t4 (16)\t2 (40)\t\t1 (17)\t\n4\t1 (4)\t0\t\t0\t\n5\t0\t0\t\t1 (17)\t\n6\t0\t1 (20)\t\t0\t\n10\t0\t0\t\t0\t\nNumber of AEs\tMean 1.56 (SD 1.04)\tMean 3.80 (SD3.56)\tp = 0.06\tMean 2.0 (SD 1.8)\t\nAE severity (max)\t\t\tBy category\t\t\n0\t3 (12)\t0\t\t1 (17)\t\n1\t10 (40)\t0\t\t0\t\n2\t6 (24)\t0\tp = 0.001\t0\t\n3\t3 (12)\t0\t\t1 (17)\t\n4\t2 (8)\t4 (80)\t\t1 (17)\t\n5\t1 (4)\t1 (20)\t\t2 (34)\t\nSeverity of AEs#\tMean 1.8 (SD 1.3)\tMean 4.2 (SD 0.45)\tp = 0.0008\tMean 3.7 (SD 2.0)\t\nEfficacy failure\t3 (12)\t0\tp = 0.57\t2 (34)\t\n# Signficant at P<0.005\n\n\n\nDiscussion\nThis is the first open-label, randomized controlled trial comparing eLVT to usual care with phenobarbital for treatment of acute seizures in resource-limited settings. Among 30 comatose CM children with recent clinical seizures, eLVT was rapidly absorbed and well tolerated. Overall eLVT PK parameters were similar to prior pediatric PK studies, but eLVT clearance was lower in patients with higher admission serum creatinine concentrations. Within 4 h of the first dose, 90% reached therapeutic levels, many reaching therapeutic levels quite rapidly. In the initial dose-finding study, 7/7 children receiving the first planned eLVT dose achieved seizure freedom. In the subsequent randomized comparison of eLVT to usual care patients, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death. Although treatment assignment was open-label, the primary and secondary EEG/seizure outcome assessments were masked. eLVT was safer (p = 0.019) than phenobarbital, which was discontinued in 3/15 subjects due to respiratory side effects. eLVT therefore is a safe, efficacious, and affordable alternative to usual care for acute symptomatic seizures in this critically ill pediatric CM population who have a high risk of acute seizures, status epilepticus and seizure-associated neurologic sequelae.\n\nSeveral limitations need to be kept in mind. First, this study provides no insights on eLVT safety in children with SCr > 2 mg/dL. None of the 140 children screened for enrollment had a SCr > 2.0 mg/dL. Caution is warranted in extrapolating the eLVT safety data here to eLVT use for acute symptomatic seizures from causes more often associated with comorbid renal insufficiency. Secondly, we had limited PK data in children with continuous electrographic seizures, [21] but one child who failed standard dose LVT received a higher loading dose while having continuous electrographic seizures and the PK data suggested absorption was delayed until after the seizure halted. Although some of the study subjects developed status epilepticus after enrollment, none of them had experienced status prior to enrollment. The exclusion of children who had received more than two doses of rescue benzodiazepines likely omitted this population from enrollment which may have made the study population less neurologically affected than the typical cerebral malaria population.\n\nMid-way through the study, the study protocol was amended at the Safety Monitoring Committee’s request based upon interim review of the data which, though not statistically significant at that time, suggested that the risk of respiratory suppression remained elevated in the PB exposed children despite the limitations on pre-enrollment benzodiazepines. This potentially affected the findings in two ways—first, withholding treatment until additional seizures occurred in the PB but not LVT group might have made the LVT treatment appear more efficacious than it would have been compared to PB if everyone in the PB comparison had actually received PB. As such, this study can only confirm that LVT is comparable to PB efficacy when PB is given for ongoing seizures that fail to respond to benzodiazepines. This Safety Monitoring Committee directed protocol change may also have impacted the study findings by making PB appear “safer” than it actually is when given for repetitive but not continuous seizures. This makes the safety findings of this study even more notable.\n\nWe also identified some potential issues related to eLVT usage among children with mild renal compromise. Since similar AEs occurred in PB allocated children with elevated admission SCr, modestly elevated admission creatinine is likely an indicator of underlying disease severity rather than high LVT concentrations causing AEs. In terms of efficacy, there was no difference between the LVT and phenobarbital for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death. The well-established respiratory safety constraints of phenobarbital were evident in this study. The only difference between LVT and usual care with phenobarbital was in the better safety profile of LVT. Given the superior safety profile of eLVT and the option of adding phenobarbital if eLVT proves ineffective, initial management with eLVT is warranted for CM-associated seizures.\n\nConclusion\nIn the setting of acute CM, eLVT is equally effective and has a more favorable side effect profile than intravenous phenobarbital. The availability of a safer ASD in resource-limited settings may result in fewer cases of untreated seizures, as clinicians may be understandably less concerned about inducing respiratory depression in these deeply comatose and critically ill children. Further studies are needed to determine if LVT can decrease neurologic sequelae in CM survivors. Brain injury occurs in ~ 135,000 child survivors of severe malaria in Africa each year. Affordable, effective neuroprotective interventions are certainly needed and would warrant changes in international malaria care guidelines.\n\nSupplementary information\n\nAdditional file 1. Study Protocol\n\n \nAdditional file 2. Graded toxicity Criteria\n\n \nAdditional file 3. Q-Q Plots for Evaluation of Normalcy\n\n \nAdditional file 4. Supplementary Table 1: Neurologic Sequelae\n\n \nAdditional file 5. Supplementary Table 2: Serious Events by Allocation\n\n \nAdditional file 6. Supplementary Table 3: Adverse Events, not Serious\n\n \n\n\nAbbreviations\nASDantiseizure drug\n\nAUCarea under the curve\n\nBCSBlantyre Coma Score\n\ncEEGcontinuous electroencephalogram\n\nCMcerebral malaria\n\nECGelectrocardiogram\n\neLVTenteral levetiracetam\n\nFOCEfirst order conditional estimation\n\nHPLChigh pressure liquid chromatography\n\nIQRinterquartile range\n\nLVTlevetiracetam\n\nNCSEnonconvulsive status epilepticus\n\nNGTnasogastric tube\n\nPKpharmacokinetic\n\nRCTrandomized controlled trial\n\nSADRsuspected adverse drug reaction\n\nSCrserum creatinine\n\nSDstandard deviation\n\nSMCstudy monitoring committee\n\nttime\n\nt1/2half-life\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12887-019-1766-2.\n\nAcknowledgements\nThe authors wish to thank the children and their parents and guardians for participation in the study. The work would not have been possible without the many skilled nurses and clinicians who provided clinical care for the children on the Paediatric Research Ward. Infrastructural support for the Paediatric Research Ward was provided by the Malawi-Liverpool-Wellcome Trust Programme. We are also grateful to Dr. Andre Fenton (Bio-Signal Corporation) for his assistance in successfully incorporating microEEG technology into this work.\n\nFinancial disclosures\nGL Birbeck reports grants from US NIH. She has served as a consultant on antimalarial treatment for GlaxoSmithKline.\n\nN Toto, D Postels, TE Taylor and KB Seydel have nothing to disclose.\n\nST Herman reports grants from NIH/NINDS, during the conduct of the study; personal fees from Eisai, Inc. and Biotie; grants from Acorda Therapeutics, Lundbeck, Inc., NeuroPace, Inc., Sage Therapeutics, UCB BioPharma, and the Epilepsy Therapy Development Project.\n\nEV Capparelli reports personal fees from Alexion, personal fees from Gilead, personal fees from Rempex, personal fees from Cempra, and personal fees from The Medicines Company.\n\nFK Dzinjalamala has nothing to disclose.\n\nS Baki reports support from Bio-Signal Group Co. and other grants outside the submitted work; In addition, Dr. Abdel Baki has a patent 61/554,743 pending, and a US patent 13/284,886. August 9, 2016.\n\nM Mallewa has nothing to disclose.\n\nJC Gardiner reports grants from University of Rochester during the conduct of the study; personal fees from Robert Wood Johnson, Janssen Pharmaceuticals, Amgen, Inc., and Quintiles, Inc. He reports serving on a Data Monitoring Committee for a Randomized Controlled Trial to assess the safety and tolerability of topiramate compared to levetiracetam sponsored by Robert Wood Johnson (Janssen Research & Development).\n\nAuthors contributions\nGLB contributed to study conception, study design, data analysis and editing. She also developed the first draft of this manuscript. STH contributed to study design, provided laboratory support for EEG assessments, provided substantive editorial input on earlier versions of this manuscript and has reviewed and approved the final work. EC contributed to study design, provided analysis for pharmacokinetic assessments, provided substantive editorial input on earlier versions of this manuscript and has reviewed and approved the final work. FKD contributed to study design, provided laboratory support for pharmacokinetic assessments, provided substantive editorial input on earlier versions of this manuscript and has reviewed and approved the final work. SAB contributed to study design, provided technical support for EEG, provided substantive editorial input on earlier versions of this manuscript and has reviewed and approved the final work. MM and DP contributed to study design, provided clinical support for acquisition of continuous EEG, provided substantive editorial input on earlier versions of this manuscript and have reviewed and approved the final work. NT provided quality assurance of data collection and management, provided support for the study conduct, provided substantive editorial input on earlier versions of this manuscript and has reviewed and approved the final work. JCG contributed to study design, led data analysis, provided substantive editorial input on earlier versions of this manuscript and has reviewed and approved the final work. TET and KBS contributed to study design, provided clinical care for subjects while hospitalized, provided substantive editorial input on earlier versions of this manuscript and have reviewed and approved the final work.\n\nFunding\nResearch reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS074409 and the National Institute of Allergy and Infectious Diseases under award number R01AI034969. The funders had no role in study design, conduct or the decision to publish. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nWritten informed consent was obtained from the parent or guardian prior to enrollment. This study was approved by the Research Ethics Committees at the University of Malawi (FWA00011868), Michigan State University (FWA00004556) and the University of Rochester (FWA00009386).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors have no conflicts of interest relevant to this article to disclose.\n==== Refs\nReferences\n1. Idro R Jenkins NE Newton CR Pathogenesis, clinical features, and neurological outcome of cerebral malaria Lancet Neurol 2005 4 12 827 840 10.1016/S1474-4422(05)70247-7 16297841 \n2. Birbeck G Molyneux M Kaplan P Seydel K Chimalizeni Y Kawaza K Taylor T The Blantyre malaria project epilepsy study (BMPES): neurologic outcomes in a prospective exposure-control study of retinopathy-positive pediatric cerebral malaria survivors Lancet Neurol 2010 9 12 1173 1181 10.1016/S1474-4422(10)70270-2 21056005 \n3. Carter JA Mung'ala-Odera V Neville BG Murira G Mturi N Musumba C Newton CR Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children J Neurol Neurosurg Psychiatry 2005 76 4 476 481 10.1136/jnnp.2004.043893 15774431 \n4. Roca-Feltrer A Carneiro I Armstrong Schellenberg JR Estimates of the burden of malaria morbidity in Africa in children under the age of 5 years Tropical Med Int Health 2008 13 6 771 783 10.1111/j.1365-3156.2008.02076.x \n5. Newton CR Warrell DA Neurological manifestations of falciparum malaria Ann Neurol 1998 43 6 695 702 10.1002/ana.410430603 9629838 \n6. Crawley J Smith S Muthinji P Marsh K Kirkham F Electroencephalographic and clinical features of cerebral malaria Arch Dis Child 2001 84 3 247 253 10.1136/adc.84.3.247 11207176 \n7. Gwer S Thuo N Idro R Ndiritu M Boga M Newton C Kirkham F Changing trends in incidence and aetiology of childhood acute non-traumatic coma over a period of changing malaria transmission in rural coastal Kenya: a retrospective analysis BMJ Open 2012 2 2 e000475 10.1136/bmjopen-2011-000475 \n8. Crawley J Waruiru C Mithwani S Mwangi I Watkins W Ouma D Winstanley P Peto T Marsh K Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study Lancet 2000 355 9205 701 706 10.1016/S0140-6736(99)07148-2 10703801 \n9. World Health Organization: Updated guideline: paediatric emergency triage, assessment and treatment. Geneva: World Health Organization; 2016. https://apps.who.int/iris/handle/10665/204463 Accessed 4August2019.\n10. Patsalos PN Clinical pharmacokinetics of levetiracetam Clin Pharmacokinet 2004 43 11 707 724 10.2165/00003088-200443110-00002 15301575 \n11. Seydel KB Kampondeni SD Valim C Potchen MJ Milner DA Muwalo FW Birbeck GL Bradley WG Fox LL Glover SJ Brain swelling and death in children with cerebral malaria N Engl J Med 2015 372 12 1126 1137 10.1056/NEJMoa1400116 25785970 \n12. Molyneux ME Taylor TE Wirima JJ Borgstein A Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children Q J Med 1989 71 265 441 459 2690177 \n13. Newton CR Chokwe T Schellenberg JA Winstanley PA Forster D Peshu N Kirkham FJ Marsh K Coma scales for children with severe falciparum malaria Trans R Soc Trop Med Hyg 1997 91 2 161 165 10.1016/S0035-9203(97)90207-8 9196757 \n14. World Health Organization Guidelines for the treatment of malaria 2010 2 Geneva World Health Organization \n15. Ratnaraj N Doheny HC Patsalos PN A micromethod for the determination of the new antiepileptic drug levetiracetam (ucb LO59) in serum or plasma by high performance liquid chromatography Ther Drug Monit 1996 18 2 154 157 10.1097/00007691-199604000-00008 8721278 \n16. Holford N Heo YA Anderson B A pharmacokinetic standard for babies and adults J Pharm Sci 2013 102 9 2941 2952 10.1002/jps.23574 23650116 \n17. Hirsch LJ LaRoche SM Gaspard N Gerard E Svoronos A Herman ST Mani R Arif H Jette N Minazad Y American clinical neurophysiology Society's standardized critical care EEG terminology: 2012 version J Clin Neurophysiol 2013 30 1 1 27 10.1097/WNP.0b013e3182784729 23377439 \n18. Fleiss J Levin B Paik M Statistical methods for rates and proportions 2003 3 New York, NY Wiley-Interscience \n19. SAS/STAT User's Guide The Power Procedure. In 2010 9.2 Cary, NC SAS Institute Inc \n20. Glauser TA Dulac O Preliminary efficacy of levetiracetam in children Epileptic Disord 2003 5 Suppl 1 S45 S50 12915341 \n21. Trinka E Cock H Hesdorffer D Rossetti AO Scheffer IE Shinnar S Shorvon S Lowenstein DH A definition and classification of status epilepticus--report of the ILAE task force on classification of status Epilepticus Epilepsia 2015 56 10 1515 1523 10.1111/epi.13121 26336950\n\n",
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"title": "A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria.",
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"abstract": "Anaphylaxis occurs in 1/5000-1/20,000 of anesthesia cases and may evolve with shock and cardiovascular collapse in up to 54% of cases. Mortality varies from 3% to 10%. Latex is the second leading cause of anaphylaxis during the perioperative period. We report a case of latex-induced anaphylactic shock refractory to the usual catecholamine treatment that was reversed with the aid of methylene blue. Exaggerated activation of the nitric oxide-cyclic guanosine monophosphate pathway is observed in refractory shock. Methylene blue selectively inhibits this pathway.",
"affiliations": "From the Anesthesiology Service, Regional Hospital Alto Vale, Rio do Sul, Santa Catarina, Brazil.",
"authors": "Da Silva|Paulo Sergio|PS|;Furtado|Paula|P|",
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"abstract": "Lithium therapy has been associated with several endocrine disorders including thyroid dysfunction, diabetes insipidus, and hyperparathyroidism. While its suppressive effect on thyroid function is well known, it is very rare to observe lithium-induced hyperthyroidism especially in the pediatric population. Here, we describe a case of lithium-induced hyperthyroidism in an adolescent female with bipolar disorder. The patient is a 17-year-old female who was treated with lithium for bipolar disorder and presented with symptoms and laboratory findings consistent with hyperthyroidism. Since thyroid autoantibodies were negative, thyroid dysfunction was attributed to lithium toxicity. Indeed, her clinical and biochemical hyperthyroid state resolved after stopping lithium therapy. Lithium-associated hyperthyroidism can occur in the pediatric population. We propose close monitoring of thyroid hormone levels in children on lithium therapy.",
"affiliations": "Children's Mercy Hospital, 3101 Broadway Blvd., Kansas City, MO 64111, USA.;Children's Mercy Hospital, 3101 Broadway Blvd., Kansas City, MO 64111, USA.;Department of Pediatric Endocrinology, Children's Mercy Hospital, 3101 Broadway Blvd., Kansas City, MO 64111, USA.",
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"fulltext": "\n==== Front\nCase Rep Endocrinol\nCase Rep Endocrinol\nCRIE\nCase Reports in Endocrinology\n2090-6501 2090-651X Hindawi \n\n10.1155/2020/1283464\nCase Report\nAn Adolescent Female with Bipolar Disorder Presenting with Lithium-Induced Hyperthyroidism\nRana Pratibha \n1\n Alba Aponte Patria \n1\n https://orcid.org/0000-0002-3428-887XBabar Ghufran gbabar@cmh.edu\n2\n \n1Children's Mercy Hospital, 3101 Broadway Blvd., Kansas City, MO 64111, USA\n\n2Department of Pediatric Endocrinology, Children's Mercy Hospital, 3101 Broadway Blvd., Kansas City, MO 64111, USA\nAcademic Editor: Lucy Mastrandrea\n\n\n2020 \n12 2 2020 \n2020 128346415 11 2019 21 1 2020 Copyright © 2020 Pratibha Rana et al.2020This 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.Lithium therapy has been associated with several endocrine disorders including thyroid dysfunction, diabetes insipidus, and hyperparathyroidism. While its suppressive effect on thyroid function is well known, it is very rare to observe lithium-induced hyperthyroidism especially in the pediatric population. Here, we describe a case of lithium-induced hyperthyroidism in an adolescent female with bipolar disorder. The patient is a 17-year-old female who was treated with lithium for bipolar disorder and presented with symptoms and laboratory findings consistent with hyperthyroidism. Since thyroid autoantibodies were negative, thyroid dysfunction was attributed to lithium toxicity. Indeed, her clinical and biochemical hyperthyroid state resolved after stopping lithium therapy. Lithium-associated hyperthyroidism can occur in the pediatric population. We propose close monitoring of thyroid hormone levels in children on lithium therapy.\n==== Body\n1. Case Report\nBipolar disorders are common in adolescents, with a lifetime prevalence of 2.5% [1] and 0.1% in children aged 9–13 years [2]. Lithium is commonly used for the treatment of bipolar disorders in children and adolescents [3]. It has been associated with several endocrine disorders including thyroid dysfunction, diabetes insipidus, and hyperparathyroidism. Its suppressive effect on thyroid function is well known; in contrast, lithium-induced hyperthyroidism is rare with a prevalence in the range of between 1% and 1.7% in the adult population [4, 5]. The first case of thyrotoxicosis in a patient treated with lithium was reported in 1974 [6]. Hyperthyroidism in lithium-treated patients has been associated with diffuse goiter, toxic multinodular goiter, and painless thyroiditis [7]. Lithium is also implicated in granulomatous thyroiditis, and it is reported to induce auto-antibody formation and autoimmunity in susceptible individuals [8]. There have not been any cases reported about lithium-induced hyperthyroidism in pediatric population. We are presenting an adolescent girl treated with lithium who presented with hyperthyroidism.\n\n2. Methods\nRetrospective chart review of the case study was carried out. Since it is a single case report, an approval from the Institutional Review Board (IRB) and consent are not required. However, when a new patient is seen in our clinic, the family signed a consent form for treatment and possible use of any clinical finding to report anonymously.\n\n3. Case Presentation\nOur patient is a 17-year-5-month-old female with bipolar disorder who was treated with lithium. She had been placed on Concerta, Abilify, and Lamictal before being switched to lithium monotherapy due to the limited success of these initial therapies. She responded well to lithium for two years until about 3-4 weeks prior to presentation, when she developed dizziness, heat intolerance, excessive sweating, tremors, and palpitations. Due to these symptoms, she stopped taking lithium and sought medical attention at her primary care provider's (PCP's) office. The PCP ordered laboratory tests which revealed a `suppressed TSH (<0.02 mcIU/mL, normal range: 0.35–5.50) and an elevated free T4 (3.5 ng/dL, normal range: 0.8–1.9), both consistent with hyperthyroidism. Her lithium level at that time was <0.3 (normal range: 0.6–1.2 mmol/L), likely due to noncompliance during the past two weeks. The PCP received these results on the weekend, and the patient was referred to the emergency department (ED) where, on examination, she was tachycardic (140 bpm), afebrile, and her blood pressure was 132/84 mmHg. Her thyroid exam revealed the presence of a nontender goiter; no nodules were palpable. Repeat laboratory tests at the ED confirmed biochemical hyperthyroidism (TSH: <0.02 mcIU/mL, total T3: 351 ng/dl, normal range: 55 to 209) and an elevated free T4 (3.7 ng/dL). There was a prolonged QT interval on her EKG. Of note, our patient had no family history of autoimmunity or thyroid disease. Thyroid suppressive therapy was initiated with methimazole, 10 mg PO 3 times a day (0.46 mg/kg/day) as advised by the endocrinologist. She was also started on propranolol (60 mg/day∼0.92 mg/kg/day). The ESR, CRP, CBC, and BMP were normal. Thyroid autoantibodies (antithyroid peroxidase antibody, antithyroglobulin antibody, and thyroid stimulating immunoglobulin) were all negative. She was advised not to restart lithium and consult her psychiatrist. She was seen in the endocrine clinic about two weeks later, after being off-lithium for four weeks; her hyperthyroid symptoms had improved; however, she still had palpitations and heat intolerance, while her heart rate and blood pressure were still above the age appropriate ranges (101 bpm and 133/74 mm hg, respectively). She had mild tongue fasciculation but no exophthalmos. Repeat thyroid function tests showed a lower free T4 level (2.0 ng/dl) as compared with two weeks ago, while the TSH was still suppressed. A subsequent endocrine visit two weeks later showed a normalized free T4 (1.5 ng/dl) and improved clinical hyperthyroidism. As a result, propranolol was discontinued, while methimazole treatment was maintained. By three months after her initial presentation, the methimazole dose was reduced (10 mg b.i.d.) due to a borderline-low (0.8 ng/dl, normal range of 0.8 to 1.9 ng/dL), Methimazole was eventually discontinued after five months of initial presentation. At her last follow-up in the endocrine clinic (seven months after diagnosis of hyperthyroidism and several weeks after stopping methimazole), she was clinically and biochemically euthyroid (Table 1).\n\n4. Discussion\nThe prevalence of bipolar disorders in adolescence ranges between 1.8% and 2.5% [9, 10]. They are considered as the fourth leading cause of disability among adolescent worldwide. In children with bipolar disorders, lithium is the only mood stabilizer approved by the FDA for acute mania and maintenance treatment [11]. In a recent meta-analysis of studies on the effects of lithium on thyroid function, the investigators compared the prevalence of hypothyroidism in patients treated with lithium with controls. The overall odds of clinical hypothyroidism were close to six times greater in lithium-treated subjects than in controls. Conversely, this study did not find any difference between patients and controls on lithium with respect to the prevalence of increased thyroid function [4]. On the contrary, lithium-induced hyperthyroidism is rare even in adults [12]; it is estimated to have the annual incidence of 0.1% [13]. Other studies have estimated the prevalence to be in the range of 1%–1.7% [5, 14]. Only a small number of children treated with lithium present with subclinical or clinical hypothyroidism, and/or goiter [15, 16], to our knowledge, ours is the first case of a pediatric patient with lithium-induced hyperthyroidism. The possible mechanism regarding lithium-induced hyperthyroidism is thought to be due to an expansion of the intrathyroidal iodine pool, induction of autoimmune hyperthyroidism (Graves' disease), and a toxic thyroid nodule or painless thyroiditis [7, 17]. In patients with primary affective disorders, thyroid autoantibodies were detected in 8 of 40 subjects treated with lithium, and only in 3 patients were treated with other psychotropic drugs. Furthermore, the lithium-treated patients exhibited significantly reduced numbers of suppressor and or cytotoxic T cells and increased B cell activity compared to those treated with drugs other than lithium [18]. Similar to amiodarone-induced toxic thyroiditis, painless thyroiditis may also be the result of a direct toxic effect of lithium on the thyroid, which seems to be the likely mechanism in our patient, in whom results of tests for thyroid antibodies remained negative. Furthermore, it has been reported that lithium-associated silent thyroiditis occurred with an incidence rate of approximately 1.3 cases per 1000 person-years, and lithium-associated thyrotoxicosis occurred with an incidence rate of approximately 2.7 cases per 1000 person-years, higher than the reported incidence rates of silent thyroiditis (<0.03–0.28 cases per 1000 person-years) and of thyrotoxicosis (0.8–1.2 cases per 1000 person-years) in the general population and calculated the odds of lithium exposure to be 4.7-fold higher in patients with thyroiditis [7]. Recently, a meta-analysis of 52 studies showed in nine of these that were cross-sectional or cohort studies describing around 2500 patients that 2.6% patients were hypothyroid [19]. Another cross-sectional study reported just one patient (1.2%) in their lithium-treated group [20]. The histopathological features of the thyroid gland showed an immunological phenomenon with lymphoid follicles and fibrosis in affected thyroid glands [21], and this autoimmune process was not detected in other prospective studies, pre- and postlithium treatment [22, 23]. In our patient, the thyroid antibodies were negative; CBC, C-reactive protein (CRP), and sedimentation rate (ESR) were normal, suggesting that a mild silent thyroiditis may have been the cause of hyperthyroidism. Miller and Daniels described that most hyperthyroid patients had serum lithium level in the therapeutic range [7]. However, our patient's lithium level was not elevated due to discontinuation of treatment 2 weeks before the levels were checked. The duration of lithium therapy in patients who develop hyperthyroidism and lithium-associated silent thyroiditis range between 6 days and 15 years. However, in some cases, thyrotoxicosis occurred 4 days to 5 months after withdrawal of lithium therapy [24], and in our patient, the duration of lithium therapy was about 2 years. In conclusion, lithium-induced hyperthyroidism is very rarely diagnosed in adults and has never been reported in children before our case. We believe it is necessary to increase awareness of the possibility of such drug-induced thyroid dysfunction in the pediatric population, especially in children with hyperthyroidism and negative thyroid autoantibodies. The transient nature of this disorder is associated with a better prognosis compared to patients with Graves' disease. Since lithium-induced hyperthyroidism may occur even after years of lithium therapy, it is advisable to regularly monitor the thyroid function in children during the whole duration of lithium treatment.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nTable 1 Hormonal profile of the patient with gradual improvements of thyroid hormone levels from being hyperthyroid to euthyroid.\n\nTimeline\tTSH (0.35–5.5 mcIU/mL)\tFree T4 (0.9–1.9 ng/dL)\tTotal T3 (55–209 ng/dL)\t\nInitial lab work\t0.01\t3.5\t \t\n2 days later\t<0.02\t3.7\t351\t\n2 weeks later\t<0.02\t2.0\t \t\n1 month later\t<0.02\t1.5\t \t\n2 months\t<0.02\t0.9\t188\t\n3 months\t0.39\t0.8\t175\t\n5 months\t2.61\t1.2\t172\t\n7 months\t2.62\t1.1\t134\n==== Refs\n1 Merikangas K. R. Akiskal H. S. Angst J. Lifetime and 12-month prevalence of bipolar spectrum disorder in the national comorbidity survey replication Archives of General Psychiatry 2007 64 5 543 552 10.1001/archpsyc.64.5.543 2-s2.0-34247536530 17485606 \n2 Costello E. J. Angold A. Burns B. J. The great smoky mountains study of youth Archives of General Psychiatry 1996 53 12 1129 1136 10.1001/archpsyc.1996.01830120067012 2-s2.0-0029750722 8956679 \n3 Grant B. Salpekar J. A. Using lithium in children and adolescents with bipolar disorder: efficacy, tolerability, and practical considerations Pediatric Drugs 2018 20 4 303 314 10.1007/s40272-018-0289-x 2-s2.0-85045280714 29651656 \n4 McKnight R. F. Adida M. Budge K. Stockton S. Goodwin G. M. Geddes J. R. Lithium toxicity profile: a systematic review and meta-analysis The Lancet 2012 379 9817 721 728 10.1016/s0140-6736(11)61516-x 2-s2.0-84857643018 \n5 Brownlie B. E. W. Wells J. E. The epidemiology of thyrotoxicosis in New Zealand: incidence and geographical distribution in north canterbury, 1983-1985 Clinical Endocrinology 1990 33 2 249 259 10.1111/j.1365-2265.1990.tb00489.x 2-s2.0-0025364832 2225482 \n6 Franklin L. M. Thyrotoxicosis developing during lithium treatment: case report The New Zealand Medical Journal 1974 79 511 p. 782 \n7 Miller K. K. Daniels G. H. Association between lithium use and thyrotoxicosis caused by silent thyroiditis Clinical Endocrinology 2001 55 4 501 508 10.1046/j.1365-2265.2001.01381.x 2-s2.0-0034787001 11678833 \n8 Sinnott M. J. McIntyre H. D. Pond S. M. Granulomatous thyroiditis and lithium therapy Australian and New Zealand Journal of Medicine 1992 22 1 p. 84 10.1111/j.1445-5994.1992.tb01716.x 2-s2.0-0026810501 \n9 Van Meter A. R. Moreira A. L. R. Youngstrom E. A. Meta-analysis of epidemiologic studies of pediatric bipolar disorder The Journal of Clinical Psychiatry 2011 72 9 1250 1256 10.4088/jcp.10m06290 2-s2.0-80052983094 21672501 \n10 Merikangas K. R. Cui L. Kattan G. Carlson G. A. Youngstrom E. A. Angst J. Mania with and without depression in a community sample of US adolescents Archives of General Psychiatry 2012 69 9 943 951 10.1001/archgenpsychiatry.2012.38 2-s2.0-84866051246 22566563 \n11 McClellan J. Kowatch R. Findling R. L. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder Journal of the American Academy of Child & Adolescent Psychiatry 2007 46 1 107 125 10.1097/01.chi.0000242240.69678.c4 2-s2.0-33845957797 17195735 \n12 Barclay M. L. Brownlie B. E. W. Turner J. G. Wells J. E. Lithium associated thyrotoxicosis: a report of 14 cases, with statistical analysis of incidence Clinical Endocrinology 1994 40 6 759 764 10.1111/j.1365-2265.1994.tb02509.x 2-s2.0-0028236939 8033366 \n13 Bocchetta A. Loviselli A. Lithium treatment and thyroid abnormalities Clinical Practice and Epidemiology in Mental Health 2006 2 1 23 28 10.1186/1745-0179-2-23 2-s2.0-33749384973 16968542 \n14 Yassa R. Saunders A. Nastase C. Camille Y. Lithium-induced thyroid disorders: a prevalence study The Journal of Clinical Psychiatry 1988 49 1 14 16 \n15 Findling R. L. Robb A. McNamara N. K. Lithium in the acute treatment of bipolar I disorder: a double-blind, placebo controlled study Pediatrics 2015 136 5 885 894 10.1542/peds.2015-0743 2-s2.0-84947217169 26459650 \n16 DeLong G. R. Aldershof A. L. Long-term experience with lithium treatment in childhood: correlation with clinical diagnosis Journal of the American Academy of Child & Adolescent Psychiatry 1987 26 3 389 394 10.1097/00004583-198705000-00019 2-s2.0-0023259234 3597294 \n17 McDermott M. T. Burman K. D. Hofeldt F. D. Kidd G. S. Lithium-associated thyrotoxicosis The American Journal of Medicine 1986 80 6 1245 1248 10.1016/0002-9343(86)90697-2 2-s2.0-0022727178 3755288 \n18 Wilson R. McKlllop J. H. Crocket G. T. The effect of lithium therapy on parameters thought to be involved in the development of autoimmune thyroid disease Clinical Endocrinology 1991 34 5 357 361 10.1111/j.1365-2265.1991.tb00305.x 2-s2.0-0025851947 2060144 \n19 Fairbrother F. Petzl N. Scott J. G. Kisely S. Lithium can cause hyperthyroidism as well as hypothyroidism: a systematic review of an under-recognised association Australian & New Zealand Journal of Psychiatry 2019 53 5 384 402 10.1177/0004867419833171 2-s2.0-85062680644 30841715 \n20 Tuncel O. K. Akdeniz F. Ozbek S. S. Kavukcu G. Kocabas G. U. Thyroid function and ultrasonography abnormalities in lithium-treated bipolar patients: a cross-sectional study with healthy controls Noro Psikiyatri Arsivi 2017 54 2 108 115 10.5152/npa.2017.12457 2-s2.0-85021068557 28680307 \n21 Kontozoglou T. Mambo N. The histopathologic features of lithium-associated thyroiditis Human Pathology 1983 14 8 737 739 10.1016/s0046-8177(83)80150-6 2-s2.0-0020503539 6873938 \n22 Myers D. H. Carter R. A. Burns B. H. Armond A. Hussain S. B. Chengapa V. K. A prospective study of the effects of lithium on thyroid function and on the prevalence of antithyroid antibodies Psychological Medicine 1985 15 1 55 61 10.1017/s0033291700020924 2-s2.0-0021923457 3922008 \n23 Calabrese J. R. Gulledge A. D. Hahn K. Skwerer R. Kotz M. Schumacher O. P. Autoimmune thyroiditis in manic depressive patients treated with lithium American Journal of Psychiatry 1985 142 11 1318 1321 10.1176/ajp.142.11.1318 2-s2.0-0022353921 3877469 \n24 Dang A. H. Hershman J. M. Lithium-associated thyroiditis Endocrine Practice 2002 8 3 232 236 10.4158/ep.8.3.232 2-s2.0-0036107639 12113638\n\n",
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"title": "An Adolescent Female with Bipolar Disorder Presenting with Lithium-Induced Hyperthyroidism.",
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{
"abstract": "Influenza A (H1N1) can rapidly progress to acute respiratory distress syndrome and pulmonary fibrosis. We describe a 45-year-old man with acute respiratory distress syndrome and progressive lung fibrosis secondary to H1N1 pneumonia who was treated for 45 days with venovenous extracorporeal membrane oxygenation as a rescue utility and bridge to bilateral lung transplantation. The patient was saved and lived well. Lung transplantation may be a viable alternative for patients with lung fibrosis secondary to H1N1-induced acute respiratory distress syndrome in very selected situations.",
"affiliations": "Department of Thoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Thoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Thoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Thoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Comprehensive Intensive Care Unit, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Thoracic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: iwuming22@zju.edu.cn.",
"authors": "Wang|Qi|Q|;Pan|Saibo|S|;Zhang|Sai|S|;Shen|Gang|G|;Huang|Man|M|;Wu|Ming|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2019.02.035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "108(4)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011024:Pneumonia, Viral; D011658:Pulmonary Fibrosis",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e233-e235",
"pmc": null,
"pmid": "30910653",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Lung Transplantation in Pulmonary Fibrosis Secondary to Influenza A Pneumonia.",
"title_normalized": "lung transplantation in pulmonary fibrosis secondary to influenza a pneumonia"
} | [
{
"companynumb": "CN-BAYER-2019-180434",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nSevere hidradenitis suppurativa (HS), under infliximab, can be associated with different forms of arthritis whose mechanism is unclear. Our objective is to establish the frequency and clinical presentation of new-onset arthritis in HS under infliximab.\n\n\nMETHODS\nSevere HS patients under infliximab were followed up between 2007-2012. New articular inflammatory manifestations were investigated by rheumatologist.\n\n\nRESULTS\nThree patients over eleven developed a polyarthritis. Mean duration of arthritis was 3 months. At treatment's stop: 2 patients improved and 1 relieved with adalimumab.\n\n\nCONCLUSIONS\nThe inflammatory rheumatism's frequency in HS under infliximab seems underestimated.",
"affiliations": "Department of rheumatology, university hospital of Nice, 151, route de Saint-Antoine-de-Ginestière, 06200 Nice, France. Electronic address: acquacalda.e@chu-nice.fr.;Department of rheumatology, university hospital of Nice, 151, route de Saint-Antoine-de-Ginestière, 06200 Nice, France.;Department of rheumatology, university hospital of Nice, 151, route de Saint-Antoine-de-Ginestière, 06200 Nice, France.;Department of rheumatology, university hospital of Nice, 151, route de Saint-Antoine-de-Ginestière, 06200 Nice, France.;Department of dermatology, university hospital of Nice, 06200 Nice, France; Inserm, U1065, centre méditerranéen de médecine moléculaire (C3M), team 12, 06100 Nice, France.;Department of rheumatology, university hospital of Nice, 151, route de Saint-Antoine-de-Ginestière, 06200 Nice, France.",
"authors": "Acquacalda|Emilie|E|;Roux|Christian Hubert|CH|;Albert|Christine|C|;Breuil|Véronique|V|;Passeron|Thierry|T|;Euller-Ziegler|Liana|L|",
"chemical_list": "D018501:Antirheumatic Agents; D000069285:Infliximab",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "82(5)",
"journal": "Joint bone spine",
"keywords": "Hidradenitis suppurativa; Infliximab; Paradoxical reaction; Spondyloarthritis",
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001168:Arthritis; D005500:Follow-Up Studies; D017497:Hidradenitis Suppurativa; D006801:Humans; D000069285:Infliximab; D008279:Magnetic Resonance Imaging; D008297:Male; D012189:Retrospective Studies",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "362-4",
"pmc": null,
"pmid": "25776450",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "New onset of articular inflammatory manifestations in patients with hidradenitis suppurativa under treatment with infliximab.",
"title_normalized": "new onset of articular inflammatory manifestations in patients with hidradenitis suppurativa under treatment with infliximab"
} | [
{
"companynumb": "FR-JNJFOC-20151009637",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Primary melanoma of the pineal gland is a rare disease entity with an overall poor prognosis. Limited data exist to appropriately guide treatment decisions. Historical case reports have showed some success using a combination of surgical resection, radiotherapy, and chemotherapy, but long-term survival has been exceedingly rare. This report presents a female patient with a primary pineal melanoma who underwent subtotal resection followed by adjuvant focal radiation to the residual tumor. Immunohistochemistry identified a strong positivity for PD-L1 (70%). After radiation, systemic therapy with pembrolizumab was initiated with the plan to treat until progression. She has now completed 33 cycles of pembrolizumab without interruptions, complications, or disease progression. At the time of writing, the patient has had an excellent clinical outcome, with a durable near-complete response of >138 weeks. To our knowledge, this is the first patient with a pineal melanoma to be managed by targeting PD-L1. Furthermore, she has achieved the second longest overall survival and the longest progression-free survival reported in the literature.",
"affiliations": "Department of Radiation Oncology.;Division of Neurosurgery, and.;Division of Medical Oncology, The University of Arizona, Tucson, Arizona.;Department of Radiation Oncology.",
"authors": "Famoso|Justin|J|;Lemole|Gerald|G|;Sundararajan|Srinath|S|;Stea|Baldassarre|B|",
"chemical_list": "D060890:B7-H1 Antigen; C423236:CD274 protein, human",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "17(10)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000368:Aged; D060890:B7-H1 Antigen; D005260:Female; D006801:Humans; D008545:Melanoma; D010870:Pineal Gland; D018714:Radiotherapy, Adjuvant",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "1148-1153",
"pmc": null,
"pmid": "31590158",
"pubdate": "2019-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Targeting PD-L1 After Adjuvant Radiation in Subtotally Resected Primary Pineal Melanoma: A Case Report and Literature Review.",
"title_normalized": "targeting pd l1 after adjuvant radiation in subtotally resected primary pineal melanoma a case report and literature review"
} | [
{
"companynumb": "US-009507513-1910USA010730",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "There is a clear consensus regarding the combined resection of organs with cancer invasion, patients with colon cancer. However, there are very few reports to our knowledge regarding the use of pancreato-duodenectomy(PD)for colon cancer patients with cancer invasion in the duodenum. We here report a colon cancer patient in whom we performed PD and right hemicolectomy, who showed favorable results with no recurrence. The patient was a 69-year-old woman. Her chief complaint was hypogastric pain. Her previous doctor performed colonoscopy and a colonoscopic biopsy, and detected a type 2 lesion, throughout the entire circumference of the transverse colon near the liver, and she was diagnosed with adenocarcinoma. From further imaging analyses, she was diagnosed as having transverse colon cancer with invasion into the superior mesenteric vein(SMV), duodenum, and pancreatic head, and No. 223 lymph node metastasis. The patient's cancer was concluded to be unresectable, and she underwent chemotherapy, namely mFOLFOX6 with cetuxiumab(Cmab). One course of mFOLFOX with Cmab, the patient decided to consult our hospital for a second opinion. We concluded that her cancer was resectable, so we performed PD, right hemicolectomy, and resection and reconstruction of a part of the SMV. The operation time was 5 hours 17 minutes, and total blood loss was 190 mL. The histopathological diagnosis was tub2, T4b(duodenum and, tissue surrounding the SMV), int, INF b, ly1, v2, PN1b, EX(+)/ND(PN+, v+), PM0(25 cm), DM0(14.3 cm), N1(1/ 20), H0, P0, M0, pStage III a. She was discharged 15 days after surgery with no complications, and thereafter received ajduvant chemotherapy(capecitabine with oxaliplatin)as an outpatient. After 3 courses, capecitabine with oxaliplatin was changed to capecitabine because she developed a nervous system disorder, and she was further treated for approximately about 6 months. She is doing well at the time of writing, with no recurrences for 2 years. We suggest that PD should be performed on colon cancer patients in which the colon cancer has invaded other organs and has been evaluated as being unresectable.",
"affiliations": "Dept. of Gastrointestinal Surgery and Pediatric Surgery, Tokyo Medical University.",
"authors": "Udo|Ryutaro|R|;Enomoto|Masanobu|M|;Tsurui|Kazushige|K|;Kuboyama|Yuu|Y|;Kuwabara|Hiroshi|H|;Shigoka|Masatoshi|M|;Ishizaki|Tetsuo|T|;Katsumata|Kenji|K|;Obikane|Hiyo|H|;Tsuchida|Akihiko|A|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(4)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D003082:Colectomy; D044684:Colon, Transverse; D003110:Colonic Neoplasms; D004386:Duodenum; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D016577:Pancreaticoduodenectomy",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "749-751",
"pmc": null,
"pmid": "29650856",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of Performed Right Colectomy with Pancreato-Duodenectomy for Transverse Colon Cancer Invased to Duodenum.",
"title_normalized": "a case of performed right colectomy with pancreato duodenectomy for transverse colon cancer invased to duodenum"
} | [
{
"companynumb": "JP-PFIZER INC-2018292056",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "An acute coronary syndrome (ACS) occurring during the course of an allergic reaction is called Kounis syndrome (KS). The second case of KS induced by diclofenac potassium (DP) is presented in this report. A 67-year-old man was brought to our emergency department with the possible diagnosis of anaphylactic shock by the ambulance staff. It emerged that widespread erythema and pruritus developed after taking DP. Then, he lost consciousness. Diffuse urticarial lesions were detected on physical examination at the emergency department. He complained of chest pain during his observation, and progressive ST segment elevation was seen in the inferior leads on serial electrocardiograms. His coronary angiography showed 100% occlusion of the right coronary artery. Then, KS was diagnosed. The patient was discharged on the second day, and he was doing well on the control visit 2 weeks later. All allergic reactions may trigger an ACS so physicians should be aware of KS and always keep that unique clinical entity in mind to recognize it promptly and direct the therapy at suppressing the allergic reaction and improving the coronary circulation simultaneously when encountering a patient with symptoms suggesting an allergic reaction and a concomitant ACS.",
"affiliations": "Department of Emergency Medicine, School of Medicine, Duzce University, Duzce, Turkey.;Department of Emergency Medicine, School of Medicine, Duzce University, Duzce, Turkey.;Department of Emergency Medicine, School of Medicine, Duzce University, Duzce, Turkey.;Department of Emergency Medicine, School of Medicine, Duzce University, Duzce, Turkey.",
"authors": "Gunes|Harun|H|;Turan Sonmez|Feruza|F|;Saritas|Ayhan|A|;Koksal|Yasin|Y|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac",
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1735-1502",
"issue": "16(6)",
"journal": "Iranian journal of allergy, asthma, and immunology",
"keywords": "Acute coronary syndrome, Anaphylaxis, Diclofenac potassium, Kounis syndrome",
"medline_ta": "Iran J Allergy Asthma Immunol",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017023:Coronary Angiography; D004008:Diclofenac; D004452:Echocardiography; D004562:Electrocardiography; D006801:Humans; D000074962:Kounis Syndrome; D008297:Male",
"nlm_unique_id": "101146178",
"other_id": null,
"pages": "565-568",
"pmc": null,
"pmid": "29338163",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Kounis Syndrome Induced by Oral Intake of Diclofenac Potassium.",
"title_normalized": "kounis syndrome induced by oral intake of diclofenac potassium"
} | [
{
"companynumb": "TR-DEXPHARM-20180048",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC POTASSIUM"
},
"drugadditional": "3",
... |
{
"abstract": "A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.",
"affiliations": "Dr Ashok Sharma's Cornea Centre, Chandigarh, India.;Dr Ashok Sharma's Cornea Centre, Chandigarh, India.",
"authors": "Sharma|Ashok|A|;Sharma|Rajan|R|",
"chemical_list": "D004279:DNA, Viral",
"country": "India",
"delete": false,
"doi": "10.4103/ijo.IJO_1379_20",
"fulltext": "\n==== Front\nIndian J Ophthalmol\nIndian J Ophthalmol\nIJO\nIndian Journal of Ophthalmology\n0301-4738\n1998-3689\nWolters Kluwer - Medknow India\n\n33463607\nIJO-69-438\n10.4103/ijo.IJO_1379_20\nCase Reports\nPresumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty\nSharma Ashok\nSharma Rajan\nDr Ashok Sharma's Cornea Centre, Chandigarh, India\nCorrespondence to: Dr. Ashok Sharma, Dr Ashok Sharma's Cornea Centre, SCO 2463-2464, Second Floor, Sector 22C, Chandigarh - 160 022, India. E-mail: asharmapgius@yahoo.com\n2 2021\n18 1 2021\n69 2 438440\n07 5 2020\n19 6 2020\n28 6 2020\nCopyright: © 2021 Indian Journal of Ophthalmology\n2021\nThis 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.\nA 78-year-old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow-up.\n\nDescemet′s stripping automated endothelial keratoplasty\nendothelial keratoplasty\nherpes simplex virus\nHSV endotheliitis\nviral endotheliitis\n==== Body\nIn recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.\n\nCase Report\n\nAn immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.\n\nAn uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.\n\nFigure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble\n\nPatient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.\n\nFigure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)\n\nDiscussion\n\nPost DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.\n\nThe second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]\n\nCorneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]\n\nConclusion\n\nA high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.\n\nDeclaration of patient consent\n\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\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n==== Refs\n1 Price MO Gorovoy M Price FW Jr Benetz BA Menegay HJ Lass JH Descemet's stripping automated endothelial keratoplasty: Three-year graft and endothelial cell survival compared with penetrating keratoplasty Ophthalmology 2013 120 246 51 23107581\n2 Shin J Ra H Rho CR Herpes simplex virus linear endotheliitis in a post-keratoplasty patient: A case report Medicine (Baltimore) 2019 98 e14191 30653172\n3 Yin D Huang A Warrow D Ritterband DC Seedor JA McCormick SA Detection of herpes simplex virus type 1 in failed descemet stripping automated endothelial keratoplasty grafts Cornea 2013 32 1189 92 23860430\n4 Menon V Saxena R Mishra R Phuljhele S Management of optic neuritis Indian J Ophthalmol 2011 5 117 22\n5 Hill JC Watson P Corticosteroids in corneal graft rejection: Oral versus single pulse therapy Ophthalmology 1991 98 329 33 2023754\n6 Anshu A Chee SP Mehta JS Tan DT Cytomegalovirus endotheliitis in Descemet's stripping endothelial keratoplasty Ophthalmology 2009 116 624 30 19195708\n7 Kasetsuwan N Tangmonkongvoragul C Concomitant herpes simplex virus and cytomegalovirusendotheliitis in immunocompetent patient BMJ Case Rep 2013 2013 bcr2012007942\n8 Kobayashi A Yokogawa H Higashide T Nitta K Sugiyama K Clinical significance of owl eye morphologic features by in vivo laser confocal microscopy in patients with cytomegalovirus corneal endotheliitis Am J Ophthalmol 2012 153 445 53 22030352\n9 Suzuki T Hara Y Uno T Ohashi Y DNA of cytomegalovirus detected by PCR in aqueous of patient with corneal endotheliitis after penetrating keratoplasty Cornea 2007 26 370 2 17413969\n10 Basilious A Chew HF Topical ganciclovir for prophylaxis of cytomegalovirus endotheliitis in endothelial keratoplasty Cornea 2019 38 120 2 30379718\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0301-4738",
"issue": "69(2)",
"journal": "Indian journal of ophthalmology",
"keywords": "Descemet's stripping automated endothelial keratoplasty; HSV endotheliitis; endothelial keratoplasty; herpes simplex virus; viral endotheliitis",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D015715:Corneal Edema; D004279:DNA, Viral; D057111:Descemet Stripping Endothelial Keratoplasty; D004728:Endothelium, Corneal; D006084:Graft Rejection; D006801:Humans; D008297:Male; D018139:Simplexvirus",
"nlm_unique_id": "0405376",
"other_id": null,
"pages": "438-440",
"pmc": null,
"pmid": "33463607",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "30653172;23860430;23667217;30379718;23107581;22030352;19195708;17413969;21350281;2023754",
"title": "Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.",
"title_normalized": "presumed herpes simplex virus endotheliitis following ultra thin descemet s stripping automated endothelial keratoplasty"
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"abstract": "Here, we present a case of an immunocompetent 37-year old male who developed Aspergillus fumigatus osteomyelitis 16 years after extensive chest wall reconstructive surgery for Ewing sarcoma. His treatment course was complicated by a severe adverse drug reaction to voriconazole, requiring the use of oral posaconazole therapy. Serum 1,3-beta-D glucan assay was utilized to dictate the duration of posaconazole therapy. The patient successfully completed 9 months of oral posaconazole therapy and has not had clinical recurrence for 9 months off antifungal therapy.",
"affiliations": "Division of Infectious Diseases, University of Maryland School of Medicine, 725 west Lombard Street, Baltimore, MD, 21201, USA. Jdoub@ihv.umaryland.edu.;Division of Infectious Diseases, University of Maryland School of Medicine, 725 west Lombard Street, Baltimore, MD, 21201, USA.",
"authors": "Doub|James B|JB|;Mathur|Poonam|P|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; D047071:beta-Glucans; C101425:posaconazole",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-020-01489-2",
"fulltext": null,
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"issn_linking": "0300-8126",
"issue": "48(6)",
"journal": "Infection",
"keywords": "1,3-beta-D-glucan; Aspergillus fumigatus; Osteomyelitis; Posaconazole; Voriconazole adverse drug reaction",
"medline_ta": "Infection",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D015142:Baltimore; D006801:Humans; D008297:Male; D010019:Osteomyelitis; D016896:Treatment Outcome; D014230:Triazoles; D047071:beta-Glucans",
"nlm_unique_id": "0365307",
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"pages": "959-963",
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"pmid": "32720130",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Duration of posaconazole therapy for Aspergillus fumigatus osteomyelitis dictated by serial monitoring of 1,3-beta-D glucan.",
"title_normalized": "duration of posaconazole therapy for aspergillus fumigatus osteomyelitis dictated by serial monitoring of 1 3 beta d glucan"
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"abstract": "BACKGROUND\nCrohn's disease (CD) is associated with a variety of extra-intestinal manifestations. Most commonly these involve the eye, skin, joints, coagulation system and liver. Cerebral manifestations of CD have been reported to a far lesser extent. The extensive detrimental impact of neurological symptoms on a patient's quality of life makes an early diagnosis and treatment particularly important. In previous case-reports, diagnosis of cerebral manifestations in CD often relied upon magnetic resonance imaging (MRI) and computed tomography (CT) alone. To our knowledge, only one case-report has documented a histologically confirmed case of cerebral lesions associated with CD so far.\n\n\nMETHODS\nA 39-year-old right-handed woman with a history of CD was referred to our hospital with etiologically unexplained Gadolinium (Gd)-enhancing cortical lesions, triggering epileptic seizures. A CT-scan of the thorax and bronchoalveolar lavage found no signs of sarcoidosis. Lumbar punctures and laboratory testing found no underlying infection or coincidental autoimmune disorders and MRI-scans showed progression of lesion load. Consequently, the patient underwent stereotactic biopsy of a cortical lesion. Histological examination revealed a mixed lympho-histiocytic and tuberculoid granulomatous inflammation surrounding small vessels and no signs for infection. After exclusion of other granulomatous diseases and the typical histological findings we diagnosed a cerebral granulomatosis as a manifestation of CD. The patient was initially started on azathioprine, which had to be switched to corticosteroids and methotrexate because of an azathioprine related pancreatitis. The patient has not suffered any further epileptic seizures to date.\n\n\nCONCLUSIONS\nCerebral manifestation of CD is a possibly underreported entity that may respond well to immunosuppressive treatment. In contrast to earlier reports of cerebral manifestations in CD, our patient showed no coincident gastrointestinal symptoms indicating an activity of CD during the progression of cortical lesion load, suggesting that similar to other extra-intestinal manifestations in CD, the activity of gastrointestinal symptoms does not necessarily reflect the activity of CD associated cerebral vasculitis. Therefore, diagnosis and therapy of cerebral manifestation may be delayed when focusing on gastrointestinal symptoms alone.",
"affiliations": "Department of Neurology and Neuroscience, Medical Center, University of Freiburg, Breisacher Straße 64, D-79106, Freiburg, Germany. konrad.whittaker@uniklinik-freiburg.de.;Department of Neuroradiology, University of Freiburg, Breisacher Straße 64, D-79106, Freiburg, Germany.;Department of Rheumatology and Clinical Immunology, University of Freiburg, Breisacher Straße 64, D-79106, Freiburg, Germany.;Department of Neuropathology, University of Freiburg, Breisacher Straße 64, D-79106, Freiburg, Germany.;Department of Clinical Pathology, University of Freiburg, Breisacher Straße 64, D-79106, Freiburg, Germany.;Department of Neurology and Neuroscience, Medical Center, University of Freiburg, Breisacher Straße 64, D-79106, Freiburg, Germany.",
"authors": "Whittaker|Konrad|K|http://orcid.org/0000-0001-7218-0328;Guggenberger|Konstanze|K|;Venhoff|Nils|N|;Doostkam|Soroush|S|;Schaefer|Hans-Eckart|HE|;Fritsch|Brita|B|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D001379:Azathioprine; D008727:Methotrexate",
"country": "England",
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"doi": "10.1186/s12883-018-1163-8",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 116310.1186/s12883-018-1163-8Case ReportCerebral granulomatosis as a manifestation of Crohn’s disease http://orcid.org/0000-0001-7218-0328Whittaker Konrad +49-761-27050010konrad.whittaker@uniklinik-freiburg.de 1Guggenberger Konstanze konstanze.guggenberger@uniklinik-freiburg.de 2Venhoff Nils nils.venhoff@uniklinik-freiburg.de 3Doostkam Soroush soroush.doostkam@uniklinik-freiburg.de 4Schaefer Hans-Eckart hans-eckart.schaefer@uniklinik-freiburg.de 5Fritsch Brita brita.fritsch@uniklinik-freiburg.de 11 grid.5963.9Department of Neurology and Neuroscience, Medical Center, University of Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany 2 grid.5963.9Department of Neuroradiology, University of Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany 3 grid.5963.9Department of Rheumatology and Clinical Immunology, University of Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany 4 grid.5963.9Department of Neuropathology, University of Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany 5 grid.5963.9Department of Clinical Pathology, University of Freiburg, Breisacher Straße 64, D-79106 Freiburg, Germany 3 10 2018 3 10 2018 2018 18 16129 1 2018 24 9 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCrohn’s disease (CD) is associated with a variety of extra-intestinal manifestations. Most commonly these involve the eye, skin, joints, coagulation system and liver. Cerebral manifestations of CD have been reported to a far lesser extent. The extensive detrimental impact of neurological symptoms on a patient’s quality of life makes an early diagnosis and treatment particularly important. In previous case-reports, diagnosis of cerebral manifestations in CD often relied upon magnetic resonance imaging (MRI) and computed tomography (CT) alone. To our knowledge, only one case-report has documented a histologically confirmed case of cerebral lesions associated with CD so far.\n\nCase presentation\nA 39-year-old right-handed woman with a history of CD was referred to our hospital with etiologically unexplained Gadolinium (Gd)-enhancing cortical lesions, triggering epileptic seizures. A CT-scan of the thorax and bronchoalveolar lavage found no signs of sarcoidosis. Lumbar punctures and laboratory testing found no underlying infection or coincidental autoimmune disorders and MRI-scans showed progression of lesion load. Consequently, the patient underwent stereotactic biopsy of a cortical lesion. Histological examination revealed a mixed lympho-histiocytic and tuberculoid granulomatous inflammation surrounding small vessels and no signs for infection. After exclusion of other granulomatous diseases and the typical histological findings we diagnosed a cerebral granulomatosis as a manifestation of CD. The patient was initially started on azathioprine, which had to be switched to corticosteroids and methotrexate because of an azathioprine related pancreatitis. The patient has not suffered any further epileptic seizures to date.\n\nConclusion\nCerebral manifestation of CD is a possibly underreported entity that may respond well to immunosuppressive treatment. In contrast to earlier reports of cerebral manifestations in CD, our patient showed no coincident gastrointestinal symptoms indicating an activity of CD during the progression of cortical lesion load, suggesting that similar to other extra-intestinal manifestations in CD, the activity of gastrointestinal symptoms does not necessarily reflect the activity of CD associated cerebral vasculitis. Therefore, diagnosis and therapy of cerebral manifestation may be delayed when focusing on gastrointestinal symptoms alone.\n\nKeywords\nCrohn’s diseaseCerebral vasculitisEpilepsyCentral nervous systemBiopsyGranulomatosishttp://dx.doi.org/10.13039/501100002714Albert-Ludwigs-Universität Freiburgissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCrohn’s disease (CD) is an autoimmune disorder that primarily affects the gastrointestinal tract, but manifests itself in other organs as well [1]. The most common sites of extra-intestinal manifestation are joints, skin, eyes, coagulation system and liver. Cerebral manifestations of CD have been reported to a far lesser extent, contrasting the relatively high number of these reports in the context of other inflammatory bowel diseases [2–4]. Most commonly, cerebral manifestations in CD are a consequence of an affection of the coagulation system or a complication of medication [1, 5]. The extensive detrimental impact of neurological manifestations on a patient’s quality of life makes early diagnosis and treatment particularly important. In previous case-reports, diagnosis of cerebral manifestation in CD often relied upon MRI and CT alone [6–10]. To our knowledge, only one case-report has documented a histologically confirmed case of a cerebral manifestation in CD [11].\n\nCase presentation\nThis 39-year-old right-handed female suffered from epileptic seizures that began to develop in early 2014. The epileptic seizures were initiated by dyscognitive seizures and secondarily evolved into tonic-clonic seizures. The patient was started on anticonvulsive medication in August 2014 (Lamotrigin and Levetiracetam). Under this regimen, which was adapted regularly, the frequency of seizures stabilized at about one seizure every six months.\n\nSome weeks prior to the first epileptic seizure, the patient had complained of novel subacute bifrontal headaches, which persisted intermittently over the course of the following months and were not directly correlated with the occurrence of epileptic seizures. Additionally, she reported a subjectively progressive impairment of her short-term memory. Her husband reported a temporary change in his wife’s personality during May 2015, which was accompanied by promiscuous behavior in social media and had not recurred since then.\n\nGastrointestinal symptoms (diarrhea, weight loss) had occurred for the first time in 2003. The diagnosis of CD was confirmed histologically via ileocolonoscopy in 2006. Symptoms were treated with a combination of steroids and mesalazine (5-ASA) from 2006 to 2008 and with methotrexate (15 mg once per week) from 2008 to 2016. The patient reported lack of gastrointestinal symptoms since 2013. Apart from nicotine abuse (25 pack-years) she reported no further comorbidities and did not suffer from any allergies. There was no family history of headaches, epilepsy, cancer and no exposure to toxic chemicals at home or at her workplace. There were no signs for lymphomatoid granulomatosis (no pulmonary and cutaneous lesions) or leukocyte oxidase deficiency (no recurrent infections). The patient did not travel outside of Europe in her entire life.\n\nManagement and outcome\nThe first isolated dyscognitive seizure was interpreted as a transient ischemic attack (aphasia) in early 2014 and the patient was started on aspirin 100 mg daily after a cerebral hemorrhage was ruled out via computed tomography. In August 2014 the first secondarily generalized seizure led to the initiation of a standard MRI of the head, showing supratentorial Gd-enhancing cortical lesions that were deemed ischemic or inflammatory in nature. A lumbar puncture revealed an inflammatory constellation (14 cells/μl, negative oligoclonal bands). Bronchoalveolar lavage (including CD4/CD8-ratio) and a CT of the lungs were performed to test for (neuro-)sarcoidosis and provided normal results with no signs of perihilar lymphadenopathy. Furthermore, laboratory tests showed normal results for IL-2 receptor, ACE, neopterin, calcium, as well as for anti-neutrophil cytoplasmic antibodies (ANCA), anti-nuclear antibody (ANA) and anti-phospholipid-antibodies. An Interferon-gamma release assay test (QuantiFERON®) remained negative. A second MRI after two months (October 2014) showed further progression of the cortical lesions. Subsequently, the immunosuppressive therapy with methotrexate was complemented with steroids (initially 80 mg prednisolone, gradual reduction to 5 mg daily). A subsequent MRI in February 2015 showed a stable lesion load. Epileptic seizures in March, June and December 2015 as well as in March 2016 did not lead to adjustments of anticonvulsant or immunosuppressive therapy or to additional diagnostic measures.\n\nIn April 2016 the patient was referred to our university center for epilepsy. Here, the dosage of the anticonvulsive medication was increased and another MRI was initiated (August 2016), which showed an increase of lesions with numerous bihemispheric, hemorrhagically imbibed lesions of the cortex, basal ganglia, midbrain and pons. Gadolinium-enhancing lesions were revealed in both corpora amygdaloidea and cortically in both inferior frontal gyri, the left frontal medial gyrus, the left postcentral gyrus as well as in temporo-occipital and occipital regions in both hemispheres. Additionally, the MRI showed bilateral hippocampal atrophy and hyperintensity (Fig. 1). A comparative assessment between the MRI-scans was made difficult by their qualitative differences. A clear progression of lesion load could therefore only be established in comparison to the MRI-scans from 2014. Another lumbar puncture confirmed the previous pleocytosis (8 cells/μl, protein 508 mg/l) and now revealed positive oligoclonal bands in the cerebrospinal fluid (CSF). Antineural (Hu, Yo, Ri, CV2/CRMP5, amphiphysin, Ma1, Ma2, SOX1, GAD65, Tr(DNER), Zic4) and autoimmune encephalitis antibodies (VGKC (LGI1, CASPR2), GABA B, NMDA, AMPA1, AMPA2) remained negative in CSF and serum in two independent laboratories. Serum analysis of ANA, ANCA, phospholipid antibodies and rheumatoid factor remained negative as well. Complement factors were at normal levels. A neuropsychological test revealed depressive symptoms and potentially related impairments in attention, executive functions and long-term memory.Fig. 1 MRI-imaging reveals progressive atrophy of the temporal structures (a, b) and a new signal increase of the corpora amygdaloidea and hippocampi in FLAIR weighted sequences (c) over the course of time. Several spots of cortical hyperintensities are present in FLAIR weighted imaging (d). A faint contrast enhancement can be detected in the bihemsipheric cortex (e) and the corpora amygdaloidea (c). Mesencephalic and cortical hemorrhage (f) suggest an inflammatory process with microvascular vasculitis or an infectious or granulomatous genesis as possible differential diagnoses\n\n\n\nIn September 2016 the patient was referred to our department of neurology via our colleagues at the university center for epilepsy in order to assess cerebral vasculitis. We performed another lumbar puncture (3 cells/μl, protein 584 mg/l) including antibody-tests for borrelia burgdorferi and treponema pallidum, polymerase chain reaction (PCR) tests for Herpes simplex viruses 1 and 2, Varicella-zoster virus, tropheryma whipplei and a HIV-test, which remained negative. An ultrasonography of the extra- and intracranial arteries of the neck and brain showed no signs of a vasculitis of the large vessels. The biomarkers for sarcoidosis (IL2-receptor, ACE, beta-2-microglobulin, lysozyme, neopterin) remained negative, as did proteinase3 antineutrophil cytoplasmic antibodies (PR3-ANCA), perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) and blood cultures. There were no abnormalities in the differential blood count and in the immunoglobulins. A fluorescein angiography of the retina was performed in the department of Neuro-ophthalmology to test for a small-vessel vasculitis and Susac’s syndrome and revealed normal results.\n\nAfter completion of above-mentioned diagnostics, an interdisciplinary consent was reached to perform a stereotactic biopsy of one of the cortical lesions. Histology revealed leptomeningeal mixed mononuclear round cell infiltrates and multifocal mixed lympho-histiocytic and tuberculoid granulomatous lesions surrounding small vessels confirming the diagnosis of a cerebral granulomatosis (Fig. 2a-h). Histological, enzyme- and immunohistochemical examination showed no signs of infection with toxoplasmosis, mycobacteria or other bacteria or fungi as well as no signs for Amyloid-Beta Related Angiitis of the Central Nervous System (ABRA). There were no caseating and no geographical necroses.Fig. 2 a, b Early granuloma formation, surrounding small blood vessels marked by asterics (*). a Immunohistochemical staining for CD3+ T-lymphocytes (brown staining). Serial sections (not depicted here) disclose an identical distribution of predominating CD4+ T-helper cells. b Serial section of the same vessel as shown in (a) at a higher magnification with CD68+ macrophages gathering at subintimal and adventitial spaces. c, d Full-blown granulomas. c Haematoxylin-Eosin staining displays a dense plasmocytic infiltrate at the left upper corner. The right lower corner encompasses a tuberculoid granuloma dominated by epithelioid cells and multinucleated Langhans-type giant cells. d A large granulomatous complex is embedded into sharply confined neuropil, highlighted by immunohistochemical staining for glial fibrillary acidic protein (brown colour). e-h Miscellaneous aspects of granuloma histiocytes. e Enzyme-histochemical staining for tartrate-resistant acid phosphatase (red colour) discloses a high activity of this particular isoenzyme of acid phosphatase, typically upregulated in mature macrophages involved in chronic lysosomal lipid degradation. f Periodic acid Schiff staining (PAS, red colour). A centrally placed foam cell contains translucent lipid vacuoles and few PAS+ ceroid-like granules. Additional smaller-sized macrophages are storing ceroid-like granules exclusively, whithout visible lipid vauoles. At the periphery of the graph, there are several gemistocytic astrocytes with large swollen PAS-negative cytoplasm. g Clustering PAS+ ceroid-storing macrophages fuse to multinucleated giant cells, partially of Touton-type (Tt). h On Giemsa-staining, some giant macrophages adopt a phenotype of sea-blue histiocytes\n\n\n\nOn the basis of the histological analysis and negative tests for infectious causes we diagnosed a cerebral granulomatosis as a manifestation of Crohn’s disease in the central nervous system and began immunosuppressive treatment with azathioprine, which had to be switched to methotrexate and corticosteroids because of an azathioprine related pancreatitis. To date, the patient has not suffered any further epileptic seizures and revealed no signs of cognitive deterioration in the outpatient follow-ups.\n\nDiscussion and conclusions\nCerebral manifestation of CD is a possibly underreported entity [5, 12, 13], which may respond well to immunosuppressive treatment [11]. In contrast to earlier reports of similar cases, our patient showed no clinical signs of an activity of CD during the progression of cortical lesion load. Similarly to other extra-intestinal manifestations in CD [14], the activity of gastrointestinal symptoms does not seem to be a reliable parameter in assessing the activity of cerebral granulomatosis. Therefore, diagnosis and therapy in CD may be delayed when the diagnostic focus lies on gastrointestinal symptoms alone. In our patient, time between symptom onset and diagnosis was two and a half years. To reduce progress of morbidity, an early stereotactic biopsy may be indicated in cases, in which MRI-scans are not sufficient for confidently assessing the etiology of progressive cerebral lesions.\n\nAbbreviations\n5-ASAMesalazine\n\nABRAAmyloid-Beta Related Angiitis of the Central Nervous System\n\nACEAngiotensin-converting enzyme\n\nANAAnti-nuclear antibody\n\nANCAAnti-neutrophil cytoplasmic antibody\n\nCDCrohn’s disease\n\nCSFCerebrospinal fluid\n\nCTComputed tomography\n\nCTComputed tomography\n\nGdGadolinium\n\nHIVHuman immunodeficiency virus\n\nMRIMagnetic resonance imaging\n\np-ANCAPerinuclear Anti-Neutrophil Cytoplasmic Antibodies\n\nPCRPolymerase chain reaction\n\nPR3-ANCA Proteinase-3 antineutrophil cytoplasmic antibodies\n\nAcknowledgements\nThe authors would like to thank their patient for participation in this study and Dr. Schneider for supplying to us the original colon biopsy.\n\nFunding\nThe article processing charge was funded by the German Research Foundation (DFG) and the University of Freiburg in the funding programme Open Access Publishing.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nAuthors’ contributions\nAll authors have read and approved the manuscript and contributed significantly to the submitted work: KW, NV and BF treated the case-patient at the Freiburg center and drafted the manuscript, KG analyzed the MRI and SD and HS analyzed the histological samples.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nBibliography\n1. Casella G Tontini GE Bassotti G Pastorelli L Villanacci V Spina L Neurological disorders and inflammatory bowel diseases World J Gastroenterol 2014 20 27 8764 8782 25083051 \n2. Unnikrishnan A Azodi S Ansari N Brown M Kamnetz J Uchiyama RC PR3ANCA related cerebral Vasculitis in ulcerative colitis presenting with orbital involvement: a case report with review of literature Case Rep Rheumatol 2014 2014 582094 25097791 \n3. Bonrath EM Rijcken E Dziewas R Vieth V Bettenworth D Senninger N Brüwer M Cerebral Vasculitis as rare Extraintestinal manifestation in ulcerative colitis: Review of the Literature and Case Report Zentralbl Chir 2010 135 4 350 353 10.1055/s-0030-1247464 20806139 \n4. Scheid R Teich N Neurologic manifestations of ulcerative colitis Eur J Neurol 2007 14 5 483 493 10.1111/j.1468-1331.2007.01718.x 17437605 \n5. Katsanos AH Kosmidou M Giannopoulos S Katsanos KH Tsivgoulis G Kyritsis AP Cerebral arterial infarction in inflammatory bowel diseases Eur J Intern Med European Federation of Internal Medicine 2014 25 1 37 44 10.1016/j.ejim.2013.08.702 \n6. Ullrich S Schinke S Both M Knop KC Kirkiles-Smith NC Gross WL Refractory central nervous system Vasculitis and gastrocnemius myalgia syndrome in Crohn’s disease successfully treated with anti-tumor necrosis factor-α antibody Semin Arthritis Rheum Elsevier Inc 2009 38 5 337 347 10.1016/j.semarthrit.2008.01.008 \n7. Schluter A Krasnianski M Krivokuca M Spielmann RP Neudecker S Hirsch W Magnetic resonance angiography in a patient with Crohn’s disease associated cerebral vasculitis Clin Neurol Neurosurg 2004 106 2 110 113 10.1016/j.clineuro.2003.09.004 15003300 \n8. Holzer K Esposito L Stimmer H Hemmer B Poppert H Cerebral vasculitis mimicking migraine with aura in a patient with Crohn's disease Acta Neurol Belg 2009 109 1 44 48 19402574 \n9. Brohee P Violon P Mavroudakis N Pirotte B Brotchi J Zegers de Beyl D Central nervous system lesions associated with Crohn’s disease J Neuroimaging 1997 7 3 195 198 10.1111/jon199773195 9237443 \n10. Garge SS Vyas PD Modi PD Ghatge S Crohns disease with central nervous system vasculitis causing subarachnoid hemorrhage due to aneurysm and cerebral ischemic stroke Ann Indian Acad Neurol 2014 17 4 444 447 10.4103/0972-2327.144035 25506170 \n11. Gekka M Sugiyama T Nomura M Kato Y Nishihara H Asaoka K Histologically confirmed case of cerebral vasculitis associated with Crohn’s disease -a case report BMC Neurol 2015 15 169 10.1186/s12883-015-0429-7 26390922 \n12. Zikou AK Kosmidou M Astrakas LG Tzarouchi LC Tsianos E Argyropoulou MI Brain involvement in patients with inflammatory bowel disease: a voxel-based morphometry and diffusion tensor imaging study Eur Radiol 2014 24 10 2499 2506 10.1007/s00330-014-3242-6 25001084 \n13. Lossos A River Y Eliakim A Steiner I Neurologic aspects of inflammatory bowel disease Neurology 1995 45 3 Pt 1 416 421 10.1212/WNL.45.3.416 7898687 \n14. Levine J Burakoff R Extraintestinal manifestations of inflammatory bowel disease Gastroenterol Hepatol 2011 7 4 235 241\n\n",
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"keywords": "Biopsy; Central nervous system; Cerebral vasculitis; Crohn’s disease; Epilepsy; Granulomatosis",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D001379:Azathioprine; D001927:Brain Diseases; D003424:Crohn Disease; D018450:Disease Progression; D005260:Female; D006099:Granuloma; D006801:Humans; D007166:Immunosuppressive Agents; D008727:Methotrexate; D020293:Vasculitis, Central Nervous System",
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"title": "Cerebral granulomatosis as a manifestation of Crohn's disease.",
"title_normalized": "cerebral granulomatosis as a manifestation of crohn s disease"
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"abstract": "We evaluated risk factors of radiation pneumonitis (RP) after whole breast irradiation following breast-conserving surgery. Four hundred and seventy-two cases underwent whole breast irradiation with tangential field following breast-conserving surgery in our hospital, between January 2005 and April 2007. Of these cases, we performed statistical analyses for 423 breasts of 413 patients, using a pulmonary dose-volume histogram. Patient characteristics, treatment regimens and irradiation methods were included as variables in the analyses on risk factors of RP. As a result, 89 breasts of 84 cases (21%) were diagnosed with RP. The version 3.0 of the NCI Common Terminology Criteria for Adverse Events was used to evaluate the grade of pneumonitis: 77 cases (18.2%) were diagnosed as Grade 1 RP, 10 cases (2.3%) as Grade 2, and 2 cases (0.5%) as Grade 3. Multivariate analysis indicated that the significant risk factors for RP were central lung distance (CLD) (>1.8 cm) and the short axis length of the radiation field. The incidence of radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome significantly correlated only with CLD. The lung volume within the radiation field was shown to be a significant risk factor for RP and radiation-induced BOOP syndrome.",
"affiliations": "Department of Radiology, the University of Tokushima Graduate School, Tokushima, Japan.",
"authors": "Kubo|Akiko|A|;Osaki|Kyosuke|K|;Kawanaka|Takashi|T|;Furutani|Shunsuke|S|;Ikushima|Hitoshi|H|;Nishitani|Hiromu|H|",
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk factors for radiation pneumonitis caused by whole breast irradiation following breast-conserving surgery.",
"title_normalized": "risk factors for radiation pneumonitis caused by whole breast irradiation following breast conserving surgery"
} | [
{
"companynumb": "JP-MYLANLABS-2020M1089129",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": "3",
... |
{
"abstract": "Abuse of psychogenic substances sold as \"bath salts\" and \"plant food\" has escalated in recent years in the United States (USA). Previous reports suggest regional differences in the primary active β-keto phenylalkylamines found in these products and the corresponding signs and symptoms reported after exposure. Currently, there are only limited studies describing the clinical effects associated with reported \"bath salts\" exposure in the USA. This study describes the clinical effects associated with \"bath salt\" and \"plant food\" exposures as reported to the poison center serving the state of North Carolina (Carolinas Poison Center). We performed a retrospective review of the Carolinas Poison Center database for all cases of reported human exposure to \"bath salt\" and \"plant food\" products from 2010 to 2011 with specific attention to clinical effects and routes of exposure. Additionally, we reviewed therapies used, trended the volume of exposure cases reported over the study period, and evaluated the distribution of calls within state counties using descriptive statistics. Carolinas Poison Center received 485 total calls and 409 reported exposure calls regarding \"bath salt\" or \"plant food\" products between January of 2010 and December of 2011. The peak of reported exposures occurred in May of 2011. Clinical effects commonly reported in the exposure cases generated from these calls included tachycardia (53.3 %, n = 218), agitated/irritable (50.4 %, n = 206), hallucination/delusions (26.7 %, n = 109), and hypertension (25.2 %, n = 103). In addition to intravenous fluids, common therapies included benzodiazepines (46.0 %, n = 188), sedation (13.4 %, n = 55), alkalinization (3.90 %, n = 16), antihistamine (4.16 %, n = 17), and intubation (3.67 %, n = 15). Haloperidol was the antipsychotic agent used most often to treat agitation (n = 40). Serious complications associated with reported exposure to \"bath salt\" and \"plant food\" products included rhabdomyolysis, renal failure, excited delirium syndrome, and death. While treatments have not been empirically determined, sedation with benzodiazepines, aggressive cooling for hyperthermic patients, and use of small doses of antipsychotics for choreoathetoid movements not controlled with benzodiazepines are not likely to be harmful.",
"affiliations": "Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC 28232, USA. christine.murphy66@gmail.com",
"authors": "Murphy|Christine M|CM|;Dulaney|Anna R|AR|;Beuhler|Michael C|MC|;Kacinko|Sherri|S|",
"chemical_list": "D052117:Benzodioxoles; D015198:Designer Drugs; D013287:Illicit Drugs; D010627:Phenethylamines; D028321:Plant Preparations; D011619:Psychotropic Drugs; D011759:Pyrrolidines; D008694:Methamphetamine; C548233:mephedrone; C554666:3,4-methylenedioxypyrovalerone; C400939:methylone",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-012-0243-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "9(1)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000328:Adult; D001494:Baths; D052117:Benzodioxoles; D016208:Databases, Factual; D015198:Designer Drugs; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D008694:Methamphetamine; D008875:Middle Aged; D009657:North Carolina; D010627:Phenethylamines; D028321:Plant Preparations; D011039:Poison Control Centers; D011619:Psychotropic Drugs; D011759:Pyrrolidines; D012189:Retrospective Studies; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D055815:Young Adult",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "42-8",
"pmc": null,
"pmid": "22733603",
"pubdate": "2013-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21691475;20581379;22271565;21824061;20675396;21477955;21171849",
"title": "\"Bath salts\" and \"plant food\" products: the experience of one regional US poison center.",
"title_normalized": "bath salts and plant food products the experience of one regional us poison center"
} | [
{
"companynumb": "US-TEVA-2021-US-1950022",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "OBJECTIVE\nA case of warfarin-induced skin necrosis (WISN) treated with protein C concentrate (human) is reported.\n\n\nCONCLUSIONS\nA 46-year-old Caucasian woman was admitted to the hospital for a herpes viral infection complicated by neutropenic fevers of unknown origin. Broad-spectrum antibiotics were initiated, as well as enoxaparin for prophylaxis of deep venous thrombosis. By hospital day 7, the patient's platelets decreased by 50%; by hospital day 8, they decreased another 50%. A test for heparin antibody was positive, and enoxaparin was stopped. Two days later, the patient developed a clot in her peripherally inserted central catheter, and warfarin and argatroban were initiated. Within 24 hours of warfarin initiation, the patient developed swelling in her feet and new lesions on her inner thigh, buttock, face, feet, fingers, and arms. She was treated with phytonadi-one and fresh frozen plasma, but these treatments failed to slow the progression of her lesions, which had turned to necrotic tissue. WISN was suspected, and warfarin therapy was discontinued after three doses. After a consultation with a hematologist, treatment with protein C concentrate (human) was initiated. Within 24 hours of treatment with this product, progression of necrosis stopped, and the patient's respiratory failure resolved. The patient underwent multiple skin grafts, and the lesions healed without extensive scarring. She experienced no adverse effects with the administration of protein C concentrate (human).\n\n\nCONCLUSIONS\nA patient with WISN was treated with protein C concentrate (human) with overall good results and no adverse effects.",
"affiliations": "LDS Hospital, Intermountain Healthcare, Salt Lake City, UT 84103, USA. alisa.stewart@imail.org <alisa.stewart@imail.org>",
"authors": "Stewart|Alisa|A|",
"chemical_list": "D000925:Anticoagulants; D011486:Protein C; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp090240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "67(11)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000925:Anticoagulants; D005260:Female; D006801:Humans; D008875:Middle Aged; D009336:Necrosis; D011486:Protein C; D012131:Respiratory Insufficiency; D012867:Skin; D012871:Skin Diseases; D016038:Skin Transplantation; D014859:Warfarin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "901-4",
"pmc": null,
"pmid": "20484212",
"pubdate": "2010-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Warfarin-induced skin necrosis treated with protein C concentrate (human).",
"title_normalized": "warfarin induced skin necrosis treated with protein c concentrate human"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-004905",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadd... |
{
"abstract": "More than 30 % of adults with epilepsy do not fully control on the currently available antiepileptic drugs (AEDs). For these and many other patients, combinations of agents, often possessing different mechanisms of actions, are employed with the aim of achieving seizure freedom or the best available prognosis in terms of reduced seizure numbers and severity. This review discusses my own approach to optimising outcomes in as many of these patients as possible by adjusting the drug burden using a combination of two, three or sometimes four or more AEDs. Modes of drug action are reviewed and practical strategies for treating different patients with drug-resistant epilepsy have been explored. Only for sodium valproate with lamotrigine is there good evidence of synergism. The final part of this practical paper consists of six individual illustrative cases with appropriate comments.",
"affiliations": "Epilepsy Unit, West Glasgow ACH-Yorkhill, Dalnair Street, Glasgow, G3 8SJ, Scotland, UK. Martin.Brodie@glasgow.ac.uk.",
"authors": "Brodie|Martin J|MJ|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1007/s11910-016-0678-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1528-4042",
"issue": "16(9)",
"journal": "Current neurology and neuroscience reports",
"keywords": "Antiepileptic drugs; Mechanisms of action; Psychiatric comorbidities; Quality of life; Rational polytherapy; Seizure freedom",
"medline_ta": "Curr Neurol Neurosci Rep",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D004347:Drug Interactions; D004361:Drug Tolerance; D004827:Epilepsy; D006801:Humans; D011788:Quality of Life; D012640:Seizures",
"nlm_unique_id": "100931790",
"other_id": null,
"pages": "82",
"pmc": null,
"pmid": "27443649",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "23911352;9577998;25064538;17940193;23016553;22393904;24828683;24911669;12849118;21982026;21899452;21306922;22220513;9184603;26471380;15876543;21434875;21090839;25917225;22282529;9127723;16618346;25242737;21665551;15662042;22170887;26507832;27255267;17628429;22882018;26352816;26749012;26432008;23205961;19702736;10448829;10660394;23750855;21686307;22551726;23021287;17040113;26296511;9449883;21075011;19914135;23591263;24361766;19889013;21426333;26920914;25851171;19949567;21763207;22573629;14694031;22417003;22136077;19364928;23106423",
"title": "Pharmacological Treatment of Drug-Resistant Epilepsy in Adults: a Practical Guide.",
"title_normalized": "pharmacological treatment of drug resistant epilepsy in adults a practical guide"
} | [
{
"companynumb": "GB-DRREDDYS-USA/UKI/16/0084162",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null... |
{
"abstract": "Varicella zoster virus (VZV) typically causes a benign disease in childhood. However, VZV can lead to severe complication in immunocompromised patients, involving skin and nearly every organ system, with significant morbidity and mortality. VZV infection occurs more frequently in patients treated with steroids. Herein, we describe a case of rapidly fatal disseminated VZV infection with cutaneous and visceral involvement in an adult AIDS patient treated with steroids.",
"affiliations": "Second Infectious Diseases Division, INMI \"L. Spallanzani\", 00149 Rome, Italy. Electronic address: elisabetta.grilli@inmi.it.;Department of Pathology, INMI \"L. Spallanzani\", 00149 Rome, Italy. Electronic address: andrea.baiocchini@inmi.it.;Department of Pathology, INMI \"L. Spallanzani\", 00149 Rome, Italy. Electronic address: franca.delnonno@inmi.it.;Second Infectious Diseases Division, INMI \"L. Spallanzani\", 00149 Rome, Italy. Electronic address: nicola.petrosillo@inmi.it.;Second Infectious Diseases Division, INMI \"L. Spallanzani\", 00149 Rome, Italy. Electronic address: vincenzo.galati@inmi.it.",
"authors": "Grilli|E|E|;Baiocchini|A|A|;Del Nonno|F|F|;Petrosillo|N|N|;Galati|V|V|",
"chemical_list": "D013256:Steroids",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6532",
"issue": "60(1)",
"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Fulminant disease; HIV; Steroid; VZV; Visceral involvement",
"medline_ta": "J Clin Virol",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D017809:Fatal Outcome; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D012867:Skin; D013256:Steroids; D014781:Viscera",
"nlm_unique_id": "9815671",
"other_id": null,
"pages": "63-6",
"pmc": null,
"pmid": "24631117",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fulminant VZV infection in an adult AIDS patient treated with steroids: a case report.",
"title_normalized": "fulminant vzv infection in an adult aids patient treated with steroids a case report"
} | [
{
"companynumb": "PHHY2014IT139563",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAdult patients with refractory/relapsed ALL have poor survival outcomes with current chemotherapies. We aimed to determine safety and efficacy of lenalidomide, an oral immunomodulator, in these patients.\n\n\nMETHODS\nThis phase 1/2 trial (EUDRACT # 2009-009372-13) included 10 patients who received 28-day cycles of oral lenalidomide 25 mg/day, days 1 through 21, in combination with oral dexamethasone 40 mg/day on days 1, 8, 15, 22. Primary endpoints were tolerance and the overall response rate (ORR). Secondary endpoints included overall survival (OS) and quality of life.\n\n\nRESULTS\nThe most common grade 3 or 4 adverse events were myelosuppression. The ORR among the participants who could be evaluated was 28.6% (95% confidence interval [CI], 0-62.2%). The median OS was 92 days (range, 43-133 days). All patients have died because of progressive disease. Quality of life remains stable during treatment cycles.\n\n\nCONCLUSIONS\nThe safety of combination therapy consisting of lenalidomide plus dexamethasone is consistent with ambulatory administration. Efficacy should be reevaluated in a larger series including patients less intensively previously treated.",
"affiliations": "a Hematology Unit , Institut de Cancérologie de la Loire , Saint Priest en Jarez , France.;a Hematology Unit , Institut de Cancérologie de la Loire , Saint Priest en Jarez , France.;b Hematology Unit , CHU Estaing , Clermont-Ferrand , France.;c Hematology Unit , CHU , Grenoble , France.;d Public Health department , Institut de Cancérologie de la Loire , Saint Priest en Jarez , France.;d Public Health department , Institut de Cancérologie de la Loire , Saint Priest en Jarez , France.;a Hematology Unit , Institut de Cancérologie de la Loire , Saint Priest en Jarez , France.;e Hematology Unit , CHU Hospices Civils de Lyon , Lyon , France.",
"authors": "Tavernier-Tardy|E|E|;Cornillon|J|J|;Molucon-Chabrot|C|C|;Cahn|J Y|JY|;Tinquaut|F|F|;Bourmaud|A|A|;Guyotat|D|D|;Thomas|X|X|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1080/10245332.2016.1255372",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-5332",
"issue": "22(4)",
"journal": "Hematology (Amsterdam, Netherlands)",
"keywords": "Acute lymphoblastic leukemia; lenalidomide; prognosis; refractory; relapse",
"medline_ta": "Hematology",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011788:Quality of Life; D016019:Survival Analysis; D013792:Thalidomide",
"nlm_unique_id": "9708388",
"other_id": null,
"pages": "217-223",
"pmc": null,
"pmid": "27848278",
"pubdate": "2017-05",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A phase 1/2 trial of lenalidomide and dexamethasone in adult patients with refractory/relapsed acute lymphoblastic leukemia.",
"title_normalized": "a phase 1 2 trial of lenalidomide and dexamethasone in adult patients with refractory relapsed acute lymphoblastic leukemia"
} | [
{
"companynumb": "FR-CELGENEUS-FRA-2014123019",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Chimeric antigen receptor T cells (CAR-T) are genetically modified T cells with a chimeric antigen receptor directed against a specific tumor-associated antigen like CD19 in lymphoma. CAR-T cells have shown encouraging activity against recurrent and refractory diffuse large B cell lymphomas (DLBCL). However concurrent use of immunosuppressive agents was prohibited in most CAR-T trials effectively excluding patients with prior solid organ transplantation (SOT) and posttransplant lymphoproliferative disorders (PTLD). We report the outcomes for three patients with PTLD refractory to immunochemotherapy 10-20 years after SOT who received CAR-T therapy between January 2018 and December 2019. One patient had an orthotopic heart transplant, the second had a deceased donor kidney transplant, and the third had a pancreas after kidney transplant (PAK). All patients developed complications of CAR-T therapy such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and acute kidney injury requiring renal replacement therapy in the two out of three patients. All patients expired after withdrawal of care due to lack of response to CAR-T therapy. In addition, the PAK patient developed acute pancreatitis after CAR-T therapy. This case series identifies the challenges of using CAR-T therapy to manage refractory PTLD in SOT recipients and its possible complications.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.;Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.",
"authors": "Krishnamoorthy|Sambhavi|S|0000-0002-4701-785X;Ghobadi|Armin|A|;Santos|Rowena D|RD|;Schilling|Joel D|JD|;Malone|Andrew F|AF|;Murad|Haris|H|;Bartlett|Nancy L|NL|;Alhamad|Tarek|T|0000-0003-4289-0817",
"chemical_list": "D000076962:Receptors, Chimeric Antigen",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.16367",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "21(2)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "bone marrow / hematopoietic stem cell transplantation; clinical decision-making; clinical research / practice; complication: malignant; hematology / oncology; kidney failure / injury; organ transplantation in general; posttransplant lymphoproliferative disorder (PTLD)",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000208:Acute Disease; D006801:Humans; D008232:Lymphoproliferative Disorders; D016377:Organ Transplantation; D010195:Pancreatitis; D000076962:Receptors, Chimeric Antigen",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "809-814",
"pmc": null,
"pmid": "33089906",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "CAR-T therapy in solid organ transplant recipients with treatment refractory posttransplant lymphoproliferative disorder.",
"title_normalized": "car t therapy in solid organ transplant recipients with treatment refractory posttransplant lymphoproliferative disorder"
} | [
{
"companynumb": "US-GILEAD-2021-0520449",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"drugadditional": null,
... |
{
"abstract": "Many patients with Lewy body dementia develop visual hallucinations and other psychiatric symptoms. These patients are hypersensitive to antipsychotic drugs. Although patients tolerate atypical better than typical antipsychotics, both types can cause major extrapyramidal side effects. The anticonvulsant mood stabilizer topiramate, which does not cause parkinsonism, has been used as adjuvant therapy for both the positive and negative symptoms of schizophrenia; these symptoms can resemble those of Lewy body dementia. This report documents a 65-year-old woman with a 3-year history of progressive dementia that over the past 2 years had become complicated by severe extrapyramidal symptoms and agitated hallucinations. Her hallucinations became daily and were disrupting to her family. She was given a clinical diagnosis of Lewy body dementia after imaging and laboratory studies ruled out other etiologies. Treatment with olanzapine relieved her psychotic symptoms but caused severe dystonias, daily myoclonic jerks, and tremors. Stopping the olanzapine and starting topiramate 25 mg daily eliminated the hallucinations and agitation without worsening her extrapyramidal side effects. However, the topiramate was stopped because the patient reportedly developed anorexia and significant weight loss. Her hallucinations returned. When topiramate was reinstated at 12.5 mg a day, her agitation resolved, although her hallucinations continued. After 6 months on this dose, her agitation was still fairly well controlled without serious side effects or worsening of her parkinsonian symptoms.",
"affiliations": "Department of Neurology, University of South Alabama, Mobile, Alabama.",
"authors": "Ochoa|Juan G|JG|",
"chemical_list": "D000927:Anticonvulsants; D014150:Antipsychotic Agents; D018696:Neuroprotective Agents; D000077236:Topiramate; D001569:Benzodiazepines; D005632:Fructose; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNN.0000000000000039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1543-3633",
"issue": "27(4)",
"journal": "Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology",
"keywords": null,
"medline_ta": "Cogn Behav Neurol",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D014150:Antipsychotic Agents; D001480:Basal Ganglia Diseases; D001569:Benzodiazepines; D005260:Female; D005632:Fructose; D006212:Hallucinations; D006801:Humans; D020961:Lewy Body Disease; D018696:Neuroprotective Agents; D000077152:Olanzapine; D011595:Psychomotor Agitation; D012559:Schizophrenia; D000077236:Topiramate; D016896:Treatment Outcome",
"nlm_unique_id": "101167278",
"other_id": null,
"pages": "222-3",
"pmc": null,
"pmid": "25539042",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Topiramate improves psychiatric symptoms in a patient with Lewy body dementia.",
"title_normalized": "topiramate improves psychiatric symptoms in a patient with lewy body dementia"
} | [
{
"companynumb": "US-ACTAVIS-2015-08350",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTracheal rupture is one of the most serious post-intubation complication. However, it is widely underestimated.\n\n\nMETHODS\nAn 86-year-old patient with a history of pancreas adenocarcinoma treated with gemcitabin was admitted in intensive care unit for an acute respiratory failure with no identified etiology. The worsening of her respiratory status required invasive mechanical ventilation. One laryngoscopy, performed by a trained operator, found a Cormack 1. Intubation was realized without stylet and the cuff inflated with a syringe. Hemodynamic instability, impaired gas exchange and an extensive subcutaneous emphysema occurred immediately. A CT-scan showed a supracarinal tracheal rupture.\n\n\nCONCLUSIONS\nThe etiological analysis of this case identifies several causes of pars membranosa fragility, such as female sex, age greater than 50 years and the short stature. The emergency intubation and the cuff inflated by a syringe were the risk factors of tracheal rupture in this patient.\n\n\nCONCLUSIONS\nSpecial care should be paid to this complication, early diagnosis has probably a prognostic value. Training operators in the use of stylets and monitoring cuff pressure are required.",
"affiliations": "Service de réanimation médicale, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75908 Paris cedex 15, France; Faculté de médecine, université Paris-Descartes, 75006 Paris, France.;Service de réanimation médicale, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75908 Paris cedex 15, France; Faculté de médecine, université Paris-Descartes, 75006 Paris, France.;Service de réanimation médicale, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75908 Paris cedex 15, France; Faculté de médecine, université Paris-Descartes, 75006 Paris, France.;Service de réanimation médicale, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75908 Paris cedex 15, France; Faculté de médecine, université Paris-Descartes, 75006 Paris, France.;Service de réanimation médicale, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 20, rue Leblanc, 75908 Paris cedex 15, France; Faculté de médecine, université Paris-Descartes, 75006 Paris, France. Electronic address: emmanuel.guerot@egp.aphp.fr.",
"authors": "Bouattour|K|K|;Prost-Lapeyre|A|A|;Hauw-Berlemont|C|C|;Diehl|J-L|JL|;Guérot|E|E|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0750-7658",
"issue": "33(11)",
"journal": "Annales francaises d'anesthesie et de reanimation",
"keywords": "Cuff pressure; Emphysème sous-cutané; Eschmann stylet; Intubation; Lésion trachéale; Mandrin d’Eschmann; Pars membranosa; Pression ballonnet; Rupture trachéale; Subcutaneous emphysema; Tracheal injury; Tracheal rupture",
"medline_ta": "Ann Fr Anesth Reanim",
"mesh_terms": "D000369:Aged, 80 and over; D003422:Critical Care; D004632:Emergency Medical Services; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D007442:Intubation, Intratracheal; D012131:Respiratory Insufficiency; D012421:Rupture; D013352:Subcutaneous Emphysema; D014132:Trachea",
"nlm_unique_id": "8213275",
"other_id": null,
"pages": "590-2",
"pmc": null,
"pmid": "25450732",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A post-intubation tracheal rupture in intensive care unit.",
"title_normalized": "a post intubation tracheal rupture in intensive care unit"
} | [
{
"companynumb": "FR-FRESENIUS KABI-FK201600444",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
... |
{
"abstract": "Treating patients with opioid use disorder (OUD) and traumatic brain injury illustrates 6 neurobiological principles about the actions of 2 contrasting opioid analgesics, morphine and fentanyl, as well as pharmacotherapies for OUD, methadone, naltrexone, and buprenorphine.\n\n\n\nThis literature review focused on a patient with traumatic brain injury who developed OUD from chronic morphine analgesia. His treatment is described in a neurobiological framework of 6 opioid action principles.\n\n\n\nThe 6 principles are (1) coactivation of neuronal and inflammatory immune receptors (Toll-like receptor 4), (2) 1 receptor activating cyclic adenosine monophosphate and β-arrestin second messenger systems, (3) convergence of opioid and adrenergic receptor types on 1 second messenger, (4) antagonist (eg, naltrexone)-induced receptor trafficking, (5) genetic μ-opioid receptor variants influencing analgesia and tolerance, and (6) cross-tolerance vs receptor antagonism as the basis of OUD pharmacotherapy with methadone or buprenorphine vs naltrexone.",
"affiliations": "Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas.;Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas.;Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas.",
"authors": "Kosten|Thomas R|TR|;Graham|David P|DP|;Nielsen|David A|DA|",
"chemical_list": "D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D002047:Buprenorphine; D009271:Naltrexone; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1001/jamapsychiatry.2018.0101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-622X",
"issue": "75(6)",
"journal": "JAMA psychiatry",
"keywords": null,
"medline_ta": "JAMA Psychiatry",
"mesh_terms": "D000701:Analgesics, Opioid; D000070642:Brain Injuries, Traumatic; D002047:Buprenorphine; D006801:Humans; D008691:Methadone; D009271:Naltrexone; D009293:Opioid-Related Disorders; D010146:Pain; D017450:Receptors, Opioid, mu",
"nlm_unique_id": "101589550",
"other_id": null,
"pages": "642-648",
"pmc": null,
"pmid": "29710079",
"pubdate": "2018-06-01",
"publication_types": "D016428:Journal Article; D016420:Comment",
"references": null,
"title": "Neurobiology of Opioid Use Disorder and Comorbid Traumatic Brain Injury.",
"title_normalized": "neurobiology of opioid use disorder and comorbid traumatic brain injury"
} | [
{
"companynumb": "US-MALLINCKRODT-T201802785",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nSevere and severe/complicated Clostridium difficile infection (CDI) can result in ICU admission, sepsis, toxic megacolon and death. In this setting, colectomy is the standard of care but it is associated with a 50% mortality.\n\n\nOBJECTIVE\nTo evaluate safety and efficacy of a sequential faecal microbiota transplantation (FMT) and antibiotic protocol in severe and severe/complicated CDI patients who are at high risk for colectomy.\n\n\nMETHODS\nAll patients with severe and severe/complicated CDI refractory to oral vancomycin ± rectal vancomycin and intravenous metronidazole therapy were offered FMT. Treatment consisted of sequential FMTs via colonoscopy with the need for repeat FMT and continued vancomycin guided by clinical response and pseudomembranes at colonoscopy.\n\n\nRESULTS\nA total of 29 patients underwent FMT between July 2013 and August 2014. The overall treatment response of endoscopic sequential FMT was 93% (27/29), with 100% (10/10) for severe CDI and 89% (17/19) for severe/complicated CDI. A single FMT was performed in 62%, two FMTs were performed in 31% and three FMTs in 7% of patients. The use of non-CDI antibiotics predicted repeat FMT (odds ratio = 17.5). The 30-day all-cause mortality after FMT was 7%, and the cumulative 3-month survival was 76%. Of the two patients who died within 30 days, one underwent colectomy and succumbed to sepsis; the other died from septic shock related to CDI.\n\n\nCONCLUSIONS\nThe success of a treatment protocol for severe and severe/complicated involving faecal microbiota transplantation and continued vancomycin in selected patients was high, and it warrants further evaluation.",
"affiliations": "Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA.;Community Hospital, Anderson, IN, USA.;Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA.;Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA.;Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.;Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA.;Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA.",
"authors": "Fischer|M|M|;Sipe|B W|BW|;Rogers|N A|NA|;Cook|G K|GK|;Robb|B W|BW|;Vuppalanchi|R|R|;Rex|D K|DK|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008795:Metronidazole; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.1111/apt.13290",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "42(4)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016360:Clostridioides difficile; D003015:Clostridium Infections; D003082:Colectomy; D003113:Colonoscopy; D000069467:Fecal Microbiota Transplantation; D005260:Female; D006801:Humans; D008297:Male; D008795:Metronidazole; D008875:Middle Aged; D012189:Retrospective Studies; D018805:Sepsis; D012772:Shock, Septic; D014640:Vancomycin",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "470-6",
"pmc": null,
"pmid": "26096320",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Faecal microbiota transplantation plus selected use of vancomycin for severe-complicated Clostridium difficile infection: description of a protocol with high success rate.",
"title_normalized": "faecal microbiota transplantation plus selected use of vancomycin for severe complicated clostridium difficile infection description of a protocol with high success rate"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2015SP001537",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional"... |
{
"abstract": "Neurological disturbances caused by lithium range from simple side effects such as benign tremor to acute reversible neurotoxicity. Rarely, lithium is reported to cause irreversible, permanent neurological sequelae most commonly manifested as cerebellar dysfunction, although other presentations have also been described. We report two cases of persistent cerebellar syndrome following acute lithium toxicity and discuss them in the light of existing literature on the subject.",
"affiliations": "Neuron Psychological Care Center, Abu Dhabi, U.A.E.;Department of Psychiatry, Government Medical College, New Civil Hospital, Surat, Gujarat, India.;Department of Psychiatry, Smt. N.H.L. Municipal Medical College and Sheth V.S. General Hospital, Ahmedabad, Gujarat, India.;Department of Psychiatry, Smt. N.H.L. Municipal Medical College and Sheth V.S. General Hospital, Ahmedabad, Gujarat, India.",
"authors": "Banwari|Girish|G|;Chaudhary|Pradhyuman|P|;Panchmatia|Ankit|A|;Patel|Nisheet|N|",
"chemical_list": "D008094:Lithium",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.182896",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-48-33110.4103/0253-7613.182896Drug WatchPersistent cerebellar dysfunction following acute lithium toxicity: A report of two cases Banwari Girish Chaudhary Pradhyuman 1Panchmatia Ankit 2Patel Nisheet 2Neuron Psychological Care Center, Abu Dhabi, U.A.E1 Department of Psychiatry, Government Medical College, New Civil Hospital, Surat, Gujarat, India2 Department of Psychiatry, Smt. N.H.L. Municipal Medical College and Sheth V.S. General Hospital, Ahmedabad, Gujarat, IndiaCorrespondence to: Dr. Girish Banwari, E-mail: drgirishbanwari@yahoo.comMay-Jun 2016 48 3 331 333 26 2 2015 23 3 2016 11 4 2016 Copyright: © Indian Journal of Pharmacology2016This 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.Neurological disturbances caused by lithium range from simple side effects such as benign tremor to acute reversible neurotoxicity. Rarely, lithium is reported to cause irreversible, permanent neurological sequelae most commonly manifested as cerebellar dysfunction, although other presentations have also been described. We report two cases of persistent cerebellar syndrome following acute lithium toxicity and discuss them in the light of existing literature on the subject.\n\nKEY WORDS\nAdverse drug reactioncerebellar dysfunctionlithiumpersistent neurological sequelae\n==== Body\nIntroduction\nNeurological disturbances caused by lithium fall on a continuum from simple side effects (e.g., benign tremor) to acute neurotoxicity manifested as coarse tremor, dysarthria, ataxia, seizures, encephalopathy and coma related to supratherapeutic lithium levels, usually reversible with drug discontinuation or dose reduction.[1]\n\nRarely, lithium is reported to cause irreversible, permanent neurological sequelae such as cerebellar impairment, dementia, parkinsonian syndromes, choreoathetosis, brain stem syndromes, and peripheral neuropathies.[1] Atypical presentations may include persistent papilledema, optic neuritis, isolated downbeat nystagmus, central pontine myelinosis, and myopathy.[2] Adityanjee suggested that these persistent sequelae may be called the Syndrome of Irreversible Lithium-Effectuated Neuro Toxicity (SILENT).[2] Persistent cerebellar dysfunction is the most commonly reported sequela as found in a review of the published cases of SILENT.[3] To qualify for a diagnosis of SILENT, lithium-induced neurological dysfunctions should occur in the absence of prior neurological illness and should persist beyond 2 months after the cessation of lithium,[3] although the syndrome remains imprecisely defined.\n\nHere, we report two cases of persistent cerebellar syndrome following acute lithium toxicity and discuss them in the light of existing literature. Both the cases presented to Department of Psychiatry, Sheth V.S. General Hospital, Ahmedabad, India.\n\nCase Reports\n\nCase 1\nA 35-year-old man diagnosed as having bipolar disorder had a history of two episodes of mania in 2004 and 2007. He was treated with lithium 1200 mg/day and olanzapine 20 mg/day (taken orally) on both the occasions, achieving remission in 3–4 months. Since then, he had always been on maintenance treatment of lithium 1200 mg/day. Just before the current admission, he experienced difficulty initiating sleep and had taken two extra tablets of lithium over and above the prescribed dose to induce sleep (total 2000 mg/day) for 2 consecutive days. He presented to the emergency room with bouts of vomiting, coarse hand tremors, and ataxic gait. He was restless but alert and oriented. He had dysarthria, finger-nose dysmetria, dysdiadochokinesia, and gaze-evoked nystagmus on examination. His brain magnetic resonance imaging (MRI), cerebrospinal fluid analysis and metabolic variables measured were normal. Abnormal laboratory investigations included serum lithium 4.42 mEq/l, creatinine 2.3 mg/dl, blood urea 68 g/dl, and thyroid-stimulating hormone (TSH) 10.52 µIU/ml. Repeat laboratory studies on the next day showed serum creatinine 4.6 mg/dl and blood urea 84 mg/dl. On examination, he had confusion, broad ataxic gait, and gross limb incoordination. He was then subjected to six sessions of hemodialysis. On day 12, his laboratory tests showed serum lithium 0.9 mEq/l, creatinine 1.2 mg/dl, blood urea 52 mg/dl, and TSH 4.51 µIU/ml. On discharge, he was still dysarthric, dysmetric on the finger-nose test, and unable to walk without support. He was only prescribed lorazepam 2 mg orally for sleep disturbance. At months 3 and 6 of follow-up, he had no manic or depressive symptoms but had an unsteady gait, saccadic dysmetria, disarticulate speech, static and intention tremors, and dysrhythmokinesia. All laboratory tests including renal and thyroid functions tested normal as did the repeat brain MRI. Serum lithium level was <0.2 mEq/l.\n\nCase 2\nA 55-year-old male had a 20-year history of bipolar disorder, with at least four manic episodes and several ill-defined depressive bouts. He had been on regular prophylactic treatment with lithium 900 mg and olanzapine 10 mg, taken orally as tablets. With a history of poor compliance to treatment for the last 1 year, he presented with severe manic features and was thus admitted. Lithium was restarted with 900 mg in two divided doses along with olanzapine 10 mg and clonazepam 2 mg (all medications were administered orally as tablets). All investigations including X-ray chest, electrocardiogram, and laboratory studies were normal. On day 3 of admission, he developed mild to moderate fever and cough with expectoration. At that time, hemogram showed a total leukocyte count 14,100/cumm, but X-ray chest showed clear lung fields. He was diagnosed as having upper respiratory tract infection by the attending physician and was prescribed tablet cefadroxil 500 mg BD. Antipyretics were not administered. On day 5, he abruptly developed lethargy, disorientation, unsteadiness, nausea, abdominal pain, and diarrhea. Laboratory investigations showed total leucocyte count 15,200/cumm, serum lithium 2.52 mEq/l; hepatic, renal, thyroid, and other metabolic parameters tested normal. Brain MRI was normal. Lithium was discontinued and the patient was transferred to the medical intensive care unit. On day 10, he regained orientation while fever, cough, and other physical complaints subsided. However, while walking, he had a broad-based stance with truncal instability and a tendency to fall. In addition, there was finger-nose and knee-heel dysmetria with prominent intention tremors, as well as an evident rebound nystagmus. In the absence of any other neurological or psychiatric manifestations, he was discharged on olanzapine 10 mg and lorazepam 1 mg (taken orally as tablets); serum lithium being 0.3 mEq/l at that time. Even at 12 months of follow-up, he had a clumsy ataxic gait, with obvious limb incoordination and scanning dysarthria.\n\nDiscussion\nLithium overdose was clearly responsible for lithium toxicity in the first case, while in the second case, the exact reason for raised serum lithium level was not discernible. In the absence of lithium overdose or use of concomitant medications known to increase lithium level, the most plausible cause of lithium toxicity appears to be fever in the setting of infection. The concomitant medications used were olanzapine and clonazepam for mania and cefadroxil for upper respiratory tract infection. None of these three drugs is documented to escalate lithium levels. Antipyretics were deliberately avoided even in the presence of fever, as they are known to increase serum lithium level. Besides, he had been on lithium and olanzapine concomitantly for many (at least 5) years without any complications.\n\nMore often than not, long-lasting neurological sequelae are preceded by acute lithium poisoning,[2] as seen in both our cases. Possible risk factors predisposing to SILENT include high serum levels during acute intoxication, presence of fever, concomitant use of other drugs (e.g., antipsychotics, tricyclic antidepressants, and anticonvulsants), rapid correction of hyponatremia or lithemia, and coexistent illness, such as hypertension, renal failure, heart failure, acute gastroenteritis, and epilepsy.[4] Acute renal decompensation in our first case and fever in the setting of infection in our second case may be contributory factors in the genesis of the persistent syndrome.\n\nDemyelination caused by lithium at multiple sites in the nervous system, including the cerebellum has been hypothesized to be responsible for the persistent deficits.[3] Neuropathologically, it is demonstrated that there is neuronal loss and gliosis in the cerebellar cortex and dentate nuclei with prominent spongy change in the cerebellar white matter.[5] There is especially a striking loss of cerebellar Purkinje cells caused by disrupted calcium homeostasis leading to plausible calcium-mediated neurotoxicity,[6] although the exact mechanisms are not well understood at this time.\n\nWe did report these two cases of lithium-induced cerebellar dysfunction to the adverse drug reaction (ADR) monitoring centre under PvPI at Smt. N.H.L. Municipal Medical College, Ahmedabad. The causality assessment was performed based on WHO criteria[7] and it was classified as a probable ADR to the drug looking into the reasonable time sequence of occurrence of the adverse event, event corresponded to what is known for the drug and event was not reasonably explained by patients’ disorder or other drugs. The reaction is termed as serious since it has led to persistent disability till the time of the last follow- up, long since lithium had been discontinued (the worldwide vigiflow number is as follows-report ID for case 1 is 2015-06069 and for case 2 is 2015-06070).\n\nConclusion\nClinicians need to be aware of the possibility of persistent neurologic sequelae that may follow acute lithium toxicity. A precise definition and operational diagnostic criteria may help in the early identification and prevention of the syndrome.[3]\n\n\nFinancial Support and Sponsorship\nNil.\n\nConflicts of Interest\nThere are no conflicts of interest.\n==== Refs\n1 Netto I Phutane VH Reversible lithium neurotoxicity: Review of the literature Prim Care Companion CNS Disord 2012 14 pii: PCC11r01197 \n2 Adityanjee The syndrome of irreversible lithium effectuated neurotoxicity J Neurol Neurosurg Psychiatry 1987 50 1246 7 3668585 \n3 Adityanjee Munshi KR Thampy A The syndrome of irreversible lithium-effectuated neurotoxicity Clin Neuropharmacol 2005 28 38 49 15714160 \n4 Porto FH Leite MA Fontenelle LF Marrocos RP Szczerback NF de Freitas MR The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT): One-year follow-up of a single case J Neurol Sci 2009 277 172 3 19046589 \n5 Schneider JA Mirra SS Neuropathologic correlates of persistent neurologic deficit in lithium intoxication Ann Neurol 1994 36 928 31 7998783 \n6 Grignon S Bruguerolle B Cerebellar lithium toxicity: A review of recent literature and tentative pathophysiology Therapie 1996 51 101 6 8763043 \n7 WHO-UMC System for Standardized Case Causality Assessment 2012 4 17 Last accessed on 2015 Feb 26 Available from: http://www.who-umc.org/Graphics/26649.pdf\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "48(3)",
"journal": "Indian journal of pharmacology",
"keywords": "Adverse drug reaction; cerebellar dysfunction; lithium; persistent neurological sequelae",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000328:Adult; D002531:Cerebellum; D006801:Humans; D008094:Lithium; D008297:Male",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "331-3",
"pmc": null,
"pmid": "27298510",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3668585;7998783;19046589;15714160;22690368;8763043",
"title": "Persistent cerebellar dysfunction following acute lithium toxicity: A report of two cases.",
"title_normalized": "persistent cerebellar dysfunction following acute lithium toxicity a report of two cases"
} | [
{
"companynumb": "AE-MYLANLABS-2016M1027134",
"fulfillexpeditecriteria": "1",
"occurcountry": "AE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LITHIUM"
},
"drugadditional": null,
... |
{
"abstract": "Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) into frontline therapeutic regimens has improved outcomes for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, patients with persistent minimal residual disease (MRD) exhibit increased risk of relapse. Combining consolidative chemotherapy with TKIs may increase rates of infectious complications, organ toxicity, hospitalization, and non-relapse mortality. Blinatumomab has demonstrated single-agent activity in patients with relapsed B-ALL or persistent MRD, including Ph + B-ALL. We have used blinatumomab concomitantly with commercially available TKIs as consolidative therapy to spare toxicities of conventional chemotherapy. We evaluated 11 adults with previously treated Ph + B-ALL who received blinatumomab concurrent with TKI (ponatinib, n = 5; dasatinib, n = 4; nilotinib, n = 1; imatinib, n = 1) to eradicate MRD or sustain MRD-negativity. Eight of 9 patients with MRD achieved BCR-ABL1 negativity (complete molecular response, CMR) after a median of one cycle; 2/2 patients without measurable disease durably maintained CMR. Cytokine release syndrome (all grade 1-2) was observed in 3/11 patients; one patient experienced transient grade 1 neurologic toxicity. Transient grade 2 transaminitis was observed in 6/11 patients, including 4/5 recipients of blinatumomab + ponatinib. This small series suggests blinatumomab + TKI is a safe and effective consolidation strategy for patients with Ph + ALL to achieve or maintain CMR.",
"affiliations": "Department of Pharmacy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. Electronic address: kinga@mskcc.org.;Department of Pharmacy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. Electronic address: pappacej@mskcc.org.;Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. Electronic address: tallmanm@mkscc.org.;Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA; Cellular Therapeutics Center, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. Electronic address: parkj6@mskcc.org.;Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA; Cellular Therapeutics Center, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. Electronic address: geyerm@mskcc.org.",
"authors": "King|Amber C|AC|;Pappacena|Jeremy J|JJ|;Tallman|Martin S|MS|;Park|Jae H|JH|;Geyer|Mark B|MB|",
"chemical_list": "D018033:Antibodies, Bispecific; D047428:Protein Kinase Inhibitors; C510808:blinatumomab; D011505:Protein-Tyrosine Kinases",
"country": "England",
"delete": false,
"doi": "10.1016/j.leukres.2019.02.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "79()",
"journal": "Leukemia research",
"keywords": "Acute lymphoblastic leukemia; Blinatumomab; Minimal residual disease; Tyrosine kinase inhibitor",
"medline_ta": "Leuk Res",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific; D000971:Antineoplastic Combined Chemotherapy Protocols; D060830:Consolidation Chemotherapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "27-33",
"pmc": null,
"pmid": "30831480",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24876563;28122741;26040495;22442346;29567798;18703743;22705993;20466853;25524800;20131302;21670084;23673859;17170120;16775235;21931113;27121472;23836561;28249141;28082340;24441288;25083322;23212150;30501869;29407585;22263567;15489916;14673054;19295545;28927784;28355115;18650471;19010823;24180494;26951627;18413841;19863538;17496201;15481055;24277073;29358182",
"title": "Blinatumomab administered concurrently with oral tyrosine kinase inhibitor therapy is a well-tolerated consolidation strategy and eradicates measurable residual disease in adults with Philadelphia chromosome positive acute lymphoblastic leukemia.",
"title_normalized": "blinatumomab administered concurrently with oral tyrosine kinase inhibitor therapy is a well tolerated consolidation strategy and eradicates measurable residual disease in adults with philadelphia chromosome positive acute lymphoblastic leukemia"
} | [
{
"companynumb": "US-AMGEN-USASP2019039647",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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"drug": [
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"activesubstance": {
"activesubstancename": "PONATINIB"
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"drugadditional": null,
... |
{
"abstract": "Enterococci are implicated in less than 2.3% of prosthetic joint infections. These infections can be difficult to treat and therapeutic failures are not uncommon. In these situations, daptomycin is a safe and effective alternative. We present a clinical case with a successful response to the prolonged use of high-dose daptomycin.",
"affiliations": "Division of Infectious Diseases, Clinica Universidad de Navarra, Pamplona, Spain; Department of Internal Medicine, Clinica Universidad de Navarra, Pamplona, Spain. Electronic address: jryuste@unav.es.;Division of Infectious Diseases, Clinica Universidad de Navarra, Pamplona, Spain.;Department of Orthopaedic Surgery, Clinica Universidad de Navarra, Pamplona, Spain.;Division of Infectious Diseases, Clinica Universidad de Navarra, Pamplona, Spain; Department of Clinical Microbiology, Clinica Universidad de Navarra, Pamplona, Spain.",
"authors": "Yuste|José Ramón|JR|;Quesada|Milena|M|;Díaz-Rada|Pablo|P|;Del Pozo|José Luis|JL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017576:Daptomycin",
"country": "Canada",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "27()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Daptomycin; Enterococcus faecalis; Prosthetic joint infection; Treatment",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D017576:Daptomycin; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D013293:Enterococcus faecalis; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008297:Male; D016459:Prosthesis-Related Infections",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "65-6",
"pmc": null,
"pmid": "25192907",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Daptomycin in the treatment of prosthetic joint infection by Enterococcus faecalis: safety and efficacy of high-dose and prolonged therapy.",
"title_normalized": "daptomycin in the treatment of prosthetic joint infection by enterococcus faecalis safety and efficacy of high dose and prolonged therapy"
} | [
{
"companynumb": "ES-CUBIST PHARMACEUTICALS, INC.-2014CBST001300",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nEndovascular coil embolization of intracranial aneurysms is associated with better outcomes and a lower mortality rate compared with surgical clip occlusion. However, a principal disadvantage of endovascular therapy is the higher rate of retreatment compared with neurosurgical clipping. Self-expandable hydrogel-coated coils were developed to reduce recanalization rates of cerebral aneurysms by promoting complete volumetric aneurysm occlusion. Herein, we report a case of brainstem hemorrhage following coil embolization of a large basilar aneurysm with hydrogel-coated coils.\n\n\nMETHODS\nA 65-year-old female with a history of hypertension, who presented with worsening headaches, right hemiplegia, and left oculomotor palsy, underwent endovascular treatment for a large basilar aneurysm. The aneurysm was treated with both hydrogel-coated coils and bare platinum coils. Hydrogel-coated coils represented 46% of the coil length in the aneurysm. The patient was discharged from the hospital with improvement of neurological deficits 6 days after the procedure. However, the patient was readmitted with perianeurysmal edema in the midbrain 23 days after coil embolization. Follow-up angiography 26 days after the procedure showed complete obliteration of the aneurysm. Two weeks later, the patient presented with a large brainstem hemorrhage and died. Pathological findings revealed intraparenchymal hemorrhage in the pons without rupture of the aneurysm.\n\n\nCONCLUSIONS\nHydrogel-coated coils may cause a marked inflammatory response that may result in intracerebral hemorrhage.",
"affiliations": "Department of Neurosurgery, Kawaguchi Municipal Medical Center.",
"authors": "Furuichi|Makoto|M|;Shimoda|Kentaro|K|;Kano|Toshikazu|T|;Satoh|Shoshi|S|;Yoshino|Atsuo|A|",
"chemical_list": "D020136:Hydrogel, Polyethylene Glycol Dimethacrylate",
"country": "Japan",
"delete": false,
"doi": "10.11477/mf.1436203130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2603",
"issue": "43(9)",
"journal": "No shinkei geka. Neurological surgery",
"keywords": null,
"medline_ta": "No Shinkei Geka",
"mesh_terms": "D000368:Aged; D001933:Brain Stem; D002533:Cerebral Angiography; D002543:Cerebral Hemorrhage; D004621:Embolization, Therapeutic; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D002532:Intracranial Aneurysm; D008279:Magnetic Resonance Imaging; D064847:Multimodal Imaging; D016896:Treatment Outcome",
"nlm_unique_id": "0377015",
"other_id": null,
"pages": "835-42",
"pmc": null,
"pmid": "26321698",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Brainstem Hemorrhage Following Embolization of a Large Basilar Aneurysm with Hydrogel-Coated Coils.",
"title_normalized": "a case of brainstem hemorrhage following embolization of a large basilar aneurysm with hydrogel coated coils"
} | [
{
"companynumb": "JP-BAYER-2015-424421",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThere are limited data on Coronavirus disease 2019 (COVID-19) in solid organ transplant patients, especially in heart transplant recipients, with only a few case reports and case series described so far. Heart transplant recipients may be at particular high risk due to their comorbidities and immunosuppressed state.\n\n\nMETHODS\nThis report describes the clinical course and the challenging management of early COVID-19 infection in two heart transplant recipients who tested positive for the SARS-CoV-2 virus in the perioperative period of the transplant procedure. The two patients developed a severe form of the disease and ultimately died despite the initiation of an antiviral monotherapy with hydroxychloroquine coupled with the interruption of mycophenolate mofetil.\n\n\nCONCLUSIONS\nThese two cases illustrate the severity and poor prognosis of COVID-19 in the perioperative period of a heart transplant. Thorough screening of donors and recipients is mandatory, and the issue of asymptomatic carriers needs to be addressed.",
"affiliations": "Department of Cardiovascular Surgery, CHU Liege, B35 SART TILMAN, 4000, Liege, Belgium. vtchanasato@chuliege.be.;Department of Cardiology, CHU Liege, Liege, Belgium.;Department of Cardiology, CHU Liege, Liege, Belgium.;Department of Cardiovascular Surgery, CHU Liege, B35 SART TILMAN, 4000, Liege, Belgium.;Department of Clinical Microbiology, CHU Liege, Liege, Belgium.;Department of Abdominal Surgery and Transplantation, CHU Liege, Liege, Belgium.;Department of Pathology, CHU Liege, Liege, Belgium.;Department of Anesthesiology, CHU Liege, Liege, Belgium.;Department of Anesthesiology, CHU Liege, Liege, Belgium.;Department of Pathology, CHU Liege, Liege, Belgium.;Department of Cardiovascular Surgery, CHU Liege, B35 SART TILMAN, 4000, Liege, Belgium.;Department of Cardiovascular Surgery, CHU Liege, B35 SART TILMAN, 4000, Liege, Belgium.;Department of Cardiovascular Surgery, CHU Liege, B35 SART TILMAN, 4000, Liege, Belgium.;Department of Cardiovascular Surgery, CHU Liege, B35 SART TILMAN, 4000, Liege, Belgium.;Department of Anesthesiology, CHU Liege, Liege, Belgium.;Department of Intensive Care, CHU Liege, Liege, Belgium.;Department of Intensive Care, CHU Liege, Liege, Belgium.;Department of Abdominal Surgery and Transplantation, CHU Liege, Liege, Belgium.;Department of Cardiovascular Surgery, CHU Liege, B35 SART TILMAN, 4000, Liege, Belgium.;Department of Cardiology, CHU Liege, Liege, Belgium.",
"authors": "Tchana-Sato|Vincent|V|http://orcid.org/0000-0001-8838-814X;Ancion|Arnaud|A|;Tridetti|Julien|J|;Sakalihasan|Natzi|N|;Hayette|Marie Pierre|MP|;Detry|Olivier|O|;Delvenne|Philippe|P|;Amabili|Philippe|P|;Senard|Marc|M|;Hougrand|Olivier|O|;Szecel|Delphine|D|;Lavigne|Jean-Paul|JP|;Minga Lowampa|Elie|E|;Ponte|Charlotte|C|;Maquoi|Isabelle|I|;Morimont|Philippe|P|;Van Den Bulck|Melissa|M|;Delbouille|Marie Helene|MH|;Defraigne|Jean Olivier|JO|;Lancellotti|Patrizio|P|",
"chemical_list": "D000962:Antimalarials; D000998:Antiviral Agents; D006886:Hydroxychloroquine; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-021-05793-6",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5793\n10.1186/s12879-021-05793-6\nCase Report\nClinical course and challenging management of early COVID-19 infection after heart transplantation: case report of two patients\nhttp://orcid.org/0000-0001-8838-814XTchana-Sato Vincent vtchanasato@chuliege.be 1 Ancion Arnaud 2 Tridetti Julien 2 Sakalihasan Natzi 1 Hayette Marie Pierre 3 Detry Olivier 4 Delvenne Philippe 5 Amabili Philippe 6 Senard Marc 6 Hougrand Olivier 5 Szecel Delphine 1 Lavigne Jean-Paul 1 Minga Lowampa Elie 1 Ponte Charlotte 1 Maquoi Isabelle 6 Morimont Philippe 7 Van Den Bulck Melissa 7 Delbouille Marie Helene 4 Defraigne Jean Olivier 1 Lancellotti Patrizio 2 1 grid.411374.40000 0000 8607 6858Department of Cardiovascular Surgery, CHU Liege, B35 SART TILMAN, 4000 Liege, Belgium \n2 grid.411374.40000 0000 8607 6858Department of Cardiology, CHU Liege, Liege, Belgium \n3 grid.411374.40000 0000 8607 6858Department of Clinical Microbiology, CHU Liege, Liege, Belgium \n4 grid.411374.40000 0000 8607 6858Department of Abdominal Surgery and Transplantation, CHU Liege, Liege, Belgium \n5 grid.411374.40000 0000 8607 6858Department of Pathology, CHU Liege, Liege, Belgium \n6 grid.411374.40000 0000 8607 6858Department of Anesthesiology, CHU Liege, Liege, Belgium \n7 grid.411374.40000 0000 8607 6858Department of Intensive Care, CHU Liege, Liege, Belgium \n20 1 2021 \n20 1 2021 \n2021 \n21 899 7 2020 12 1 2021 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThere are limited data on Coronavirus disease 2019 (COVID-19) in solid organ transplant patients, especially in heart transplant recipients, with only a few case reports and case series described so far. Heart transplant recipients may be at particular high risk due to their comorbidities and immunosuppressed state.\n\nCase presentation\nThis report describes the clinical course and the challenging management of early COVID-19 infection in two heart transplant recipients who tested positive for the SARS-CoV-2 virus in the perioperative period of the transplant procedure. The two patients developed a severe form of the disease and ultimately died despite the initiation of an antiviral monotherapy with hydroxychloroquine coupled with the interruption of mycophenolate mofetil.\n\nConclusions\nThese two cases illustrate the severity and poor prognosis of COVID-19 in the perioperative period of a heart transplant. Thorough screening of donors and recipients is mandatory, and the issue of asymptomatic carriers needs to be addressed.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s12879-021-05793-6.\n\nKeywords\nSevere acute respiratory syndrome coronavirus 2 (SARS-Cov-2)Coronavirus disease 2019 (COVID-19)Heart transplantationAsymptomatic carrierCase reportissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nIn the current context of coronavirus disease 2019 (COVID-19), the management of patients with end-stage heart failure on the transplant waiting list, and of heart transplant recipients (HTR) is challenging. To date, only a few case reports or small case series of COVID-19 in HTR have been described in China, Spain, Germany, and the United States, with mainly HTR who were remote from transplant and on chronic immunosuppressive drugs [1–8]. The limited data published so far have shown that the clinical presentation of COVID-19 in those patients did not differ from non-transplant patients or other solid organ transplant recipients [1, 2, 5, 6, 8]. However, the case fatality rate in some case series varied from 23% to up to 33% [6, 8, 9]. Newly HTR constitute a particularly vulnerable cohort for severe COVID-19 infection due to high levels of immunosuppression and frequent comorbidities. Unfortunately, the clinical characteristics and the management of COVID-19 in this subgroup of patients remain largely unknown. Herein, we report on two HTR who developed and ultimately died from severe COVID-19 a few days after their urgent transplant procedure (TP). Both were completely asymptomatic at their admission in our center with no respiratory complaints. These cases highlight the clinical course of these two patients and the difficulties encountered in their management.\n\nCases presentation\nRecipient 1 (Fig. 1)\nOn March 17, 2020, a 59-year-old man with end-stage ischemic heart disease was admitted for heart transplant after being on the waiting list for approximately 12 months. He was obese and had a history of mitral annuloplasty surgery 13 years earlier. The last weeks before admission, his clinical condition had worsened with rhythmic instability due to recurrent tachycardia treated by internal electric shocks on several occasions. At home and upon admission, there were no obvious fever or respiratory symptoms. Laboratory findings did not reveal any particular anomaly with a normal hemogram, renal function and C-reactive protein (CRP) (4.4 mg/L, nl: 0–5). The cross match with the donor was negative. Given the COVID-19 pandemic, he was screened for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by reverse transcriptase polymerase chain reaction (RT-PCR) assay targeting E and RdRP genes on nasopharyngeal swab (NPS) [10]. The donor was also screened for SARS-Cov-2 infection and was negative.\nFig. 1 Clinical course of Recipient 1 (a) and Recipient 2 (b). From admission and day of surgery (HTx) to death highlighting the SARS-CoV-2 RNA load (Log10 copies/ml), the ward and ICU length of stay, diagnostic and therapeutic interventions such as chest CT, myocardial biopsy, BAL, initiation of antibiotics, and HCQ. a MM was withheld on POD 16. The clinical deterioration observed on POD 14 was close to the peak of the viral load observed on POD 16. b MM was withheld on POD 20. We can see that the deterioration of the patient’s clinical status on POD 19 coincides with a peak of the viral load. The SARS-CoV-2 RNA load is expressed by log10 copies per milliliter. Two RT-PCR assays were used due to a change in the testing method of the laboratory. The first target is the E and RdRP gene (Corman V.) The second test is the automated Cobas© SARS-CoV-2 molecular test (Cobas 6800 Roche) targeting the E and ORF1ab genes. Only the E gene is illustrated in the figure. ABt, antibiotics; BAL, bronchoalveolar lavage; Chest CT, chest computed tomography; HTx, heart transplantation; HCQ, hydroxychloroquine; ICU, intensive care unit; MM, mycophenolate mofetil; POD, postoperative day; RT-PCR, reverse transcriptase polymerase chain reaction\n\n\n\nThe graft was transplanted in the orthotopic position. He was easily weaned off cardiopulmonary bypass (CPB) and transferred to the intensive care unit (ICU) on mild inotropic support. Quickly after his arrival in the ICU, he became hemodynamically unstable despite adequate filling and required an escalation of inotropic and vasopressor support. Upon arrival in the OR and after performing a transesophageal echocardiography (TEE), a cardiac tamponade was excluded, and it was decided to go for a surgical revision due to stenosis of the superior vena cava anastomosis. At the end of the intervention, the patient who regained hemodynamic stability was transferred to the ICU.\n\nThe induction therapy included a standard triple regimen of decreasing doses of methylprednisolone, a calcineurin inhibitor (tacrolimus) to obtain trough levels between 8 and 10 μg/L, and an antimetabolite, mycophenolate mofetil (MM) 1000 mg twice daily. Anti-infectious prophylaxis included sulfamethoxazole 800 mg and trimethoprim 160 mg three times a week and valganciclovir hydrochloride 450 mg once a day.\n\nThe results of the preoperative SARS-CoV-2 RT-PCR analysis returned positive on POD 2. Therefore, according to the hospital protocol, the patient received 200 mg of hydroxychloroquine (HCQ) twice daily from POD 2 to POD 7 after a loading dose of 400 mg twice daily.\n\nThe immediate postoperative period was marked by the occurrence of right ventricular dysfunction and low cardiac output syndrome requiring a further increase in the doses of dobutamine and norepinephrine, as well as the administration of inhaled nitric oxide to overcome refractory hypoxia. He developed acute renal failure requiring renal replacement therapy. The situation gradually improved until POD14, when the respiratory exchanges started to deteriorate, and chest computed tomography (CT) revealed bilateral ground-glass opacities compatible with a COVID-19 infection (Fig. 2). On the same day, right cardiac catheterization demonstrated mild postcapillary pulmonary hypertension with a slightly reduced cardiac index. The myocardial biopsy did not demonstrate cellular or humoral rejection. However, analysis by electron microscopy revealed viral-like particles within endothelial cells but not in cardiomyocytes.\nFig. 2 Chest X-ray and CT of recipient 1 (a) and recipient 2 (b. a) Progressive occurrence of pulmonary lesions during the postoperative course. The black arrows illustrate the ground-glass opacity lesions compatible with COVID-19 infection on POD 14. The blue arrows illustrate bilateral parenchymal patchy consolidations at POD 25. b Progressive occurrence of pulmonary lesions during the postoperative course until readmission in the intensive care unit on POD 20, where we can clearly see the ground-glass opacities lesions compatible with COVID-19 infection at POD 19 (black arrow), and bilateral patchy consolidations at POD 20 (blue arrow). POD, postoperative day\n\n\n\nBacterial infection was confirmed by the isolation of Klebsiella oxytoca in bronchoalveolar lavage (BAL) (> 106 CFU/ml) and in blood cultures. The patient was treated with cefepime for 10 days. SARS-coV-2 RT-PCR performed on BAL fluid revealed a high viral load (7.4 log10 copies/mL). At that time, MM was withheld, and methylprednisolone was reduced to 16 mg daily. Unfortunately, the patient’s respiratory exchanges continued to deteriorate with ineffective prone positioning. Venovenous extracorporeal membrane oxygenation (ECMO) was not considered in this immunosuppressed patient with more than 14 days of mechanical ventilation. He died on POD 27 of refractory hypoxia and multiorgan failure. Additionally, the surgeon tested positive for SARS-CoV-2 on POD 5.\n\nRecipient 2 (Fig. 1)\nThe second patient was a 56-year-old woman with decompensated hypertrophic heart disease who had been on the waiting list for more than 12 months. Her past medical history included surgery for left pulmonary vein stenosis in 2015. She did not have anti-HLA antibodies. At the time of transplant, she was in the cardiology ward on inotropic support for a new episode of heart failure. Indeed, in the past 3 months, she had been admitted three times for recurrent episodes of heart failure treated with dobutamine. In the ward, she had no fever or symptoms suggestive of respiratory infections. The biology performed before the heart transplant demonstrated normal white blood cell count (WBC) (6.15 103/mm3; nl: 4.6–10.10), slight anemia (Hg 10 g/dL, nl: 11.7–15), mild renal failure (creatinemia 1.11 mg/dL; nl 0.55–1.02), and inflammatory syndrome (CRP 15.6 mg/L; nl 0–5). The cross match with the donor was negative. As the first recipient, she benefitted from systematic SARS-CoV-2 screening by RT-PCR on NPS 2 days before the TP.\n\nTP was performed with a donation after circulatory death (DCD) heart procurement procedure as described by our group [11]. The donor tested negative for SARS-CoV-2. After retrieval, the heart graft was transported to a contiguous OR where the aforementioned TP, as well as the re-exploration just a few hours earlier, were carried out. Usual OR cleaning and changing of the whole respiratory circuit as well as the CO2 sampling line were performed between the two procedures. The graft was transplanted in the orthotopic position. She was easily weaned off CPB and transferred to the ICU.\n\nThe induction therapy and anti-infectious prophylaxis were the same as for the first recipient. The preoperative SARS-CoV-2 RT-PCR performed on NPS was negative. However, given the patient’s indirect contact with the first recipient through OR, another NPS was performed on POD 2. The result was reported to be weakly positive the same day. Therefore, from POD 2 to POD 7, the patient received 200 mg of HCQ twice daily, after a loading dose of 400 mg twice daily.\n\nThere were no postoperative complications. Consequently, the patient was discharged from the ICU and transferred to an isolation ward on POD4. The right heart catheterization assessment was unremarkable, and the myocardial biopsy did not show rejection. As for the first patient, analysis by electron microscopy showed the presence of viral-like elements within endothelial cells but not in cardiomyocytes (Fig. 3). However, histological signs of endotheliitis or viral antigen immunoreactivity were not observed in the biopsy specimen (Fig. 3).\nFig. 3 Electron microscopy (a-b) and immunohistology (c-d) of heart tissue from recipient 2. a-b Transmission electron microscopy representative examples demonstrating particles whose morphology is compatible with coronavirus particles (arrows). c-d Absence of immunoreactivity for the viral nucleocapsid protein (c) which contrasts with the intense staining in the positive control (lung tissue specimen of a SARS-CoV-2 infected hamster) (d). Transmission electron microscopy. Tissues were fixed at 4 °C in 4% glutaraldehyde (Laborimpex, Brussels, Belgium) in phosphate buffer at pH 7.4 and postfixed in 1% osmium tetroxide (Laborimpex, Brussels, Belgium) for 1 H at 4 °C. They were then dehydrated in graded (70, 90, 100%) ethanol solutions (VWR International, Leuven, Belgium) and propylene oxide (Laborimpex, Brussels, Belgium), embedded in epon (SERVA, Zandhoven, Belgium) and hardened at 60 °C. Semi-thin sections were stained with 0.5% toluidine blue and examined by light microscopy. Ultra-thin sections (80 nm) were stained with uranyl acetate (Fluka, Bornem, Belgium) and lead citrate (Leica, Aartselaar, Belgium). These sections were examined using an EM 910 transmission electron microscope (60 kV) (Zeiss, Belgium). Immunohistology Sections were deparaffinized and rehydrated in graded alcohols. After endogenous peroxydase inhibition with H2O2 (3%), nonspecific binding sites were blocked with the Protein Block Serum-Free solution (Dako). Slides were incubated for 1H at room temperature with a rabbit polyclonal antibody against the SARS-CoV-2 recombinant fusion nucleoprotein (ABclonal). Immunodetection was performed with the Polyview plus AP-Rabbit and alkaline phosphatase (Enzo Life Sciences)\n\n\n\nHer clinical course was uneventful until POD 19, when she became febrile, and described breathing difficulties with a gradual decrease in her oxygen saturation requiring nasal oxygen supplementation. The chest CT revealed some ground-glass opacities lesions predominant on the right lung (Fig. 2). SARS-CoV-2 RT-PCR performed on BAL fluid tested strongly positive (8 log10 copies/mL). Despite any evidence of infection, empirical antibiotic therapy based on azithromycin was initiated for 7 days following recommendations of the infectious disease team. After progressive worsening of her respiratory status, the patient was readmitted to the ICU on POD20, where prompt invasive ventilation coupled to prone positioning was required. At that time, MM was withheld. ECMO was not considered in the context of immunosuppression with more than 10 days of mechanical ventilation. Her clinical status continued to decline. Klebsiella pneumoniae was identified in few quantity (104 copies/ml) by PCR (filmArray pneumonia panel) on bronchial aspirate on POD 34, but was not found on standard Gram staining and culture which only revealed contamination by oropharyngeal flora. However, given the clinical context (recent TP, rising CRP and WBC), the patient was treated with meronem following recommendations of the infectious disease team. She passed away on POD 35 from refractory hypoxemic respiratory failure.\n\nDiscussion and conclusion\nThe global pandemic of COVID-19 has severely challenged the health care systems that face the battle to limit the spread of the SARS-CoV-2 while providing the treatment and care that will save lives. In most countries, cardiac surgery activity has been restricted to urgent or emergent cases, including heart transplantation. The safety of continuing this procedure during the current COVID-19 outbreak is, however, unknown. The literature on this topic is still scant. HTR appears to be at particular high risk for both acquisition of COVID-19 infection and progression to severe disease due to high rates of comorbidities, immunosuppression, and multiple healthcare contacts [12].\n\nLi et al. were the first to report the clinical course of two HTR with COVID-19. However, TP was performed 32 and 194 months before the infection, respectively [1]. The two patients presented with variable levels of severity, one mild, the other more severe and requiring prolonged hospitalization. Both patients survived the infection. Fernando-Ruiz et al. reported the occurrence of COVID-19 among 4 HTR in a single center in Spain. The median interval from transplantation was 12.6 years (range, 8.7–17.9 years). One patient died 10 days after admission for respiratory failure, one patient was still in the ICU, and two patients survived and were discharged home [3]. Since these initial reports, other papers describing the clinical course of COVID-19 in HTR have been published from Germany and the United States. They also featured HTR who were remote from transplant and were mostly receiving relatively low-dose maintenance immunosuppression [2, 4, 5, 7–9]. Recently, Latif et al. described a single-center case series of 28 HTR with a confirmed diagnosis of COVID-19 in the United States. The median time from HT was 8.6 years, and the case fatality rate was 25% [6]. Singhvi et al. also described a single -center case series of 22 HTR in the disease epicenter in New York. The median time from HT was 4.6 years, and the overall mortality was 22.7%, reaching 26.3% in hospitalized patients [9]. Finally, Rivinius et al. reported 21 HTR with COVID-19 in a recent nation-wide survey of all HT centers in Germany during the first months of the pandemic. The overall mortality in their study was 33.3% [8].\n\nTo our knowledge, our report is the first to highlight the clinical course of two HTR for whom viral carriage was confirmed by RT-PCR performed on NPS during the perioperative period. Both patients developed severe COVID-19 infection and ultimately died. The two patients had significant lymphopenia and elevation of inflammatory biomarkers such as CRP. However, the interpretation of the laboratory findings is complicated by confounding factors such as the recent transplant surgery, and the initiation of high doses of immunosuppressive drugs (MM). Laboratory findings are displayed in Fig. 4, Additional files 1 and 2, and Table 1. Histopathological analysis of the myocardial biopsy specimens of both patients did not demonstrate cellular or humoral rejection. However, analysis by electron microscopy revealed viral-like particles within myocardial endothelial cells but not in cardiomyocytes. SARS-CoV-2 gains entry to human cells by binding to the angiotensin-converting enzyme 2 receptor which is expressed in cardiac myocytes. In a case report of a 69-year-old patient with COVID-19 and cardiogenic shock, endomyocardial biopsy revealed viral like particles within interstitial cytopathic macrophages but not in cardiomyocytes or endothelial cells [13]. The coronary microvasculature and endothelium may be at risk for viral entry due to SARS-Cov-2 receptor expression on these cells. Indeed, Vargaz et al. found evidence of direct viral invasion of endothelial cells in several organs of patients with COVID-19 infection using electron microscopic images [14]. Both endotheliitis and cytokine release may play a major role in the pathophysiology of COVID-19 infection and may explain the association between cardiovascular disease and increased morbidity of this illness. In our patients, histological signs of endotheliitis or viral antigen immunoreactivity were not detected in the biopsy specimens suggesting a direct cytolytic effect of the virus unlikely but rather a pathophysiology mechanism based on cytokine release or immune response. This may result in systemic alteration of the microcirculatory function in different vascular beds, causing vasoconstriction, organ ischaemia, inflammation and a pro-coagulant state [14]. It is also likely that the underlying frailty of both patients, related to the heart failure condition, may have contributed to their unfavorable outcome.\nFig. 4 Laboratory findings (Blood count and inflammatory markers) of Recipients 1 (A) and 2 (B). CRP, C-reactive protein; LDH, Lactate dehydrogenase; WBC, White cell blood count\n\nTable 1 Laboratory studies of recipient 1 and recipient 2 throughout their clinical course\n\nCRP C reactive protein, CK Creatinine kinase, LDH Lactate dehydrogenase, hs High sensitivity, WBC White cell blood count\n\n\n\nDefining the precise mechanism of the viral transmission process in our report is challenging. At the time of both procedures, exposure investigations and contact tracing were not performed preoperatively. Recipient 1 was an unknown asymptomatic carrier before the surgery. It appeared later on that he lived in an area of high incidence for COVID-19 infection. Recipient 2 had been hospitalized for 9 days at the time of organ offer. Her preoperative SARS-CoV-2 screening test performed 2 days before the TP was negative, but she further tested positive on POD2. Transmission could theoretically have occurred through inhalation of the first recipient’s viral particles aerosolized in the OR. However, given the number of typical air changes per hour and the associated reduction in airborne contaminants, the possibility of OR transmission is relatively low [15]. Another possibility is contamination in the early preoperative period. The second recipient was never in contact with the first patient’s surgeon during her stay before transplantation. Among the health care workers (HCWs) with exposure to both patients from their hospital admission to their death, only the surgeon of the first procedure tested positive soon after the intervention. However, at that time, testing was only performed among HCWs who exhibited symptoms suggestive of SARS-Cov-2 infection; therefore, asymptomatic HCWs in close contact with both patients were not tested. After both HTR tested positive for SARS-CoV-2, inquiries were carried out among their close relatives and no cases of COVID-19 were reported. Consequently, the origin of viral transmission was never explained for recipient 2.\n\nPractically, recently updated guidance documents from major transplant societies recommend not performing heart transplantation if the donor or the recipient is screened positive for SARS-CoV-2 [16, 17]. However, as illustrated in our cases, the lack of a rapid diagnostic test, the high proportion of asymptomatic carriers [18] capable of transmitting the infection among patients’ acquaintance, the high rate of false negative tests [19], the possibility of donor-recipient transmission, and the absence of massive COVID-19 testing all currently contribute to the impossibility of timely identification of patients who should not receive an emergency transplant.\n\nThe decision to perform two heart TP in the midst of a pandemic with no rapid preoperative testing available to rule out COVID-19 infection could be seriously questioned. However, at the time of both TP, all Belgian transplant centers were still pursuing their program. We were at the beginning of the pandemic in Belgium with 1486 COVID-19 confirmed cases and 14 deaths in the whole country (Additional file 3) [20]. There were 500 patients with COVID-19 hospitalized with 100 in the ICU in the whole country. In addition, our hospital’s prevalence of COVID-19 cases was low (28 patients). The two patients were transplanted just before the beginning of the nationwide lockdown (18th March 2020), and there was no indication that they were infected. At that period (17th March 2020), the ISHLT suggested proceeding with transplantation in waitlisted patients as long as there was no recent exposure or symptoms compatible with COVID-19 in the previous 2 weeks. Furthermore, RT-PCR for SARS-Cov-2 was also recommended depending on timing and testing availability [16]. Despite the fact that the first patient was called in from home, he had experienced recurrent episodes of life-threatening arrhythmia with a worsening of his clinical status the weeks before his transplant, and the second patient was in the cardiologic ward for a new episode of heart failure requiring inotropic support.\n\nQuestions remain on the optimal management of immunosuppression in transplant recipients with Covid-19. Current guidelines from expert associations recommend considering holding MM, mammalian target of rapamycin inhibitors or azathioprine in cases of moderate/severe COVID-19 infection, though specific data are still lacking at this time in the literature [16]. However, whether immunosuppression therapy can modify the course of the disease with either the benefit of a reduced immunological reaction or a greater risk of severe manifestation remains uncertain. In a literature review of published cases of COVID-19 in HTR performed at the beginning of the pandemic, Decker et al. found that immunosuppressive agents have been partially discontinued or reduced in dose in 71.8% of patients [21]. The elevated mortality rate in several case series of COVID-19 among HTR on chronic immunosuppressive therapy does not suggest a protective effect of the immunosuppressive drugs on the course of the infection [6, 8, 9]. However, further studies are needed to evaluate the impact of immunosuppressive therapy on the pathogenesis and outcomes of COVID-19 infection among HTR. In our two asymptomatic patients, we initially continued immunosuppressive drugs without any particular adjustment of the dose while prescribing HCQ known to improve viral clearance. Despite this, the evolution was unfavorable with the appearance of symptoms within 15 days, the standard incubation period for the virus. Even worse, the viral load remained high in both patients despite the interruption of MM in both cases. As confirmed by several recent clinical trials [22, 23], antiviral monotherapy with HCQ was ineffective in both cases. We did not observe any toxicity of that drug in either patient. The potential benefit of other antiviral and immunomodulator drugs has not been tested. The two patients eventually died. Mortality rates associated with COVID-19 increase sharply with age and in patients with underlying cardiovascular diseases such as heart failure [24–26]. Therapy for an overt disease is seriously lacking at the moment, although several promising molecules are still under active clinical investigations. Nonetheless, potential interactions between these medications and immunosuppressive drugs and the choice of the appropriate molecules according to clinical phenotype could add other challenges.\n\nThese two cases illustrate very well the severity and poor prognosis of COVID-19 infection in the immediate aftermath of a heart transplant. Moreover, our report highlights the problematic of asymptomatic carriers and of the delay in turnover time for COVID-19 testing results in HT. As transplant clinicians, we must be very careful about continuing the transplant program in this COVID-19 period. After these two cases, our heart transplant program was temporarily suspended. Our center has now increased its testing capacity as well as the use of serological testing. Our transplant policy is now in accordance with updated recommendations of major transplant societies. Donors and recipients are thoroughly screened to exclude infection and rule out any close contact with a person at risk or diagnosed with COVID-19 in the days preceding the transplant. The TP is not performed before obtaining the RT-PCR test results. In addition, after the procedure, patients should be regularly tested for COVID-19.\n\nSupplementary Information\n\nAdditional file 1: Fig. 5-suppinfo Evolution of the viral load and the absolute lymphocyte count in recipient 1\n\n Additional file 2: Fig. 6-suppinfo Evolution of the viral load and the absolute lymphocyte count in recipient 2.\n\n Additional file 3: Fig. 7-suppinfo Total confirmed COVID-19 deaths and cases in Belgium. (https://www.ecdc.europa.eu/en/covid-19-pandemic). The blue arrow represents the date of the two transplant procedures. The confirmed counts shown here are lower than the total counts. The main reason for this is limited testing and challenges in the attribution of the cause of death (Source: European CDC-Situation update Worldwide-Last updated 29th June, 11).\n\n \n\nAbbreviations\nCOVID-19Coronavirus disease 2019\n\nCPBCardiopulmonary bypass\n\nCRPC reactive protein\n\nCTComputed tomography\n\nDCDDonation after circulatory death\n\nECMOExtracorporeal membrane oxygenation\n\nHCQHydroxychloroquine\n\nHTRHeart transplant recipients\n\nICUIntensive care unit\n\nISHLTThe international society for heart and lung transplantation\n\nMMMycophenolate mofetil\n\nNPSNasopharyngeal swab\n\nOROperating room\n\nPODPostoperative day\n\nRT-PCRReverse transcriptase polymerase chain reaction\n\nSARS-coV-2Severe acute respiratory syndrome coronavirus 2\n\nTEETransesophageal echocardiography\n\nTPTransplant procedure\n\nWBCWhite blood cell count\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nVincent Tchana-Sato and Arnaud Ancion contributed equally to this article.\n\nJean Olivier Defraigne and Patrizio Lancellotti are co senior authors.\n\nAcknowledgements\nNone.\n\nConflict of interest\nThere is no conflict of interest provided.\n\nAuthors’ contributions\nVTS and AA were the main contributors to drafting the manuscript; JT and OD contributed to data collection and literature search; NS, MPH, PD, and OH contributed to drafting the manuscript, data collection and data analysis; NS, PA, MS, DS, JPL, EML, CP, IM, PM, MVDB, and MHD helped to treat both patients; JOD and PL contributed to the final manuscript review. All authors have read and approved the manuscript.\n\nFunding\nThis report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAvailability of data and materials\nThe data that support the findings of this report are available from the corresponding author upon reasonable request.\n\nEthics approval and consent to participate\nAs a case report, our paper did not require any referral to our institutional clinical ethics committee. As both patients ultimately died, consent to participate is not applicable.\n\nConsent for publication\nWritten consent was obtained from both patient families for publication of both cases, as well as the accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Li F, Cai J, Dong N. First cases of COVID-19 in heart transplantation from China. J Heart Lung Transplant. 2020;0(0) [cited 2020 Apr 25]. Available from: https://www.jhltonline.org/article/S1053-2498(20)31467-4/abstract.\n2. Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, et al. COVID-19 in solid organ transplant recipients: initial report from the US epicenter. Am J Transplant. [cited 2020 Apr 27];n/a(n/a). Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/ajt.15941.\n3. Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: a single-center case series from Spain. Am J Transplant. 2020;20:1849–58.\n4. Kates OS, Fisher CE, Stankiewicz-Karita HC, Shepherd AK, Church EC, Kapnadak SG, et al. Earliest cases of coronavirus disease 2019 (COVID-19) identified in solid organ transplant recipients in the United States. Am J Transplant. 2020;20:1885–90.\n5. Mathies D, Rauschning D, Wagner U, Mueller F, Maibaum M, Binnemann C, et al. A case of SARS-CoV-2-pneumonia with successful antiviral therapy in a 77-year-old male with heart transplant. Am J Transplant. 2020;20:1925–9.\n6. Latif F, Farr MA, Clerkin KJ, Habal MV, Takeda K, Naka Y, et al. Characteristics and outcomes of recipients of heart transplant with coronavirus disease 2019. JAMA Cardiol. 2020:e202159. 10.1001/jamacardio.2020.2159. Epub ahead of print. PMID: 32402056; PMCID: PMC7221850.\n7. Holzhauser L, Lourenco L, Sarswat N, Kim G, Chung B, Nguyen AB. Early experience of COVID-19 in 2 heart transplant recipients: case reports and review of treatment options. Am J Transplant. 2020;20(10):2916–27.\n8. Rivinius R, Kaya Z, Schramm R, Boeken U, Provaznik Z, Heim C, et al. COVID-19 among heart transplant recipients in Germany: a multicenter survey. Clin Res Cardiol. 2020;109(12):1531–9.\n9. Singhvi A Barghash M Lala-Trindade A Mitter SS Parikh A Oliveros E Challenges in heart transplantation during COVID-19: a single-center experience J Heart Lung Transplant 2020 39 9 894 903 10.1016/j.healun.2020.06.015 32891266 \n10. Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al.Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25(3):2000045. 10.2807/1560-7917.ES.2020.25.3.2000045. Erratum in: Euro Surveill. 2020 Apr;25(14): Erratum in: Euro Surveill. 2020 Jul;25(30): PMID: 31992387; PMCID: PMC6988269.\n11. Tchana-Sato V Ledoux D Detry O Hans G Ancion A D’Orio V Successful clinical transplantation of hearts donated after circulatory death using normothermic regional perfusion J Heart Lung Transplant Off Publ Int Soc Heart Transplant 2019 38 6 593 598 10.1016/j.healun.2019.02.015 \n12. DeFilippis E, Farr M, Givertz M. Challenges in heart transplantation in the era of COVID-19. Circulation. 2020;141(25):2048–51.\n13. Tavazzi G Pellegrini C Maurelli M Belliato M Sciutti F Bottazzi A Myocardial localization of coronavirus in COVID-19 cardiogenic shock Eur J Heart Fail 2020 22 5 911 915 10.1002/ejhf.1828 32275347 \n14. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet Lond Engl. 2020.\n15. Centers for Disease Control and prevention guidelines for environmental infection control in health care facilities (2003). (https://www.cdc.gov/infectioncontrol/guidelines/environmental/appendix/air.html#tableb1). Accessed 29 June 2020.\n16. ISHLT Guidance from the international society of heart and lung transplantation regarding the SARS-CoV-2 pandemic: Mars,17,2020 (Revised May ,13, 2020) https://ishlt.org/ishlt/media/documents/SARS-CoV-2_-Guidance-for-Cardiothoracic-Transplant-and-VAD-centers.pdf\n17. Vogelaar DS, Shouwweg H, Leiden K. Position statement of the Belgian Transplantation Society (BTS) and the National Belgian Transplant Council (NTC) on organ procurement and organ transplantation during the COVID-19 epidemic in Belgium. 2020. https://www.basl.be/wp-content/uploads/2020/04/BTS_NTC_position-statement-transplantation-COVID_final.pdf\n18. Gandhi M, Yokoe DS, Havlir DV. Asymptomatic transmission, the Achilles’ heel of current strategies to control Covid-19. N Engl J Med. 2020;382(22):2158–60.\n19. Tahamtan A, Ardebili A. Real-time RT-PCR in COVID-19 detection: issues affecting the results. Expert Rev Mol Diagn. 2020;20(5):453–4.\n20. Belgian institute for health (Sciensano) COVID-19. (https://epistat.wiv-isp.be/covid). Accessed 29 June 2020.\n21. Decker A, Welzel M, Laubner K, Grundmann S, Kochs G, Panning M, et al. Prolonged SARS-CoV-2 shedding and mild course of COVID-19 in a patient after recent heart transplantation. Am J Transplant. [cited 2020 Sep 15];n/a(n/a). Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/ajt.16133.\n22. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A randomized trial of Hydroxychloroquine as Postexposure prophylaxis for Covid-19. N Engl J Med. 2020;383:517–25.\n23. Geleris J Sun Y Platt J Zucker J Baldwin M Hripcsak G Observational study of Hydroxychloroquine in hospitalized patients with Covid-19 N Engl J Med 2020 382 25 2411 2418 10.1056/NEJMoa2012410 32379955 \n24. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846–8.\n25. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802–10.\n26. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):811–18.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "Asymptomatic carrier; Case report; Coronavirus disease 2019 (COVID-19); Heart transplantation; Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000962:Antimalarials; D000998:Antiviral Agents; D000086382:COVID-19; D015897:Comorbidity; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D006886:Hydroxychloroquine; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D000086402:SARS-CoV-2; D066027:Transplant Recipients",
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"pubdate": "2021-01-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Clinical course and challenging management of early COVID-19 infection after heart transplantation: case report of two patients.",
"title_normalized": "clinical course and challenging management of early covid 19 infection after heart transplantation case report of two patients"
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"abstract": "A 73-year-old man with liver cirrhosis and advanced chronic kidney disease was admitted to our hospital due to bilateral lower leg edema and appetite loss. Furosemide to treat fluid retention markedly decreased extracellular water compared with intracellular water, but the addition of tolvaptan equally decreased both with a greater diuretic response than furosemide alone. Furthermore, tolvaptan administration increased the plasma colloid osmotic pressure, which might facilitate the shift of fluid from the extravascular space to the intravascular space. This is the first case showing different effects on the fluid distribution between furosemide and additional tolvaptan in the same patient.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Department of Clinical Engineering, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan.",
"authors": "Nagayama|Izumi|I|;Masuda|Takahiro|T|;Nakagawa|Saki|S|;Murakami|Takuya|T|;Ohara|Ken|K|;Matsuoka|Ryo|R|;Kobayashi|Takahisa|T|;Maeshima|Akito|A|;Akimoto|Tetsu|T|;Saito|Osamu|O|;Muto|Shigeaki|S|;Nagata|Daisuke|D|",
"chemical_list": "D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004232:Diuretics; D000077602:Tolvaptan; D005665:Furosemide",
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"doi": "10.2169/internalmedicine.2174-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3071332210.2169/internalmedicine.2174-18Case ReportDifferent Effects on Fluid Distribution between Tolvaptan and Furosemide in a Liver Cirrhosis Patient with Chronic Kidney Disease Nagayama Izumi 1Masuda Takahiro 1Nakagawa Saki 1Murakami Takuya 1Ohara Ken 1Matsuoka Ryo 2Kobayashi Takahisa 1Maeshima Akito 1Akimoto Tetsu 1Saito Osamu 1Muto Shigeaki 1Nagata Daisuke 1\n1 Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Japan\n2 Department of Clinical Engineering, Jichi Medical University, JapanCorrespondence to Dr. Takahiro Masuda, takam@jichi.ac.jp\n\n1 2 2019 1 6 2019 58 11 1587 1591 22 9 2018 27 11 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 73-year-old man with liver cirrhosis and advanced chronic kidney disease was admitted to our hospital due to bilateral lower leg edema and appetite loss. Furosemide to treat fluid retention markedly decreased extracellular water compared with intracellular water, but the addition of tolvaptan equally decreased both with a greater diuretic response than furosemide alone. Furthermore, tolvaptan administration increased the plasma colloid osmotic pressure, which might facilitate the shift of fluid from the extravascular space to the intravascular space. This is the first case showing different effects on the fluid distribution between furosemide and additional tolvaptan in the same patient. \n\ntolvaptanfurosemideliver cirrhosisbioimpedance analysisextracellular waterintracellular water\n==== Body\nIntroduction\nLoop diuretics like furosemide have been widely used for the treatment of fluid retention and edema associated with heart failure, renal dysfunction and liver cirrhosis (1,2). However, loop diuretics increase the risk of a worsening renal function and hyponatremia, which are poor prognostic factors (1,3-5). Tolvaptan, an oral arginine vasopressin V2 receptor antagonist that inhibits water reabsorption in the renal collecting duct, is also used against excess fluid due to congestive heart failure, chronic kidney disease (CKD) and liver cirrhosis (2). This agent can increase the urine volume without decreasing the renal function and activating the sympathetic nervous system and renin-angiotensin-aldosterone system (2).\n\nSeveral studies using bioelectric impedance analyses (BIA), a non-invasive method for assessing the body composition, have shown that the loop diuretic furosemide predominantly lowers the extracellular water (ECW), including the intravascular volume, instead of the intracellular water (ICW) (6,7). However, we recently reported that tolvaptan decreases the ECW and ICW equally without exacerbating the kidney function (8).\n\nNo report has yet compared the effects of these two agents on the fluid distribution (ECW and ICW) in the same patient. We therefore evaluated the effects of these two diuretics in a liver cirrhosis patient with advanced CKD.\n\nCase Report\nA 73-year-old man with bilateral lower leg edema and appetite loss was referred and admitted to our hospital. He had been diagnosed with hepatitis C infection at 38 years of age and liver cirrhosis at 53 years of age. He had received peginterferon alfa 2a from 63 years of age. The two laparoscopic radiofrequency ablation procedures for hepatocellular carcinoma were performed at 68 and 72 years of age. He had been diagnosed with hypertension at 40 years of age and with CKD [estimated glomerular filtration rate (eGFR) 50-55 mL/min/1.73 m2] 3 years before admission. He developed bilateral lower leg pitting edema and abdominal fullness 3 months before admission, and his primary physician started furosemide (10 mg/day) 1 month later. However, his body weight increased by about 10 kg, so he was referred and admitted to our department.\n\nOn admission, he was taking furosemide (10 mg/day), irbesartan (100 mg/day), allopurinol (100 mg/day), amlodipine (5 mg/day) and hydroxyzine (40 mg/day), and peginterferon alfa 2a was given at 90 μg per 3 weeks subcutaneously. He was alert and oriented at the time of admission. An examination showed a body height of 168 cm, weight of 65.7 kg, blood pressure of 120/60 mmHg and heart rate of 61 beats/min. Spider angioma was seen on the chest, and the bilateral lower legs were edematous. A laboratory examination revealed the following results: hemoglobin, 11.3 g/dL; platelet count, 13.2×104/μL; prothrombin time-international normalized ratio 1.30, total bilirubin; 0.86 mg/dL; aspartate aminotransferase (AST) 28 IU/L; alanine aminotransferase (ALT) 14 IU/L; alkaline phosphatase (ALP) 267 IU/L; γ-glutamyl transpeptidase (γGTP) 13 U/L; blood urea nitrogen (BUN), 55 mg/dL; serum creatinine (sCr), 2.03 mg/dL; eGFR, 26.1 mL/min/1.73 m2 (CKD stage 4); uric acid 6.9 mg/dL; total protein, 5.6 g/dL; serum albumin, 2.2 g/dL; serum sodium, 142 mEq/L; serum potassium, 5.3 mEq/L; serum chloride, 113 mEq/L; brain natriuretic peptide 99.7 pg/mL; C3 64 mg/dL (normal range 86-160 mg/dL); C4 19 mg/dL (normal range 17-45 mg/dL); serum IgA 730 mg/dL (normal range 110-410 mg/dL); urine protein-to-creatinine ratio 1.94 g/gCr; urine red blood cells 10-19/HPF; urine N-acetyl-β-D-glucosaminidase (NAG) 37 U/gCr (normal range 1.0-6.2 U/gCr) and urine β2-microglobulin ＜50 μg/L. Membranoproliferative glomerulonephritis or IgA nephropathy was assumed as his primary renal disease because of the existence of hepatitis C infection, moderate proteinuria and hematuria, a mild decrease in the serum complement and an increase in the serum IgA level. Chest X-ray showed a dull costophrenic angle on the right side without pulmonary congestion, and the cardiothoracic ratio was 47%. Abdominal computed tomography revealed advanced atrophy of the liver with an irregular surface and ascites around the liver. Bilateral renal atrophy was observed (kidney size: right 8.6×4.1 cm, left 8.7×4.2 cm). Ultrasound cardiography demonstrated a normal cardiac function (left ventricular ejection fraction: 85%). His Child-Pugh score was 9 points (grade B).\n\nThe hospital course is shown in Fig. 1. The daily dose of furosemide 20 mg did not sufficiently increase the urine volume (500-800 mL/day) after 7 days and worsened the renal function (sCr: 2.03 vs. 2.39 mg/dL, BUN: 55 vs. 63 mg/dL, serum uric acid: 6.9 vs. 7.5 mg/dL) without increasing the levels of tubular damage marker [urine NAG: 37 vs. 16.8 U/gCr (Day 4)] (9). The mineralocorticoid receptor (MR) antagonist canrenoic acid was then added (100 mg/day), and furosemide was increased to 80 mg/day on Day 7. However, the body water as measured by a BIA device (InBody S10; InBody Japan, Tokyo, Japan) (8,10) did not markedly change for a further 6 days (Fig. 1, 2) while the BUN and BUN/sCr ratio did increase (BUN: 63 vs. 76 mg/dL, BUN/sCr ratio: 26.4 vs. 32.6), suggesting the existence of mild intravascular dehydration. Canrenoic acid was replaced with another MR antagonist spironolactone (50 mg/day) on Day 12, and tolvaptan (3.75 mg/day) was added on Day 13. Thereafter, the urine volume increased to around 2,000 mL/day, and the body weight decreased by about 5 kg for 7 days without the apparent exacerbation of the renal function (sCr: 2.33 vs. 2.19 mg/dL, BUN: 76 vs. 82 mg/dL) (Fig. 1). Furthermore, the body water [ECW, ICW and total body water (TBW)] clearly decreased after the initiation of tolvaptan (Fig. 1, 2). Furosemide was discontinued after 5 days of tolvaptan administration (Fig. 1), because the body weight had decreased sufficiently (approximately 5 kg/5 days) and increased NH3 (353 ug/dL) with consciousness disturbance and constipation (2 days) were noted. The intravenous supplementation of branched-chain amino acids (BCAAs) (200 mL/day) as a treatment for hepatic encephalopathy quickly reduced the NH3 level the next day (136 μg/dL), and the NH3 level remained below 200 μg/dL under treatment with tolvaptan and spironolactone. During the 8-day intravenous supplementation of BCAAs, the BUN increased from 78 to 93 mg/dL, while the sCr decreased from 2.35 to 1.71 mg/dL (Fig. 1). After switching to only oral BCAA supplementation (50 g/day), the BUN returned to 62 mg/dL (Day 30) (Fig. 1).\n\nFigure 1. The clinical course and serial changes in the urine volume, blood urea nitrogen (BUN), serum creatinine (sCr), body weight (BW) and intracellular water (ICW) and extracellular water (ECW). BIA: bioelectric impedance analyses, BCAAs: branched-chain amino acids\n\nFigure 2. Changes in the extracellular water (ECW), intracellular water (ICW) and total body water (TBW) after admission. The ECW, ICW and TBW were clearly decreased after the initiation of tolvaptan (TLV). Day 0: the day of admission\n\nThe bioelectrical impedance analysis (BIA) showed that furosemide predominantly decreased the ECW over the ICW (-7.9% vs. -2.9%) for the first 7 days (Fig. 3A), while the administration of tolvaptan decreased the ECW and ICW similarly and to a greater degree than furosemide alone (-13.8% vs. -15.7%) (Fig. 3A). Consequently, the ratio of ECW to TBW (ECW/TBW) was decreased by furosemide treatment (0.429 vs. 0.416) but slightly increased by adding tolvaptan (0.410 vs. 0.416) for 7 days (Fig. 3B). Furthermore, the administration of tolvaptan increased the plasma osmolality (301 vs. 318 mOsm/kg) and plasma colloid osmotic pressure (14.8 vs. 21.8 mmHg) (11) accompanied by an increase in the serum albumin (2.1 vs. 2.6 g/dL) for 6 days (Fig. 3C). The serum sodium was increased by adding tolvaptan (137 vs. 141 mEq/L) but was decreased by furosemide alone (142 vs. 136 mEq/L) for 7 days.\n\nFigure 3. Furosemide predominantly decreased the extracellular water (ECW), but tolvaptan decreased the intracellular water (ICW) and ECW similarly for 7 days from the baseline of each treatment (A). Furosemide decreased the ratio of the ECW to the total body water (TBW) (ECW/TBW) and colloid osmotic pressure, whereas tolvaptan increased both parameters (B and C).\n\nDiscussion\nThe novel finding of this case is the different effects on the fluid distribution between furosemide and tolvaptan in the same patient, where furosemide predominantly decreases the ECW compared with the ICW while tolvaptan administered together with other diuretics equally decreases the ICW and ECW with a greater diuretic response than furosemide alone. Furthermore, the administration of tolvaptan increased the plasma colloid osmotic pressure, which might facilitate the shifting of fluid from the extravascular space to the intravascular space, while furosemide alone decreased the plasma colloid osmotic pressure.\n\nSeveral studies have shown that loop diuretics predominantly decrease the ECW compared with the ICW (6,7,12). However, we recently reported that tolvaptan induces an equivalent reduction rate of ECW and ICW (8). Thus far, no report has evaluated the differences between furosemide and tolvaptan on fluid distribution in the same patient. Generally, a major driving force of fluid movement from the extravascular to the intravascular compartment is the oncotic pressure gradient (13). A recent review proposed that loop diuretics induce a rapid reduction in the intravascular volume and pressure diminishes the intracapillary hydrostatic pressure (13). This may be either a transient or an ongoing imbalance in fluids residing in the intravascular and extravascular compartments, which results in the plasma refill rate being exceeded (13). In contrast, the review proposed that a vasopressin V2 antagonist would increase the oncotic pressure in response to free-water diuresis, thereby leading to the movement of fluid from the interstitial to the intravascular compartment (13). In the present case, an increase in the plasma colloid osmotic pressure (+47.9%) was seen 6 days after tolvaptan administration, which might have been the driving force of the fluid shifting from the interstitial to the intravascular compartment.\n\nIn addition, the administration of tolvaptan increased the serum sodium concentration, a major determinant of tonicity (effective osmolality) (14), which might have induced the shifting of fluid from the intracellular to the interstitial space, although furosemide alone decreased the serum sodium concentration for the first week. Consequently, the increases in the plasma colloid osmotic pressure and serum sodium concentration after tolvaptan administration might have contributed to the equivalent reduction in the ECW and ICW in this case. It was recently reported that the sugar-protein glycocalyx, which covers the endothelium, plays an important role in the maintenance of an oncotic gradient across the endothelial barrier (15). Thus, a further examination may be necessary to determine whether or not glycocalyx contributes to the differences in the effects on fluid distribution between furosemide and tolvaptan.\n\nThe present patient was a responder to tolvaptan, showing a reduction in body weight of approximately 5 kg/week, which more than matches the “responder criteria” (cut-off value for body weight loss of 1.5 kg/week) (16). Tolvaptan is reportedly effective for ameliorating fluid retention in patients with liver cirrhosis with ascites (17,18) and advanced CKD (8,19,20), but a low serum sodium level (＜130 mEq/L) is associated with non-responsiveness to tolvaptan (18). In addition, recent studies have shown that tolvaptan exerts a diuretic action even in patients with low serum albumin levels (18,21,22). Because tolvaptan blocks the vasopressin V2 receptor from the basolateral side of the tubules, it is not dependent on the GFR provided the renal blood flow (RBF) is maintained (2). Furthermore, unlike furosemide, tolvaptan exerts diuretic action without binding to albumin, so hypoalbuminemia does not cause diuretic resistance when tolvaptan is given (2). The present patient had liver cirrhosis and advanced CKD (stage 4) with normal serum sodium and low serum albumin levels, so he was expected to be a good responder to tolvaptan. Indeed, the clear diuretic response for tolvaptan might have contributed to the increase in the serum albumin level and plasma colloid osmotic pressure, acting as a driving force for the fluid shift from the interstitial to the intravascular compartment. However, as shown in this case, the careful monitoring and management of excessive diuresis and resultant hepatic encephalopathy is necessary, especially in patients who show a good response to tolvaptan.\n\nA potential limitation in the present case is that the effect of tolvaptan alone on the fluid distribution remains unclear, as tolvaptan was added after treatment with the diuretics furosemide and spironolactone. Similar to the present case, we previously experienced 2 cases in which tolvaptan was administered in addition to furosemide and spironolactone; there as well, tolvaptan equally decreased the ECW and ICW (-5.9% vs. -5.3%) (8). Furthermore, tolvaptan added to a loop diuretic without spironolactone also exerted roughly the same reductive effect on the ECW and ICW in our previous cases (-7.6% vs. -7.0%, p=0.425) (8). As drug use regulations in Japan do not permit monotherapy with tolvaptan for the treatment of fluid retention, the effects of tolvaptan monotherapy, such as in autosomal dominant polycystic kidney disease patients and/or a head-to-head animal study of furosemide and tolvaptan using a BIA device (22), must be clarified. In addition, the single effect of spironolactone on fluid distribution must also be evaluated, as some interaction between spironolactone and other diuretics may exist.\n\nIn conclusion, this case highlights the different effects on the fluid distribution between furosemide and additional tolvaptan in the same patient, where furosemide predominantly decreases the ECW compared with the ICW while tolvaptan administration equally decreases the ICW and ECW with a greater diuretic response than furosemide alone. Furthermore, the administration of tolvaptan increased the plasma colloid osmotic pressure, which might facilitate shifting fluid from the extravascular space to the intravascular space.\n\n\nThis case was presented at the 47th Eastern Regional Meeting of the Japanese Society of Nephrology.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nCleland JG , Coletta A , Witte K \nPractical applications of intravenous diuretic therapy in decompensated heart failure . Am J Med \n119 : S26 -S36 , 2006 .17113397 \n2. \nMori T , Ohsaki Y , Oba-Yabana I , Ito S \nDiuretic usage for protection against end-organ damage in liver cirrhosis and heart failure . Hepatol Res \n47 : 11 -22 , 2017 .26990144 \n3. \nDamman K , Navis G , Voors AA , et al \nWorsening renal function and prognosis in heart failure: systematic review and meta-analysis . J Card Fail \n13 : 599 -608 , 2007 .17923350 \n4. \nHirano T , Yamamura Y , Nakamura S , Onogawa T , Mori T \nEffects of the V(2)-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats . J Pharmacol Exp Ther \n292 : 288 -294 , 2000 .10604960 \n5. \nMatsue Y , Suzuki M , Seya M , et al \nTolvaptan reduces the risk of worsening renal function in patients with acute decompensated heart failure in high-risk population . J Cardiol \n61 : 169 -174 , 2013 .23159210 \n6. \nVasavada N , Agarwal R \nRole of excess volume in the pathophysiology of hypertension in chronic kidney disease . Kidney Int \n64 : 1772 -1779 , 2003 .14531810 \n7. \nSoderberg M , Hahn RG , Cederholm T \nBioelectric impedance analysis of acute body water changes in congestive heart failure . Scand J Clin Lab Invest \n61 : 89 -94 , 2001 .11347985 \n8. \nMasuda T , Murakami T , Igarashi Y , et al \nDual impact of tolvaptan on intracellular and extracellular water in chronic kidney disease patients with fluid retention . Intern Med \n55 : 2759 -2764 , 2016 .27725533 \n9. \nMasuda T , Akimoto T , Ando Y , et al \nChanges in the urinary excretion of beta2-microglobulin (beta 2MG) and N-acetyl-beta-D-glucosaminidase (NAG) during treatment for lupus nephritis . Intern Med \n47 : 287 -290 , 2008 .18277031 \n10. \nMasuda T , Ohara K , Murakami T , et al \nSodium-glucose cotransporter 2 inhibition with dapagliflozin ameliorates extracellular volume expansion in diabetic kidney disease patients . POJ Diabetes Obes \n1 : 1 -8 , 2017 .\n11. \nNitta S , Ohnuki T , Ohkuda K , Nakada T , Staub NC \nThe corrected protein equation to estimate plasma colloid osmotic pressure and its development on a nomogram . Tohoku J Exp Med \n135 : 43 -49 , 1981 .7324049 \n12. \nNg Kam Chuen MJ , Lip GY , Macfadyen RJ \nPerforming repeated noninvasive bedside measures of volume response to intravenous furosemide in acute pulmonary edema: a feasibility assessment . Cardiovasc Ther \n27 : 89 -95 , 2009 .19426245 \n13. \nGoldsmith SR , Bart BA , Burnett J \nDecongestive therapy and renal function in acute heart failure: time for a new approach? \nCirc Heart Fail \n7 : 531 -535 , 2014 .24847128 \n14. \nStookey JD , Purser JL , Pieper CF , Cohen HJ \nPlasma hypertonicity: another marker of frailty? \nJ Am Geriatr Soc \n52 : 1313 -1320 , 2004 .15271119 \n15. \nOkada H , Takemura G , Suzuki K , et al \nThree-dimensional ultrastructure of capillary endothelial glycocalyx under normal and experimental endotoxemic conditions . Crit Care \n21 : 261 , 2017 .29058634 \n16. \nHiramine Y , Uojima H , Nakanishi H , et al \nResponse criteria of tolvaptan for the treatment of hepatic edema . J Gastroenterol \n53 : 258 -268 , 2018 .28664229 \n17. \nKogiso T , Kobayashi M , Yamamoto K , et al \nThe outcome of cirrhotic patients with ascites is improved by the normalization of the serum sodium level by tolvaptan . Intern Med \n56 : 2993 -3001 , 2017 .28943585 \n18. \nHayashi M , Abe K , Fujita M , Okai K , Takahashi A , Ohira H \nAssociation between the serum sodium levels and the response to tolvaptan in liver cirrhosis patients with ascites and hyponatremia . Intern Med \n57 : 2451 -2458 , 2018 .29607963 \n19. \nKatsumata M , Hirawa N , Sumida K , et al \nEffects of tolvaptan in patients with chronic kidney disease and chronic heart failure . Clin Exp Nephrol \n21 : 858 -865 , 2017 .28190113 \n20. \nTominaga N , Kida K , Inomata T , et al \nComparison of the effects of tolvaptan and furosemide on renal water and sodium excretion in patients with heart failure and advanced chronic kidney disease: a subanalysis of the K-STAR study . Clin Exp Nephrol \n2018 (Epub ahead of print).\n21. \nTakada T , Masaki T , Hoshiyama A , Toki T , Kamata Y , Shichiri M \nTolvaptan alleviates excessive fluid retention of nephrotic diabetic renal failure unresponsive to furosemide . Nephrology (Carlton) \n23 : 883 -886 , 2018 .29665203 \n22. \nTakagi K , Sato N , Ishihara S , et al \nEffects of tolvaptan on urine output in hospitalized heart failure patients with hypoalbuminemia or proteinuria . Heart Vessels \n33 : 413 -420 , 2018 .29063302\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(11)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "bioimpedance analysis; extracellular water; furosemide; intracellular water; liver cirrhosis; tolvaptan",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004232:Diuretics; D004359:Drug Therapy, Combination; D004487:Edema; D018495:Fluid Shifts; D005665:Furosemide; D006801:Humans; D007866:Leg; D008103:Liver Cirrhosis; D008297:Male; D051436:Renal Insufficiency, Chronic; D000077602:Tolvaptan",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1587-1591",
"pmc": null,
"pmid": "30713322",
"pubdate": "2019-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10604960;11347985;14531810;15271119;17113397;17923350;18277031;19426245;23159210;24847128;26990144;27725533;28190113;28664229;28943585;29058634;29063302;29607963;29665203;29934667;7324049",
"title": "Different Effects on Fluid Distribution between Tolvaptan and Furosemide in a Liver Cirrhosis Patient with Chronic Kidney Disease.",
"title_normalized": "different effects on fluid distribution between tolvaptan and furosemide in a liver cirrhosis patient with chronic kidney disease"
} | [
{
"companynumb": "JP-OTSUKA-2019_023538",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOLVAPTAN"
},
"drugadditional": "3",
"d... |
{
"abstract": "We investigate the impact of granulocyte-colony stimulating factor (G-CSF) primary prophylaxis (G-PP, N = 83) versus no G-PP (N = 579) on safety and efficacy of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) in the ECHELON-1 study of previously untreated stage III/IV classical Hodgkin lymphoma. G-PP was associated with lower incidence of ≥ grade 3 neutropenia (29% versus 70%) and febrile neutropenia (11% versus 21%). Fewer dose delays (35% versus 49%), reductions (20% versus 26%), and hospitalizations (29% versus 38%) were observed. Seven neutropenia-associated deaths occurred in the A + AVD arm; none received G-PP. A + AVD with G-PP was associated with decreased risk of a modified progression-free survival event by 26% compared with A + AVD alone (95% CI: 0.40-1.37). G-PP reduced the rate and severity of adverse events, including febrile neutropenia, reduced treatment delays, dose reductions, and discontinuations, and may thus improve efficacy outcomes. These data support G-PP for all patients treated with A + AVD.",
"affiliations": "Memorial Sloan Kettering Cancer Center, New York City, NY, USA.;Oxford Cancer and Hematology Center, Churchill Hospital, Oxford, UK.;Maria Sklodowska-Curie Memorial Institute and Oncology Center, Warsaw, Poland.;Institute of Hematology Seragnoli, University of Bologna, Bologna, Italy.;Department of Clinical Haematology, Austin Hospital, Melbourne, Australia.;Institut Català d'Oncologia-Hospitalet, Hospital Quirón Dexeus, Barcelona, Spain.;University of Debrecen, Faculty of Medicine, Debrecen, Hungary.;Seoul National University Hospital, Seoul, Republic of Korea.;Petrov Research Institute of Oncology, St. Petersburg, Russia.;Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Hematology Service, Hospital das Clinicas HCFMUSP, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.;Memorial Sloan Kettering Cancer Center, New York City, NY, USA.;BC Cancer Centre for Lymphoid Cancer, Vancouver, Canada.;Seattle Genetics, Bothell, WA, USA.;Seattle Genetics, Bothell, WA, USA.;Millennium Pharmaceuticals, Cambridge, MA, USA.;Millennium Pharmaceuticals, Cambridge, MA, USA.;Millennium Pharmaceuticals, Cambridge, MA, USA.;Research and Clinical Innovation, Antoine-Lacassagne Cancer Center, Nice, France.",
"authors": "Straus|David|D|;Collins|Graham|G|;Walewski|Jan|J|;Zinzani|Pier Luigi|PL|;Grigg|Andrew|A|;Sureda|Anna|A|;Illes|Arpad|A|;Kim|Tae Min|TM|;Alekseev|Sergey|S|;Specht|Lena|L|;Buccheri|Valeria|V|;Younes|Anas|A|;Connors|Joseph|J|;Forero-Torres|Andres|A|;Fenton|Keenan|K|;Gautam|Ashish|A|;Purevjal|Indra|I|;Liu|Rachael|R|0000-0001-6033-4510;Gallamini|Andrea|A|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor; D014747:Vinblastine; D000079963:Brentuximab Vedotin",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2020.1791846",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "61(12)",
"journal": "Leukemia & lymphoma",
"keywords": "Hodgkin lymphoma; brentuximab vedotin; frontline therapy; growth factor; primary prophylaxis",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D000079963:Brentuximab Vedotin; D016179:Granulocyte Colony-Stimulating Factor; D006689:Hodgkin Disease; D006801:Humans; D014747:Vinblastine",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2931-2938",
"pmc": null,
"pmid": "32842815",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Primary prophylaxis with G-CSF may improve outcomes in patients with newly diagnosed stage III/IV Hodgkin lymphoma treated with brentuximab vedotin plus chemotherapy.",
"title_normalized": "primary prophylaxis with g csf may improve outcomes in patients with newly diagnosed stage iii iv hodgkin lymphoma treated with brentuximab vedotin plus chemotherapy"
} | [
{
"companynumb": "US-AMGEN-USASP2021052365",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "Various cutaneous manifestations have been observed in patients with COVID-19 infection. However, the skin side effects of the medications used for COVID-19, such as famotidine, have not been studied. <P> Objective: This case series aim to present our challenge to define cutaneous manifestations between famotidine and COVID-19. <P> Methods: We identified patients from Imam Khomeini hospital complex who were admitted to the ward with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) taking famotidine and having cutaneous rash. Clinical data were obtained through observation and intervention. <P> Results: We found 4 SARS-COV-2 patients with cutaneous manifestations. The mean (±SD) age of the patients was 57±2 years, 3 patients were men, and COVID-19 symptoms began 10±3 days before admission. The most common symptoms were cough and shortness of breath. All the patients were admitted for hypoxemic respiratory failure. Patients received famotidine for gastrointestinal prophylaxis, and all 4 patients developed Acral macular mountainous skin lesion in the upper and lower extremities, then we discontinued famotidine and lesions were recovered completely in all patients. <P> Conclusion: These cases prompted us to inform clinicians about cutaneous complications of famotidine in COVID-19 patients.",
"affiliations": "Department of Infectious Diseases, Imam-Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran. Iran.;Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran. Iran.;Department of Infectious Diseases, Imam-Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran. Iran.;Department of Infectious Diseases, Imam-Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran. Iran.;Department of Infectious Diseases, Imam-Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran. Iran.",
"authors": "Salehi|Mohammadreza|M|;Khalili|Hossein|H|;Jahani|Zahra|Z|;Rasoolinegad|Mehrnaz|M|;Ghiasvanad|Fereshte|F|",
"chemical_list": null,
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886316666211005102711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": null,
"journal": "Current drug safety",
"keywords": "Adverse Effect; COVID-19; Cutaneous Lesions; Famotidine; Rash; Red Spot; SARS COV-2",
"medline_ta": "Curr Drug Saf",
"mesh_terms": null,
"nlm_unique_id": "101270895",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34636306",
"pubdate": "2021-10-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Famotidine Possible Cutaneous Rash in Covid-19 Patients: An Adverse Effect Case Series.",
"title_normalized": "famotidine possible cutaneous rash in covid 19 patients an adverse effect case series"
} | [
{
"companynumb": "IR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-315884",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FAMOTIDINE"
},
"drug... |
{
"abstract": "OBJECTIVE\nTo report a case of lamotrigine-induced tubulointerstitial nephritis and uveitis (TINU)-atypical Cogan syndrome.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nA 16-year-old boy with traumatic brain injury and seizures presented to the emergency department with facial swelling, rash, and back pain several days after increasing lamotrigine dose secondary to a breakthrough seizure. Creatinine, urine β2 microglobulin, and eosinophils were elevated. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme, and complement were normal. Renal biopsy showed acute granulomatous tubulointerstitial nephritis. Lamotrigine was discontinued, intravenous steroids were initiated, and the patient was discharged on Ativan and prednisone. Subsequently, he was diagnosed with bilateral anterior uveitis (vision 20/30 bilaterally) and started on prednisolone and cyclopentolate. Two months later, he developed a branch retinal artery occlusion in the right eye (vision 20/70) and bilateral ocular hypertension for which timolol-brimonidine and dorzolamide were added. Neuroimaging and hypercoagulability workup was unremarkable. Vision and intraocular pressure improved, while uveitis remained recalcitrant. Several months later, the patient developed central serous retinopathy in the right eye (vision 20/30). Prednisone was stopped but restarted due to methotrexate intolerance. A month later, he reported dizziness and was diagnosed with severe bilateral sensorineural hearing loss. Brain magnetic resonance imaging showed foci of perivascular, subcortical, and cochlear enhancement. Transtympanic Decadron injections and infliximab infusions were initiated. At the final visit, vision remained at 20/30 with trace anterior chamber reaction bilaterally while on timolol-brimonidine, dorzolamide, and prednisolone.\n\n\nCONCLUSIONS\nAn idiosyncratic drug reaction should be considered in the differential diagnosis of TINU-atypical Cogan syndrome.",
"affiliations": "Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA - USA.;Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA - USA.",
"authors": "Kolomeyer|Anton M|AM|;Kodati|Shyam|S|",
"chemical_list": "D000927:Anticonvulsants; D005938:Glucocorticoids; D014227:Triazines; D005477:Fluprednisolone; D011239:Prednisolone; C015808:difluprednate; D000077213:Lamotrigine; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "26(1)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D055952:Cogan Syndrome; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D005477:Fluprednisolone; D005938:Glucocorticoids; D006801:Humans; D000077213:Lamotrigine; D018810:Magnetic Resonance Angiography; D008297:Male; D009395:Nephritis, Interstitial; D011239:Prednisolone; D011241:Prednisone; D041623:Tomography, Optical Coherence; D014227:Triazines; D014605:Uveitis",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "e14-6",
"pmc": null,
"pmid": "26350991",
"pubdate": "2015-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lamotrigine-induced tubulointerstitial nephritis and uveitis-atypical Cogan syndrome.",
"title_normalized": "lamotrigine induced tubulointerstitial nephritis and uveitis atypical cogan syndrome"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2015-04544",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditiona... |
{
"abstract": "Incidental soft tissue lumps in the scalp are a common presenting complaint in clinical practice. However, they may signify more sinister underlying pathologies. Our report examines a 63-year-old man presenting with impaired co-ordination in his left hand following a 3-month history of a painless left retroauricular scalp lump. MRI revealed a large left occipital soft tissue mass eroding through the underlying skull with infiltration into the underlying cerebellum and temporal lobe. Open biopsy confirmed a diagnosis of high-grade intracranial neuroendocrine tumour (NET). At approximately 5 months following successful tumour resection and adjuvant chemotherapy, he developed tumour recurrence and was subsequently palliated, and died at 1 year post diagnosis. Herein, we review other cases of primary intracranial NET, clinical findings, histopathological features and prognosis.",
"affiliations": "Neurosurgery, Southampton University Hospitals NHS Trust, Southampton, UK.;School of Medicine, Cardiff University, Cardiff, UK sharouffh@cardiff.ac.uk.;School of Medicine, Cardiff University, Cardiff, UK.;Department of Neurosurgery, University Hospital of Wales, Cardiff University, Cardiff, UK.",
"authors": "Manivannan|Susruta|S|http://orcid.org/0000-0001-5905-2073;Sharouf|Feras|F|http://orcid.org/0000-0002-3034-3392;Lammie|George|G|;Leach|Paul|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236856",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "endocrine cancer; neurosurgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001932:Brain Neoplasms; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D018358:Neuroendocrine Tumors; D012535:Scalp",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33619129",
"pubdate": "2021-02-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Unusual cause of a painless soft tissue mass of the scalp: a rare presentation of primary intracranial neuroendocrine neoplasm.",
"title_normalized": "unusual cause of a painless soft tissue mass of the scalp a rare presentation of primary intracranial neuroendocrine neoplasm"
} | [
{
"companynumb": "GB-HIKMA PHARMACEUTICALS USA INC.-GB-H14001-21-03645",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstancename": "CARBOPLATIN"
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"... |
{
"abstract": "Mitoxantrone is a promising new agent developed in an attempt to find drugs with a broad spectrum of antitumor activity and devoid of cardiotoxicity. In a phase II clinical trial for refractory metastatic breast cancer, we observed congestive heart failure in four of 31 high-risk patients either during or after treatment with this drug. This report calls attention to that observation, and recommendation is made that further evaluation of this agent include careful cardiac monitoring.",
"affiliations": null,
"authors": "Schell|F C|FC|;Yap|H Y|HY|;Blumenschein|G|G|;Valdivieso|M|M|;Bodey|G|G|",
"chemical_list": "D000880:Anthraquinones; D000970:Antineoplastic Agents; D008942:Mitoxantrone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-5960",
"issue": "66(8)",
"journal": "Cancer treatment reports",
"keywords": null,
"medline_ta": "Cancer Treat Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D000880:Anthraquinones; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D004341:Drug Evaluation; D005260:Female; D006333:Heart Failure; D006801:Humans; D008875:Middle Aged; D008942:Mitoxantrone; D009362:Neoplasm Metastasis; D012306:Risk",
"nlm_unique_id": "7607107",
"other_id": null,
"pages": "1641-3",
"pmc": null,
"pmid": "7105054",
"pubdate": "1982-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Potential cardiotoxicity with mitoxantrone.",
"title_normalized": "potential cardiotoxicity with mitoxantrone"
} | [
{
"companynumb": "US-PFIZER INC-202200829349",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nTo estimate maternal outcome after conservative management of placenta accreta.\n\n\nMETHODS\nThis retrospective multicenter study sought to include all women treated conservatively for placenta accreta in tertiary university hospital centers in France from 1993 to 2007. Conservative management was defined by the obstetrician's decision to leave the placenta in situ, partially or totally, with no attempt to remove it forcibly. The primary outcome was success of conservative treatment, defined by uterine preservation. The secondary outcome was a composite measure of severe maternal morbidity including sepsis, septic shock, peritonitis, uterine necrosis, fistula, injury to adjacent organs, acute pulmonary edema, acute renal failure, deep vein thrombophlebitis or pulmonary embolism, or death.\n\n\nRESULTS\nOf the 40 university hospitals that agreed to participate in this study, 25 institutions had used conservative treatment at least once (range 1-46) and had treated a total of 167 women. Conservative treatment was successful for 131 of the women (78.4%, 95% confidence interval [CI] 71.4-84.4%); of the remaining 36 women, 18 had primary hysterectomy and 18 had delayed hysterectomy (10.8% each, 95% CI 6.5-16.5%). Severe maternal morbidity occurred in 10 cases (6.0%, 95% CI 2.9-10.7%). One woman died of myelosuppression and nephrotoxicity related to intraumbilical methotrexate administration. Spontaneous placental resorption occurred in 87 of 116 cases (75.0%, 95% CI 66.1-82.6%), with a median delay from delivery of 13.5 weeks (range 4-60 weeks).\n\n\nCONCLUSIONS\nConservative treatment for placenta accreta can help women avoid hysterectomy and involves a low rate of severe maternal morbidity in centers with adequate equipment and resources.",
"affiliations": "From the Departments of Obstetrics and Gynecology, Angers University Hospital, Angers; Rouen University Hospital, Charles Nicolle, Rouen; Rennes University Hospital, Rennes; Maternité Port-Royal Hospital, Cochin APHP, University René Descartes, Paris; Centre Hospitalier Intercommunal de Créteil, University of Paris XII, Henri Mondor, Créteil; Conception Hospital, University of Mediterranee, Marseille; North Hospital, University of Mediterranee, Marseille; Antoine Béclère Hospital, University Paris Sud, Paris; Kremlin-Bicètre Hospital, University Paris Sud, Paris; Tours University Hospital, Tours; Nantes University Hospital, Nantes; CHU La Milétrie Hospital, University of Poitiers, Poitiers; Hôpital Necker-Enfants Malades, University René Descartes, Paris; Caen University Hospital, Caen; and Hôpital Bichat Claude-Bernard, APHP, University Paris-VII, Paris, France.",
"authors": "Sentilhes|Loïc|L|;Ambroselli|Clémence|C|;Kayem|Gilles|G|;Provansal|Magali|M|;Fernandez|Hervé|H|;Perrotin|Franck|F|;Winer|Norbert|N|;Pierre|Fabrice|F|;Benachi|Alexandra|A|;Dreyfus|Michel|M|;Bauville|Estelle|E|;Mahieu-Caputo|Dominique|D|;Marpeau|Loïc|L|;Descamps|Philippe|P|;Goffinet|François|F|;Bretelle|Florence|F|",
"chemical_list": "D010120:Oxytocics",
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0b013e3181d066d4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "115(3)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D000328:Adult; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D010120:Oxytocics; D010921:Placenta Accreta; D006473:Postpartum Hemorrhage; D011247:Pregnancy; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "526-534",
"pmc": null,
"pmid": "20177283",
"pubdate": "2010-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Maternal outcome after conservative treatment of placenta accreta.",
"title_normalized": "maternal outcome after conservative treatment of placenta accreta"
} | [
{
"companynumb": "FR-PFIZER INC-2016584251",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "A 27-year old caucasian male was diagnosed 2.7 years after kidney transplantation with Epstein-Barr virus (EBV)-associated smooth muscle tumors in liver and spleen. The reduction in immunosuppression and conversion from tacrolimus to sirolimus did not lead to a regression of the tumors. Additionally, the patient developed a cellular rejection of his renal allograft, which was successfully treated. A combined approach with stereotactic radiofrequency ablation (SRFA) and surgical resection was effective in the treatment of the tumors.",
"affiliations": "Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.;Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.;Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.;Institute of Pathology, Friedrich-Alexander University of Erlangen-Nuremberg, University Hospital of Erlangen, Erlangen, Germany.;Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.;Department of Internal Medicine IV, Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria.",
"authors": "Pircher|C|C|http://orcid.org/0000-0002-0549-456X;Schneeberger|S|S|;Boesmueller|C|C|;Agaimy|A|A|;Zoller|H|H|;Bale|R|R|;Henninger|B|B|;Mayer|G|G|;Neuwirt|H|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12860",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "20(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Epstein-Barr virus; kidney transplantation; smooth muscle tumors",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D020031:Epstein-Barr Virus Infections; D006084:Graft Rejection; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008099:Liver; D008297:Male; D016634:Radiosurgery; D020123:Sirolimus; D018235:Smooth Muscle Tumor; D013154:Spleen; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e12860",
"pmc": null,
"pmid": "29427352",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A rare case of Epstein-Barr virus-associated hepatosplenic smooth muscle tumors after kidney transplantation.",
"title_normalized": "a rare case of epstein barr virus associated hepatosplenic smooth muscle tumors after kidney transplantation"
} | [
{
"companynumb": "AT-ALKEM LABORATORIES LIMITED-AT-ALKEM-2018-00876",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "Triple negative breast cancer (TNBC) has poor prognosis without targetable mutations. The combination of lenvatinib and pembrolizumab has shown clinical activity in different types of solid tumors.\nWe report a case of one patient with metastatic TNBC who has been heavily pretreated. The patient had been treated with multiple lines (≥ 8 lines) of chemotherapy without durable clinical responses. Her tumor regressed significantly under the combination of lenvatinib and immune checkpoint inhibitor, and remains stable for 10 months.\nThe combination of lenvatinib and immune checkpoint inhibitor may have significant clinical activity in selective patients with heavily pretreated metastatic TNBC.",
"affiliations": "Department of Medical Oncology & Molecular Therapeutics, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA, United States.;Department of Medical Oncology & Molecular Therapeutics, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA, United States.;Department of Medical Oncology & Molecular Therapeutics, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA, United States.",
"authors": "Lee|Jin Sun|JS|;Yost|Susan E|SE|;Yuan|Yuan|Y|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.582185",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.582185\nOncology\nCase Report\nCase Report: Significant Response to the Combination of Lenvatinib and Immune Checkpoint Inhibitor in a Patient With Heavily Pretreated Metastatic Triple Negative Breast Cancer\nLee Jin Sun Yost Susan E. Yuan Yuan \n*\n \nDepartment of Medical Oncology & Molecular Therapeutics, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA, United States\n\nEdited by: Brian J. Czerniecki, Moffitt Cancer Center, United States\n\nReviewed by: Melinda L. Telli, Stanford University, United States; Patrick Dillon, University of Virginia, United States\n\n*Correspondence: Yuan Yuan, yuyuan@coh.org\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology\n\n\n11 1 2021 \n2020 \n10 58218510 7 2020 25 11 2020 Copyright © 2021 Lee, Yost and Yuan2021Lee, Yost and YuanThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background\nTriple negative breast cancer (TNBC) has poor prognosis without targetable mutations. The combination of lenvatinib and pembrolizumab has shown clinical activity in different types of solid tumors.\n\nCase Presentation\nWe report a case of one patient with metastatic TNBC who has been heavily pretreated. The patient had been treated with multiple lines (≥ 8 lines) of chemotherapy without durable clinical responses. Her tumor regressed significantly under the combination of lenvatinib and immune checkpoint inhibitor, and remains stable for 10 months.\n\nConclusions\nThe combination of lenvatinib and immune checkpoint inhibitor may have significant clinical activity in selective patients with heavily pretreated metastatic TNBC.\n\ntriple negative breast cancerlenvatinibimmune checkpoint inhibitorspembrolizumabpersonalized treatment\n==== Body\nIntroduction\nTriple negative breast cancer (TNBC) is associated with impaired clinical outcome compared with other types of breast cancer (1). While breast cancer has improved survival outcomes contributed by hormone and HER2 targeted therapy in the past decades, TNBC remains a non-targetable disease without significant advances in survival outcomes (2). The median overall survival (OS) of metastatic TNBC (mTNBC) is about 12 months with treatment (3).\n\nCurrently, mTNBC has limited treatment options including cytotoxic chemotherapy, and the response is poor after prior treatment. A recent clinical trial of the PD-L1 inhibitor atezolizumab combined with nab-paclitaxel demonstrated a significant clinical benefit, with median duration of response of 8.5 months and median progression free survival (PFS) prolonged by 2.5 months in PD-L1 positive group (4). The results are not fulfilling considering this is a first line therapy.\n\nLenvatinib is a multiple kinase inhibitor against VEGFR1, VEGFR2, and VEGFR3 that has been used as a single agent for advanced thyroid cancer and hepatocellular carcinoma (HCC). Its single use has not been proven for breast cancer. Immune checkpoint inhibitors (ICIs) are extensively used in different types of malignant tumors, and the PD-1 inhibitor pembrolizumab has been studied as a single agent showing a modest response in heavily pretreated mTNBC (5, 6). The early clinical trial of lenvatinib combined with pembrolizumab has demonstrated antitumor activity in multiple solid tumors including advanced endometrial cancer (7, 8). A phase 2 study of lenvatinib plus pembrolizumab in previously treated solid tumors including mTNBC is ongoing (NCT03797326), and the prelim result was recently presented (9).\n\nHerein, we report a case of the patient with heavily pretreated mTNBC who achieved remarkable responses to the combination of lenvatinib and immune checkpoint inhibitors. The patient provided consent to publish their information and images.\n\nCase\nThe patient is a 47 years old female with a history of childhood acute lymphoblastic leukemia at age 15, who was in remission after intensive chemotherapy followed by allogenic hematopoietic stem cell transplantation. Patient was diagnosed with breast cancer in July 2013. The initial stage was cT3N2 and pathology was reported as TNBC. She was treated with neoadjuvant chemotherapy (docetaxel and cyclophosphamide) followed by skin sparing mastectomy in October 2013. She received adjuvant chemotherapy (epirubicin and vinorelbine) until March 2014.\n\nDue to rising CA 27-29 in September 2015, PET/CT was performed and showed new lymphadenopathy in the left supra- and infraclavicular and subpectoral area, as well as left axilla. Pathology from fine needle aspiration confirmed mTNBC. She was started on the first line capecitabine in December 2015. She received “immunotherapy (agent name was unknown)” in Germany in 2016 along with intermittent capecitabine. Due to progression of the disease she was enrolled in a clinical trial (unknown name) in July 2016, but developed progression in September 2016. Since then she was treated with multiple lines including third line of carboplatin and gemcitabine started in October 2016, fourth line of pembrolizumab in July 2017, fifth line of carboplatin and nab-paclitaxel in October 2017, sixth line of eribulin in August 2018, seventh line of bicalutamide for AR positivity of the tumor in January 2019, ixabepilone in February 2019, paclitaxel with palliative radiation in April 2019, and nab-paclitaxel and atezolizumab in July 2019.\n\nPET/CT in October 2019 showed increased anterior chest wall mass, right axillary lymph nodes, and mesenteric lymph nodes. Patient visited our institution to seek second opinion in November 2019, and lenvatinib combined with an ICI was recommended. Consequently, the patient was started with lenvatinib 20mg p.o. daily along with the continuation of atezolizumab 840 mg i.v. every 2 weeks from January 2020. After 4 weeks of lenvatinib use, the dose of lenvatinib reduced by 50% (10 mg daily) due to fatigue per the outside oncology note. Patient transferred her care to our institution in May 2020, then atezolizumab was switched to pembrolizumab. The dose of lenvatinib was increased up to 18 mg daily combined with pembrolizumab without significant fatigue or other toxicities. The patient has experienced grade 2 leukopenia and neutropenia once, which improved to grade 1 without medical intervention. Currently patient is on lenvatinib 18 mg daily plus pembrolizumab with significant response for 10 months. PET/CT and images of gross tumor before treatment with lenvatinib combined with ICI are shown in \nFigures 1\n and \n2\n. The pain from a large mass was resolved and the sternal wound was healed, and minimal bleeding from the necrotic tumor was as noted as in \nFigure 1\n; D is the most recent picture with well healed wound).\n\nFigure 1 PET/CT before and after lenvatinib plus pembrolizumab on patient 1. (A) PET/CT demonstrates the chest well tumor before treatment. (B) PET/CT demonstrates near complete response of the chest well tumor.\n\nFigure 2 Gross tumor before and after treatment with lenvatinib plus pembrolizumab of patient 1. (A) shows the initial tumor. (B–D) shows the gross change of the tumor by the timeline.\n\nDiscussion\nThe multiple kinase inhibitor lenvatinib has anti-angiogenic activity that inhibits vascular endothelial growth factor receptors (VEGFR) 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor-a (PDGFRa), tyrosine-kinase receptor KIT, and rearranged during transfectin receptor (RET). Lenvatinib has shown activity in different types of tumors with manageable toxicity profiles (10). Lenvatinib was approved for first line treatment in unresectable HCC after its efficacy was proven in a phase 3 trial (11).\n\nIn addition to lenvatinib’s anti-angiogenic activity, several studies in mouse tumor models have shown antitumor immune activation and increased antitumor activity when combined with a PD-1 inhibitor. Zhang et al. demonstrated lenvatinib-induced antitumor immunity by enhancing tumor-infiltrating natural killer (NK) cells (12). Kato et al. reported that lenvatinib modulated cancer immunity in the tumor microenvironment by reducing tumor associated macrophages (TAMs) and showed enhanced antitumor activity by activation of the interferon pathway when combined with a PD-1 inhibitor (13).\n\nThe efficacy of lenvatinib combined with pembrolizumab has been evaluated in multiple types of solid tumors (8). A study that included metastatic renal cell carcinoma, endometrial cancer, squamous cell carcinoma of the head and neck, melanoma, non-small cell lung cancer, or urothelial cancer that progressed after approved therapies (or did not have available standard treatment), demonstrated promising antitumor activity with manageable toxicity. The combination of lenvatinib and pembrolizumab has been approved by the FDA for endometrial cancer based on KEYNOTE-146 trial. A total of 108 patients who had previously treated for advanced endometrial cancer were enrolled in this study. The objective response rate (ORR) at 24 weeks was 38.0%, and median PFS was 7.4 months (14).\n\nICIs are an emerging treatment option for solid tumors, and the efficacy of ICIs are currently being evaluated for mTNBC. The KEYNOTE-086 trial evaluated pembrolizumab single agent for mTNBC and demonstrated an ORR of 21.4% in a previously untreated group and 5.5% in a heavily pretreated group (6, 15). A phase 1 trial with the single agent atezolizumab reported similar results. In this study, the ORRs were 24% in first-line but only 6% in second or greater lines (16). The poor response rates from single agent ICIs, especially in pretreated mTNBC, have led to ICI-based combination treatments (\nTable 1\n).\n\nTable 1 Clinical trials evaluating ICIs combined treatment for triple negative breast cancer.\n\nTrial\tLine of Treatment\tMedications\tNumber of patients\tResults\t\nIMPassion 130 (4)\t1st line\tNab-paclitaxel +/- atezolizumab\t450 vs 449\tmPFS of 7.2 and 5.5 months\t\nENHANCE-1 (17)\t≤2 prior lines\tEribulin + pembrolizumab\t149\tORR of 23.4% (25.8% with 0 prior line and 21.8% with 1–2 prior lines group)\t\nKEYNOTE-355 (18) \t1st line\tChemotherapy +/-Pembrolizumab\t566 vs 281\tmPFS of 7.5 vs 5.6 months\t\nTONIC (19)\tPreviously treated\tInduction with low-dose chemotherapy, irradiationor no induction followed by nivolumab\t70\tORR of 17% with no induction, 8% with radiation, 8% with cyclophosphamide, 23% with cisplatin, 35% with doxorubicin\t\nIMPassion 131 (20)\t1st line\tPaclitaxel +/- atezolizumab\t431 vs 220\tmPFS 5.7 vs 5.6 months\t\nLEAP-005 (9)\t2nd and 3rd line\tLenvatinib + pembrolizumab\t31 of TNBC*\tORR of 29%\t\nmPFS, median progression free survival; ORR, objective response rate; *Multicohort study with 31 patients with TNBC.\n\nRecent studies have emphasized the critical role of the tumor microenvironment (TME) (21). The presence of CD8+ tumor-infiltrating lymphocytes that are reactive to clonal neoantigens are associated with durable clinical benefit of the treatment with ICIs (22). In contrast, TAMs have an immunosuppressive function which can be a potential therapeutic target (23, 24). Activation of NK cells has also been associated with prolonged survival and increased response to ICIs (25). The immunomodulatory property of lenvatinib may sensitize TME to ICIs and improve efficacy when combined with ICIs (12, 13).\n\nThe patient in this case showed significant responses to lenvatinib combined with ICIs, after treated with 8 lines of chemotherapy without any significant response. The combination of lenvatinib and ICI requires further investigation to identify predictive biomarkers for response and to provide personalized treatment for patients with metastatic TNBC.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nEthics Statement\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAll authors contributed to the article and approved the submitted version. JL designed the report. JL and SY wrote the manuscript. JL and SY collected the patient’s clinical data. YY were responsible for the conception and revision of the manuscript. YY carried out the clinical management of the patient.\n\nConflict of Interest\nYY has contracted research sponsored by Merck, Eisai, Novartis, Puma, Genentech, and Pfizer; is a consultant for Puma, and is on the Speakers Bureau for Eisai.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1 \nPal SK Childs BH Pegram M \nTriple negative breast cancer: unmet medical needs\n. Breast Cancer Res Treat (2011 ) 125 (3 ):627–36. 10.1007/s10549-010-1293-1 \n\n2 \nWang R Zhu Y Liu X Liao X He J Niu L \nThe Clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer\n. BMC Cancer (2019 ) 19 (1 ):1091 . 10.1186/s12885-019-6311-z \n31718602 \n3 \nAly A Shah R Hill K Botteman MF \nOverall survival, costs and healthcare resource use by number of regimens received in elderly patients with newly diagnosed metastatic triple-negative breast cancer\n. Future Oncol (2019 ) 15 (9 ):1007–20. 10.2217/fon-2018-0407 \n\n4 \nSchmid P Adams S Rugo HS Schneeweiss A Barrios CH Iwata H \nAtezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer\n. N Engl J Med (2018 ) 379 (22 ):2108–21. 10.1056/NEJMoa1809615 \n\n5 \nNanda R Chow LQM Dees EC Berger R Gupta S Geva R \nPembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study\n. J Clin Oncol (2016 ) 34 (21 ):2460–7. 10.1200/JCO.2015.64.8931 \n\n6 \nAdams S Schmid P Rugo HS Winer EP Loirat D Awada A \nPembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study\n. Ann Oncol (2019 ) 30 (3 ):397 –404\n. 10.1093/annonc/mdy517 \n30475950 \n7 \nMakker V Rasco D Vogelzang NJ Brose MS Cohn AL Mier J \nLenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial\n. Lancet Oncol (2019 ) 20 (5 ):711–8. 10.1016/S1470-2045(19)30020-8 \n\n8 \nTaylor MH Lee C-H Makker V Rasco D Dutcus CE Wu J \nPhase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors\n. J Clin Oncol (2020 ) 38 (11 ):1154–63. 10.1200/JCO.19.01598 \n\n9 \nLwin Z Gomez-Roca C Saada-Bouzid E Yanez E Longo Muñoz F Im S-A \nLEAP-005: Phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumours\n. Ann Oncol (2020 ) 31 (suppl_4 ):S1142–215. 10.1016/j.annonc.2020.08.2271 \n\n10 \nCapozzi M De Divitiis C Ottaiano A von Arx C Scala S Tatangelo F \nLenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment\n. Cancer Manag Res (2019 ) 11 :3847–60. 10.2147/CMAR.S188316 \n\n11 \nKudo M Finn RS Qin S Han K-H Ikeda K Piscaglia F \nLenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial\n. Lancet (2018 ) 391 (10126 ):1163–73. 10.1016/S0140-6736(18)30207-1 \n\n12 \nZhang Q Liu H Wang H Lu M Miao Y Ding J \nLenvatinib promotes antitumor immunity by enhancing the tumor infiltration and activation of NK cells\n. Am J Cancer Res (2019 ) 9 (7 ):1382–95.\n13 \nKato Y Tabata K Kimura T Yachie-Kinoshita A Ozawa Y Yamada K \nLenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway\n. PLoS One (2019 ) 14 (2 ):e0212513 . 10.1371/journal.pone.0212513 \n30811474 \n14 \nMakker V Taylor MH Aghajanian C Oaknin A Mier J Cohn AL \nLenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer\n. J Clin Oncol (2020 ) 38 (26 ):2981–92. 10.1200/JCO.19.02627 \n\n15 \nAdams S Loi S Toppmeyer D Cescon DW De Laurentiis M Nanda R \nPembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study\n. Ann Oncol (2019 ) 30 (3 ):405–11. 10.1093/annonc/mdy518 \n\n16 \nEmens LA Cruz C Eder JP Braiteh F Chung C Tolaney SM \nLong-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study\n. JAMA Oncol (2019 ) 5 (1 ):74 . 10.1001/jamaoncol.2018.4224 \n30242306 \n17 \nTolaney SM Kalinsky K Kaklamani VG D’Adamo DR Aktan G Tsai ML \nA phase Ib/II study of eribulin (ERI) plus pembrolizumab (PEMBRO) in metastatic triple-negative breast cancer (mTNBC) (ENHANCE 1)\n. J Clin Oncol (2020 ) 38 (15_suppl ):1015–5. 10.1200/JCO.2020.38.15_suppl.1015 \n\n18 \nCortes J Cescon DW Rugo HS Nowecki Z Im S-A Yusof MM \nKEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer\n. J Clin Oncol (2020 ) 38 (15_suppl ):1000–0. 10.1200/JCO.2020.38.15_suppl.1000 \n\n19 \nVoorwerk L Slagter M Horlings HM Sikorska K van de Vijver KK de Maaker M \nImmune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial\n. Nat Med (2019 ) 25 (6 ):920–8. 10.1038/s41591-019-0432-4 \n\n20 \nMiles DW Gligorov J André F Cameron D Schneeweiss A Barrios CH \nPrimary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC)\n. Ann Oncol (2020 ) 31 (suppl_4 ):S1142–S121. 10.1016/j.annonc.2020.08.2243 \n\n21 \nZemek RM Chin WL Nowak AK Millward MJ Lake RA Lesterhuis WJ \nSensitizing the Tumor Microenvironment to Immune Checkpoint Therapy\n. Front Immunol (2020 ) 11 :223. 10.3389/fimmu.2020.00223 \n32133005 \n22 \nMcGranahan N Furness AJS Rosenthal R Ramskov S Lyngaa R Saini SK \nClonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade\n. Science (2016 ) 351 (6280 ):1463–9. 10.1126/science.aaf1490 \n\n23 \nHamilton MJ Bosiljcic M LePard NE Halvorsen EC Ho VW Banáth JP \nMacrophages Are More Potent Immune Suppressors Ex Vivo Than Immature Myeloid-Derived Suppressor Cells Induced by Metastatic Murine Mammary Carcinomas\n. J Immunol (2014 ) 192 (1 ):512–22. 10.4049/jimmunol.1300096 \n\n24 \nViitala M Virtakoivu R Tadayon S Rannikko J Jalkanen S Hollmén M \nImmunotherapeutic Blockade of Macrophage Clever-1 Reactivates the CD8 + T-cell Response against Immunosuppressive Tumors\n. Clin Cancer Res (2019 ) 25 (11 ):3289–303. 10.1158/1078-0432.CCR-18-3016 \n\n25 \nBarry KC Hsu J Broz ML Cueto FJ Binnewies M Combes AJ \nA natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments\n. Nat Med (2018 ) 24 (8 ):1178–91. 10.1038/s41591-018-0085-8\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "immune checkpoint inhibitors; lenvatinib; pembrolizumab; personalized treatment; triple negative breast cancer",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "582185",
"pmc": null,
"pmid": "33505906",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "32133005;30345906;29942093;30717602;21161370;32167863;30475950;30922731;31718602;31392076;31961766;30811474;30755440;31086347;27138582;24285836;29433850;26940869;31118801;30242306;30475947",
"title": "Case Report: Significant Response to the Combination of Lenvatinib and Immune Checkpoint Inhibitor in a Patient With Heavily Pretreated Metastatic Triple Negative Breast Cancer.",
"title_normalized": "case report significant response to the combination of lenvatinib and immune checkpoint inhibitor in a patient with heavily pretreated metastatic triple negative breast cancer"
} | [
{
"companynumb": "US-EISAI MEDICAL RESEARCH-EC-2021-087376",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "LENVATINIB"
},
"drugadditional... |
{
"abstract": "A review of 12 patients with proven Aspergillus osteomyelitis was undertaken between July 2004 and October 2007. Aspergillus fumigatus was most commonly identified (n = 9). Voriconazole was commonly administered (11/12; 91.7%), and 9 (75.0%) underwent surgery. Seven (58.3%) responded to treatment, and 12-week mortality was 25.0% (3/12). Survival was improved with surgical intervention (P = 0.05).",
"affiliations": "Thomas Jefferson University, Philadelphia, PA, USA. david.horn@jefferson.edu",
"authors": "Horn|David|D|;Sae-Tia|Sutthichai|S|;Neofytos|Dionissios|D|",
"chemical_list": "D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1016/j.diagmicrobio.2008.12.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-8893",
"issue": "63(4)",
"journal": "Diagnostic microbiology and infectious disease",
"keywords": null,
"medline_ta": "Diagn Microbiol Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D001228:Aspergillosis; D001230:Aspergillus; D001232:Aspergillus fumigatus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D011743:Pyrimidines; D016896:Treatment Outcome; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "8305899",
"other_id": null,
"pages": "384-7",
"pmc": null,
"pmid": "19249181",
"pubdate": "2009-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Aspergillus osteomyelitis: review of 12 cases identified by the Prospective Antifungal Therapy Alliance registry.",
"title_normalized": "aspergillus osteomyelitis review of 12 cases identified by the prospective antifungal therapy alliance registry"
} | [
{
"companynumb": "US-JNJFOC-20190732557",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe most frequent and most feared complication after laparoscopic sleeve gastrectomy (LSG) is gastric leak (GL). We hypothesize that botulinum neurotoxin (botulinum type A (BTX-A)) injection into the pyloric sphincter muscle at the time of operation may decrease the risk of postoperative GL.\n\n\nMETHODS\nConsecutive patients with morbid obesity (MO) treated by LSG were enrolled. Patients were randomly allocated into two groups: group I (intrapyloric BTX-A injection was performed) and group II (no injection was performed). The primary outcome measure was number of patients developing GL. Secondary outcome measures were percent of excess weight loss, postoperative complications, and their management.\n\n\nRESULTS\nOne hundred and fifteen patients (86 (74.8 %) females) were randomized into two groups of 57 patients (group I) and 58 patients (group II). Four patients in group II developed GL versus no patient in group I (P = 0.04). Ten patients in group I and two in group II developed refractory epigastric pain (P = 0.01). Other complication rates were comparable for both groups. Mean preoperative BMI of patients in both groups had significantly decreased from 54.64 ± 6.82 to 42.99 ± 5.3 at 6 months and to 39.09 ± 5.14 at 12 months (P < 0.001).\n\n\nCONCLUSIONS\nLSG is an effective, safe, and minimally invasive procedure for treatment of MO. No patient in whom pyloric BTX-A injection was performed developed postoperative GL versus four patients in whom injection was not performed. The difference in GL rate was statistically significant, thus favoring the use of pyloric BTX-A injection during LSG.",
"affiliations": "General and Endocrine Surgery, Mansoura Faculty of Medicine, Mansoura University, Gomhoria St., Mansoura, Egypt. tamyousif@yahoo.com.;General Surgery, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.;General Surgery, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.;General Surgery, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.;General Surgery, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.;General Surgery, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.",
"authors": "Youssef|Tamer|T|;Abdalla|Emad|E|;El-Alfy|Khalid|K|;Dawoud|Ibrahim|I|;Morshed|Mosaad|M|;Farid|Mohamed|M|",
"chemical_list": "D001905:Botulinum Toxins",
"country": "United States",
"delete": false,
"doi": "10.1007/s11695-015-1794-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8923",
"issue": "26(3)",
"journal": "Obesity surgery",
"keywords": "Botulinum neurotoxin type A; Gastric leak; Laparoscopic sleeve gastrectomy; Morbid obesity",
"medline_ta": "Obes Surg",
"mesh_terms": "D000328:Adult; D015992:Body Mass Index; D001905:Botulinum Toxins; D005260:Female; D005743:Gastrectomy; D006801:Humans; D010535:Laparoscopy; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid; D011183:Postoperative Complications; D011184:Postoperative Period; D016896:Treatment Outcome; D015431:Weight Loss; D055815:Young Adult",
"nlm_unique_id": "9106714",
"other_id": null,
"pages": "494-504",
"pmc": null,
"pmid": "26198617",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "19572113;25485740;25435298;23400600;19039596;18954593;24079064;9365919;18098403;11396545;18023813;22752283;21329779;15451898;19381737;26035487;18923879;23023201;15130224;21556930;20574787;15603641;7677463;23989054;24748473;19506979;22476829;22179470;24728866;17458616;19936855;20551815;21818647;18535864;16197783;15273542;19918859;20094819;19463583;24078867;20835778;18098398;8613045",
"title": "Impact of Botulinum Neurotoxin Pyloric Injection During Laparoscopic Sleeve Gastrectomy on Postoperative Gastric Leak: a Clinical Randomized Study.",
"title_normalized": "impact of botulinum neurotoxin pyloric injection during laparoscopic sleeve gastrectomy on postoperative gastric leak a clinical randomized study"
} | [
{
"companynumb": "EG-IPSEN BIOPHARMACEUTICALS, INC.-2016-02544",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ABOBOTULINUMTOXINA"
},
"d... |
{
"abstract": "Valproic acid (VPA) is rarely used in neonatal period. In children under 2 years old, serious adverse effects are appear to be more frequent.\n\n\n\nThe aim of our study is to report the adverse effects observed in a population of full-term newborns treated with VPA.\n\n\n\nFull-term newborns, hospitalized at the Toulouse CHU, who presented with neonatal seizures and who received long-term treatment with VPA between 2004 and 2014 were included.\n\n\n\nFor 5 of the 123 newborns treated with VPA, treatment had to be discontinued due to adverse effects. Three patients presented with disturbances in consciousness within 48 hours of treatment initiation, one case with a moderate overdose and two with hyperammoniemia (157 and 327 μmol/L) without any drug overdose or underlying liver or metabolic disease (VPA-induced hyperammonemic encephalopathy). Two patients presented with secondary hematological alterations. No patient presented with liver toxicity or exacerbation of an underlying metabolic disease.\n\n\n\nWhile the serious adverse effects of VPA noted were all reversible with the discontinuation of the treatment, the occurrence of encephalopathies with hyperammoniemia is a serious complication that is potentially lethal and calls for close clinical monitoring of newborns treated with valproate. We provide precautions for the implementation and follow-up of VPA in newborns.",
"affiliations": "Service de Neurologie Pédiatrique, Hôpital des Enfants, Toulouse Cedex, France.;Service de Pharmacologie clinique et médicale, Faculté de Médecine de Toulouse, Toulouse, France.;Service de Pharmacologie clinique et médicale, Faculté de Médecine de Toulouse, Toulouse, France.;Service d'hépatologie et Maladies Métaboliques, Hôpital des Enfants, Toulouse Cedex, France.;Service de Neurologie Pédiatrique, Hôpital des Enfants, Toulouse Cedex, France.",
"authors": "Baudou|E|E|;Benevent|J|J|;Montastruc|J L|JL|;Touati|G|G|;Hachon LeCamus|C|C|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0038-1676035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0174-304X",
"issue": "50(1)",
"journal": "Neuropediatrics",
"keywords": null,
"medline_ta": "Neuropediatrics",
"mesh_terms": "D000927:Anticonvulsants; D056486:Chemical and Drug Induced Liver Injury; D003244:Consciousness Disorders; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D022124:Hyperammonemia; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D012640:Seizures; D014635:Valproic Acid",
"nlm_unique_id": "8101187",
"other_id": null,
"pages": "31-40",
"pmc": null,
"pmid": "30453358",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Adverse Effects of Treatment with Valproic Acid during the Neonatal Period.",
"title_normalized": "adverse effects of treatment with valproic acid during the neonatal period"
} | [
{
"companynumb": "PHHY2018FR169564",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nOnly few cases of myasthenia gravis (MG) associated with small-cell lung cancer (SCLC) have been reported, and cases positive for acetylcholine receptor antibody (AChR-ab) are even rarer. The efficacy of standard MG treatment, such as cholinesterase inhibitor therapy, immunosuppressive therapy using steroids and immunosuppressive drugs, plasma exchange, and intravenous immune globulin (IVIg), for these cases is unclear.\nA 71-year-old man complained of bilateral eyelid ptosis. He also presented with dysphagia and masticatory muscle fatigue after chewing. The edrophonium test was positive, and the serum AChR-ab level was increased; therefore, the patient was diagnosed with MG. Computed tomography scan showed a nodule on the left upper lobe of the lung and mediastinal lymphadenopathy. Further examination revealed the lesion as SCLC. Finally, he was diagnosed with AChR-ab-positive MG associated with SCLC.\n\n\nRESULTS\nOral pyridostigmine and tacrolimus were administered to treat MG; however, his symptoms worsened. Therefore, methylprednisolone and IVIg were administrated, which temporarily improved his symptoms. However, they remained uncontrolled. Meanwhile, chemotherapy with carboplatin and etoposide was administered to treat his SCLC. The lesions shrunk, and the MG symptoms and serum AChR-ab level also improved.\n\n\nCONCLUSIONS\nAChR-ab-positive MG may develop as a comorbidity of SCLC. In such cases, management might require treatment for SCLC in addition to the standard MG treatment to stabilize the MG symptoms.",
"affiliations": "Department of Respiratory Disease, Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital, Naka-ku.;Department of Respiratory Disease, Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital, Naka-ku.;Department of Respiratory Medicine, Mazda Hospital, Aki-gun.;Department of Neurology, Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital, Naka-ku, Hiroshima, Japan.;Department of Neurology.;Department of Respiratory Medicine, Hiroshima City Hiroshima Citizens Hospital, Naka-ku, Hiroshima.;Department of Respiratory Disease, Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital, Naka-ku.;Department of Respiratory Disease, Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital, Naka-ku.;Department of Respiratory Disease, Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital, Naka-ku.;Department of Respiratory Disease, Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital, Naka-ku.;Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan.",
"authors": "Yamasaki|Masahiro|M|;Funaishi|Kunihiko|K|;Saito|Naomi|N|;Yonekawa|Tomomi|T|;Yamawaki|Takemori|T|;Ihara|Daisuke|D|;Daido|Wakako|W|;Ishiyama|Sayaka|S|;Deguchi|Naoko|N|;Taniwaki|Masaya|M|;Hattori|Noboru|N|",
"chemical_list": "D001323:Autoantibodies; D011950:Receptors, Cholinergic",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000010541",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7974",
"issue": "97(17)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D001323:Autoantibodies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009157:Myasthenia Gravis; D011950:Receptors, Cholinergic; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e0541",
"pmc": null,
"pmid": "29703032",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18815398;17986328;21519527;19934775;3014217;28608304;25467140;7791277;8306783;23952102",
"title": "Acetylcholine receptor antibody-positive myasthenia gravis associated with small-cell lung cancer: A case report.",
"title_normalized": "acetylcholine receptor antibody positive myasthenia gravis associated with small cell lung cancer a case report"
} | [
{
"companynumb": "JP-BAUSCH-BL-2018-022254",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Sirolimus is an immunosuppressant used to prevent graft versus host disease in allogeneic hematopoietic stem cell transplant recipients. It has a large volume of distribution (12 ± 7.5 l/kg) and within the intravascular space ∼95% of it is bound to red blood cells. Because of potential toxic effects at high trough levels, therapeutic drug monitoring is recommended for sirolimus. We present a case of severe hepatic dysfunction due to Hepatitis B and sirolimus toxicity, in a 51-year-old male stem cell transplant recipient. An automated red cell exchange decreased his blood sirolimus level from 22.6 to 10.3 ng/ml (55% reduction) and improved his liver enzymes. Re-equilibration of sirolimus from other compartments to the blood necessitated a series of four red cell exchanges, after which the sirolimus level was 4.7 ng/ml. Although the patient ultimately succumbed to multiorgan failure, red cell exchange may be considered for acute removal of sirolimus in selected patients.",
"affiliations": "Transfusion Medicine and Apheresis Service, UMass Memorial Medical Center, Worcester, Massachusetts.;Transfusion Medicine and Apheresis Service, UMass Memorial Medical Center, Worcester, Massachusetts.;Transfusion Medicine and Apheresis Service, UMass Memorial Medical Center, Worcester, Massachusetts.;Transfusion Medicine and Apheresis Service, UMass Memorial Medical Center, Worcester, Massachusetts.;University of Massachusetts Medical School, Worcester, Massachusetts.;Transfusion Medicine and Apheresis Service, UMass Memorial Medical Center, Worcester, Massachusetts.;Transfusion Medicine and Apheresis Service, UMass Memorial Medical Center, Worcester, Massachusetts.;Transfusion Medicine and Apheresis Service, UMass Memorial Medical Center, Worcester, Massachusetts.;Transfusion Medicine and Apheresis Service, UMass Memorial Medical Center, Worcester, Massachusetts.",
"authors": "Galera|Pallavi|P|;Martin|Hannah C|HC|;Welch|Linda|L|;Sulmasy|Paula|P|;Cerny|Jan|J|;Greene|Mindy|M|;Vauthrin|Michelle|M|;Bailey|Jeffrey A|JA|;Weinstein|Robert|R|",
"chemical_list": "D007166:Immunosuppressive Agents; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21381",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "30(6)",
"journal": "Journal of clinical apheresis",
"keywords": "apheresis; drug overdose; immunosuppression; liver failure; stem cell transplant",
"medline_ta": "J Clin Apher",
"mesh_terms": "D001781:Blood Component Removal; D016903:Drug Monitoring; D017707:Erythrocyte Transfusion; D004912:Erythrocytes; D017809:Fatal Outcome; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D017093:Liver Failure; D008297:Male; D008875:Middle Aged; D020123:Sirolimus",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "367-70",
"pmc": null,
"pmid": "25619898",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Automated red blood cell exchange for acute drug removal in a patient with sirolimus toxicity.",
"title_normalized": "automated red blood cell exchange for acute drug removal in a patient with sirolimus toxicity"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0077480",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,... |
{
"abstract": "Purpose Rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is the standard of care in previously untreated diffuse large B-cell lymphoma (DLBCL). Obinutuzumab (G) is a glycoengineered, type II, anti-CD20 monoclonal antibody. GOYA was a randomized phase III study that compared G-CHOP with R-CHOP in patients with previously untreated advanced-stage DLBCL. Methods Patients (N = 1,418) were randomly assigned to receive eight 21-day cycles of G (n = 706) or R (n = 712), plus six or eight cycles of CHOP. Primary end point was investigator-assessed progression-free survival (PFS). Results After median observation of 29 months, the number of investigator-assessed PFS events was similar between G (201; 28.5%) and R (215; 30.2%), stratified hazard ratio was 0.92 (95% CI, 0.76 to 1.11; P = .39), and 3-year PFS rates were 70% and 67%, respectively. Secondary end points of independently reviewed PFS, other time-to-event end points, and tumor response rates were similar between arms. In exploratory subgroup analyses, patients with germinal-center B cell-like subtype had a better PFS than did patients with activated B cell-like subtype, irrespective of treatment. Frequencies of grade 3 to 5 adverse events (AEs; 73.7% v 64.7%, respectively) and serious AEs (42.6% v 37.6%, respectively) were higher with G-CHOP compared with R-CHOP. Fatal AE frequencies were 5.8% for G-CHOP and 4.3% for R-CHOP. The most common AEs were neutropenia (G-CHOP, 48.3%; R-CHOP, 40.7%), infusion-related reactions (G-CHOP, 36.1%; R-CHOP, 23.5%), nausea (G-CHOP, 29.4%; R-CHOP, 28.3%), and constipation (G-CHOP, 23.4%; R-CHOP, 24.5%). Conclusion G-CHOP did not improve PFS compared with R-CHOP in patients with previously untreated DLBCL. AEs reported with G were consistent with the known safety profile. Biomarker analyses may help define a future role for G in DLBCL.",
"affiliations": "Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.;Umberto Vitolo, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin; Angelo Michele Carella, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera e Universitaria San Martino-IST, Genoa; Antonio Pinto, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS, Naples; Maurizio Martelli, Sapienza University, Rome, Italy; Marek Trněný, Charles University, General Hospital, Prague; David Belada, Charles University Hospital, Hradec Králové, Czech Republic; John M. Burke, Rocky Mountain Cancer Centers, Aurora, CO; US Oncology Research, The Woodlands, TX; Neil Chua, Cross Cancer Institute, University of Alberta, Edmonton, Alberta; Laurie H. Sehn, British Columbia Cancer Agency and the University of British Columbia, Vancouver, British Columbia, Canada; Pau Abrisqueta, University Hospital Vall d'Hebron, Barcelona, Spain; Judit Demeter, Semmelweiss University, Budapest, Hungary; Ian Flinn, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Xiaonan Hong, Fudan University Shanghai Cancer Center, Shanghai; Yuan-Kai Shi, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China; Won Seog Kim, Samsung Medical Center, Sunkyunkwan University School of Medicine, Seoul, Republic of Korea; Yoichi Tatsumi, Kinki University Hospital, Osaka, Japan; Mikkel Z. Oestergaard, Günter Fingerle-Rowson, Olivier Catalani, and Tina Nielsen, F. Hoffman-La Roche, Basel, Switzerland; and Michael Wenger, Genentech, South San Francisco, CA.",
"authors": "Vitolo|Umberto|U|;Trněný|Marek|M|;Belada|David|D|;Burke|John M|JM|;Carella|Angelo Michele|AM|;Chua|Neil|N|;Abrisqueta|Pau|P|;Demeter|Judit|J|;Flinn|Ian|I|;Hong|Xiaonan|X|;Kim|Won Seog|WS|;Pinto|Antonio|A|;Shi|Yuan-Kai|YK|;Tatsumi|Yoichi|Y|;Oestergaard|Mikkel Z|MZ|;Wenger|Michael|M|;Fingerle-Rowson|Günter|G|;Catalani|Olivier|O|;Nielsen|Tina|T|;Martelli|Maurizio|M|;Sehn|Laurie H|LH|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; C543332:obinutuzumab; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2017.73.3402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "35(31)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "3529-3537",
"pmc": null,
"pmid": "28796588",
"pubdate": "2017-11-01",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Previously Untreated Diffuse Large B-Cell Lymphoma.",
"title_normalized": "obinutuzumab or rituximab plus cyclophosphamide doxorubicin vincristine and prednisone in previously untreated diffuse large b cell lymphoma"
} | [
{
"companynumb": "IT-JNJFOC-20171110686",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
... |
{
"abstract": "Delayed haemolytic anaemia has been reported in association with intravenous artesunate treatment in patients with severe Plasmodium falciparum malaria, and furthermore, oral artemisinin-based combination therapies including artemether-lumefantrine (AL) have also been incriminated. However, definite cases of delayed haemolytic anaemia associated with AL appear to be scarce, as reported cases were often treated concomitantly with other anti-malarials. In this study, we report a severe case of delayed haemolytic anaemia following AL alone in a Japanese traveller with severe parasitaemia caused by numerous P. falciparum parasites and a few P. vivax parasites. We also stress the need by further studies to differentiate between delayed haemolytic anaemia and blackwater fever, the latter being another malaria-related haemolytic condition, more clearly than they are now.",
"affiliations": "Department of Infectious Diseases, Nagoya City East Medical Centre, Nagoya, Japan.;Department of Pharmacy, Nagoya City East Medical Centre, Nagoya, Japan.;Division of Parasitology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Internal Medicine, Shin-Yamanote Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan. Electronic address: kimumiki@shinyamanote.jp.",
"authors": "Hasegawa|Chihiro|C|;Kudo|Masaharu|M|;Maruyama|Haruhiko|H|;Kimura|Mikio|M|",
"chemical_list": "D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000077332:Artesunate; D000077549:Artemether; D000078102:Lumefantrine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2017.10.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "24(3)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Artemether-lumefantrine; Blackwater fever; Delayed haemolytic anaemia; High parasitaemia; Plasmodium falciparum",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000743:Anemia, Hemolytic; D000962:Antimalarials; D000077549:Artemether; D037621:Artemisinins; D000077332:Artesunate; D001742:Blackwater Fever; D004359:Drug Therapy, Combination; D004983:Ethanolamines; D005449:Fluorenes; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum; D008297:Male; D010963:Plasmodium falciparum; D010966:Plasmodium vivax; D012008:Recurrence; D055815:Young Adult",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "216-219",
"pmc": null,
"pmid": "29127021",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe delayed haemolytic anaemia associated with artemether-lumefantrine treatment of malaria in a Japanese traveller.",
"title_normalized": "severe delayed haemolytic anaemia associated with artemether lumefantrine treatment of malaria in a japanese traveller"
} | [
{
"companynumb": "PHJP2015JP006924",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LOXOPROFEN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Primary aldosteronism with a prevalence of 8 % of hypertension and 20 % of pharmacologically resistant hypertension is the most common secondary cause of hypertension. Yet, the diagnosis is missed in the vast majority of patients. Current clinical practice guidelines recommend screening for primary aldosteronism in patients with sustained elevation of blood pressure (BP) ≥150/100 mmHg if possible prior to initiation of antihypertensive therapy, and in patients with resistant hypertension, spontaneous or diuretic-induced hypokalemia, adrenal incidentaloma, obstructive sleep apnea, a family history of early onset of hypertension or cerebrovascular accident <age 40, and first-degree relatives of patients with primary aldosteronism. Clinical and laboratory methods of screening, confirmatory testing, subtype classification, and medical and surgical management are systematically reviewed and illustrated with a clinical case.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, P.O. Box 801414, Charlottesville, VA, 22908-1414, USA. rmc4c@virginia.edu.",
"authors": "Carey|Robert M|RM|",
"chemical_list": "D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone",
"country": "United States",
"delete": false,
"doi": "10.1007/s11886-016-0774-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1523-3782",
"issue": "18(10)",
"journal": "Current cardiology reports",
"keywords": "Aldosterone; Hypertension; Laparoscopic adrenalectomy; Mineralocorticoid receptor antagonist; Primary aldosteronism",
"medline_ta": "Curr Cardiol Rep",
"mesh_terms": "D000315:Adrenalectomy; D000077545:Eplerenone; D006801:Humans; D006929:Hyperaldosteronism; D006973:Hypertension; D007008:Hypokalemia; D010535:Laparoscopy; D008403:Mass Screening; D000451:Mineralocorticoid Receptor Antagonists; D017410:Practice Guidelines as Topic; D015995:Prevalence; D013148:Spironolactone",
"nlm_unique_id": "100888969",
"other_id": null,
"pages": "97",
"pmc": null,
"pmid": "27566330",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "26724178;25636049;18391085;26918291;26865201;26975712;23092384;25594330;21700477;25347508;27045024;15001583;19008719;23753408;26787761;26408271;26886564;15983235;23245609;12493255;21502568;15837256",
"title": "Diagnosing and Managing Primary Aldosteronism in Hypertensive Patients: a Case-Based Approach.",
"title_normalized": "diagnosing and managing primary aldosteronism in hypertensive patients a case based approach"
} | [
{
"companynumb": "US-PFIZER INC-2016464940",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMILORIDE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nCarbon dioxide (CO2) as a contrast agent has been in use as early as the 1920s for visualization of retroperitoneal structures. Digital subtraction angiography (DSA) using CO2 as a contrast agent for vascular imaging was developed in the 1980s. Currently, CO2 angiography is an alternative agent in patients with chronic kidney disease (CKD) and those who are at risk of developing contrast-induced nephropathy. However, CO2 causes neurotoxicity if the gas inadvertently enters the cerebrovascular circulation leading to fatal brain injury.\n\n\nMETHODS\nA 71-year-old female with h/o sickle cell trait, hypertension, obesity, metastatic renal cell cancer status post nephrectomy, bone metastasis, chronic kidney disease was admitted for elective embolization of the humerus bone metastasis. Given the high probability of contrast-induced nephropathy, CO2 angiography was chosen for embolization of the metastasis. During the procedure, the patient became unresponsive. Emergent medical management with hyperventilation, 100% fraction oxygen inhalation was performed. Her neuroimaging showed global cerebral edema. An intracranial pressure monitor was placed which confirmed intracranial hypertension. Hyperosmolar therapy was administered with no improvement in clinical examination. She progressed to brain stem herniation. Given poor prognosis, the family opted for comfort measures and the patient expired.\n\n\nCONCLUSIONS\nInadvertent carbon dioxide entry into cerebrovascular circulation during angiography can cause fatal brain injury. Caution must be exercised while performing CO2 angiography in blood vessels above the diaphragm.",
"affiliations": "Neurocritical care, Cerebrovascular Center, Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA. Electronic address: madihah.hepburn@gmail.com.;Neurocritical care, Cerebrovascular Center, Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.;Rangaraya Medical college, Kakinada, Andhra Pradesh, India.;Neurocritical care, Cerebrovascular Center, Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA. Electronic address: danid@ccf.org.;Neurocritical care, Cerebrovascular Center, Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA. Electronic address: georgep@ccf.org.;Neurocritical care, Cerebrovascular Center, Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA; Medical Director, Neurocritical Care, Cleveland Clinic Akron General Hospital, Akron, Ohio, USA. Electronic address: neweyc@ccf.org.",
"authors": "Hepburn|Madihah|M|;Mullaguri|Naresh|N|;Battineni|Anusha|A|;Dani|Dhimant|D|;George|Pravin|P|;Newey|Christopher R|CR|",
"chemical_list": "D003287:Contrast Media; D002245:Carbon Dioxide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2020.105350",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "29(12)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Carbon dioxide angiography: Gas embolism; Cerebral edema",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D000792:Angiography; D001859:Bone Neoplasms; D001929:Brain Edema; D002245:Carbon Dioxide; D003287:Contrast Media; D004618:Embolism, Air; D004621:Embolization, Therapeutic; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006811:Humerus; D007680:Kidney Neoplasms",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "105350",
"pmc": null,
"pmid": "33254372",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fatal Brain Injury Following Carbon Dioxide Angiography.",
"title_normalized": "fatal brain injury following carbon dioxide angiography"
} | [
{
"companynumb": "US-ALSI-202000454",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CARBON DIOXIDE"
},
"drugadditional": null,
... |
{
"abstract": "While on a critical care placement in a medical admissions unit, a 29-year-old with a history of heroin misuse was admitted following a paracetamol overdose.",
"affiliations": "University of Nottingham.",
"authors": "Lee|Sarah|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.7748/ns2011.09.26.4.29.p6463",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-6570",
"issue": "26(4)",
"journal": "Nursing standard (Royal College of Nursing (Great Britain) : 1987)",
"keywords": null,
"medline_ta": "Nurs Stand",
"mesh_terms": null,
"nlm_unique_id": "9012906",
"other_id": null,
"pages": "29",
"pmc": null,
"pmid": "27316004",
"pubdate": "2011-09-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Boundaries between nurses and patients must be clearly defined.",
"title_normalized": "boundaries between nurses and patients must be clearly defined"
} | [
{
"companynumb": "US-JNJFOC-20160627600",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nWe evaluated the activity and safety of the combination of topotecan, cisplatin and bevacizumab in patients with recurrent or persistent carcinoma of the cervix.\n\n\nMETHODS\nEligible patients had persistent or recurrent cervical cancer not amenable to curative intent treatment. No prior chemotherapy for recurrence was allowed. Treatment consisted of cisplatin 50 mg/m(2) day 1, topotecan 0.75 mg/m(2) days 1, 2 and 3 and bevacizumab 15 mg/kgday 1 every 21 days until disease progression or limiting toxicity. The primary endpoint was progression free survival at 6 months. We explored PET/CT as a potential early indicator of response to therapy.\n\n\nRESULTS\nTwenty-seven eligible patients received a median of 3 treatment cycles (range, 1-19). Median follow-up was 10 months (range, 1.7-33.4). The 6-month PFS was 59% (80% CI: 46-70%). In 26 evaluable patients, we observed 1 CR (4%; 80% CI: 0.4-14%) and 8 PR (31%; 80% CI: 19-45%) lasting a median of 4.4 months. Ten patients had SD (39%; 80% CI: 25-53%) with median duration of 2.2 months. Median PFS was 7.1 months (80% CI: 4.7-10.1) and median OS was 13.2 months (80% CI: 8.0-15.4). All patients were evaluated for toxicity. Grade 3-4 hematologic toxicity was common (thrombocytopenia 82% leukopenia 74%, anemia 63%, neutropenia 56%). Most patients (78%) required unanticipated hospital admissions for supportive care and/or management of toxicities.\n\n\nCONCLUSIONS\nThe addition of bevacizumab to topotecan and cisplatin results in an active but highly toxic regimen. Future efforts should focus on identification of predictive biomarkers of prolonged response and regimen modifications to minimize toxicity.",
"affiliations": "Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO, USA. israel.zighelboim@sluhn.org",
"authors": "Zighelboim|Israel|I|;Wright|Jason D|JD|;Gao|Feng|F|;Case|Ashley S|AS|;Massad|L Stewart|LS|;Mutch|David G|DG|;Powell|Matthew A|MA|;Thaker|Premal H|PH|;Eisenhauer|Eric L|EL|;Cohn|David E|DE|;Valea|Fidel A|FA|;Alvarez Secord|Angeles|A|;Lippmann|Lynne T|LT|;Dehdashti|Farrokh|F|;Rader|Janet S|JS|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000068258:Bevacizumab; D019772:Topotecan; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "130(1)",
"journal": "Gynecologic oncology",
"keywords": null,
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002945:Cisplatin; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008875:Middle Aged; D064847:Multimodal Imaging; D009364:Neoplasm Recurrence, Local; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D014057:Tomography, X-Ray Computed; D019772:Topotecan; D002583:Uterine Cervical Neoplasms; D055815:Young Adult",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "64-8",
"pmc": null,
"pmid": "23591400",
"pubdate": "2013-07",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "14584662;11121641;7508337;22237781;15911865;21296855;19139430;23109699;12377329;14714296;15284262;2807004;16647106;22402886;19720909;3894589;20308664;12829126;10486457;3943757;22014958;3679922;21747087;16741317;15930314;15337563;10655437",
"title": "Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer.",
"title_normalized": "multicenter phase ii trial of topotecan cisplatin and bevacizumab for recurrent or persistent cervical cancer"
} | [
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"companynumb": "US-CIPLA LTD.-2018US19034",
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"abstract": "BACKGROUND\nPatients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.\n\n\nMETHODS\nThe patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.\n\n\nCONCLUSIONS\nOral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.",
"affiliations": "Pharmacy, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101, Japan. yuki0715asai@gmail.com.;Department of Cardiovascular Surgery, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101, Japan.;Pharmacy, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101, Japan.;Pharmacy, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101, Japan.;Department of Cardiovascular Surgery, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101, Japan.;Department of Cardiovascular Surgery, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101, Japan.;Pharmacy, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101, Japan.",
"authors": "Asai|Yuki|Y|http://orcid.org/0000-0002-1933-8592;Sato|Tomoaki|T|;Kito|Daisuke|D|;Yamamoto|Takanori|T|;Hioki|Iwao|I|;Urata|Yasuhisa|Y|;Abe|Yasuharu|Y|",
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"fulltext": "\n==== Front\nJ Pharm Health Care Sci\nJ Pharm Health Care Sci\nJournal of Pharmaceutical Health Care and Sciences\n2055-0294 BioMed Central London \n\n193\n10.1186/s40780-021-00193-z\nCase Report\nCombination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist’s proposal: a case report\nhttp://orcid.org/0000-0002-1933-8592Asai Yuki yuki0715asai@gmail.com 1 Sato Tomoaki 2 Kito Daisuke 1 Yamamoto Takanori 1 Hioki Iwao 2 Urata Yasuhisa 2 Abe Yasuharu 1 1 grid.505758.a0000 0004 0621 7286Pharmacy, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie 514-1101 Japan \n2 grid.505758.a0000 0004 0621 7286Department of Cardiovascular Surgery, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojincho, Tsu, Mie 514-1101 Japan \n3 3 2021 \n3 3 2021 \n2021 \n7 1026 12 2020 11 2 2021 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nPatients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.\n\nCase presentation\nThe patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70–80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100–120 mmHg and the urine volume increased.\n\nConclusions\nOral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.\n\nKeywords\nChronic heart failureCombination therapyDroxidopaHeart failure with preserved ejection fractionHeart failure with reduced ejection fractionHypotensionMidodrineissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nWhile it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].\n\nMany reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.\n\nCase presentation\nThe patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).\nFig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)\n\n\n\nIn HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.\nFig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%\n\n\n\nDiscussion and conclusions\nHypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.\n\nWhile a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.\n\nMidodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.\n\nDespite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.\n\nBased on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.\n\nAbbreviations\nCHDFContinuous hemodiafiltration\n\nCHFChronic heart failure\n\nCTRCardiothoracic ratio\n\nDBPDiastolic blood pressure\n\nEFEjection fraction\n\nHFpEFHeart failure with preserved ejection fraction\n\nHFrEFHeart failure with reduced ejection fraction\n\nHRHeart rate\n\nNANoradrenaline\n\nSBPSystolic blood pressure\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNot applicable.\n\nAuthors’ contributions\nAll authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll the data generated or analyzed in this study are included in the published article.\n\nEthics approval and consent to participate\nBecause this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.\n\nConsent for publication\nWritten informed consent was obtained from the patient afterwards.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Felker GM Lee KL Bull DA Bull DA Redfield MM Stevenson LW Goldsmith SR Le Winter MM Deswal A Rouleau JL Ofili EO Anstrom KJ Hernandez AF SE MN Velazquez EJ Kfoury AG Chen HH Givertz MM Semigran MJ Bart BA Mascette AM Braunwald E O'Connor CM NHLBI Heart Failure Clinical Research Network Diuretic strategies in patients with acute decompensated heart failure Diuretic strategies in patients with acute decompensated heart failure N Engl J Med 2011 364 797 805 10.1056/NEJMoa1005419 21366472 \n2. Pitt B Zannad F Remme WJ Cody R Castaigne A Perez A Palensky J Wittes J The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone evaluation study investigators N Engl J Med 1999 341 709 717 10.1056/NEJM199909023411001 10471456 \n3. Pitt B Remme W Zannad F Neaton J Martinez F Roniker B Bittman R Hurley S Kleiman J Gatlin M Eplerenone post-acute myocardial infarction heart failure efficacy and survival study investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction N Engl J Med 2003 348 1309 1321 10.1056/NEJMoa030207 12668699 \n4. Valente MAE Voors AA Damman K Veldhuisen DJV Massie BM O'Connor CM Metra M Ponikowski P Teerlink JR Cotter G Davison B Cleland JGF Givertz MM Bloomfield DM Fiuzat M Dittrich HC Hillege HL Diuretic response in acute heart failure: clinical characteristics and prognostic significance Eur Heart J 2014 35 1284 1293 10.1093/eurheartj/ehu065 24585267 \n5. Mayo Foundation for Medical Education and Research. Low blood pressure (hypotension) - symptoms and causes. 2017 https://www.mayoclinic.org/diseases-conditions/low-blood-pressure/symptomscauses/syc-20355465 .\n6. Martín-Pérez M Michel A Ma M Rodríguez LAG Development of hypotension in patients newly diagnosed with heart failure in UK general practice: retrospective cohort and nested case-control analyses BMJ Open 2019 9 e028750 10.1136/bmjopen-2018-028750 \n7. Shah N Madanieh R Alkan M Dogar MU Kosmas CE Vittorio TJ A perspective on diuretic resistance in chronic congestive heart failure Ther Adv Cardiovasc Dis 2017 11 271 278 10.1177/1753944717718717 28728476 \n8. Kaufmann H Freeman R Biaggioni I Low P Pedder S Hewitt LA Mauney J Feirtag M Mathias CJ NOH301 investigators. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial Neurology. 2014 83 328 335 10.1212/WNL.0000000000000615 24944260 \n9. Hauser RA Hewitt LA Isaacson S Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A) J Parkinsons Dis 2014 4 57 65 10.3233/JPD-130259 24326693 \n10. Isaacson S Vernino S Ziemann A Rowse GJ Kalu U White WB Long-term safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension J Am Soc Hypertens 2016 10 755 762 10.1016/j.jash.2016.07.010 27614923 \n11. Low PA Gilden JL Freeman R Sheng KN McElligott MA Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine study group JAMA. 1997 277 1046 1051 10.1001/jama.1997.03540370036033 9091692 \n12. Ward CR Gray JC Gilroy JJ Kenny RA Midodrine: a role in the management of neurocardiogenic syncope Heart. 1998 79 45 49 10.1136/hrt.79.1.45 9505918 \n13. Yusuf S Pitt B Davis CE Hood WB Jr Cohn JN Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions N Engl J Med 1992 327 685 691 10.1056/NEJM199209033271003 1463530 \n14. Satoh M Haga T Hosaka M Hosaka M Obara T Metoki H Murakami T Kikuya M Inoue R Asayama K Mano N Ohkubo T Imai Y The velocity of antihypertensive effects of seven angiotensin II receptor blockers determined by home blood pressure measurements J Hypertens 2016 34 1218 1223 10.1097/HJH.0000000000000902 27027425 \n15. Yancy CW Lopatin M Stevenson LW Marco TD Fonarow GC ADHERE Scientific Advisory Committee and Investigators Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the acute decompensated heart failure National Registry (ADHERE) database J Am Coll Cardiol 2006 47 76 84 10.1016/j.jacc.2005.09.022 16386668 \n16. Eguchi K Hoshide S Kario K Effects of Celiprolol and Bisoprolol on blood pressure, vascular stiffness, and Baroreflex sensitivity Am J Hypertens 2015 28 858 867 10.1093/ajh/hpu245 25577782 \n17. Zakir RM Folefack A Saric M Berkowitz RL The use of midodrine in patients with advanced heart failure Congest Heart Fail 2009 15 108 111 10.1111/j.1751-7133.2008.00042.x 19522958 \n18. Katoh J Ohsaka G Treatment of orthostatic hypotension in cervical cord injury with Amezinium Metilsulfate J Phys Ther Sci 1998 10 27 29 10.1589/jpts.10.27 \n19. Kapoor JR Heidenreich PA Role of heart rate as a marker and mediator of poor outcome for patients with heart failure Curr Heart Fail Rep 2012 9 133 138 10.1007/s11897-012-0086-8 22351045 \n20. Holmes C Whittaker N Heredia-Moya J Goldstein DS Contamination of the norepinephrine prodrug droxidopa by dihydroxyphenylacetaldehyde Clin Chem 2009 56 832 838 10.1373/clinchem.2009.139709 \n21. White WB Hewitt LA Mehdirad AA Impact of the norepinephrine Prodrug Droxidopa on the QTc interval in healthy individuals Clin Pharmacol Drug Dev 2018 7 332 340 10.1002/cpdd.393 29024579 \n22. White WB Hauser RA Rowse GJ Ziemann A Hewitt LA Cardiovascular safety of Droxidopa in patients with symptomatic neurogenic orthostatic hypotension Am J Cardiol 2017 119 1111 1115 10.1016/j.amjcard.2016.11.066 28159196\n\n",
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"keywords": "Chronic heart failure; Combination therapy; Droxidopa; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Hypotension; Midodrine",
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"abstract": "A 59-year-old male patient suffered three life-threatening instent thromboses after an initial resuscitation due to an ST-segment elevation myocardial infarction of the anterior cardiac wall. With a high-risk profile for heparin-induced thrombocytopenia (HIT), he was placed on argatroban after the second reinfarction. Under this apparently appropriate treatment, a third reinfarction occurred, and the patient had to undergo high-risk cardiac bypass surgery. Later on, a deep vein thrombosis and an intracardiac thrombus formed. Despite a positive screening test for HIT and a single positive result in the heparin-induced platelet aggregation test, we are not convinced that HIT was the only underlying cause for this 'catastrophic thrombotic syndrome'. We speculate that a massive generation of thrombin, reflected in consistently high D dimers and the need of copious amounts of a direct thrombin inhibitor, triggered the set of events. With this case report, we want to raise awareness for cardiac complications in patients with complex clotting disorders and share our experience in the diagnostic and therapeutic management of such an unusual scenario.",
"affiliations": "Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.;Institute for Immunology and Transfusion Medicine, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.;Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.;Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.",
"authors": "Heid|Julia|J|;Greinacher|Andreas|A|;Katus|Hugo A|HA|;Müller|Oliver J|OJ|http://orcid.org/0000-0001-8223-2638",
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"journal": "BMJ case reports",
"keywords": "adult intensive care; clinical diagnostic tests; interventional cardiology; ischaemic heart disease; venous thromboembolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000925:Anticoagulants; D000991:Antithrombins; D001120:Arginine; D001364:Awareness; D001780:Blood Coagulation Tests; D001026:Coronary Artery Bypass; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D010644:Phenprocoumon; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D000072657:ST Elevation Myocardial Infarction; D013449:Sulfonamides; D013921:Thrombocytopenia; D013927:Thrombosis; D016896:Treatment Outcome; D014463:Ultrasonography; D020246:Venous Thrombosis",
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"title": "Idiopathic catastrophic thrombosis with happy ending.",
"title_normalized": "idiopathic catastrophic thrombosis with happy ending"
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"abstract": "Hemiparesis has been reported in hemolytic uremic syndrome (HUS), however electrophysiological findings associated with this syndrome have not been well-characterized, and alternating hemiparesis presentations have not been reported. We present detailed electrophysiological and clinical findings in a case of alternating hemiparesis corresponding to alternating focal contralateral delta slowing on prolonged EEG monitoring in a case of HUS with COVID-19 positivity. A 24-year-old woman was admitted with bloody diarrhea, acute kidney injury, and focal seizures initially presumed due to Escherichia coli 0157:H7 Shiga-like toxin-related hemolytic uremic syndrome (ST-HUS). After admission, the patient tested positive for COVID-19. Continuous EEG monitoring revealed diffuse polymorphic delta slowing. Around 24 hours into the admission, the delta slowing became focal in the right hemisphere and was associated with a left hemiparesis. Around three days later, the clinical and EEG pattern reversed, showing left hemisphere slowing and an associated right hemiparesis. Additionally, 14 Hz positive spikes were observed throughout the recording period. Neuroimaging, including CT and MRI, was negative for acute ischemia throughout. The patient subsequently recovered over several days with no residual neurologic abnormalities.",
"affiliations": "Division of Epilepsy, Mayo Clinic, Rochester, MN, USA.;Division of Critical Care and Hospital Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.;Division of Epilepsy, Mayo Clinic, Rochester, MN, USA.;Division of Critical Care and Hospital Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA.",
"authors": "Simpson|Hugh D|HD|;Johnson|Erica|E|;Britton|Jeffrey|J|;Braksick|Sherri|S|",
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"fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864\nElsevier\n\nS2589-9864(21)00042-3\n10.1016/j.ebr.2021.100468\n100468\nCase Report\nAlternating hemiparesis in the context of hemolytic uremic syndrome and COVID-19 positivity\nSimpson Hugh D. Simpson.Hugh@mayo.edu\na1⁎\nJohnson Erica b1\nBritton Jeffrey a\nBraksick Sherri b\na Division of Epilepsy, Mayo Clinic, Rochester, MN, USA\nb Division of Critical Care and Hospital Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, USA\n⁎ Corresponding author. Simpson.Hugh@mayo.edu\n1 These authors contributed equally to this work.\n\n05 7 2021\n2021\n05 7 2021\n16 1004686 5 2021\n29 6 2021\n30 6 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHighlights\n\n• Alternating hemiparesis may occur in hemolytic uremic with coincident COVID-19.\n\n• Lateralized EEG findings may occur despite a generalized physiologic disturbance.\n\n• These deficits can exist in the absence of stroke or seizure and may be reversible.\n\n• Recognition of this phenomenon may prevent unnecessary overtreatment.\n\nHemiparesis has been reported in hemolytic uremic syndrome (HUS), however electrophysiological findings associated with this syndrome have not been well-characterized, and alternating hemiparesis presentations have not been reported. We present detailed electrophysiological and clinical findings in a case of alternating hemiparesis corresponding to alternating focal contralateral delta slowing on prolonged EEG monitoring in a case of HUS with COVID-19 positivity. A 24-year-old woman was admitted with bloody diarrhea, acute kidney injury, and focal seizures initially presumed due to Escherichia coli 0157:H7 Shiga-like toxin-related hemolytic uremic syndrome (ST-HUS). After admission, the patient tested positive for COVID-19. Continuous EEG monitoring revealed diffuse polymorphic delta slowing. Around 24 hours into the admission, the delta slowing became focal in the right hemisphere and was associated with a left hemiparesis. Around three days later, the clinical and EEG pattern reversed, showing left hemisphere slowing and an associated right hemiparesis. Additionally, 14 Hz positive spikes were observed throughout the recording period. Neuroimaging, including CT and MRI, was negative for acute ischemia throughout. The patient subsequently recovered over several days with no residual neurologic abnormalities.\n\nKeywords\n\nEEG\nHemolytic uremic syndrome\nHemiparesis\nHemiplegia\nCOVID19\n==== Body\n1 Introduction\n\nHemolytic uremic syndrome (HUS) refers to a triad of clinical findings consisting of microangiopathic hemolytic anemia, thrombocytopenia, and acute oliguric renal failure. It is most typically associated with Shiga toxin-producing E. Coli or Shigella infections (and thus ST-HUS, or Shiga toxin-related HUS). These infections manifest with painful diarrhea that may be bloody, with or without fever. The HUS typically follows the diarrheal illness by several days. ST-HUS is mainly reported in children, and is uncommon in adults [1]. Neurological involvement in HUS is associated with severe disease and poorer prognosis [2], and may be a trigger for more aggressive therapies including plasma exchange or eculizumab.\n\nNeurologic manifestations have been previously described in the setting of ST-HUS [2], [3], and may include seizures, stroke, hemiparesis/hemiplegia, extrapyramidal syndromes, myoclonus, dysphasia, cortical blindness, altered mental status, and coma. While some of these impairments may be transient, some are not, resulting in persistent deficits, epilepsy, and even death. Magnetic resonance imaging (MRI) in ST-HUS has been reported to show symmetric subcortical T2 hyperintensities and diffusion abnormalities, and/or stroke [2], [4]. Electroencephalographic (EEG) abnormalities, mostly identified on 20–40 minute routine recordings, that have been reported include generalized slowing, focal slowing, and interictal epileptiform activity [5], [6], and status epilepticus in two cases [7], [8]. EEG findings rapidly improved with plasma exchange in at least one case [8].\n\nNeurological manifestations of COVID-19 infection have been published extensively over the last 12 months [9]. Altered mental state, headache, dysguesia, and anosmia are common clinical manifestations, whereas ischemic stroke and other serious manifestations (e.g. seizures, encephalitis, myelitis, Guillain-Barre syndrome) appear to be rare.\n\nHere we present detailed clinical and EEG findings in a case of alternating hemiparesis in HUS and COVID-19.\n\n2 Case report\n\nA 24-year-old right-handed female with a past medical history significant for focal segmental glomerulosclerosis presented with acute onset nausea, emesis, bloody diarrhea and acute kidney injury. Diagnostic evaluation revealed Shiga toxin-producing E. coli 0157:H7. Over five days, she developed progressive oliguric renal failure requiring transfer to a tertiary care hospital for initiation of eculizumab. Her initial course was also notable for mild hypoxemia requiring oxygen 1–4 liters by nasal cannula.\n\nWhile en route to our institution, she had two witnessed episodies of tonic posturing in both upper extremities suggesting focal seizures. She therefore received midazolam. On arrival to the Emergency Department, vital signs showed tachycardia and an oxygen saturation of 94% on 4 liters of oxygen by nasal cannula. She was stuporous and had anasarca. COVID-19 nasal swab PCR returned positive while serum antibodies were negative. Admission chest x-ray revealed right greater than left pleural effusions and hazy, perihilar infiltrates, suggestive of fluid overload. She did not receive COVID-19-directed therapy due to her renal failure (GFR < 15 mL/min) and concurrent use of eculizumab for HUS. After medical stabilization including initiation of levetiracetam (1000 mg IV loading dose), she was transferred to the medical intensive care unit (ICU) for further management.\n\nIn the ICU, she had a witnessed seizure involving left eye gaze deviation and tonic posturing of the bilateral upper extremities, requiring 2 mg of intravenous lorazepam, an additional dose of levetiracetam (2500 mg), and initiation of valproic acid (2000 mg IV loading dose followed by 250 mg tid). She continued to be stuporous and was placed on prolonged EEG monitoring to exclude ongoing electrographic seizures. Continuous EEG revealed diffuse medium amplitude (60–90 µV) 0.5–3 Hz polymorphic delta slowing. Over the first several hours of the recording, a marked asymmetry developed (Fig. 1A), with resolution of the left hemispheric slowing but persistent focal slowing in the right hemisphere. The slowing was initially intermittent, but then became continuous and was maximal in the right temporal head region (F8, T8, P8). Clinically, a left hemiplegia was present. She had a CT head and CTA head/neck that were negative for an acute cerebrovascular event. The EEG was subsequently discontinued as no seizures were recorded. She remained stable for 24 hours then experienced another seizure, described as left head turn, leftward gaze deviation, clonic activation of the right neck (sternocleidomastoid muscle), forced right elbow flexion, and partial right finger flexion. Following this event, she developed a right hemiparesis. An extra 1000 mg of IV valproate was given, and maintenance dosing increased to 500 mg tid. Prolonged EEG monitoring was restarted and showed asymmetric slowing involving the left hemispheric derivations greater than right (Fig. 1B). Again, the slowing was continuous and was now maximal in the left temporal head region (F7, T7, P7). MRI brain was performed and did not show any evidence of ischemic stroke, or any other definite cause for the symptoms. 14 Hz positive spike bursts (ctenoids) were also observed throughout monitoring (Fig. 2). Continuous EEG monitoring was discontinued as no seizures were detected and the patient was clinically improving.Fig. 1 EEG findings of alternating focal slowing. EEG during drowsiness, longitudinal bipolar montage (low frequency filter = 1 Hz, high frequency filter = 30 Hz). (A) During a period of left hemiplegia, continuous delta slowing was noted over the right hemispheric derivations, maximal in the right temporal head region (F8, T8, P8). Quantitative EEG (qEEG) showed accentuation of delta on the right on the asymmetry spectrogram tool (red arrow), and a denser delta band on the right on the rhythmicity spectrogram tool (blue arrows). (B) About 24 hours later, a right hemiparesis was noted. The EEG showed resolution of the right hemispheric slowing, and the presence of continuous delta slowing over the left hemispheric region, maximal in the left temporal head region (F7, T7, P7). QEEG shows increased left sided delta asymmetry (red arrow), and denser delta band on the left (blue arrows).\n\nFig. 2 EEG findings of 14 Hz positive spike bursts. EEG during drowsiness, longitudinal bipolar montage (low frequency filter = 1 Hz, high frequency filter = 30 Hz). (A) 14 Hz positive spikes (“ctenoids”) were noted throughout the recording. These have also been seen in encephalopathies due to Reye syndrome. (B) Quantitative analysis, showing a sharp peak at 14 Hz (red arrow).\n\nOver the next 72 hours, the hemiparesis gradually resolved. The patient experienced no further seizures during the remainder of her recovery. She was discharged to an inpatient rehab facility 19 days after her initial admission, for further physical and occupational therapy due to deconditioning from her medical illness and prolonged hospitalization. After discharge, anti-seizure medications were gradually discontinued, and she showed no neurologic sequelae at last follow-up.\n\n3 Discussion\n\nAlthough HUS is rare, with an incidence of 0.5 to 6.1 per 100 000 (highest in children under 5 years, lowest in adults age 50–59) [1], [10], neurological involvement is common, and generally reported in 25–50% [5], [10]. The true incidence of neurological abnormalities may be even higher, as shown when detailed clinical testing was performed in one series of 42 patients (including cognitive and neuropsychological testing), demonstrating all 42 patients had some demonstrable abnormality [6].\n\nA variety of neurologic findings have been described in HUS. In one study of 50 patients, 14 had neurological involvement, and hemiparesis was observed in two [5]. EEG in the 14 patients showed mostly diffuse slowing. When present, focal abnormalities on EEG (slowing or epileptiform discharges) did not appear to correlate with clinical exam findings. MRI revealed ischemic stroke in one patient and in the remainder non-specific symmetric T2 FLAIR and/or diffusion abnormalities in the basal ganglia, corpus callosum, and frontal white matter. In another study of 52 patients with HUS, paraparesis and tetraparesis were described, but not hemiparesis [6]. EEG abnormalities were limited to diffuse but frontal predominant 2–3 Hz delta slowing, with no focal abnormalities described. MRI abnormalities included bilateral symmetric T2 hyperintensities in the brainstem, basal ganglia, and corpus callosum. One patient had a syndrome consistent with PRES (posterior reversible encephalopathy syndrome). Another report described 52 patients with initial severe neurologic involvement [2]. In this series, 37 had seizures and seven had hemiparesis or hemiplegia. EEG findings were not described. MRI was performed in 29 patients, revealing abnormalities on T2 and diffusion weighted sequences in essentially all parts of the brain, as well as hemorrhagic lesions. None of these studies described alternating hemiplegia, and only a few described continuous EEG findings.\n\nCtenoids, also referred to as 14 and 6-Hz positive bursts, are a recognized benign variant without clinical significance [11], [12]. However, ctenoids have been described in cases of Reye syndrome [13], a severe encephalopathy and hepatic dysfunction which is triggered by salicylates in the context of a predisposing inborn error of metabolism. The occurrence of ctenoids in our patient may have been a coincidence of no relevance to the patient’s severe encephalopathy, in which case a follow-up prolonged EEG after recovery may be informative. However, their previously reported presence in Reye’s raises the possibility as to whether this rare EEG finding could be an uncommon EEG feature in severe encephalopathies, and as an unexplained feature of this patient’s EEG.\n\nWith respect to the COVID-19 positivity in our case, we note that respiratory manifestations of COVID-19 were mild (and perhaps also referable to fluid overload in the setting of oliguria) and other clinical findings typically associated with COVID-19 were absent. Hence while it is possible that COVID-19 infection contributed to the pathophysiology of the patient’s neurologic presentation, ultimately its role is uncertain. EEG findings in COVID-19 have been well-described and range from diffuse slowing, to interictal discharges, periodic patterns, and seizures/status epilepticus [14], [15]. A high incidence of seizures and status epilepticus has been reported [14], [15], both of which have been associated with worse clinical outcomes [15]. However, in the absence of seizures/status epilepticus or stroke, focal slowing with corresponding focal neurological deficit (alternating or not) has not been described. It is worth noting that most of the patients included in the existing COVID-19 literature also suffered from severe hypoxia, which our patient did not have. Though speculative, hypoxia likely contributed to the severe abnormalities seen on EEG in this group of patients.\n\nThe specific pathophysiology of the neurologic presentation in our case is not clear. The alternating focal slowing on EEG suggests a lateralized physiologic disturbance in cerebral function. While the MRI did show some non-specific T2 FLAIR and diffusion abnormalities similar to those reported previously in HUS, no imaging abnormalities were present that would fully account for the clinical picture. The thrombotic microangiopathy and/or endothelial dysfunction associated with both HUS and COVID could perhaps account for the alternating hemiplegia presentation in this patient [16]. Cortical spreading depression (CSD), a wave of neuronal and glial depolarization associated with ion shifts and cerebrovascular changes, is another possible pathophysiologic mechanism that may have accounted for the transient deficits in this patient. CSD may be seen following subarachnoid hemorrhage and stroke, and has been posited to contribute to migraine aura, including the motor aura seen in hemiplegic migraine [17]. Of note, several paroxysmal hemiplegic migraine variants, including alternating hemiplegia of childhood, familial hemiplegic migraine type 2, and sporadic hemiplegic migraine are associated with mutations in the ATP1A2 gene, which codes for a sodium/potassium ATPase [18]. Other familial hemiplegic migraine types demonstrate associations with channelopathies secondary to CACNA1a and SCN1A gene mutations [19]. The patient had no prior history to suggest either of these mutations, however if further occurrences such as this were to develop, genetic investigations could be considered to determine if mutations such as these involving neuronal activation and suppression are present.\n\n4 Conclusion\n\nAlternating focal slowing with a corresponding reversible alternating hemiparesis or hemiplegia may occur in severe HUS complicated by COVID-19, though it is unclear if COVID-19 contributed to this finding or not. It is important for clinicians to recognize that such findings may occur in the absence of seizures or stroke, providing the basis for the possibility of a favorable prognosis when counseling patients and families in the acute setting. Ultimately, the pathophysiology of this phenomenon in this case remains unclear. The application of other diagnostic modalities in the future, such as FDG-PET and perfusion imaging, could be helpful in improving understanding of the underlying mechanisms in such patients.\n\nEthical Statement\n\nThe authors have no relevant financial or non-financial relationships to disclose. Informed consent was waived as part of the Institutional Review Board approval for the study.\n\nCRediT authorship contribution statement\n\nHugh D. Simpson: Investigation, Data curation, Writing - original draft. Erica Johnson: Investigation, Writing - original draft. Jeffrey Britton: Conceptualization, Writing - review & editing, Supervision. Sherri Braksick: Conceptualization, Writing - review & editing, Supervision.\n\nDeclaration of Competing Interest\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==== Refs\nReferences\n\n1 Noris M. Remuzzi G. Hemolytic uremic syndrome J Am Soc Nephrol 16 4 2005 1035 1050 10.1681/ASN.2004100861 15728781\n2 Nathanson S. Kwon T. Elmaleh M. Charbit M. Launay E.A. Harambat J. Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome Clin J Am Soc Nephrol 5 7 2010 1218 1228 10.2215/CJN.08921209 20498239\n3 Hosaka T. Nakamagoe K. Tamaoka A. Hemolytic uremic syndrome-associated encephalopathy successfully treated with corticosteroids Intern Med 56 21 2017 2937 2941 10.2169/internalmedicine.8341-16 28943538\n4 Jeong Y.K. Kim I.-O. Kim W.S. Hwang Y.S. Choi Y. Yeon K.M. Hemolytic uremic syndrome: MR findings of CNS complications Pediatr Radiol 24 8 1994 585 586 10.1007/BF02012739 7724282\n5 Bauer A. Loos S. Wehrmann C. Horstmann D. Donnerstag F. Lemke J. Neurological involvement in children with E. coli O104:H4-induced hemolytic uremic syndrome Pediatr Nephrol 29 9 2014 1607 1615 10.1007/s00467-014-2803-x 24664191\n6 Weissenborn K. Donnerstag F. Kielstein J.T. Heeren M. Worthmann H. Hecker H. Neurologic manifestations of E coli infection-induced hemolytic-uremic syndrome in adults Neurology 79 14 2012 1466 1473 10.1212/WNL.0b013e31826d5f26 22993286\n7 Braksick S.A. Martinez-Thompson J.M. Wijdicks E.F.M. Steak and Stupor: seizures and E. coli O157 infection Pract Neurol 17 1 2017 39 41 10.1136/practneurol-2016-001477 27671993\n8 Pascual-Leone A. Dhuna A.K. Janousek S.T. Talwar D. EEG correlation of improvement in hemolytic-uremic syndrome after plasma infusion Pediatr Neurol 6 4 1990 269 271 10.1016/0887-8994(90)90120-P 2206160\n9 Ellul M.A. Benjamin L. Singh B. Lant S. Michael B.D. Easton A. Neurological associations of COVID-19 Lancet Neurol 19 9 2020 767 783 10.1016/S1474-4422(20)30221-0 32622375\n10 Ylinen E. Salmenlinna S. Halkilahti J. Jahnukainen T. Korhonen L. Virkkala T. Hemolytic uremic syndrome caused by Shiga toxin–producing Escherichia coli in children: incidence, risk factors, and clinical outcome Pediatr Nephrol 35 9 2020 1749 1759 10.1007/s00467-020-04560-0 32323005\n11 Tatum W.O. Husain A.M. Benbadis S.R. Kaplan P.W. Normal adult EEG and patterns of uncertain significance J. Clin. Neurophysiol. 23 3 2006 194 207 10.1097/01.wnp.0000220110.92126.a6 16751720\n12 Ebersole J.S. Husain A.M. Nordli D.R. Current Practice of Clinical Electroencephalography. Fourth 2014 Wolters Kluwer Health Philadelphia, PA\n13 Drury I. 14-and-6 Hz positive bursts in childhood encephalopathies Electroencephalogr Clin Neurophysiol 72 6 1989 479 485 10.1016/0013-4694(89)90224-1 2471616\n14 Galanopoulou A.S. Ferastraoaru V. Correa D.J. Cherian K. Duberstein S. Gursky J. EEG findings in acutely ill patients investigated for SARS-CoV-2/COVID-19: A small case series preliminary report Epilepsia Open 5 2 2020 314 324 10.1002/epi4.v5.210.1002/epi4.12399 32537529\n15 Lin L, Al‐Faraj A, Ayub N, Bravo P, Das S, Ferlini L, et al. Electroencephalographic Abnormalities are Common in <scp>COVID</scp> ‐19 and are Associated with Outcomes. Ann Neurol 2021:ana.26060. 10.1002/ana.26060.\n16 Siddiqi H.K. Libby P. Ridker P.M. COVID-19 – A vascular disease Trends Cardiovasc Med 31 1 2021 1 5 10.1016/j.tcm.2020.10.005 33068723\n17 Cozzolino O. Marchese M. Trovato F. Pracucci E. Ratto G.M. Buzzi M.G. Understanding spreading depression from headache to sudden unexpected death Front Neurol 9 2018 10.3389/fneur.2018.00019\n18 Lagman-Bartolome A.M. Lay C. Pediatric Migraine Variants: a Review of Epidemiology, Diagnosis, Treatment, and Outcome Curr Neurol Neurosci Rep 15 2015 1 14 10.1007/s11910-015-0551-3\n19 Bartolini E. Campostrini R. Kiferle L. Pradella S. Rosati E. Chinthapalli K. Epilepsy and brain channelopathies from infancy to adulthood Neurol Sci 41 4 2020 749 761 10.1007/s10072-019-04190-x 31838630\n\n",
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"abstract": "Dermatological emergencies include a number of clinical conditions usually accompanied by systemic symptoms that can lead to life-threatening complications. From the broad spectrum of life-threatening dermatoses, three cases are presented: a case of febrile ulceronecrotic Mucha-Habermann disease (FUMHD), a case of pemphigus vulgaris mimicking Stevens-Johnson syndrome (SJS), and a case of toxic epidermal necrolysis (TEN). Those cases were considered extreme, and presented to illustrate the positive outcome of timely intensive dermatological care. An interdisciplinary approach is essential in the diagnosis, treatment, management, and follow up of patients with life-threatening dermatoses.",
"affiliations": "Professor Carmen Maria Sălăvăstru, MD, PhD 2nd Clinic of Dermatology, Colentina Clinical Hospital, Buchares,t Romania; galati1968@yahoo.com.",
"authors": "Maria Sălăvăstru|Carmen|C|;Severin|Elena|E|;Moisa|Mihaela|M|;Fritz|Klaus|K|;Tiplica|Sorin|S|",
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"title": "Extreme dermatology--the intensive care skills of dermatologists in three case presentations of acute skin failure.",
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"abstract": "Some severe life-threatening conditions could be misdiagnosed during the current COVID-19 pandemic.",
"affiliations": "Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Cardiology Unit Center Hospital of Monluçon Monluçon France.;Department of Cardiology Clermont-Ferrand University Hospital Clermont-Ferrand France.",
"authors": "Endamena|Gislain Beyina|GB|;Temgoua|Mazou Ngou|MN|https://orcid.org/0000-0002-2476-3550;Chanseaume|Sylvain|S|;Hilic|Enver|E|;Camus|Lise|L|;Chanseaume|Alexandra|A|;Mischie|Alexandru|A|;Kane|Karamoko|K|;Diallo|Nouhoun|N|;Assi|Sami|S|;Eschalier|Romain|R|",
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"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/ccr3.4708\nCCR34708\nClinical Image\nClinical Images\nWhen COVID‐19 delays the management of an urgent heart condition: A rare case of a spontaneous dissection of two coronary arteries\nENDAMENA et al.\nEndamena Gislain Beyina 1\nTemgoua Mazou Ngou https://orcid.org/0000-0002-2476-3550\n1 2 neurotemgoua@yahoo.fr\n\nChanseaume Sylvain 1\nHilic Enver 1\nCamus Lise 1\nChanseaume Alexandra 1\nMischie Alexandru 1\nKane Karamoko 1\nDiallo Nouhoun 1\nAssi Sami 1\nEschalier Romain 3\n1 Cardiology Unit Center Hospital of Monluçon Monluçon France\n2 Department of Internal Medicine and Specialities Faculty of Medicine and Biomedical Sciences Yaoundé Cameroon\n3 Department of Cardiology Clermont‐Ferrand University Hospital Clermont‐Ferrand France\n* Correspondence\nMazou Ngou Temgoua, Clermont‐Ferrand University, France.\nEmail: neurotemgoua@yahoo.fr\n\n30 8 2021\n9 2021\n9 9 10.1002/ccr3.v9.9 e0470804 7 2021\n02 5 2021\n30 7 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nSome severe life‐threatening conditions could be misdiagnosed during the current COVID‐19 pandemic.\n\nSome severe life‐threatening conditions could be misdiagnosed during the current COVID‐19 pandemic.\n\nCOVID‐19\ndelay management\nspontaneous coronary arteries dissection\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:30.08.2021\nEndamenaGB, TemgouaMN, ChanseaumeS, et al. When COVID‐19 delays the management of an urgent heart condition: A rare case of a spontaneous dissection of two coronary arteries. Clin Case Rep. 2021;9 :e04708. 10.1002/ccr3.4708\n\nFunding information\n\nNone\n==== Body\n1 INTRODUCTION\n\nCOVID‐19 is a worldwide crisis with a great impact in health structures. Delay in the management of routine medical conditions has been reported during this pandemic. We describe the case of a spontaneous dissection of two coronary arteries which has been initially misclassified as a case of COVID‐19 infection and managed lately.\n\nSpontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS) and sudden death. It is defined as a separation within the coronary artery wall secondary to intramural hemorrhage, with or without tearing of the intima, thus modifying arterial architecture with the creation of a true and false channels. The starting point is often an intimal breach or even a hemorrhage of the vasa vasorum.1 SCAD preferentially affects the young population with almost no traditional cardiovascular risk factors and especially female with a sex ratio M/F of 1/5.2 It is responsible for 0.1%–0.4% of all acute coronary syndromes.3 It is an important cause of ACS in women and represents approximately 25% of acute coronary syndromes in women under 50 years old.4 It has the same clinical presentation as acute coronary syndromes secondary to plaque ruptures. Many triggering factors are mentioned in the occurrence of a SCAD including physical or emotional stress.5\n\nCurrently, the whole world experiences a very stressful condition generated by COVID‐19 pandemic. Since the beginning of this pandemic, healthcare facilities precisely emergency room are overcrowded. So, with that massive influx of patients, many other diseases are misdiagnosed.6 Xiang et al. in their study analyzing the management and outcomes of patients with ST segment elevation myocardial infarction during the COVID‐19 pandemic in China found an important decrease of the hospitalized patient with ST segment elevation myocardial infarction still the outbreak of COVID‐19 pandemic. Also, they found a delay in management that patients according to the reperfusion strategy.6 Similarly, Rashid et al. found a decline of acute myocardial infarction‐related hospitalization associated with a raise in the number of cases of out‐of‐hospital cardiac arrest since the beginning of this pandemic, particularly after the implementation of social confinement measures during the COVID‐19 outbreak in England. Consequently, the reorganization of hospital services and medical staff in response to COVID‐19 outbreak affected routine management of other diseases.7 Through this case, we wanted to show the harmful influence of the current pandemic in the management of potential life‐threatening issue as SCAD.\n\n2 CASE PRESENTATION\n\nThis is a 61‐year‐old patient, an active smoker at 20 pack‐years, in full professional activity during the period of total confinement, has presented a presyncope in the morning around 09.50 am without chest pain, or loss of consciousness or fall with notion of chills a few hours earlier. She was transported by the firefighters at 10:30 am for the Montluçon Hospital Center. The patient was received around 11:40 am and referred to its sector hospital (Gueret Hospital Center) in accordance with the COVID‐19 Plan from the Regional Health Agency for screening as suspected of coronavirus infection 19. On arrival at the emergency room of this health facility, an electrocardiogram carried out revealed an apicolateral and inferior persistent ST segment elevation with mirror image on anterior area (Figure 1). Then, the patient has been transported to the initial center for emergency coronary angiography where she arrived at 3:30 pm. Coronary angiography was performed and revealed the presence of a thrombus in the distal anterior interventricular artery with the appearance of \"stick insect,\" a thrombus on the dominant circumflex artery obstructing the second marginal with a \"radish tail\" aspect and a right network free from any atheromatous lesion (Figure 2). Transthoracic cardiac ultrasound found good biventricular systolo‐diastolic function with a left ventricular ejection fraction of 69%, no abnormalities in segmental and global kinetics of the left ventricle. Troponin I was 2465 pg/ml, Creatine phosphokinase at 1874 pg/ml, C‐reactive protein 1.1 mg/L, leukocytes at 13,81.109/L. The medical treatment included glycoprotein IIb / IIIa inhibitor, double anti‐aggregation platelet and anticoagulant (unfractionated heparin), beta‐blocker (bisoprolol) on Day 1 hospitalization. Bisoprolol has been changed to ivabradine because the patient remained tachycardic with low blood pressure. We noted on the Day 3 electrocardiogram, presence of a Q wave of apicolateral and inferior necrosis with persistence of the elevation from the same territory. Treatment with acetylsalicylic acid, clopidogrel, ivabradine, and inhibitor of the proton pump was given as an exit treatment. Magnetic resonance imaging (MRI) was performed on an outpatient basis at one month and found: a sequelae of infero‐latero‐moderate, infero‐septo‐average, latero‐apical, infero‐apical, and septo‐apical with thinning of the middle and apical walls measuring, respectively, 3mm and 4mm, a left ventricular ejection fraction of 47%.\n\nFIGURE 1 12‐Limbs electrocardiogram showing an infero‐lateral ST segment elevation\n\nFIGURE 2 Coronary artery image showing a type 1 spontaneous dissection of the distal interventricular artery and a type 2 dissection of the second marginal\n\nCoronarography control with optical coherence tomography (OCT) performed two months later allowed to highlight a complete healing of the lesions (Figure 3). OCT does not highlighted the intimal breach (Figure 4).\n\nFIGURE 3 Coronarographic control after 2 months\n\nFIGURE 4 Optical coherence tomography image\n\n3 DISCUSSION\n\nFormerly assimilated to a classic acute coronary syndrome, the diagnosis of SCAD was based mainly on the presence of an intimal radiolucent flap associated with a contrast in the arterial wall on coronary angiography. Currently, studies on SCAD permit to establish a classification into 3 angiographic types8: Type 1 (representing the classic description with intimal flap), type 2 (extensive and diffuse tubular lesions with a plane of dissection not visible which may result in complete coronary occlusion), and type 3 (multiple focal tubular lesions due to intramural hematoma mimicking atherosclerosis).\n\nOur patient presented a feature of a double dissection with a type 1 lesion on the distal anterior interventricular artery and a type 2 lesion on the second left marginal. Type 2, sometimes resulting in compression of the vascular lumen due to intramural hematoma without intimal flap, it is the most frequently encountered in the different series representing 67% of cases. Type 1 follow‐up with an intimal flap which represents 29% of cases. Type 3 mimicking atherosclerotic lesions is only found in 4% of cases.8 The descending anterior interventricular artery is usually the most affected during SCAD. However, polyarterial lesions could be found in a range of 20%−25% of cases.9\n\nPatients with SCAD generally have arterial fragility without atheroma or calcifications which may limit the progression of coronary dissection. This fragility can be acquired during pregnancy, oral contraception, hormone therapy, systemic inflammatory diseases, congenital condition as in fibromuscular dysplasia, Marfan disease, syndrome Ehlers‐Danlos, connectivitis, or even idiopathic.10, 11 In the series by Saw et al assessing the baseline characteristics, predisposing factors, and clinical outcomes of 168 patients with a SCAD, the association with a detailed screening of other non‐coronary arterial disease had revealed that 72% of these patients also presented with fibromuscular dysplasia.5 However, our patient did not present clinical elements that could suggest any of the above conditions cited. These changes in the arterial wall are generally not sufficient to explain SCAD. This pathology appears to be multifactorial. An extrinsic trigger appears essential, such as emotional stress, intense physical exercise, or maneuvers such as Valsalva.10, 11 This is also mentioned in the series by Saw et al. In this study, physical or emotional stress was implicated as triggering factors in 56% of cases.5 Likewise, in our patient, we could clearly evoke an emotional and important professional stress. In fact, concomitantly with the occurrence of this case of spontaneous dissection of two coronary arteries, we were living a period of general confinement in France due to the COVID‐19 pandemic. Very anxiety‐provoking situation both professional and personal for our patient who continue to carry out her professional activities despite the high risk of contracting a particularly fatal viral disease. We therefore think that the strong stress at the same time emotional, physical, and professional would be the triggering factor. Direct link between SARS‐COV2 and SCAD is not clear but as there is a strong relationship between cardiovascular disease and COVID‐19, future studies are needed in this field.12 The clinical presentation of a SCAD is similar to that of an acute coronary syndrome by rupture atherosclerotic plaque. In more than half of the cases, we note electrocardiographic changes as ST segment elevation associated with elevation of enzymes myocardial (troponin). The rest of the cases will present as acute non‐ST elevation coronary syndromes.13\n\nSome may also present with short‐term life‐threatening ventricular arrhythmias and others still in cardiac arrest. In our case, we had a typical electrocardiographic presentation of a myocardial infarction with infero‐lateral ST segment elevation and an anterior mirror image. Of course, we had an enzymatic movement with elevation of troponins I. In the study done by the Mayo Clinic in the United States of America with the highest number of patients with spontaneous coronary arteries dissection, aimed at determining the prevalence of coronary tortuosity in these patients, it appears that tortuosity of coronary arteries is a risk factor for SCAD and even recurrence.13\n\nAs part of the SCAD, coronary angiography remains the first‐line examination and sometimes allows to visualize thrombi in the real channel, but it makes it difficult to visualize hematoma of the artery wall. It also helps to determine the type of lesion. It is therefore systematically recommended an association with intravascular imaging as optical coherence tomography (OCT) or intravascular ultrasonography (IVUS). The optical coherence tomography has better resolution than intravacular ultrasonography. It allows to confirm the guide's position in the real channel, detail the site of the wall hematoma and intimal breach, to facilitate an accurate assessment of the size of the artery and optimize stent expansion in the event of underlying angioplasty.14 However, OCT therefore allows a detailed overview of the arterial anatomy of patients.15 This technique is limited by its lack of visualizing deep layers of the arterial wall.15 Compared to intravascular ultrasound, OCT is clearly superior in terms of the location of the initial intimal lesion and in the exploration of the intimo‐medial membrane (intimal flap).15, 16\n\nThe treatment of SCAD could be medical generally without stenting and the prognostic is generally good.14 Our treatment consists of an antiplatelet drug, a beta‐blocker in order to reduce the pressure shearing action on the arterial wall and thus stop intramural bleeding favorizing the repair of intimal breach. The myocardial sequelae were found after one month in our patient probably because of the association of two coronary arteries involvement and the delay of management. Although these sequelae have disappeared after two months with good medical therapy.\n\n4 CONCLUSION\n\nSpontaneous dissection of coronary arteries is a rare cause of acute coronary syndrome. As for takotsubo cardiomyopathy, it should always be evoked in young female with thoracic pain in the context of severe stress. The health practitioners should be more alerted especially during this current pandemic.\n\nCONFLICT OF INTEREST\n\nNone.\n\nAUTHOR CONTRIBUTIONS\n\nGBE: Manuscript writing. MNT: Critical revision. RE: Supervision. All the authors: Management of the case.\n\nETHICAL APPROVAL\n\nFormal ethical approval from the University Research Ethics Board was not required for the completion of this study.\n\nINFORMED CONSENT\n\nWritten informed consent for publication of this case report was obtained from the patient.\n\nACKNOWLEDGMENTS\n\nWe acknowledge the patient who have accepted to participate in this study and also all the administrative staff of hospital center of Montlucon. Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 BerradaNEM, ZaimiA, EzzouakA, et al. Post‐partum acute coronary syndrome secondary to spontaneous coronary dissection: report of a case. Pan Afr Med J. 2015;20 :249.26161172\n2 TweetMS, HayesSN, PittaSR, et al. Clinical features, management and prognosis of spontaneous coronary artery dissection. Circulation. 2012;126 (5 ):579‐588.22800851\n3 MortensenKH, ThuesenL, KristensenIB. Spontaneous coronary artery dissection: a Western Denmark Heart Registry study. Catheter Cardiovasc Interv. 2009;Nov 1. 74 (5) :710‐717.\n4 SawJ, AymongE, ManciniGB, et al. Nonatherosclerotic coronary artery disease in young women. Canadian J Cardiol. 2014;30 (7 ):814‐819.\n5 SawJ, AymongE, SedlakT, et al. Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes. Circ Cardiovasc Interv. 2014;7 (5 ):645‐655.25294399\n6 XiangD, XiangX, ZhangW, et al. Management and Outcomes of Patients With STEMI During the COVID‐19 Pandemic in China. J Am Coll Cardiol. 2020;15 (10 ):1318‐1324.\n7 RashidM, GaleCP, CurzenN, et al. Impact of Coronavirus Disease 2019 Pandemic on the Incidence and Management of Out‐of‐Hospital Cardiac Arrest in Patients Presenting With Acute Myocardial Infarction in England. J Am Heart Assoc. 2019;2020 (9 ):e018379.\n8 TweetMS, EleidMF, BestPJ, et al. Spontaneous coronary artery dissection: revascularization versus conservative therapy. Circ Cardiovasc Interv. 2014;7 (6 ):777‐786.25406203\n9 ShahidA. Spontaneous coronary artery dissection. Vol. 14, N ° 38 ‐ 22 Feb 2017.\n10 SawJ, ManciniGBJ, HumphriesKH. Contemporary review on spontaneous coronary artery dissection. J Am Coll Cardiol. 2016;68 (3 ):297‐312.27417009\n11 YipA, SawJ. Spontaneous coronary artery dissection ‐ a review. Cardiovasc Diagn Ther. 2015;5 :37‐48.25774346\n12 ElapiN, LicastroN, ProvenzanoM, AndreucciM, de FranciscisS, SerraR. Cardiovascular disease as a biomarker for an increased risk of COVID‐19 infection and related poor prognosis. Biomark Med. 2020;14 (9 ):713‐716.32426991\n13 EleidMF, GuddetiRR, TweetMS, et al. Coronary artery tortuosity in spontaneous coronary artery dissection: angiographic characteristics and clinical implications. Circ Cardiovasc Interv. 2014;7 :656‐662.25138034\n14 AlfonsoF, BastanteT, RiveroF. Spontaneous coronary artery dissection. Circ J. 2014;78 (9 ):2099‐2110.25131524\n15 AlfonsoF, PauloM, GonzaloN, et al. Diagnosis of spontaneous coronary artery dissection by optical coherence tomography. J Am Coll Cardiol. 2012;59 :1073‐1079.22421300\n16 PauloM, SandovalJ, LennieV, et al. Combined use of OCT and IVUS in spontaneous coronary artery dissection. JACC Cardiovasc Imaging. 2013;6 :830‐832.23747066\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(9)",
"journal": "Clinical case reports",
"keywords": "COVID‐19; delay management; spontaneous coronary arteries dissection",
"medline_ta": "Clin Case Rep",
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"pubdate": "2021-09",
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"title": "When COVID-19 delays the management of an urgent heart condition: A rare case of a spontaneous dissection of two coronary arteries.",
"title_normalized": "when covid 19 delays the management of an urgent heart condition a rare case of a spontaneous dissection of two coronary arteries"
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"abstract": "The involvement of myocardium and pericardium at the same time is very uncommon as first manifestation of juvenile idiopathic arthritis with systemic onset (soJIA).\n\n\n\nA fourteen years-old boy, referred with symptoms of acute gastroenteritis, developed a perimyocarditis as first manifestation of Still's Disease, after only one day from the admission. The rheumatologic disease was not responding to glucocorticoid treatment. The use of anakinra was the key point of the therapy and after its administration the patient started to recover fastly.\n\n\n\nThis case report describes cardiac involvement as first sign of soJIA and the successful use of anakinra inducing remission of soJIA not-responding to steroid therapy.",
"affiliations": "Array. silvia.ciancia.18@gmail.com.;Pediatric Rheumatology Unit, Santa Maria Nuova Hospital, Reggio Emilia, Italy. michela.cappella@asmn.re.it.;Pediatric Rheumatology Unit, Santa Maria Nuova Hospital, Reggio Emilia, Italy. alessandro.defanti@asmn.re.it.;Postgraduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena and Reggio Emilia, Italy. lorenzo.iughetti@unimore.it.",
"authors": "Ciancia|Silvia|S|;Cappella|Michela|M|;De Fanti|Alessandro|A|;Iughetti|Lorenzo|L|",
"chemical_list": "D053590:Interleukin 1 Receptor Antagonist Protein",
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"doi": "10.23750/abm.v91i4.9093",
"fulltext": "\n==== Front\nActa Biomed\nActa Biomed\nActa Bio Medica : Atenei Parmensis\n0392-4203\n2531-6745\nMattioli 1885 Italy\n\n33525302\nACTA-91-45\n10.23750/abm.v91i4.9093\nCase Report\nPerimyocarditis as first sign of systemic onset juvenile idiopathic arthritis treated successfully with anakinra: a case-based review\nCiancia Silvia 1\nCappella Michela 2\nDe Fanti Alessandro 2\nIughetti Lorenzo 1\n1 Postgraduate School of Pediatrics, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena and Reggio Emilia, Italy\n2 Pediatric Rheumatology Unit, Santa Maria Nuova Hospital, Reggio Emilia, Italy\nCorrespondence: Silvia Ciancia Policlinico di Modena – Azienda Ospedaliero-Universitaria, Largo del Pozzo, 71, 41125 Modena (MO), Italia Tel. +390594224719 Fax +390594224034 E-mail: silvia.ciancia.18@gmail.com\n2020\n15 9 2020\n91 4 e202004513 12 2019\n13 12 2019\nCopyright: © 2020 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA\n2020\nThis work is licensed under a Creative Commons Attribution 4.0 International License\nBackground:\n\nThe involvement of myocardium and pericardium at the same time is very uncommon as first manifestation of juvenile idiopathic arthritis with systemic onset (soJIA).\n\nCase:\n\nA fourteen years-old boy, referred with symptoms of acute gastroenteritis, developed a perimyocarditis as first manifestation of Still’s Disease, after only one day from the admission. The rheumatologic disease was not responding to glucocorticoid treatment. The use of anakinra was the key point of the therapy and after its administration the patient started to recover fastly.\n\nConclusions:\n\nThis case report describes cardiac involvement as first sign of soJIA and the successful use of anakinra inducing remission of soJIA not-responding to steroid therapy. (www.actabiomedica.it)\n\narthritis\nidiopathic\njuvenile\nmyocarditis\nperimyocarditis\ninterleukin\nanakinra\n==== Body\nBackground\n\nSystemic onset juvenile idiopathic arthritis (so-JIA) is a chronic inflammatory disease characterized by high spiking quotidian fever and arthritis associ-ated with evanescent rash, lymphadenopathy, hepato-splenomegaly and serositis (1). JIA is one of the most common pediatric chronic diseases and is classified in seven subtypes by the International League of Associations for Rheumatology (ILAR) classification (2).\n\nSoJIA includes about 10-20% of all JIA patients (3). Several studies showed the role of innate immune system in soJIA, resulting in increased production of pro-inflammatory cytokines (4-6), that explains the role played in therapy by biological drugs such as anakinra. Cardiac involvement as onset manifestation is very rare in pediatric population, representing at most a complication of the disease.\n\nCase presentation\n\nA 14-years-old boy presented with fever, vom-iting, diarrhea, signs of dehydration, loss of appetite, severe weakness, arthromyalgias diffused to the entire body, headache and pharyngodynia since a week. Physi-cal examination revealed pharyngitis with cervical lymphadenopathy, pain in left iliac region during the palpation of the abdomen and hepatosplenomegaly. Three days before his pediatrician prescribed antibiotic therapy for throat inflammation.\n\nBlood tests showed neutrophilic leukocytosis (white cells 16.140/mm3 with 84% of neutrophils) and an important increase of C-reactive protein (35.58 mg/dl, normal value <0.01 mg/dl) and creatine phosphokinase (476 U/l, normal value <50 U/l). Procalcitonin was only mildly increased (0.84 ng/ml, normal value <0.50 ng/ml). Sinus rhythm with diffuse repolarization abnormalities were evident on the electrocardiogram. Chest X-rays was completely normal.\n\nTo correct the dehydration the patient was admitted in our unit.\n\nDuring the first day of admission the boy presented epigastric pain, profuse sweating, paleness and mild bradycardia with normal blood pressure level for age. On electrocardiogram a diffuse ST elevation was present, troponin was consistently high (28.36 ng/ml, normal range 0-0.4 ng/ml) and echocardiography revealed a slight layer of pericardial effusion without reduction of ejection fraction (EF 60%) but with a mild contractile dysfunction of posterobasal segments of the ventricular septum. The boy was developing a perimyocarditis in the context of an acute gastrointestinal infection. To prevent complications of perimyocarditis and onset of malignant arrhythmias, the patients was admitted to the intensive care unit for 48 hours. During this time his clinical conditions were stable and the level of troponin on the second day after the admission showed a dramatic reduction (7.37 ng/ml, NR 0-0.4 ng/ml).\n\nFeatures of perimyocarditis reversed within 72 hours and clinical situation was stabilized but the boy still presented twice-a-day high spiking fever, weakness and arthromyalgias increasing in severity. Abdominal ultrasounds confirmed the enlargement of liver and spleen; on blood tests CPK was increased (576 U/L), the same were CRP (39.42 mg/dl) and white cells count (18670/mm3), ESR was high (80 mm/h), ferritin raised (285.3 ng/ml, normal range 7-140 ng/ml), anemia developed (Hb 11.7 g/dl, normal range for age 12-15.2 g/dl). Pharyngeal swabs for viruses (Adenovirus, Influenza virus type A/B, Parainfluenza virus type 1/2/3/4, Rhinovirus A/B/C, RSV type A/B, Bocavirus, Coronavirus 229E, Coronavirus NL63, Coronavirus OC43, Metapneumovirus, Enterovirus) and bacteria (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis) were negative, serological tests showed positive IgG for EBV and CMV associated to negative IgM and negative IgM and IgG for: Mycoplasma pneumoniae, Chlamydophila pneumoniae, Borrelia burgdoferi, Bartonella, Brucella spp, Salmonella typhi/paratyphi, Parvovirus B19, Adenovirus, TORCH complex, HIV. For Enterovirus also IgA were measured and were negative. Tuberculosis tests were negative (PCR for DNA research on sputum and Mantoux test negative, QuantiFERON indeterminate). Blood cultures (for aerobic and anaerobic bacteria and fungi) did not grow any organism, stool culture (Salmonella, Shigella, Campylobacter) were negative. Antistreptolysin O titer was negative. Therefore, the main infectious agents were excluded. Screening for autoantibodies was negative: antinuclear antibodies (ANA), anti-double stranded DNA antibodies (anti ds-DNA), anti-Saccharomyces cerevisiae antibodies (ASCA), anti-neutrophil cytoplasmic antibodies (ANCA) titers were within normal limits. In the suspicion of rheumatic condition, serum amyloid A was measured and the level was raised (586 mg/dl, normal range 1-3 mg/dl).\n\nThe persistence of fever, the presence of general-ized lymph nodes enlargement, severe arthromyalgias, hepatosplenomegaly, the recent perimyocarditis, and finally the appearance of an evanescent and itchy pink rash on his trunk in presence of elevation of blood markers of systemic inflammation, allowed us to make the diagnosis of systemic onset juvenile idiopathic arthritis (soJIA) characterized by perimyocarditis as first sign of onset.\n\nPulse intravenously methylprednisolone was then administered for three days and after that oral corticosteroid therapy with prednisone was started. Because fever and arthritis were persistent, after six days a second try with high-doses steroid bolus was made. Abdominal ultrasounds showed the resolution of splenomegaly with spleen of normal size, but he-patomegaly was still present. Cardiological follow-up showed the resolution of myocarditis, troponin value was negative, but the slight layer of pericardial effusion was persistent. In four days fever and arthromyalgias appeared again, with a prevalent involvement of knees. The blood tests showed increased value of white cells (34.750/mmc, neutrophils 92%), CRP (7.37 mg/dl), ESR (35 mm/h), ferritin (757 ng/ml). In consideration of the persistent systemic inflammation despite the corticosteroid treatment, we decided to enhance the therapy by adding anakinra, a biological drug. The day after the start of the second-line therapy fever vanished permanently, in five days inflammation index returned to normal values, only a mild pain to both knees persisted. The echocardiography per-formed after one week showed the disappearance of the pericardial effusion.\n\nDuring the subsequent follow-up, the boy showed a good compliance to the therapy. The glucocorticoids daily dose was progressively reduced and the patient continued his treatment with anakinra with good control of symptoms. After two and a half months cardiac MRI was performed to assess any damage: morphology and volume of left ventricle were preserved, the ejection fraction was 63%. The study of segmentary kinetics of the left ventricle documented the presence of mild hypokinesia of the mid-lateral wall. The delayed enhancement showed minute hyperintense areas into the distal portion of the mid-lateral wall of the left ventricle as scar fibrosis after myocarditis.\n\nDiscussion\n\nThe most interesting aspect of our case is the onset of Still’s disease with cardiac involvement. Pericarditis as onset manifestation of soJIA is included in diagnostic criteria (even if this manifestation is rare in pediatric population) but involvement of cardiac muscle is exceptional.\n\nWe performed a research in PUBMED database (including Medline) combining word “myocarditis” with “Still’s disease” and “systemic onset juvenile idiopathic arthritis”. After removing duplicate records, a total of 100 papers was found. Of this group, 66 records were excluded because not pertinent and 19 records were excluded because referred to adult patients. Of the 15 records left, 3 were excluded because neither the abstract or the full-paper were available. Considering the last 10 papers, only 2 of them referred to case reports of patients in pediatric age presenting myocarditis as onset manifestation of systemic onset juvenile idiopathic arthritis (table 1).\n\nTable 1. Flow-chart of study selection\n\n\t\n\nMondal and colleagues described a case of an 11-years-old child with congestive heart failure as presentation of soJIA. Acute myocarditis without evidence of pericarditis was the etiology for congestive heart failure (7). Myocarditis leading to congestive heart failure, associated to perimyocarditis in a patient with cervical spondylitis without any peripheral joint involvement at onset of soJIA is described by Ghosh (8).\n\nSvantesson et al. followed up thirty-three patients with soJIA for 4 to 24 years and found that cardiac involvement occurred in 42%, with myocarditis or perimyocarditis having a worse prognosis that pericarditis; anyway cardiac involvement in these cases was a complication of the disease and not an onset manifestation (9). In a similar study Svantesson et al. followed up 320 patients with JIA, only 4.7% developed cardiac involvement and perimyocarditis was diagnosed in only 2 children (10). Miller et al. described three cases of children with myocarditis and soJIA. Also in these cases myocarditis occurred on a background of severe, active systemic disease (11). A retrospective study of Goldenberg et al. on 172 patients affected by soJIA described 13 patients presenting cardiac involvement during the first years of disease: seven patients developed pericarditis, four perimyocarditis and two myocarditis. Among the patients with myocarditis, three died of septicemia during active disease (12). An Italian work on 83 juvenile rheumatoid arthritis patients described the cardiac involvement in 4 patients. Also in those cases the cardiac disease was a complication of soJIA, and was not present at the onset of the disease. Only one patient developed perimyocarditis. In all of them treatment with prednisone was sufficient to induce the resolution of the acute complication (13). Ward et al. described a case of a Chinese 16-years old patient diagnosed with systemic onset juvenile idiopathic arthritis. The authors attributed the cardiac involvement to a myocarditis but the clinical history and the exams referred seems to be more suggestive of pericarditis and possibly endocardial involvement than cardiac muscle disease (no raise in creatine kinase levels, no report about troponin levels, normal echocardiographies) (14). From literature review another interesting case emerged: Zeft and colleagues described the case of 10 years-old boy presenting isolated myocarditis without pericardial involvement 17 months after onset of soJIA, while he was on treatment with NSAID, prednisone, low dose cyclosporine and anakinra. The symptoms started mildly and were first associated to a viral illness; in approximately 3 weeks the boy started to complain evening chest pain; two days later his clinical conditions worsened but he was discharged again because apparently he presented only with mild symptoms and signs at physical examination, even if his chest X-rays documented his heart size within the upper limits of normal. The boy died at home 2 days later. At autopsy patchy peribronchial inflammation and isolated myocarditis emerged. Because no signs of severe systemic inflammation were found, macrophage activation syndrome was excluded. Immunosuppression due to medications he was taking could have facilitated infectious myocarditis (no viral etiology has been demonstrated) but it is also possible that incompletely controlled disease could have led to myocardial inflammation. Cardiac related adverse effect are not listed for anakinra administration (15). A recent review on cardiac involvement in juvenile idiopathic arthritis conclude that subclinical cardiovascular involvement begins shortly after the onset of the disease and worsen with disease duration. It constitutes the second common cause of mortality in this class of patients. If pericarditis represents the most common but often benign cardiac involvement with a prevalence of 30-36%, myocarditis is a rare event (frequency from 1.2% to 10%) but can be life threatening (15). Myocardial involvement is normally due to chronic inflammation, subclinical vasculitis, damage of the endothelium, fibrosis, thus it is often correlated to a longer duration of disease. In consideration of this, cardiac involvement usually represents a complication of soJIA.\n\nHence, as onset manifestation of soJIA, like in our patient, perimyocarditis is exceptional. In our patient myocarditis was diagnosed on the basis of cardiac enzyme elevation and echocardiography findings; endomyocardial biopsy was not performed to confirm the diagnosis because of its invasivity. Pericarditis was diagnosed on electrocardiogram abnormalities and on echocardiography revelation of pericardial effusion.\n\nThe other interesting aspect of our case was the efficacy of anakinra to induce the remission of the disease, after the failure of the corticosteroid therapy. Anakinra is a recombinant form of human IL-1 receptor that binds to IL-1 with a competitive mechanism. In Still’s disease, it is approved in children aged more than 8 months or with body weight >10 kg, with a dosage of 1-2 mg/kg/day up to 100 mg/day (as for adult patients, with body weight >50 kg). According to the latest recommendations for the treatment of Juvenile Idiopathic Arthritis from the American College of Rheumatology, the use of anakinra as initial therapy is indicated for children with physician global assessment ≥5 irrespective of the AJC (active joint count) or for children with physician global assessment <5 and AJC >0 (17). Nigrovic talked about a “window of opportunity” for treatment of soJIA, in which anakinra represents an excellent choice (18). Unluckily, sometimes anakinra seems to be not highly effective on arthritis symptoms, with patients having a partial response (19). Our patient had an extraordinary response on the side of systemic and biochemical features, but a not complete remission of arthritis, persisting at knees, but mildly. Even if there are not enough data about the early use of anakinra to threat soJIA presenting with heart involvement at the onset, there are a few case reports of adult-onset Still’s disease complicated by myocarditis at the onset, in which anakinra has successfully been used in patients resistant to high-doses of corticosteroids (20-22). Luconi et. al described a case of a 17 years-old young man presenting myocarditis at the onset of his adult onset Still’s disease: anakinra was prescribed as third line therapy (first line therapy NSAIDs associated to colchicine, second line therapy pulse corticosteroids ev, then oral prednisone associated to methotrexate). Only after the start of anakinra there was a spectacular improvement of clinical conditions, laboratory values and transthoracic echography findings (23).\n\nConclusions\n\nPericarditis is the most common form of cardiac involvement in SoJIA and it is usually self-limiting. Myocardial involvement (with or without pericardial effusion) is rare but potentially life-threatening. The early recognition of this rare manifestation, at the onset of the disease or as a secondary complication, is necessary to prevent severe outcomes. The early use of anakinra can dramatically improve the evolution of soJIA.\n\nConflict of interest:\n\nEach author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article\n==== Refs\nReferences\n\n1 Shenoi S Wallace CA Diagnosis and Treatment of Systemic Juvenile Idiopathic Arthritis J. of Pediatrics Jun 16, 2016\n2 Petty RE International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001 J Rheumatol 2004 31 2 390 14760812\n3 Cimaz R Systemic-onset of juvenile idiopathic arthritis Autoimmunity Reviews 2016 15 931 934 27392503\n4 Barnes MG Subtype-specific peripheral blood gene expression profiles in recent onset juvenile idiopathic arthritis Arthritis Rheum 2009 60 210212\n5 Ishikawa S Abnormal expression of the genes involved in cytokine networks and mitochondrial function in systemic juvenile idiopathic arthritis identified by DNA microarray analysis Ann Rheum Dis 2009 68 264 72 18388159\n6 Ogilvie EM Khan A Hubank M Kellam P Woo P Specific gene expression profiles in systemic juvenile idiopathic arthritis Arthritis Rheum 2007 56 1954 65 17530721\n7 Mondal R Sarkar S Ghoshal A Sabui T Congestive Heart Failure: An Uncommon Presentation of Systemic Onset Juvenile Idiopathic Arthritis (SOJIA) Indian J Pediatr (January 2013) 80 1 67 69\n8 Ghosh JB Juvenile Idiopathic Arthritis-Its Rare Presentation Indian J Pediatr (February 2012) 79 2 262 264\n9 Svantesson H Akesson A Eberhardt K Elborgh R Prognosis in juvenile rheumatoid arthritis with systemic onset. A follow-up study Scand J Rheumatol 1983 12 2 139 44 6857171\n10 Svantesson H Björkhem G Elborgh R Cardiac involvement in juvenile rheumatoid arthritis. A follow-up study Acta Paediatr Scand 1983 May 72 3 345 50 6880720\n11 Miller JJ 3rd French JW Myocarditis in juvenile rheumatoid arthritis Am J Dis Child 1977 Feb 131 2 205 9 835539\n12 Goldenberg J Ferraz MB Pessoa AP Symptomatic cardiac involvement in juvenile rheumatoid arthritis Int J Cardiol 1992 Jan 34 1 57 62 1548110\n13 Cottafava F Cosso D Guglieri F Cardiac involvement in juvenile rheumatoid arthritis Minerva Pediatr 1991 Jul-Aug 43 7-8 505 9 Italian 1944004\n14 Ward SC Wiselka MJ Nicholson KG Still’s disease and myocarditis associated with recent mumps infection Postgrad Med J 1988 Sep 64 755 693 5 3251224\n15 Zeft AS Menon SC Miller D Fatal myocarditis in a child with systemic onset juvenile idiopathic arthritis during treatment with an interleukin 1 receptor antagonist Pediatr Rheumatol Online J 2012 Apr 10 10 8 22490470\n16 Koca B Sahin S Adrovic A Barut K Kasapcopur O Cardiac involvement in juvenile idiopathic arthritis Rheumatol Int 2017 Jan 37 1 137 142 Epub 2016 Jul 14. Review 27417551\n17 Ringold S 2013 Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for the Medical Therapy of Children With Systemic Juvenile Idiopathic Arthritis and Tuberculosis Screening Among C Arthritis and rheumatism 2013 65 2499 2512 24092554\n18 Nigrovic PA Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol 2014 66 140513\n19 Giancane G Minoia F Davì S Bracciolini G Consolaro A Ravelli A IL-1 Inhibition in Systemic Juvenile Idiopathic Arthritis Front. Pharmacol 2016 7 467 27999545\n20 Piel-Julian ML Early use of anakinra in adult-onset Still’s disease myocarditis Scand J Rheumatol 2018 Nov 47 6 511 512 Epub 2018 Jan 2 29291663\n21 Choi AD Moles V Fuisz A Weissman G Cardiac magnetic resonance in myocarditis from adult onset Still’s disease successfully treated with anakinra Int J Cardiol 2014 172 1 e225 e227 24461482\n22 Oehler E Valour F Hachulla E Ghawche F Myopericarditis as the presenting manifestation of adult Still’s disease Rev Med Interne 2014 35 12 827 830 24309545\n23 Luconi N Myocarditis in a young man with adult onset Still’s disease successfully treated with Il-1 blocker Int J Cardiol 2015 189 220 2 Epub 2015 Apr 11. Review 25897909\n\n",
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"issue": "91(4)",
"journal": "Acta bio-medica : Atenei Parmensis",
"keywords": null,
"medline_ta": "Acta Biomed",
"mesh_terms": "D000293:Adolescent; D001171:Arthritis, Juvenile; D006760:Hospitalization; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D016896:Treatment Outcome",
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"pubdate": "2020-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14760812;21625834;3251224;27999545;22490470;29291663;27392503;835539;24092554;24461482;19565513;24309545;17530721;1944004;27417551;6880720;24623686;25897909;22161583;18388159;27499217;1548110;6857171",
"title": "Perimyocarditis as first sign of systemic onset juvenile idiopathic arthritis treated successfully with anakinra: a case-based review.",
"title_normalized": "perimyocarditis as first sign of systemic onset juvenile idiopathic arthritis treated successfully with anakinra a case based review"
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"abstract": "BACKGROUND\nOlaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC).\n\n\nMETHODS\nIn this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM).\n\n\nRESULTS\n18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS.\n\n\nCONCLUSIONS\nOlaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted.\n\n\nBACKGROUND\nThis clinical trial was registered on ClinicalTrials.gov as NCT01296763.",
"affiliations": "The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;Columbia University Medical Center, New York, NY, USA.;Columbia University Medical Center, New York, NY, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.;The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.",
"authors": "Yarchoan|Mark|M|;Myzak|Melinda C|MC|;Johnson|Burles A|BA|;De Jesus-Acosta|Ana|A|;Le|Dung T|DT|;Jaffee|Elizabeth M|EM|;Azad|Nilofer S|NS|;Donehower|Ross C|RC|;Zheng|Lei|L|;Oberstein|Paul E|PE|;Fine|Robert L|RL|;Laheru|Daniel A|DA|;Goggins|Michael|M|",
"chemical_list": "D014408:Biomarkers, Tumor; D010793:Phthalazines; D010879:Piperazines; D016685:Mitomycin; D000077146:Irinotecan; D002945:Cisplatin; C531550:olaparib; D002166:Camptothecin",
"country": "United States",
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"doi": "10.18632/oncotarget.17237",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 284541221723710.18632/oncotarget.17237Research PaperOlaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer Yarchoan Mark 1Myzak Melinda C. 1Johnson Burles A. III1De Jesus-Acosta Ana 1Le Dung T. 1Jaffee Elizabeth M. 1Azad Nilofer S. 1Donehower Ross C. 1Zheng Lei 1Oberstein Paul E. 2Fine Robert L. 2Laheru Daniel A. 1Goggins Michael 11 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA2 Columbia University Medical Center, New York, NY, USACorrespondence to:Michael Goggins,mgoggins@jhmi.edu4 7 2017 19 4 2017 8 27 44073 44081 24 2 2016 13 3 2017 Copyright: © 2017 Yarchoan et al.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nOlaparib is an oral inhibitor of polyadenosine 5’-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC).\n\nPatients and Methods\nIn this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM).\n\nResults\n18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS.\n\nConclusions\nOlaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted.\n\nTrial registration\nThis clinical trial was registered on ClinicalTrials.gov as NCT01296763.\n\nolaparibpancreatic cancerBRCA2irinotecancisplatin\n==== Body\nINTRODUCTION\nPancreatic ductal adenocarcinoma is an aggressive malignancy and the fourth most common cause of cancer-related deaths in the United States [1, 2]. Only 20-30% of patients with pancreatic ductal adenocarcinoma have resectable disease at diagnosis, and the majority of patients who undergo resection subsequently relapse [3, 4]. Despite the recent development of novel gemcitabine or 5-FU-based combination chemotherapy regimens, the median overall survival for patients with metastatic disease is less than one year [5, 6]. This highlights the continued need for novel and effective therapies for pancreatic ductal adenocarcinoma.\n\nOlaparib (AZD2281, Lynparza™) is an oral inhibitor of polyadenosine 5’-diphosphoribose [poly-(ADP-ribose)] polymerization (PARP), an enzyme essential in the repair of DNA [7–9]. In tumors with defects in homologous DNA repair, PARP inhibition results in the accumulation of single-strand breaks, which are converted during replication to irreparable DNA double-strand breaks and cellular death by apoptosis. Cells with defects in double-strand break repair such as those from BRCA defects are hypersensitive to PARP inhibition, a process called synthetic lethality [10, 11]. Multiple PARP inhibitors have been approved or are in clinical development for ovarian and other cancers. Although PARP inhibitors have clinical activity in cancers without known defects in homologous DNA repair, preclinical and clinical trials have shown higher clinical response rates in patients with tumors harboring such defects [12, 13].\n\nMolecular alterations in homologous DNA repair are known to occur in a subset of pancreatic cancers. Inherited genetic factors account for approximately 5-10% of pancreatic cancer, and BRCA2 is the most common known germline mutation identified [14]. In addition to BRCA2, other germline mutations that have been implicated in pancreatic ductal adenocarcinoma include BRCA1, PALB2, other Fanconi anemia pathway members, and other homologous DNA repair pathways [15, 16]. In one recent cohort study of over 300 patients with pancreatic cancer, pathologic germline mutations in BRCA2 were identified in 3.3%, BRCA1 mutations in 1.2%, and PALB2 in 0% [17]. Somatic mutations affecting genes involved in homologous DNA repair are also identified in a small percentage of pancreatic cancers [18]. In a basket study of single-agent olaparib in patients with a germline BRCA1/2 mutation, encouraging signs of activity were observed in the subset of patients with advanced pancreatic cancer, with 5 of 23 (21.7%) obtaining an objective response to therapy and multiple patients with stable disease [19]. These results suggested that PARP inhibitors may be effective in the subset of patients with pancreatic ductal adenocarcinoma harboring defects in DNA repair.\n\nPARP inhibitors may also augment the anti-tumor effects of DNA-damaging agents in cancers. Regimens combining PARP inhibitors with cytotoxic agents have synergistic activity in multiple preclinical models [10, 20, 21], but have been limited by unacceptable hematologic toxicity at higher doses [22, 23]. Irinotecan, cisplatin, and mitomycin C (ICM) is an active chemotherapy regimen in pancreatic cancer that has moderate toxicity [24]. In preclinical work (RLF), ICM was highly effective at inducing DNA damage (PARP activity, and apoptosis) in pancreatic cancer cell lines. In an unpublished pilot study of ICM (without olaparib) from our group (RLF), 7 of 10 patients with a known pathologic BRCA mutation, and 6 of 20 patients with sporadic pancreatic cancer had an objective response to therapy. The treatment combination was also well tolerated with no grade 3 or 4 toxicities.\n\nIn this phase 1 dose-escalation trial, we evaluated the safety and tolerability of olaparib in combination with low-doses of irinotecan and cisplatin (olaparib plus IC), escalating to IC with olaparib plus mitomycin C (olaparib plus ICM), in patients with advanced metastatic pancreatic cancer. We hypothesized that the addition of a PARP inhibitor to low doses of cytotoxic agents would be safe and would potentiate the tumor response to the cytotoxic agents, especially in patients with DNA repair pathway deficiencies.\n\nRESULTS\nPatients\nIn total, 18 patients with pancreatic cancer were enrolled and received treatment at Johns Hopkins Kimmel Cancer Center (N=16) and at Columbia University Medical Center (N=2). The clinicopathological characteristics of the patients entered in this study are shown in Table 1. The majority of patients were heavily pretreated, with 13 of 18 (72%) having received 2 or more prior systemic therapies for pancreatic cancer. Two patients (11%) had undergone prior BRCA testing and had a known BRCA2 mutation. None of the other patients enrolled had known or suspected defects in homologous DNA repair.\n\nTable 1 Baseline patient characteristics\nCharacteristic\t\t\nAge, years\t\t\n Median\t60\t\n Range\t33–76\t\nSex, number (%)\t\t\n Male\t9 (50%)\t\n Female\t9 (50%)\t\nRace, number (%)\t\t\n White\t16 (89%)\t\n Hispanic\t1 (6%)\t\n African-American\t1 (6%)\t\nECOG performance status\t\t\n 0\t5 (28%)\t\n 1\t13 (72%)\t\nDisease stage\t\t\n Locally advanced\t1 (6%)\t\n Metastatic\t17 (94%)\t\nPrior therapy\t\t\n Chemotherapy\t16 (89%)\t\n Radiotherapy\t6 (33%)\t\n Pancreaticoduodenectomy\t5 (28%)\t\nPrior number of chemotherapy regimens\t\t\n 0\t2 (11%)\t\n 1\t3 (17%)\t\n 2 or more\t13 (72%)\t\nTotal number of target lesions\t\t\n 1\t1 (6%)\t\n 2\t4 (22%)\t\n 3\t9 (50%)\t\n >= 4\t4 (22%)\t\nBRCA 1/2 mutation status\t\t\n Positive\t2 (11%)\t\n Unknown\t16 (89%)\t\n Negative\t0\t\nSequence of dose levels studied and DLTs\nThe original dose-escalation strategy is outlined in Table 2.\n\nTable 2 Dose-escalation strategy\nDoseLevel\tIrinotecan\tCisplatin\tOlaparib\tMitomycin C\t\n−1\tIrinotecan 70 mg/m2 on days 1 and 8\tCisplatin 25 mg/m2 on days 1 and 8\t50mg twice a day on days 1 and 8\tNone\t\n1\tIrinotecan 70 mg/m2 on days 1 and 8\tCisplatin 25 mg/m2 on days 1 and 8\t100 mg twice a day on days 1 and 8\tNone\t\n2\tIrinotecan 70 mg/m2 on days 1 and 8\tCisplatin 25 mg/m2 on days 1 and 8\t100mg twice a day on days 1–3, 8–10\tNone\t\n3\tIrinotecan 70 mg/m2 on days 1 and 8\tCisplatin 25 mg/m2 on days 1 and 8\t200 mg twice a day on days 1–3, 8–10\tNone\t\n4\tIrinotecan 70 mg/m2 on days 1 and 8\tCisplatin 25 mg/m2 on days 1 and 8\t200 mg twice a day on days 1–12\tNone\t\n5\tIrinotecan 70 mg/m2 on days 1 and 8\tCisplatin 25 mg/m2 on days 1 and 8\tMTD from dose level escalation (−1 to 4)\t5 mg/m2 on day 1\t\nTreatment days are in reference to a 28-day treatment cycle\n\nDose level 1 (olaparib 100 mg twice-daily on days 1 and 8 plus IC) enrolled six patients. One of the six patients experienced a DLT of grade 4 neutropenia lasting 7 days. Per protocol, the investigators recommended increasing the treatment dose level to level 2.\n\nDose level 2 (olaparib 100mg twice daily on days 1-3 and 8-10 plus IC) enrolled six patients. One of the patients experienced colonic obstruction at the end of the first cycle of therapy and ultimately died as a result of this complication, but this adverse event was attributed to disease progression rather than drug toxicity and was not considered a DLT. Three of the six patients on dose level 2 experienced a DLT of grade 4 neutropenia lasting greater than 7 days, and the investigators recommended reducing treatment dose to the previous dose level. Therefore, dose levels 3 and 4 were not pursued and olaparib 100 mg twice daily on days 1 and 8 plus IC was selected as the MTD to which mitomycin C was added in dose level 5.\n\nDose level 5 (olaparib 100 mg twice daily on days 1 and 8 plus ICM) enrolled six patients. Two of these patients experienced a DLT of grade 4 neutropenia lasting greater than 7 days, and one patient experienced a DLT of grade 3 neutropenic fever. Based on these three DLTs, olaparib 100 mg plus ICM was determined to be too toxic for further clinical study.\n\nSafety and tolerability\nAll 18 patients were evaluable for safety and tolerability. Four patients (22%) discontinued therapy because of drug toxicity, and ten patients (56%) required dose delays or reductions because of toxicity. Treatment-related adverse events are shown Table 3. Overall, grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities pertained to hematologic toxicity and included neutropenia (89%), lymphopenia (72%), and anemia (22%).\n\nTable 3 Adverse events\nEvent\tAny grade\tGrade 3-4\t\n\tNo of Patients\t%\tNo of Patients\t%\t\nCardio-renal\t\t\t\t\t\n Atrial fibrillation\t1\t6%\t\t\t\n Elevated creatinine\t5\t28%\t1\t6%\t\n Elevated phosphate\t2\t11%\t\t\t\n Elevated glucose\t3\t17%\t\t\t\n Hypoalbuminemia\t2\t11%\t\t\t\n Hypokalemia\t3\t17%\t1\t6%\t\n Hypomagnesemia\t3\t17%\t\t\t\n Hyponatremia\t2\t11%\t1\t6%\t\n Hypophosphatemia\t2\t11%\t1\t6%\t\nConstitutional\t\t\t\t\t\n Dehydration\t1\t6%\t\t\t\n Fatigue\t8\t44%\t1\t6%\t\nDermatologic\t\t\t\t\t\n Alopecia\t3\t17%\t\t\t\nGastrointestinal\t\t\t\t\t\n Anorexia\t3\t17%\t\t\t\n Hematemesis\t2\t11%\t1\t6%\t\n Hiccups\t1\t6%\t1\t6%\t\n Diarrhea\t1\t6%\t\t\t\n Elevated liver function tests\t4\t22%\t1\t6%\t\n Hematochezia\t1\t6%\t\t\t\n Nausea or vomiting\t12\t67%\t1\t6%\t\nHEENT\t\t\t\t\t\n Epistaxis\t2\t11%\t2\t11%\t\nHematologic\t\t\t\t\t\n Anemia\t14\t78%\t4\t22%\t\n Elevated PT/PTT\t4\t22%\t4\t22%\t\n Bleeding or bruising\t1\t6%\t\t\t\n Lymphopenia\t15\t83%\t13\t72%\t\n Myelodysplastic Syndrome\t2\t11%\t2\t11%\t\n Neutropenia\t16\t89%\t16\t89%\t\n Thrombocytopenia\t12\t67%\t1\t6%\t\nInfectious\t\t\t\t\t\n Sepsis\t1\t6%\t\t\t\n Febrile neutropenia\t4\t22%\t4\t22%\t\n Fever\t2\t11%\t\t\t\nNeurologic\t\t\t\t\t\n Subdural hematoma\t1\t6%\t1\t6%\t\nThere were 10 drug-related serious adverse events (SAEs) reported. These SAEs included febrile neutropenia (n=3), myelodysplastic syndrome (MDS) (n=2), atrial fibrillation, severe anemia, hematemesis, and a subdural hematoma that occurred in the setting of drug-related thrombocytopenia. Of the three patients who received 12 or more cycles of therapy, two developed MDS. Both patients who developed MDS were in dose level 1 (IC plus olaparib 100 mg twice daily on days 1 and 8) and had experienced an objective clinical response to therapy. Both patients had experienced cytopenias related to therapy that was managed with granulocyte-colony stimulating factor (G-CSF) injections. The first patient who developed MDS had a known BRCA2 mutation and had obtained no prior systemic therapy for pancreatic cancer. After receiving approximately 2 years of treatment on study with olaparib reduced down to 25 mg bid on day one of each cycle only (in combination with IC), the patient developed worsening cytopenias. A bone marrow aspirate demonstrated dysplastic cell maturation, and chromosomal analysis showed monosomy 7 consistent with therapy-related MDS. The patient received azacitidine treatment for MDS but died from acute myeloid leukemia (AML) almost five years after study initiation. The second patient had received two prior regimens before enrolling on this study, and was on study treatment for approximately one year before discontinuation for disease progression. Approximately six months after discontinuation from study treatment, the patient developed worsening cytopenias and a bone marrow biopsy demonstrated multilineage abnormalities and a borderline increase in blasts consistent with therapy-related MDS.\n\nClinical activity\nFive patients came off study because of toxicity (n=4) or clinical progression (n=1) prior to the first restaging scan. Therefore, 13 patients (72%) were evaluable for clinical activity. The best tumor response for each patient is shown in Figure 1. Three patients experienced a partial response (PR) as a best response to therapy and there were no complete responses (CRs). The ORR for evaluable patients was 23%. Two of the patients who experienced a PR were treated in dose level 1, and one was treated in dose level 5. Five patients (46%) had stable disease (SD) as a best response to therapy. The disease control rate (CR+PR+SD) was 62%. Among the two patients with known BRCA2 mutations, one experienced a durable PR lasting over four years until death from AML, and the other had stable disease lasting approximately three months as a best response to therapy.\n\nFigure 1 Best tumor response for each evaluable patient\nThe two patients with known BRCA2 mutations are noted. Several patients developed progressive disease because of progression in non-target lesions or the development of new lesions.\n\nDISCUSSION\nIn this study, we found that the combination of olaparib at a dose level of 100 mg twice daily on days 1 and 8 plus ICM had an unacceptable tolerability profile for further study. Treatment with this dose of olaparib plus IC alone was also associated with substantial hematologic toxicity including grade ≥3 drug-related neutropenia, lymphopenia, anemia. Although MDS is a known potential complication of olaparib, the rate of MDS in the present study was higher than we had anticipated, and was higher than previous studies of olaparib monotherapy. In a prior single-arm trial of olaparib monotherapy, MDS/AML was confirmed in 6/298 (2%) of patients [19, 28]. The olaparib dose used in this study was lower than the standard approved monotherapy dose of 300 mg bid daily. In a randomized study of olaparib (300mg BD vs placebo) the incidence of MDS was 1.47% in the olaparib arm and 0.78% in the placebo arm) [29]. In the present study, MDS/AML was observed in 11.1% of patients, albeit in a small sample size. This number may be an underrepresentation of the risk of MDS/AML from the current treatment regimen because many of the patients were on therapy for only a relatively brief time due to intolerance to therapy, and others died of progressive disease before MDS/AML would have developed. The risk of treatment-related MDS/AML is likely related to the duration of drug exposure [19], and therefore it is notable that two out of three patients who remained on study for more than 12 cycles developed MDS/AML in the current study. MDS and AML are clonal processes that arise when hematopoietic progenitor cells acquire specific driver mutations [29]. Although there is no evidence that olaparib alone acts as a mutagenic agent, the combination of chemotherapy-induced DNA damage coupled with an impairment of compensatory DNA repair as a result of PARP inhibition with olaparib may explain the possible MDS signal observed in this study.\n\nPARP inhibitors have previously been successfully combined with chemotherapy in other clinical settings. For example, a recent randomized trial of olaparib plus paclitaxel reportedly only modestly increased rates of neutropenia than paclitaxel monotherapy (30% vs 23%), and no cases of MDS [30]. Olaparib was also successfully combined with gemcitabine in pancreatic cancer without any unmanageable or unexpected toxicities [22]. However, other attempts to combine olaparib with cisplatin-containing regimens have resulted in significant hematologic toxicity [23]. This may be related to the potentiation of cisplatin activity with even intermittent PARP inhibition. Thus, infrequent low-dose olaparib can produce clinically meaningful toxicity when combined with specific chemotherapy regimens. Although PARP inhibitors and DNA damaging agents are a rational drug combination with encouraging signs of activity in preclinical models [10, 20, 21], future clinical trials of combination therapies that include PARP inhibitor should be vigilant about monitoring for hematologic toxicity.\n\nEncouraging evidence of clinical activity was observed in this trial, including a BRCA2 mutation positive patient who had a remarkable and durable response. However, treatment with ICM alone (without olaparib) also demonstrated clinical benefit in a previous unpublished trial from our group (RLF), and was generally well tolerated. Therefore, the substantial toxicity and modest efficacy observed in present study from the addition of a PARP inhibitor to this prior regimen did not support advancement of this treatment combination into phase 2. Multiple additional studies testing olaparib and other PARP inhibitors to treat pancreatic cancer are ongoing. Use of olaparib monotherapy in the maintenance setting (NCT02184195), or in combination therapy with regimens less likely to cause hematologic toxicity such as irinotecan alone (NCT00576654), may be more successful strategies to incorporate PARP inhibitors into the management of pancreatic cancer. Additionally, the use of PARP inhibitors in pancreatic cancer harboring DNA repair pathway deficiencies may result in higher response rates than were observed in this study, which included patients not selected for such mutations. Limitations of this study include the absence of somatic or germline sequencing data on the majority of participants, and the absence of absence of correlative or pharmacokinetic data for the study agents. Additionally, it is not possible to distinguish the toxicity and efficacy contributions of each component of the studied olaparib plus ICM treatment regimen.\n\nIn summary, the combination of olaparib with the DNA damaging regimen IC and ICM was not well tolerated and caused frequent hematologic adverse events. PARP inhibitors continue to be promising therapeutic agents for pancreatic cancer, particularly in the subset of patients with tumors harboring DNA repair pathway deficiencies, and alternative clinical approaches to incorporating these agents into the management of pancreatic cancer should be investigated.\n\nMETHODS\nEligibility\nPatients were eligible for the study if they were 18 years or older with histologic or cytologic confirmation of unresectable pancreatic ductal adenocarcinoma; Eastern Cooperative Oncology Group (ECOG) performance status of ≤2; life expectancy of ≥ 12 weeks; and adequate hematologic, hepatic, and renal function. Measurable disease according to RECIST 1.1 criteria was also required. The presence of a BRCA mutation or other cancer DNA repair pathway deficiency was not an eligibility requirement. However, an attempt was made to enrich the study population with patients harboring tumors with DNA repair pathway deficiency who might in theory be most likely to achieve a favorable clinical response to PARP inhibitor-based therapy. This was achieved by providing priority enrollment to patients with known BRCA1/2 mutations, Jewish individuals (~6% of whom are estimated to carry a germline BRCA1/2 mutation [25]), and patients with familial pancreatic cancer (who are thought to be enriched for defects in homologous DNA repair).\n\nAny number of prior chemotherapy regimens were allowed; however, prior treatment with a PARP inhibitor or more than one drug component of the ICM regimen was not permitted. Additionally, in an attempt to restrict enrollment to patients with adequate hematologic reserve, patients were required to have received ≤12 months of chemotherapy in the metastatic setting. Prior surgery, chemotherapy or other investigational therapies were not permitted within three weeks of the initiation of study treatment. Prior radiation therapy was not permitted within four weeks of the start of study treatment.\n\nStudy design\nWe used a standard 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) in this phase 1 dose-escalation trial. The MTD was defined as the highest dose level for which at most 1 out of 6 patients experienced a dose limited toxicity (DLT) during the first cycle of treatment. If 0 of 3 patients had a DLT, the escalation was continued to the next dose level. If 1 of 3 patients had a DLT then 3 more patients were enrolled at that dose. If 1 of 6 patients had a DLT then the escalation was continued. If 2 or more patients treated at a particular dose level had a DLT the dose was reduced to the previous dose level. Subjects continued to receive the specified doses for their cohort until disease progression or toxicity. In the event of drug toxicity, dose reductions of each drug used were based on the clinician's best judgment.\n\nThe predetermined dose levels are listed in Table 2. In dose levels 1 to 4, a dose of 70mg/m2 of irinotecan and 25mg/m2 of cisplatin on days 1 and 8 were studied in combination with escalating doses and frequency of olaparib (100 mg twice daily on days 1 and 8 in dose level 1, up to 200 mg twice daily on days 1-12 in dose level 4) of a 28-day cycle. If patients did not tolerate the starting dose (dose level 1), the frequency of olaparib therapy could be further reduced to once every month (dose level -1). If patients were cisplatin-intolerant or had neuropathy, the protocol allowed for the substitution of carboplatin for cisplatin at a dose of AUC = 3. Once an optimal dose level of olaparib plus IC was obtained (dose levels -1 to 4), then mitomycin C was added to the regimen at a dose of 5 mg/m2 on day 1 of each cycle (dose level 5). Granulocyte-colony stimulating factor (G-CSF) was not administered prophylactically unless patients developed persistent neutropenia or febrile neutropenia. In such cases, G-CSF was generally continued prophylactically to limit future episodes of febrile neutropenia.\n\nParticipants were enrolled at two academic medical centers, Johns Hopkins Kimmel Cancer Center and Columbia University Medical Center. All patients provided written informed consent for this study. Olaparib was supplied by the Investigational Products Supply (IPS) section of AstraZeneca. The protocol was approved by the Institutional Review Board (IRB) at both study sites, and complied with the International Ethical Guidelines for Biomedical Research Involving Human Subjects and the Declaration of Helsinki. The trial was registered under ClinicalTrials.gov as NCT01296763.\n\nResponse assessments\nThe primary objective of the study was to determine the MTD. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was implemented for adverse event monitoring [26]. A DLT was defined in the protocol as treatment delay of >2 weeks for reasons of toxicity; or thrombocytopenia with platelets <25k for ≥7 days; or grade 4 neutropenia lasting ≥7 days; or grade 3 or 4 febrile neutropenia; or grade ≥3 non-hematological toxicities excluding grade 3 diarrhea, nausea/vomiting, fatigue, lethargy and gamma-glutamyltransferase (GGT) elevation during the first cycle of therapy.\n\nDisease assessments (computed tomography or magnetic resonance imaging) were performed every other cycle of therapy. The objective response rate (ORR) was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 [27]. Upon progression of disease, patients were monitored for long-term adverse events and survival.\n\nStatistical analysis\nThe study protocol allowed a maximum of 30 patients to be enrolled in this phase 1 trial to determine the MTD of olaparib in combination with ICM. Descriptive statistics were used to describe the safety and tolerability of the treatment regimen, as no formal statistical comparisons of the data were performed. Patients who developed DLTs requiring discontinuation of the treatment regimen were censored for the efficacy outcomes at the time of discontinuation. Reasonable attempts were made to establish updated responses for patients who withdrew for toxicity prior to scheduled assessments.\n\nWe thank the clinical staff at Johns Hopkins and Columbia University, including the nurses and data managers from both institutions, for their clinical care and data collection. We also thank the patients and their families for participating in this study.\n\nDISCLOSURES\n\nDr. Goggins has received royalties from Myriad Genetics as a co-discoverer of PALB2 as a pancreatic cancer susceptibility gene.\n\nFUNDING\n\nThis work was partially supported by a National Institutes of Health grant (T32 CA009071, to M.Y. and B.A.J.), and a grant from the National Cancer Institute at the National Institutes of Health (NCI RC2CA148346, to M.G. and R.L.F.).\n\nAbbreviations\nAEsadverse events\n\nAMLacute myeloid leukemia\n\nCRcomplete response\n\nCTCAEThe National Cancer Institute Common Terminology Criteria for Adverse Events\n\nDLTdose limited toxicity\n\nECOGEastern Cooperative Oncology Group\n\nGGTgamma-glutamyltransferase\n\nICirinotecan plus cisplatin\n\nICMirinotecan plus cisplatin plus mitomycin C\n\nMDSmyelodysplastic syndrome\n\nMTDmaximum tolerated dose\n\nORRobjective response rate\n\nPARPpolyadenosine 5’-diphosphoribose polymerization\n\nPDACpancreatic ductal adenocarcinoma\n\nPRpartial response\n\nRECISTResponse Evaluation Criteria in Solid Tumors\n\nSDstable disease\n==== Refs\nREFERENCES\n1 Miller KD Siegel RL Lin CC Mariotto AB Kramer JL Rowland JH Stein KD Alteri R Jemal A Cancer treatment and survivorship statistics, 2016 CA Cancer J Clin 2016 66 271 89 10.3322/caac.21349 27253694 \n2 Siegel RL Miller KD Jemal A Cancer statistics, 2016 CA Cancer J Clin 2016 66 7 30 10.3322/caac.21332 26742998 \n3 Li D Xie K Wolff R Abbruzzese JL Pancreatic cancer Lancet London, England 2004 363 1049 57 10.1016/S0140-6736(04)15841-8 15051286 \n4 Mahipal A Frakes J Hoffe S Kim R Management of borderline resectable pancreatic cancer World J Gastrointest Oncol 2015 7 241 9 10.4251/wjgo.v7.i10.241 26483878 \n5 Conroy T Desseigne F Ychou M Bouché O Guimbaud R Bécouarn Y Adenis A Raoul JL Gourgou-Bourgade S de la Fouchardière C Bennouna J Bachet JB Khemissa-Akouz F FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 364 1817 25 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10.1016/S0140-6736(10)60893-8 20609468 \n9 Fong PC Boss DS Yap TA Tutt A Wu P Mergui-Roelvink M Mortimer P Swaisland H Lau A O’Connor MJ Ashworth A Carmichael J Kaye SB Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers N Engl J Med 2009 361 123 34 10.1056/NEJMoa0900212 19553641 \n10 Rottenberg S Jaspers JE Kersbergen A van der Burg E Nygren AOH Zander SAL Derksen PWB de Bruin M Zevenhoven J Lau A Boulter R Cranston A O’Connor MJ High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs Proc Natl Acad Sci 2008 105 17079 84 10.1073/pnas.0806092105 18971340 \n11 Ashworth A A Synthetic Lethal Therapeutic Approach: Poly(ADP) Ribose Polymerase Inhibitors for the Treatment of Cancers Deficient in DNA Double-Strand Break Repair J Clin Oncol 2008 26 3785 90 10.1200/JCO.2008.16.0812 18591545 \n12 Mateo J Carreira S Sandhu S Miranda S Mossop H Perez-Lopez R Nava Rodrigues D Robinson D Omlin A Tunariu N Boysen G Porta N Flohr P DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer N Engl J Med 2015 373 1697 708 10.1056/NEJMoa1506859 26510020 \n13 Mirza MR Monk BJ Herrstedt J Oza AM Mahner S Redondo A Fabbro M Ledermann JA Lorusso D Vergote I Ben-Baruch NE Marth C Mądry R Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer N Engl J Med 2016 375 2154 64 10.1056/NEJMoa1611310 27717299 \n14 Murphy KM Brune KA Griffin C Sollenberger JE Petersen GM Bansal R Hruban RH Kern SE Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17% Cancer Res 2002 62 3789 93 12097290 \n15 JJones S Hruban RH Kamiyama M Borges M Zhang X Parsons DW Lin JCH Palmisano E Brune K Jaffee EM Iacobuzio-Donahue CA Maitra A Parmigiani G Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene Science 2009 324 217 217 10.1126/science.1171202 19264984 \n16 van der Heijden MS Yeo CJ Hruban RH Kern SE Fanconi anemia gene mutations in young-onset pancreatic cancer Cancer Res 2003 63 2585 8 12750283 \n17 Holter S Borgida A Dodd A Grant R Semotiuk K Hedley D Dhani N Narod S Akbari M Moore M Gallinger S Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma J Clin Oncol 2015 33 3124 9 10.1200/JCO.2014.59.7401 25940717 \n18 Bailey P Chang DK Nones K Johns AL Patch AM Gingras MC Miller DK Christ AN Bruxner TJC Quinn MC Nourse C Murtaugh LC Harliwong I Genomic analyses identify molecular subtypes of pancreatic cancer Nature 2016 531 47 52 10.1038/nature16965 26909576 \n19 Kaufman B Shapira-Frommer R Schmutzler RK Audeh MW Friedlander M Balmana J Mitchell G Fried G Stemmer SM Hubert A Rosengarten O Steiner M Loman N Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation J Clin Oncol 2015 33 244 50 10.1200/JCO.2014.56.2728 25366685 \n20 Michels J Vitale I Galluzzi L Adam J Olaussen KA Kepp O Senovilla L Talhaoui I Guegan J Enot DP Talbot M Robin A Girard P Cisplatin Resistance Associated with PARP Hyperactivation Cancer Res 2013 73 2271 80 10.1158/0008-5472.CAN-12-3000 23554447 \n21 Cheng H Zhang Z Borczuk A Powell CA Balajee AS Lieberman HB Halmos B PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells Carcinogenesis 2013 34 739 49 10.1093/carcin/bgs393 23275151 \n22 Bendell J O’Reilly EM Middleton MR Chau I Hochster H Fielding A Burke W Burris H Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer Ann Oncol 2015 26 804 11 10.1093/annonc/mdu581 25573533 \n23 Rajan A Carter CA Kelly RJ Gutierrez M Kummar S Szabo E Yancey MA Ji J Mannargudi B Woo S Spencer S Figg WD Giaccone G A Phase I Combination Study of Olaparib with Cisplatin and Gemcitabine in Adults with Solid Tumors Clin Cancer Res 2012 18 2344 51 10.1158/1078-0432.CCR-11-2425 22371451 \n24 Slater S Shamash J Wilson P Gallagher CJ Slevin ML Irinotecan, cisplatin and mitomycin in inoperable gastro-oesophageal and pancreatic cancers - a new active regimen Br J Cancer 2002 87 850 3 10.1038/sj.bjc.6600553 12373598 \n25 Ferrone CR Levine DA Tang LH Allen PJ Jarnagin W Brennan MF Offit K Robson ME BRCA Germline Mutations in Jewish Patients With Pancreatic Adenocarcinoma J Clin Oncol 2008 27 433 8 10.1200/JCO.2008.18.5546 19064968 \n26 National Institute of Cancer Common Terminology Criteria for Adverse Events (CTCAE) Common Terminology Criteria for Adverse Events v4.0 (CTCAE) NIH Publ 2009 4 03 71 10.1080/00140139.2010.489653 \n27 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 47 10.1016/j.ejca.2008.10.026 19097774 \n28 Kim G Ison G Mckee AE Zhang H Tang S Gwise T Sridhara R Lee E Tzou A Philip R Chiu HJ Ricks TK Palmby T CCR Perspectives in Drug Approval FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy Clin Cancer Res 2015 21 4257 61 10.1158/1078-0432.CCR-15-0887 26187614 \n29 Ledermann JA Harter P Gourley C Friedlander M Vergote I Rustin G Scott C Meier W Shapira-Frommer R Safra T Matei D Fielding A Spencer S Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial The lancet oncology 2016 17 1579 89 27617661 \n30 Bang Y Boku N Chin K Lee K Park SH Qin S Rha SY Shen L Xu N Im S Locker G Rowe P Shi X Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy: Phase III GOLD s OncologyPRO Ann Oncol 2016 27 1 36\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(27)",
"journal": "Oncotarget",
"keywords": "BRCA2; cisplatin; irinotecan; olaparib; pancreatic cancer",
"medline_ta": "Oncotarget",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D002166:Camptothecin; D002945:Cisplatin; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms; D010793:Phthalazines; D010879:Piperazines; D019233:Retreatment; D016896:Treatment Outcome",
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"pages": "44073-44081",
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"pubdate": "2017-07-04",
"publication_types": "D016428:Journal Article",
"references": "12097290;12373598;12750283;15051286;18591545;18971340;19064968;19097774;19264984;19553641;20609467;20609468;21561347;22371451;23275151;23554447;24131140;25366685;25573533;25940717;26187614;26483878;26510020;26742998;26909576;27253694;27617661;27717299;29103871",
"title": "Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer.",
"title_normalized": "olaparib in combination with irinotecan cisplatin and mitomycin c in patients with advanced pancreatic cancer"
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"abstract": "Malignant bone disease can cause significant morbidity. Monthly zoledronic acid (ZOL) reduces skeletal complications; however, limited data are available regarding long-term safety. We aimed to assess efficacy and safety of ZOL beyond 1 year of treatment. We prospectively evaluated 73 patients; breast cancer (n = 29), castrate-resistant prostate cancer (n = 13), multiple myeloma (n = 31) from 2006 to 2008 in 19 cancer centres. All patients were diagnosed with bone disease and had completed 1-2 years of monthly ZOL (4 mg) and received a further 1-2 years of therapy following contemporary guidelines for managing risks of osteonecrosis of the jaw (ONJ) and renal toxicity. Overall rates of skeletal-related events (SREs), renal impairment and ONJ were assessed. Over the additional 1 year of treatment, only 5.5% (n = 4) of patients developed a new SRE. The overall Kaplan-Meier estimate for SRE incidence after 48 weeks on study was 6.75% (95 CI: 2.5-17.3). Although 51% of patients reported serious adverse events, only two cases were suspected as ZOL related. No patients had confirmed ONJ. The observed incidence of new renal impairment was 11% (none due to ZOL). Our study confirms the benefit over risk of continuing monthly ZOL for at least 2 years in patients with advanced cancer involving bone.",
"affiliations": "Launceston General Hospital, Launceston, TAS., Australia.;Haematology & Oncology Clinics of Australia - Southport, Southport, Qld, Australia.;John Fawkner Cancer Trial Centre, Coburg, Vic., Australia.;Griffith University, The Tweed Hospital, Tweed Heads, NSW, Australia.;Redcliffe Hospital, Redcliffe, Qld, Australia.;Novartis Pharmaceuticals Australia Pty Ltd, North Ryde, NSW, Australia.;Manly Hospital, Manly, NSW, Australia.",
"authors": "Khalafallah|A A|AA|http://orcid.org/0000-0002-2399-3311;Slancar|M|M|;Cosolo|W|W|;Abdi|E|E|;Chern|B|B|;Woodfield|R J|RJ|;Copeman|M C|MC|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "England",
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"doi": "10.1111/ecc.12638",
"fulltext": "\n==== Front\nEur J Cancer Care (Engl)Eur J Cancer Care (Engl)10.1111/(ISSN)1365-2354ECCEuropean Journal of Cancer Care0961-54231365-2354John Wiley and Sons Inc. Hoboken 10.1111/ecc.12638ECC12638Original ArticleOriginal ArticlesLong‐term safety of monthly zoledronic acid therapy beyond 1 year in patients with advanced cancer involving bone (LoTESS): A multicentre prospective phase 4 study Khalafallah A.A. MD, FRACP, MB, CHBhttp://orcid.org/0000-0002-2399-3311Haematologist, Professor of Medicinealhossain.khalafallah@utas.edu.au \n1\n\n2\nSlancar M. MB, BS, FRACPOncologist\n3\nCosolo W. MB, BS, FRACPOncologist\n4\nAbdi E. MB, BS, MDOncologist\n5\nChern B. MB, BS, FRACPOncologist\n6\nWoodfield R.J. PhDOncologist\n7\nCopeman M.C. MB, BS, FRACPOncologist\n8\nBriscoe K. Catley L. Chirgwin J. Craft P. Frydenberg M. Hamilton K. Hill J. Irving I. Lowenthal R. Sullivan A. Thompson J. Watson A‐M. Woodward N. \n1 \nLaunceston General Hospital\nLaunceston\nTAS.\nAustralia\n\n2 \nMenzies Research Institute\nFaculty of Health Sciences\nUniversity of Tasmania\nLaunceston\nTAS.\nAustralia\n\n3 \nHaematology & Oncology Clinics of Australia – Southport\nSouthport\nQld\nAustralia\n\n4 \nJohn Fawkner Cancer Trial Centre\nCoburg\nVic.\nAustralia\n\n5 \nGriffith University\nThe Tweed Hospital\nTweed Heads\nNSW\nAustralia\n\n6 \nRedcliffe Hospital\nRedcliffe\nQld\nAustralia\n\n7 \nNovartis Pharmaceuticals Australia Pty Ltd\nNorth Ryde\nNSW\nAustralia\n\n8 \nManly Hospital\nManly\nNSW\nAustralia\n* Correspondence\n\nA. Khalafallah, Launceston General Hospital, Launceston, TAS., Australia.\n\nEmail: alhossain.khalafallah@utas.edu.au\n30 1 2017 3 2018 27 2 10.1111/ecc.2018.27.issue-2e1263805 12 2016 © 2017 The Authors. European Journal of Cancer Care Published by John Wiley & Sons Ltd.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.Malignant bone disease can cause significant morbidity. Monthly zoledronic acid (ZOL) reduces skeletal complications; however, limited data are available regarding long‐term safety. We aimed to assess efficacy and safety of ZOL beyond 1 year of treatment. We prospectively evaluated 73 patients; breast cancer (n = 29), castrate‐resistant prostate cancer (n = 13), multiple myeloma (n = 31) from 2006 to 2008 in 19 cancer centres. All patients were diagnosed with bone disease and had completed 1–2 years of monthly ZOL (4 mg) and received a further 1–2 years of therapy following contemporary guidelines for managing risks of osteonecrosis of the jaw (ONJ) and renal toxicity. Overall rates of skeletal‐related events (SREs), renal impairment and ONJ were assessed. Over the additional 1 year of treatment, only 5.5% (n = 4) of patients developed a new SRE. The overall Kaplan–Meier estimate for SRE incidence after 48 weeks on study was 6.75% (95 CI: 2.5–17.3). Although 51% of patients reported serious adverse events, only two cases were suspected as ZOL related. No patients had confirmed ONJ. The observed incidence of new renal impairment was 11% (none due to ZOL). Our study confirms the benefit over risk of continuing monthly ZOL for at least 2 years in patients with advanced cancer involving bone.\n\nbone metastasislong‐term safetyosteonecrosis of the jawrenal impairmentzoledronic acidNovartis Pharmaceuticals Australia Pty Ltd source-schema-version-number2.0component-idecc12638cover-dateMarch 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:16.04.2018\n\n\nKhalafallah \nAA \n, \nSlancar \nM \n, \nCosolo W \n, et al. Long-term safety of monthly zoledronic acid therapy beyond 1 year in patients with advanced cancer involving bone (LoTESS): A multicentre prospective phase 4 study . Eur J Cancer Care . 2018 ;27 :e12638\nhttps://doi.org/10.1111/ecc.12638\n\n\n\n\nFunding information\n\n\nThis research was supported by Novartis Pharmaceuticals Australia Pty Ltd. Novartis employee‐authors were involved in the writing of this manuscript; however, Novartis had no role in the decision to submit this manuscript for publication.\n==== Body\n1 Introduction\nBone disease associated with different types of cancer can cause a significant burden on patients, often resulting in disability that compromises cancer treatment (Berenson, 2005; Hillner et al., 2003; Morgan et al., 2012). It remains a major challenge for clinicians to control malignant disease, while at the same time offering an effective supportive treatment to reverse, prevent or at least slow the progression of the bone disease or skeletal events associated with different types of cancer (Crawford, McNulty, Kraut, & Turowski, 2009; Hillner et al., 2003; Theriault et al., 1999; Vogel et al., 2004).\n\nAn important approach for those patients who have been diagnosed with, or developed bone disease as part of their underlying cancer, is to offer bisphosphonate therapy to alter bone metabolism and control bone remoulding and hence, prevent further episodes of bone disease progression (Lacy et al., 2006; Morgan et al., 2012; van Poznak et al., 2011).\n\nMany guidelines and consensus agreements recommend the use of bisphosphonate therapy for patients with bone involvement secondary to their malignant disease (Berenson, 2005; Brantus et al., 2011; Cassinello Espinosa, Gonzalez Del Alba Baamonde, Rivera Herrero, & Holgado Martin, 2012; Kyle et al., 2007; Lacy et al., 2006).\n\nZoledronic acid (ZOL) is a well‐recognised supportive treatment for patients with bone disease associated with haematological malignancies such as multiple myeloma (MM), as well as in non‐haematological malignancies such as metastatic breast and prostate cancers (Gnant et al., 2011; Kohno et al., 2005; Morgan et al., 2010; Rosen et al., 2003; Saad et al., 2004).\n\nZoledronic acid (4 mg) reduces skeletal‐related events (SREs) in patients with bone involvement from breast cancer (BrCa), MM or castrate‐resistant prostate cancer (CRPC) (Kohno et al., 2005; Rosen et al., 2003; Saad et al., 2004). Regular ZOL treatment has also been shown to prolong survival in MM patients (Morgan et al., 2010). However, patients in pivotal trials in advanced cancer settings were often not treated beyond 1 year (Rosen et al., 2003; Saad et al., 2004), and uncertainties remained over prolonged use of ZOL. Consequently, most treatment guidelines recommend the use of ZOL for at least 1 year with continuation at the physician's discretion (Hillner et al., 2003; Kyle et al., 2007; Lacy et al., 2006; van Poznak et al., 2011). In addition, increases in the incidence of osteonecrosis of the jaw (ONJ) and renal impairment were reported in patients receiving ZOL for time periods longer than 2 years (Bamias et al., 2005; Oh et al., 2007). These concerns prompted some oncologists to cease ZOL therapy after 1 or 2 years, despite the possible benefits in reducing SREs with longer therapy (Lacy et al., 2006).\n\nSince 2003, guidelines have been instituted to reduce the risks of renal impairment and ONJ in patients treated with ZOL (Berenson, 2005; Brantus et al., 2011; Cassinello Espinosa et al., 2012; Hillner et al., 2003; Kyle et al., 2007; Marx, Sawatari, Fortin, & Broumand, 2005). Currently, serum creatinine is monitored for renal function before each dose, with an initial dose reduction from the standard 4 mg based on pre‐treatment creatinine clearance, or treatment interruption based on the level of serum creatinine increase during treatment. A dental exam and all invasive procedures should be performed before initiating ZOL treatment, and prophylactic antibiotics are recommended for necessary dental procedures during treatment (Marx et al., 2005). Implementation of these guidelines should allow for the safe use of ZOL beyond 1 or 2 years, without increased risks of ONJ or renal impairment. Furthermore, patients would continue to have a reduced risk of SREs.\n\n1.1 Aims of the study\nThis prospective, safety, observational, multicentre study was conducted in patients with bone involvement from BrCa, CRPC or MM who had already been treated with ZOL for 12–24 months. Treatment on study would continue every 4 weeks for an extra year. The incidences of ONJ, new renal impairment and SREs in this patient population were determined to guide safe clinical practices in this setting.\n\n2 Subjects and methods\n2.1 Patient population\nEligible patients were ≥18 years of age, with a confirmed diagnosis of BrCa, CRPC or MM with bone involvement verified by imaging. All patients had to have received at least 12 months (defined as a minimum of nine doses) of ZOL and could have received up to 24 months (defined as a minimum of 18 doses) of ZOL. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients who received treatment with a bisphosphonate other than ZOL, and had impaired renal function (creatine clearance <30 ml/min), active dental problems (infection of the teeth or jaw, exposed bone, or dental or fixture trauma), recent (<6 weeks) or planned dental/jaw surgeries, a current or prior diagnosis of ONJ, or a history of slow healing after dental procedures were excluded. All patients provided written informed consent before the initiation of any study procedure in accordance with the Declaration of Helsinki, and the study was approved by the Independent Ethics Committee or Institutional Review Board for each Centre.\n\nA total of 19 cancer treatment centres enrolled 73 patients from 2006 to 2008; BrCa (n = 29; 40%), CRPC (n = 13; 18%) and MM (n = 31; 42%) (Table 1). Most patients were Caucasian, and there were a similar number of men and women overall, although all BrCa patients were women, CRPC patients were men, and the majority of patients with MM were men (74%).\n\nTable 1 Patient demographics and baseline disease characteristics\n\nDemographic variable\tBrCa (n = 29)\tCRPC (n = 13)\tMM (n = 31)\tOverall (N = 73)\t\nAge, mean years (SD)\t57 (9.7)\t71 (9.6)\t61 (10.6)\t61 (11.1)\t\nMale sex (%)\t0\t100\t74.2\t49.3\t\nRace (%)\t\nCaucasian\t96.6\t100\t100\t98.6\t\nIndian\t3.4\t0\t0\t1.4\t\nPrior antineoplastic therapy, n (%)\t\nChemotherapy\t25 (86.2)\t10 (76.9)\t24 (77.4)\t59 (80.8)\t\nRadiotherapy\t21 (72.4)\t3 (23.1)\t10 (32.3)\t34 (46.6)\t\nSurgery\t26 (89.7)\t4 (30.8)\t2 (6.5)\t32 (43.8)\t\nPrior skeletal‐related event, n (%)\t\n0\t12 (41.4)\t7 (53.8)\t7 (22.6)\t26 (35.6)\t\n1\t7 (24.1)\t2 (15.4)\t8 (25.8)\t17 (23.3)\t\n2\t5 (17.2)\t1 (7.7)\t10 (32.3)\t16 (21.9)\t\n3\t3 (10.3)\t3 (23.1)\t3 (9.7)\t9 (12.3)\t\n4\t2 (6.9)\t0\t0\t2 (2.7)\t\n≥5\t0\t0\t3 (9.7)\t3 (4.1)\t\nMean creatinine clearance,a (mL/min)\t96.8\t90.8\t92.3c\n\t93.8\t\nRenal impairment,b\nn (%)\t5 (17.2)\t5 (38.5)\t8 (26.7)c\n\t18 (25.0)\t\nBrCa, breast cancer; CRPC, castrate‐resistant prostate cancer; MM, multiple myeloma; SD, standard deviation.\n\na Calculated by Cockcroft–Gault formula.\n\nb Creatinine clearance <60 ml/min.\n\nc One patient had unknown creatinine clearance and renal impairment.\n\nJohn Wiley & Sons, Ltd2.2 Study design and treatment\nThis phase 4, multicentre, single‐arm study was conducted in Australia. During the study period of 1 year, all patients continued on ZOL 4 mg intravenous infusion every 4 weeks (−7/+14 days) at the discretion of their treating physician. In patients with renal impairment, any adjustments to ZOL dosage made previous to study entry were continued. It was recommended that all patients also be supplemented with daily oral Vitamin D (400 IU) and calcium (500 mg). Patients were managed with the latest guidelines on oral and renal safety for bisphosphonates.\n\nThe study number is CZOL446EAU22 and was prospectively registered in the clinicaltrials.gov with the identifier number NCT00434447.\n\n2.3 Study objectives\nThe objectives of this safety study were to define the incidence of ONJ, new renal impairment, and SREs. In addition, overall safety was monitored. New renal impairment was defined as an increase in serum creatinine levels of greater than 44 μmol/L for patients with baseline creatinine less than 125 μmol/L, or an increase in greater than 88 μmol/L for patients with baseline creatinine greater or equal to 125 μmol/L. SREs were defined as presence of pathologic bone fractures, spinal cord compression, surgery to bone, the need for radiation therapy to bone, hypercalcemia, or change in antineoplastic treatment.\n\n2.4 Study assessments\nAt each infusion visit, patients had a physical (including oral hygiene) assessment of vital signs, SREs, and performance status (ECOG criteria), and a blood sample for serum creatinine, calcium, magnesium and potassium levels. Every 6 months, patients also had a haematology assessment (erythrocytes, leucocytes, platelets and haemoglobin). Patients had routine assessments for bone disease (yearly bone scans for BrCa and CRPC and a yearly skeletal survey for MM). Suspected or symptomatic SREs were confirmed by imaging (bone scan or X‐ray). Disease progression and deaths from all causes were also documented.\n\nAdverse events (AEs) were continuously monitored and graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI‐CTCAE) version 3.0. Possible cases of ONJ were defined by exposed bone in the maxillofacial area that occurred either spontaneously or was induced by dental surgery with no evidence of healing for more than 3–6 weeks after appropriate care. The possible ONJ cases did not have to be associated with infection or pain, but must have developed in the absence of prior radiation to the head or neck. A diagnosis of ONJ was considered medically significant (jeopardised the patient or may have required medical or surgical intervention) and was followed as a serious AE.\n\n2.5 Populations analysed\nThe entry criteria required only that the patients had bone metastatic disease from an indicated setting of BrCa, PCa or MM and that they had already been receiving ZOL for 12 months, hence screen fails per se were low.\n\nBased on the available information, all 73 patients were screened and attended the baseline visit. Two patients were deemed as protocol violations due to lack of bone involvement.\n\nSeven (9.6%) of 73 patients had protocol deviations noted, and one patient withdrew consent as they did not wish to receive the full recommended dose of ZOL. Protocol violations included dose change/reduction (n = 2), insufficient doses (n = 1), screening failure (n = 2) lack of bone involvement (n = 1) and use of another bisphosphonate (n = 1). No patient was excluded from analysis with regard to efficacy (SREs) or ONJ due to protocol deviations. A patient who did not have a baseline serum creatinine value was excluded from analysis with regard to renal impairment, since changes from baseline could not be calculated.\n\nAs the trial was an open‐label observational study, all 73 (100%) patients were included in the intent to treat and safety populations. All patients attended the screening and baseline visits.\n\nAt week 12, 88% of the overall group, and 93%, 85% and 84% for BrCa, CRPC, and MM cancer subgroups, respectively, remained on study medication. The continuation rates for BrCa, CRPC, and MM subgroups were at week 28 (77%, 83%, 62% and 77%), week 44 (66%, 69%, 39% and 74) and end of study (96%, 100%, 69% and 97%) respectively.\n\n2.6 Statistical methods\nDescriptive statistics were used for patient demographics and exposure to ZOL. Kaplan–Meier estimates were used for the rate of ONJ, new renal impairment and SREs. The incidence of renal impairment was calculated as the total number of events divided by the total patient‐years on study.\n\n3 Sample size calculation\nSeveral hypotheses were developed regarding rates of ONJ and renal impairment in patients receiving ZOL for longer than 12 months. Rate of ONJ was considered to be less than 5%; consistent with the approximately 3% rate estimated at 3 years in patients with BrCa or MM treated with ZOL for up to 2 years (Hoff et al., 2008). Rate of renal impairment was also considered to be less than 5% based on the rates of increases in serum creatinine levels among patients receiving ZOL reported from an open‐label study in community centres (Vogel et al., 2004). Rate of SRE incidence was considered to be similar to those observed in the large phase 3 studies (Rosen et al., 2003; Saad et al., 2004).\n\nAssumptions were made for a 25% dropout rate and having a majority of enrolled patients with BrCa or MM. Based on the available data, an estimated 200 patients were necessary to allow for statistical analyses of ONJ, renal impairment, and SREs with 95% confidence intervals (CI). However, because of slow enrolment the study was closed after 73 patients had enrolled.\n\n4 Results\n4.1 Patients\nAt study entry, 25% of patients had some degree of renal impairment (defined as serum creatinine above the institutional upper limit of normal). All patients had a performance status of 0 (51%) or 1 (49%). Mean prior duration of ZOL therapy was 16 (standard deviation [SD], 3.5) months, which was similar for all disease types. Most patients (78%) had received at least 12 infusions of ZOL prior to study entry.\n\nEarly withdrawal (before completing the additional 1 year of ZOL therapy on study) occurred in 37% (n = 27) of patients: BrCa 31% (n = 9); CRPC 69% (n = 9); MM 29% (n = 9). Of these patients, 26% had disease progression, 26% had AEs and 26% had a protocol violation. Six patients (8%) died while on study: disease progression the cause in four patients (2 CRPC, 1 BrCa, and 1 MM), myocardial infarction in one patient with CRPC, and pneumonia in one patient with MM. These deaths were not considered linked to the study drug. In total, 46 (63%) patients completed the study.\n\n4.2 Exposure and safety\nThe mean number of infusions of ZOL received on study was 9.4 per patient (SD, 4.4): 10.5 infusions for each BrCa patient, 6.4 infusions for CRPC and 9.7 infusions for MM. The median overall exposure to ZOL on study was 365 days (95 confidence interval [CI], 302–370 days): 353 days for BrCa, 197 days for CRPC, and 370 days for MM. Treatment compliance with ZOL infusions ranged from 96% at Visit 3 to 73% at Visit 15. Patients with CRPC tended to show lower compliance compared with BrCa and MM.\n\nA total of 60 (82%) patients experienced at least 1 non‐serious AE (Table 2). The most common overall AEs (≥5%) were gastrointestinal (55%) and musculoskeletal (52%). However, infections were most common in patients with MM. A total of 37 (51%) patients experienced at least one serious AE (SAE; ≥5%) on study: 45% of BrCa patients; 77% of CRPC patients; and 45% of MM patients (Table 3). Two patients had SAEs considered as possibly related to ZOL by the investigator; a patient with jaw pain (not found to be ONJ) and a patient with periorbital cellulitis. No patient developed symptomatic hypocalcaemia and no patient had confirmed ONJ while on study. The binomial upper 95 CI for incidence of ONJ on study was 4.9%.\n\nTable 2 Non‐serious adverse events (≥5%) by system organ class\n\n\tPatients, n (%)\t\nBrCa (n = 29)\tCRPC (n = 13)\tMM (n = 31)\tOverall (n = 73)\t\nAny AE\t26 (89.7)\t13 (100)\t21 (67.7)\t60 (82.2)\t\nBlood and lymphatic\t4 (13.8)\t5 (38.5)\t4 (12.9)\t13 (17.8)\t\nGastrointestinal\t18 (62.1)\t10 (76.9)\t12 (38.7)\t40 (54.8)\t\nGeneral and administration site\t14 (48.3)\t7 (53.8)\t8 (25.8)\t29 (39.7)\t\nInfections/infestations\t11 (37.9)\t6 (46.2)\t14 (45.2)\t31 (42.5)\t\nInjury, poisoning, procedural\t3 (10.3)\t0\t2 (6.5)\t5 (6.8)\t\nMetabolism and nutrition\t7 (24,1)\t5 (38.5)\t9 (29.0)\t21 (28.8)\t\nMusculoskeletal and connective tissue\t18 (62.1)\t7 (53.8)\t13 (41.9)\t38 (52.1)\t\nNeoplasms\t2 (6.9)\t1 (7.7)\t1 (3.2)\t4 (5.5)\t\nNervous system\t13 (44.8)\t3 (23.1)\t11 (35.5)\t27 (37.0)\t\nPsychiatric\t4 (13.8)\t4 (30.8)\t5 (16.1)\t13 (17.8)\t\nRenal and urinary\t3 (10.3)\t2 (15.4)\t3 (9.7)\t8 (11.0)\t\nRespiratory, thoracic, and mediastinal\t9 (31.0)\t2 (15.4)\t5 (16.1)\t16 (21.9)\t\nSkeletal related\t8 (27.6)\t2 (15.4)\t2 (6.5)\t12 (16.4)\t\nSkin and subcutaneous tissue\t8 (27.6)\t2 (15.4)\t5 (16.1)\t15 (20.5)\t\nVascular\t6 (20.7)\t1 (7.7)\t2 (6.50\t9 (12.3)\t\nAE, adverse event; BrCa, breast cancer; CRPC, castrate‐resistant prostate cancer; MM, multiple myeloma.\n\nJohn Wiley & Sons, LtdTable 3 Serious adverse events (≥5%) by system organ class\n\n\tPatients, n (%)\t\nBrCa (n = 29)\tCRPC (n = 13)\tMM (n = 31)\tOverall (n = 73)\t\nAny SAE\t13 (44.8)\t10 (76.9)\t14 (45.2)\t37 (50.7)\t\nBlood and lymphatic\t2 (6.9)\t1 (7.7)\t1 (3.2)\t4 (5.5)\t\nGastrointestinal\t2 (6.9)\t0\t2 (6.5)\t4 (5.5)\t\nGeneral and administration site\t0\t3 (23.1)\t4 (12.9)\t7 (9.6)\t\nInfections/infestations\t4 (13.8)\t3 (23.1)\t8 (25.8)\t15 (20.5)\t\nPneumonia\t0\t1 (7.7)\t4 (12.9)\t5 (6.8)\t\nMetabolism and nutrition\t1 (3.4)\t2 (15.4)\t3 (9.7)\t6 (8.2)\t\nMusculoskeletal and connective tissue\t6 (20.7)\t1 (7.7)\t4 (12.9)\t11 (15.1)\t\nNervous system\t2 (6.9)\t1 (7.7)\t1 (3.2)\t4 (5.5)\t\nBrCa, breast cancer; CRPC, castrate‐resistant prostate cancer; MM, multiple myeloma; SAE, serious adverse event.\n\nJohn Wiley & Sons, LtdThe incidence of new renal impairment was 11% (n = 6), but with considerable variation among tumour types (13% [n = 3] in BrCa, 38% [n = 3] in CRPC, and 0% for MM). Because the incidence of new renal impairment was low and patients with renal impairment at baseline improved, the mean and median creatinine clearance values over the course of the study were not affected (Table 4). The overall Kaplan–Meier estimate of new renal impairment at 336 days on study was 16% (95 CI; 8.6–28.7). Among eight patients with rises in serum creatinine judged clinically significant, the maximum creatinine level observed was 212 μmol/L. No cases of renal impairment were suspected to be due to ZOL.\n\nTable 4 Assessment of renal function on studya\n\n\n\tBrCa (n = 29)\tCRPC (n = 13)\tMM (n = 31)\tOverall (n = 73)\t\nDay 28\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t97.4 (30.62)\t88.8 (53.45)\t95.3 (51.64)\t95.0 (44.06)\t\nMedian (range)\t98.4 (50.9–167.0)\t60.8 (36.1–188.0)\t82.3 (39.1–252.0)\t86.6 (36.1–252.0)\t\nRenal impairment, n (%)\t4 (14.3)\t6 (50.0)\t7 (24.1)\t17 (24.6)\t\nDay 56\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t91.5 (27.61)\t86.6 (48.41)\t92.8 (39.16)\t91.2 (36.05)\t\nMedian (range)\t94.9 (41.7–131.0)\t78.8 (35.3–174.0)\t86.5 (38.5–199.0)\t88.2 (35.3–199.0)\t\nRenal impairment, n (%)\t5 (18.5)\t5 (45.5)\t5 (19.2)\t15 (23.4)\t\nDay 84\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t90.9 (28.27)\t98.8 (64.01)\t95.0 (47.34)\t93.7 (42.4)\t\nMedian (range)\t96.4 (32.7–149.0)\t100.8 (39.8–241.0)\t95.2 (31.7–252.0)\t95.8 (31.7–252.0)\t\nRenal impairment, n (%)\t5 (19.2)\t4 (44.4)\t5 (21.7)\t14 (24.1)\t\nDay 112\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t95.6 (27.21)\t101.4 (61.06)\t96.2 (45.6)\t96.6 (40.2)\t\nMedian (range)\t104.1 (39.5–141.0)\t87.7 (41.9–192.0)\t92.3 (37.1–239.0)\t96.6 (37.1–239.0)\t\nRenal impairment, n (%)\t3 (12.0)\t3 (42.9)\t5 (20.0)\t11 (19.3)\t\nDay 140\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t97.7 (31.59)\t95.2 (68.48)\t93.69 (40.78)\t95.6 (41.23)\t\nMedian (range)\t105.6 (39.9–154.0)\t74.1 (38.4–246.0)\t92.3 (29.2–191.0)\t94.2 (29.2–246.0)\t\nRenal impairment, n (%)\t4 (16.0)\t4 (50.0)\t7 (28.0)\t15 (25.9)\t\nDay 196\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t95.6 (30.89)\t118.1 (74.51)\t98.7 (40.14)\t100.2 (43.00)\t\nMedian (range)\t103.0 (30.6–141.0)\t120.7 (31.3–241.0)\t88.8 (30.7–173.0)\t100.4 (30.6–241.0)\t\nRenal impairment, n (%)\t3 (12.5)\t3 (37.5)\t3 (14.3)\t9 (17.0)\t\nDay 224\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t96.0 (29.07)\t106.3 (70.67)\t95.7 (44.21)\t97.0 (41.14)\t\nMedian (range)\t99.2 (39.2–141.0)\t94.1 (46.2–235.0)\t97.3 (33.4–207.0)\t97.3 (33.4–235.0)\t\nRenal impairment, n (%)\t3 (12.5)\t2 (33.3)\t6 (26.1)\t11 (20.8)\t\nDay 252\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t94.6 (32.33)\t106.7 (57.15)\t102.6 (43.39)\t99.5 (39.99)\t\nMedian (range)\t96.6 (39.2–163.0)\t114.0 (41.5–176.0)\t101.1 (34.5–214.0)\t97.8 (34.5–214.0)\t\nRenal impairment, n (%)\t4 (17.4)\t2 (33.3)\t3 (13.6)\t9 (17.6)\t\nDay 280\t\nCreatinine clearance (ml/min)\t\nMean (SD)\t103.8 (29.02)\t124.5 (77.07)\t104.1 (46.92)\t106.1 (43.71)\t\nMedian (range)\t109.5 (48.4–149.0)\t113.4 (44.2–252.0)\t90.8 (33.0–227.0)\t105.5 (33.0–252.0)\t\nRenal impairment, n (%)\t2 (10.0)\t1 (20.0)\t5 (22.7)\t8 (17.0)\t\nBrCa, breast cancer; CRPC, castrate‐resistant prostate cancer; MM, multiple myeloma; SD, standard deviation.\n\na Creatinine clearance was calculated by Cockcroft–Gault formula, and renal impairment was defined by creatinine clearance <60 ml/min.\n\nJohn Wiley & Sons, Ltd4.3 Efficacy\nOn study, only 5.5% (n = 4) of patients developed at least one new confirmed SRE: one patient with BrCa and three patients with MM (Table 5). Two patients with MM had more than one confirmed SRE during the study; however, no patient had more than three confirmed SREs on study. The overall Kaplan–Meier estimate for SRE incidence at 336 days on study was 6.75% (95 CI; 2.5–17.3). The median time to first on study SRE could not be determined because there were too few events.\n\nTable 5 Incidence of confirmed new SREs on study\n\nNumber of SRE events\tPatients, n (%)\t\nBrCa (n = 29)\tCRPC (n = 13)\tMM (n = 31)\tOverall (n = 73)\t\n1\t1 (3.4)\t0\t1 (3.2)\t2 (2.7)\t\n2\t0\t0\t1 (3.2)\t1 (1.4)\t\n3\t0\t0\t1 (3.2)\t1 (1.4)\t\nBrCa, breast cancer; CRPC, castrate‐resistant prostate cancer; MM, multiple myeloma; SRE, skeletal‐related event.\n\nJohn Wiley & Sons, Ltd4.4 Treatment compliance\nDetails of the number and timing of doses of ZOL were recorded on the case report form (CRF). Concomitant medications and significant non‐drug therapies prior to study start and during the study, were also recorded on the relevant CRF. Compliance was assessed by the investigator and/or study personnel at each visit by recording the number and timing ZOL doses received by each patient and this information was recorded on the CRF. Early termination in the study occurred in 31% of the BrCa, 69% of the HRPC and 29% of the MM groups.\n\n4.5 Concomitant treatments\nAll medications were coded using a hierarchical coding dictionary (WHO DRUG). The most frequently used concomitant medications included; pain medications such as paracetamol, acetylsalicylic acid, oxycodone hydrochloride, steroids such as dexamethasone; antiemetics such as metoclopramide hydrochloride; and finally laxative therapy with coloxyl.\n\n5 Discussion\nSeveral guidelines have incorporated bisphosphonate treatment for patients with cancer associated with bone disease, until there is either a significant decline in their performance status or where no discontinuation criteria has been provided (Hillner et al., 2003; Kyle et al., 2007; Lacy et al., 2006; van Poznak et al., 2011). However, the majority of bisphosphonate studies only evaluated treatment for 2 years or less, with approximately 11%–36% of patients completing the studies and considered eligible for further treatment (Morgan et al., 2010; Rosen et al., 2003; Saad et al., 2004; Theriault et al., 1999). Few prospective and retrospective studies have reported on the efficacy and safety of bisphosphonate treatment beyond 2 years (Crawford et al., 2009; Dearnaley, Mason, Parmar, Sanders, & Sydes, 2009; Gnant et al., 2011; La Verde et al., 2008; Morgan et al., 2012). This small, prospective, observational study helps to confirm the safety and ongoing efficacy of monthly treatment with ZOL for 2–3 years in patients with malignant disease involving bone, in the era of new safety guidelines.\n\nIn recent years, it has become clear that a small percentage of patients being treated with ZOL may develop ONJ, but this was not formally documented when the study was conceived.\n\nAt that time, concerns had been expressed that up to 30% of patients receiving ZOL for more than 1 year would develop ONJ, based initially, on an internet survey of myeloma patients. As a consequence, several institutions either stopped ZOL therapy for (particularly) myeloma patients, or limited its duration to 1 year out of concern that longer therapy might be associated with a relatively high risk of ONJ (Durie, Katz, & Crowley, 2005). Furthermore, at the time of analysis, there was no data available pertaining to extending the use of ZOL beyond 1 year. Therefore, this study was conceived to document more precisely the rate of ONJ in patients receiving ZOL for more than 1 year. The relatively small study size was ample to verify if ONJ occurred in 10%–30% of patients, as had been suggested. Certainly, the results of our study showed a much lower incidence of ONJ than was previously anticipated.\n\nIn this study, no cases of ONJ were reported in patients managed according to contemporary guidelines; the 95% upper CI estimate for ONJ incidence was <5%. These results are consistent with the low incidence of ONJ in patients continuing with monthly ZOL in recent long‐term studies (≤5%) and in studies implementing the new safety guidelines (≤6.7%) (Dimopoulos et al., 2009; Gnant et al., 2011; Morgan et al., 2012; Ripamonti et al., 2009). Among patients with MM who received ZOL treatment before preventive dental measures, in one study (n = 38), the incidence of ONJ (albeit not adjudicated) was 26% (Dimopoulos et al., 2009). Thus, prevention of ONJ during bisphosphonate treatment appears effective with these guidelines.\n\nPatients on ZOL therapy also require regular renal monitoring. While the Kaplan–Meier estimate of incidence of new renal impairment in this study was 16% during the additional 12 months, this complication was mild to moderate in all affected patients and may not have been due to ZOL. Compared with the large bisphosphonate studies, which had renal AE rates of 2.3% in CRPC (N = 643) to 10.7% in BrCa and MM (N = 1,648) (Rosen et al., 2003; Saad et al., 2002), the renal AE incidence rate of 11% in this study with primarily BrCa and MM patients was reasonable. However, in other long‐term studies, the incidence of renal effects ranged from none in patients with BrCa (N = 1,803) to 7% in patients with MM experiencing acute renal failure (N = 1,960) (Gnant et al., 2011; Morgan et al., 2012). Differing patient baseline characteristics and definitions for renal endpoints may account for the wide variations reported for renal impairment. Nevertheless, the results from this study showed no increasing renal toxicities with long‐term ZOL treatment.\n\nEfficacy of ZOL treatment in this study was determined by the event rate of SREs, which was <7% by Kaplan–Meier estimate. However, it should be noted that assessments of bone disease beyond the yearly scan or survey were at the discretion of the treating physician and the event rate of SREs was low. Hence, the strength of ZOL efficacy may be diluted. In other long‐term studies, SRE rates were not an endpoint; therefore, there is no basis for a comparison of continuing efficacy (Dearnaley et al., 2009; Gnant et al., 2011; Morgan et al., 2012). In the large bisphosphonate study in patients with BrCa and MM evaluating treatment for the first 2 years, the SRE rates were approximately 1 event per year for ZOL in the overall population and in patients with BrCa (Rosen et al., 2003). In patients with CRPC receiving ZOL, the SRE rate was 0.8 per year (Saad et al., 2004). Thus, the event rate in this study is consistent with an ongoing benefit of ZOL in reducing SREs in this high‐risk population.\n\nAlthough our study had a small number of patients, it is worth noting that there is a lack of data regarding long‐term safety of ZOL in this cohort of patients. Furthermore, our study was prospectively designed and conducted at multiple centres to ensure the diversity and quality of the source of data. The patient population constitutes a sample of patients relevant to clinical practice, in that a decision needs to be made at 2 years whether to continue bisphosphonate treatment. This decision is based, in part, on balancing the risks of renal and dental AEs, with the expected benefits. Nonetheless, we acknowledge some limitations of our study, inherent with the observational nature of the trial and the relatively small number of patients. In addition, physician discretion governed further assessments of bone disease that possibly may or may not add some bias to the results.\n\nIn conclusion, this prospective multicentre study helps to confirm the benefit over risk of continuing monthly ZOL for 2–3 years in patients with advanced cancer involving bone, managed according to ONJ and renal safety guidelines.\n\nConflicts of interest\nProf Khalafallah, Prof Abdi and Drs Slancar, Cosolo, and Chern report no conflicts of interest. Dr Woodfield is an employee of Novartis Oncology, and Dr Copeman is a consultant to Novartis Oncology.\n\nAcknowledgments\nWe acknowledge the contribution of the following LoTESS study investigators and their patients: Dr K. Briscoe (North Coast Cancer Institute, QLD Australia), Dr L. Catley (Mater Hospital, Brisbane, QLD, Australia), Dr J. Chirgwin (Box Hill Hospital & Maroondah Breast Hospital, VIC, Australia), Dr P. Craft (Canberra Hospital, ACT, Australia), Dr M. Frydenberg (Monash Medical Centre, Melbourne, VIC, Australia), Dr K. Hamilton (Ballarat Hospital, VIC, Australia), Dr J. Hill (Wagga Wagga Hospital, NSW, Australia), Dr I. Irving (Townsville Hospital, QLD, Australia), Prof R. Lowenthal (Royal Hobart Hospital, TAS, Australia), Dr A. Sullivan (Concord Repatriation Hospital, NSW, Australia), Dr J. Thompson (Frankston Hospital, VIC, Australia), Dr A‐M. Watson (Liverpool Hospital, NSW, Australia), Dr N. Woodward (Princess Alexandra Hospital, QLD, Australia). We gratefully acknowledge the contribution of Dr Kevin Lynch, Ms Gillian Ryan and Dr Annie Solterbeck (Statistical Revelations). We thank the participating patients, their families, research coordinators, and nurses; and Tamalette Loh (ProEd Communications, Inc.®) for providing editorial assistance with a previous version of the manuscript.\n==== Refs\nReferences\n\n\nBamias , A. \n, \nKastritis , E. \n, \nBamia , C. \n, \nMoulopoulos , L. A. \n, \nMelakopoulos , I. \n, \nBozas , G. \n,… \nDimopoulos , M. A. \n (2005 ). Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors . Journal of Clinical Oncology , 23 (34 ), 8580 –8587 .16314620 \n\n\nBerenson , J. R. \n (2005 ). Recommendations for zoledronic acid treatment of patients with bone metastases . Oncologist , 10 (1 ), 52 –62 .15632252 \n\n\nBrantus , J. F. \n, \nRoemer‐Becuwe , C. \n, \nCony‐Makhoul , P. \n, \nSalino , S. \n, \nFontana , A. \n, \nDebourdeau , P. \n,… \nBiron , P. \n (2011 ). Practice guidelines of the use of bisphosphonates in solid tumours with bone metastases and in multiple myeloma . La Revue de Médecine Interne , 32 (8 ), 494 –505 .21376431 \n\n\nCassinello Espinosa , J. \n, \nGonzalez Del Alba Baamonde , A. \n, \nRivera Herrero , F. \n, & \nHolgado Martin , E. \n (2012 ). SEOM guidelines for the treatment of bone metastases from solid tumours . 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Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid . Annals of Oncology , 20 (1 ), 117 –120 .18689864 \n\n\nDurie , B. G. \n, \nKatz , M. \n, & \nCrowley , J. \n (2005 ). Osteonecrosis of the jaw and bisphosphonates . New England Journal of Medicine , 353 (1 ), 99 –102 .\n\n\nGnant , M. \n, \nMlineritsch , B. \n, \nStoeger , H. \n, \nLuschin‐Ebengreuth , G. \n, \nHeck , D. \n, \nMenzel , C. \n,… \nGreil , R. \n (2011 ). Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early‐stage breast cancer: 62‐month follow‐up from the ABCSG‐12 randomised trial . The Lancet Oncology , 12 (7 ), 631 –641 .21641868 \n\n\nHillner , B. E. \n, \nIngle , R. T. \n, \nChlebowski , J. \n, \nGralow , G. C. \n, \nYee , N. A. \n, \nJanjan , J. A. \n,… \nBrown , S. \n (2003 ). American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer . Journal of Clinical Oncology , 21 (21 ), 4042 –4057 .12963702 \n\n\nHoff , A. O. \n, \nToth , B. B. \n, \nAltundag , K. \n, \nJohnson , M. M. \n, \nWarneke , C. L. \n, \nHu , M \n.,… \nHortobagyi , G. N \n. (2008 ). Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates . Journal of Bone and Mineral Research \n23 (6 ): 826 –836 .18558816 \n\n\nKohno , N. \n, \nAogi , K. \n, \nMinami , H. \n, \nNakamura , S. \n, \nAsaga , T. \n, \nIino , Y. \n,… \nTakashima , S. \n (2005 ). Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: A randomized, placebo‐controlled trial . Journal of Clinical Oncology , 23 (15 ), 3314 –3321 .15738536 \n\n\nKyle , R. A. \n, \nYee , G. C. \n, \nSomerfield , M. 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E. \n, \nSawatari , Y. \n, \nFortin , M. \n, & \nBroumand , V. \n (2005 ). Bisphosphonate‐induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment . Journal of Oral and Maxillofacial Surgery , 63 (11 ), 1567 –1575 .16243172 \n\n\nMorgan , G. J. \n, \nDavies , F. E. \n, \nGregory , W. M. \n, \nCocks , K. \n, \nBell , S. E. \n, \nSzubert , A. J. \n,… \nChild , J. A. \n (2010 ). First‐line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): A randomised controlled trial . The Lancet , 376 (9757 ), 1989 –1999 .\n\n\nMorgan , G. J. \n, \nDavies , F. E. \n, \nGregory , W. M. \n, \nSzubert , A. J. \n, \nBell , S. E. \n, \nDrayson , M. T. \n,… \nChild , J. A. \n (2012 ). Effects of induction and maintenance plus long‐term bisphosphonates on bone disease in patients with multiple myeloma: The Medical Research Council Myeloma IX Trial . Blood , 119 (23 ), 5374 –5383 .22498739 \n\n\nOh , W. K. \n, \nProctor , K. \n, \nNakabayashi , M. \n, \nEvan , C. \n, \nTormey , L. K. \n, \nDaskivich , T. \n,… \nDuh , M. S. \n (2007 ). The risk of renal impairment in hormone‐refractory prostate cancer patients with bone metastases treated with zoledronic acid . Cancer , 109 (6 ), 1090 –1096 .17311345 \n\n\nvan Poznak , C. H. \n, \nTemin , S. \n, \nYee , G. C. \n, \nJanjan , N. A. \n, \nBarlow , W. E. \n, \nBiermann , J. S. \n,… \nvon Roenn , J. H. \n (2011 ). American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone‐modifying agents in metastatic breast cancer . Journal of Clinical Oncology , 29 (9 ), 1221 –1227 .21343561 \n\n\nRipamonti , C. I. \n, \nManiezzo , M. \n, \nCampa , T. \n, \nFagnoni , E. \n, \nBrunelli , C. \n, \nSaibene , G. \n,… \nCislaghi , E. \n (2009 ). Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan . Annals of Oncology , 20 (1 ), 137 –145 .\n\n\nRosen , L. S. \n, \nGordon , D. \n, \nKaminski , M. \n, \nHowell , A. \n, \nBelch , A. \n, \nMackey , J. \n,… \nSeaman , J. J. \n (2003 ). Long‐term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double‐blind, multicenter, comparative trial . Cancer , 98 (8 ), 1735 –1744 .14534891 \n\n\nSaad , F. \n, \nGleason , D. M. \n, \nMurray , R. \n, \nTchekmedyian , S. \n, \nVenner , P. \n, \nLacombe , L. \n,… \nChen , B. \n (2002 ). A randomized, placebo‐controlled trial of zoledronic acid in patients with hormone‐refractory metastatic prostate carcinoma . Journal of the National Cancer Institute , 94 (19 ), 1458 –1468 .12359855 \n\n\nSaad , F. \n, \nGleason , D. M. \n, \nMurray , R. \n, \nTchekmedyian , S. \n, \nVenner , P. \n, \nLacombe , L. \n,… \nZheng , M. \n (2004 ). Long‐term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone‐refractory prostate cancer . Journal of the National Cancer Institute , 96 (11 ), 879 –882 .15173273 \n\n\nTheriault , R. L. \n, \nLipton , A. \n, \nHortobagyi , G. N. \n, \nLeff , R. \n, \nGluck , S. \n, \nStewart , J. F. \n,… \nReitsma , D. J. \n (1999 ). Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo‐controlled trial. Protocol 18 Aredia Breast Cancer Study Group . Journal of Clinical Oncology , 17 (3 ), 846 –854 .10071275 \n\n\nVogel , C. L. \n, \nYanagihara , R. H. \n, \nWood , A. J. \n, \nSchnell , F. M. \n, \nHenderson , C. \n, \nKaplan , B. H. \n,… \nHohneker , J. A. \n (2004 ). Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy . Oncologist , 9 (6 ), 687 –695 .15561812\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0961-5423",
"issue": "27(2)",
"journal": "European journal of cancer care",
"keywords": "bone metastasis; long-term safety; osteonecrosis of the jaw; renal impairment; zoledronic acid",
"medline_ta": "Eur J Cancer Care (Engl)",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D001847:Bone Diseases; D004164:Diphosphonates; D005260:Female; D006801:Humans; D007093:Imidazoles; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011446:Prospective Studies; D000077211:Zoledronic Acid",
"nlm_unique_id": "9301979",
"other_id": null,
"pages": "e12638",
"pmc": null,
"pmid": "28134499",
"pubdate": "2018-03",
"publication_types": "D017429:Clinical Trial, Phase IV; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": "12359855;15561812;28134499;15632252;21131037;22721794;10071275;16901028;19909013;21641868;21343561;18558816;15738536;16243172;19674936;17311345;22498739;18647964;17515569;21376431;18663482;18689864;15173273;14534891;16314620;12963702;16000365",
"title": "Long-term safety of monthly zoledronic acid therapy beyond 1 year in patients with advanced cancer involving bone (LoTESS): A multicentre prospective phase 4 study.",
"title_normalized": "long term safety of monthly zoledronic acid therapy beyond 1 year in patients with advanced cancer involving bone lotess a multicentre prospective phase 4 study"
} | [
{
"companynumb": "AU-PFIZER INC-2018128250",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHOLECALCIFEROL"
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"drugadditional": null,
... |
{
"abstract": "Recently, combination therapy including immune checkpoint inhibition (ICI) has proven to be effective as first-line therapy for patients with metastatic renal cell carcinoma. Although the first-line combination therapies with ICI have shown clinical benefit, a number of patients require second-line treatment. We report a 60-year-old man with metastatic renal cell carcinoma who was treated with pazopanib soon after nivolumab plus ipilimumab combination therapy. He experienced Grade 3 disseminated intravascular coagulation (DIC). We suspect that this was caused by an interaction between pazopanib and nivolumab even though ICI therapy was discontinued. He was treated with thrombomodulin and platelet transfusion and recovered from DIC. Treatment with pazopanib was subsequently restarted. No evidence of DIC was observed thereafter. This severe adverse reaction may have been induced by an interaction between activated proinflammatory immune cells and cytokines from an exacerbated inflammatory state and pazopanib. This report highlights the need to perform careful monitoring of patients who receive molecular targeted therapy after ICI-based immunotherapy.",
"affiliations": "Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan.",
"authors": "Hashimoto|Mamoru|M|;Nakayama|Takahito|T|;Fujimoto|Saizo|S|;Inoguchi|Shunsuke|S|;Nishimoto|Mitsuhisa|M|;Kikuchi|Takashi|T|;Adomi|Shogo|S|;Banno|Eri|E|;De Velasco|Marco A|MA|;Saito|Yoshitaka|Y|;Shimizu|Nobutaka|N|;Mori|Yasunori|Y|;Minami|Takafumi|T|;Fujita|Kazutoshi|K|;Nozawa|Masahiro|M|;Nose|Kazuhiro|K|;Yoshimura|Kazuhiro|K|;Uemura|Hirotsugu|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000001230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": null,
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": null,
"nlm_unique_id": "9100823",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34486537",
"pubdate": "2021-08-27",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Disseminated intravascular coagulation induced by pazopanib following combination therapy of nivolumab plus ipilimumab in a patient with metastatic renal cell carcinoma.",
"title_normalized": "disseminated intravascular coagulation induced by pazopanib following combination therapy of nivolumab plus ipilimumab in a patient with metastatic renal cell carcinoma"
} | [
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-103810",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nThe tremendous increase in the use of drugs has considerably increased their side effects.\n\n\nOBJECTIVE\nThe aim of this work is to demonstrate Dress syndrome induced by levetiracetam an anti-epileptic drug.\n\n\nMETHODS\nWe describe a skin eruption observed in an-hospitalized in an intensive care unit patient who received levetiracetam.\n\n\nRESULTS\nAccording to morphology of the rash and the laboratory findings the rash fulfills the criteria for Dress syndrome.\n\n\nCONCLUSIONS\nLevetiracetam may induce Dress syndrome.",
"affiliations": "Department of Dermatology, Thriassio General Hospital, Athens, Greece.",
"authors": "Eleni|K|K|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": "10.1111/jdv.12346",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "29(2)",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D000927:Anticonvulsants; D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "377-378",
"pmc": null,
"pmid": "24397826",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dress syndrome induced by levetiracetam.",
"title_normalized": "dress syndrome induced by levetiracetam"
} | [
{
"companynumb": "GR-ENDO PHARMACEUTICALS INC-LEVE20150002",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nWe present a case of a patient with a left-sided stroke and occlusion of all aortic arch great vessels who was treated successfully with endovascular intervention followed by delayed cardiothoracic revascularization.\n\n\nMETHODS\nA 46-year-old man presented with acute onset of dense right hemiparesis, facial droop, and aphasia with an initial National Institute of Health Stroke Score of 15. The patient was taken for emergent angiography after failing intravenous tissue plasminogen activator thrombolysis. Dedicated angiography of the aortic arch revealed occlusion of all great vessels, including the right brachiocephalic, left common carotid, and left subclavian artery. Delayed arterial filling of the right brachiocephalic and left subclavian artery by aberrant collaterals was seen. More distally, flow into the bilateral subclavian arteries, right common carotid artery, and left vertebral artery was appreciated. Serial balloon angioplasty of the left common carotid artery origin reconstituted flow. Subsequent selective angiogram of the left internal carotid artery revealed a proximal middle cerebral artery occlusion. Intra-arterial injection of tissue plasminogen activator followed by mechanical thrombectomy and intracranial stenting restored flow in the middle cerebral artery. Two months later the patient underwent aortic arch reconstruction with bifurcated graft to the brachiocephalic artery and left common carotid artery. At 1-year follow-up, the patient's examination revealed almost complete resolution of right hemiparesis with minimal hand weakness and mild expressive aphasia.\n\n\nCONCLUSIONS\nWe report a rare case of occlusion of all aortic arch great vessels. Combined endovascular intervention and surgical revascularization resulted in an excellent durable outcome.",
"affiliations": "Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia, USA.;Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia, USA.;Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia, USA. Electronic address: jreavey-cantwell@mcvh-vcu.edu.",
"authors": "Brzezicki|Grzegorz|G|;Machinis|Theofilos|T|;Reavey-Cantwell|John|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "82(3-4)",
"journal": "World neurosurgery",
"keywords": "Angioplasty; Aortic arch reconstruction; Arterial occlusive disease; Intracranial stenting; Mechanical thrombolysis; Stroke",
"medline_ta": "World Neurosurg",
"mesh_terms": "D001013:Aorta, Thoracic; D001157:Arterial Occlusive Diseases; D002548:Cerebral Revascularization; D057510:Endovascular Procedures; D006801:Humans; D008297:Male; D008875:Middle Aged; D019635:Neurosurgical Procedures; D020521:Stroke; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "535.e17-21",
"pmc": null,
"pmid": "24055566",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Occlusion of all aortic arch great vessels: acute revascularization to perform endovascular stroke therapy.",
"title_normalized": "occlusion of all aortic arch great vessels acute revascularization to perform endovascular stroke therapy"
} | [
{
"companynumb": "US-ROCHE-1497497",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,
... |
{
"abstract": "Objective: Antiphospholipid antibodies (aPL) are risk factors for thrombosis and adverse pregnancy outcomes (APO). The management of the so called \"aPL carriers\" (subjects with aPL positivity without the clinical criteria manifestations of APS) is still undefined. This study aims at retrospectively evaluating the outcomes and the factors associated with APO and maternal complications in 62 pregnant aPL carriers. Methods: Medical records of pregnant women regularly attending the Pregnancy Clinic of 3 Rheumatology centers from January 1994 to December 2015 were retrospectively evaluated. Patients with concomitant autoimmune diseases or other causes of pregnancy complications were excluded. Results: An aPL-related event was recorded in 8 out of 62 patients (12.9%) during pregnancy: 2 thrombosis and 6 APO. At univariate analysis, factors associated with pregnancy complications were acquired risk factors (p:0.008), non-criteria aPL manifestations (p:0.024), lupus-like manifestations (p:0.013), and triple positive aPL profile (p:0.001). At multivariate analysis, only the association with a triple aPL profile was confirmed (p:0.01, OR 21.3, CI 95% 1.84-247). Patients with triple aPL positivity had a higher rate of pregnancy complications, despite they were more frequently receiving combined treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) at prophylactic dose. Conclusion: This study highlights the importance of risk stratification in pregnant aPL carriers, in terms of both immunologic and non-immunologic features. Combination treatment with LDA and LMWH did not prevent APO in some cases, especially in carriers of triple aPL positivity. Triple positive aPL carriers may deserve additional therapeutic strategies during pregnancy.",
"affiliations": "Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.;Immunorheumatology Research Laboratory, Istituto Auxologico Italiano, Milan, Italy.;Rheumatology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.;Division of Clinical Rheumatology, ASST Pini-CTO, Milan, Italy.;Rheumatology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.;Division of Clinical Rheumatology, ASST Pini-CTO, Milan, Italy.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.;Obstetrics and Gynaecology Unit, ASST Spedali Civili, Brescia, Italy.;Obstetrics and Gynaecology Unit, ASST Spedali Civili, Brescia, Italy.;Obstetrics and Gynaecology Unit, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Immunorheumatology Research Laboratory, Istituto Auxologico Italiano, Milan, Italy.;Cardiology Clinic, Department of Cardiac Thoracic and Vascular Sciences, Thrombosis Centre, University of Padova, Padova, Italy.;Rheumatology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.;Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.",
"authors": "Lazzaroni|Maria-Grazia|MG|;Fredi|Micaela|M|;Andreoli|Laura|L|;Chighizola|Cecilia Beatrice|CB|;Del Ross|Teresa|T|;Gerosa|Maria|M|;Kuzenko|Anna|A|;Raimondo|Maria-Gabriella|MG|;Lojacono|Andrea|A|;Ramazzotto|Francesca|F|;Zatti|Sonia|S|;Trespidi|Laura|L|;Meroni|Pier-Luigi|PL|;Pengo|Vittorio|V|;Ruffatti|Amelia|A|;Tincani|Angela|A|",
"chemical_list": "D017152:Antibodies, Antiphospholipid; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D053482:beta 2-Glycoprotein I; D001241:Aspirin",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2019.01948",
"fulltext": "\n==== Front\nFront ImmunolFront ImmunolFront. Immunol.Frontiers in Immunology1664-3224Frontiers Media S.A. 10.3389/fimmu.2019.01948ImmunologyOriginal ResearchTriple Antiphospholipid (aPL) Antibodies Positivity Is Associated With Pregnancy Complications in aPL Carriers: A Multicenter Study on 62 Pregnancies Lazzaroni Maria-Grazia 12*Fredi Micaela 12Andreoli Laura 12Chighizola Cecilia Beatrice 34Del Ross Teresa 5Gerosa Maria 67Kuzenko Anna 5Raimondo Maria-Gabriella 67Lojacono Andrea 18Ramazzotto Francesca 8Zatti Sonia 8Trespidi Laura 9Meroni Pier-Luigi 3Pengo Vittorio 10Ruffatti Amelia 5Tincani Angela 12111Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy2Rheumatology and Clinical Immunology Unit, ASST Spedali Civili, Brescia, Italy3Immunorheumatology Research Laboratory, Istituto Auxologico Italiano, Milan, Italy4Rheumatology Unit, Istituto Auxologico Italiano, Milan, Italy5Rheumatology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy6Division of Clinical Rheumatology, ASST Pini-CTO, Milan, Italy7Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy8Obstetrics and Gynaecology Unit, ASST Spedali Civili, Brescia, Italy9Obstetrics and Gynaecology Unit, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy10Cardiology Clinic, Department of Cardiac Thoracic and Vascular Sciences, Thrombosis Centre, University of Padova, Padova, Italy11I.M. Sechenov First Moscow State Medical University, Moscow, RussiaEdited by: Amr Sawalha, University of Pittsburgh, United States\n\nReviewed by: Jason S. Knight, University of Michigan, United States; Michael Dan Lockshin, Hospital for Special Surgery, United States\n\n*Correspondence: Maria-Grazia Lazzaroni mariagrazialazzaroni@gmail.comThis article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology\n\n14 8 2019 2019 10 194804 6 2019 01 8 2019 Copyright © 2019 Lazzaroni, Fredi, Andreoli, Chighizola, Del Ross, Gerosa, Kuzenko, Raimondo, Lojacono, Ramazzotto, Zatti, Trespidi, Meroni, Pengo, Ruffatti and Tincani.2019Lazzaroni, Fredi, Andreoli, Chighizola, Del Ross, Gerosa, Kuzenko, Raimondo, Lojacono, Ramazzotto, Zatti, Trespidi, Meroni, Pengo, Ruffatti and TincaniThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Objective: Antiphospholipid antibodies (aPL) are risk factors for thrombosis and adverse pregnancy outcomes (APO). The management of the so called “aPL carriers” (subjects with aPL positivity without the clinical criteria manifestations of APS) is still undefined. This study aims at retrospectively evaluating the outcomes and the factors associated with APO and maternal complications in 62 pregnant aPL carriers.\n\nMethods: Medical records of pregnant women regularly attending the Pregnancy Clinic of 3 Rheumatology centers from January 1994 to December 2015 were retrospectively evaluated. Patients with concomitant autoimmune diseases or other causes of pregnancy complications were excluded.\n\nResults: An aPL-related event was recorded in 8 out of 62 patients (12.9%) during pregnancy: 2 thrombosis and 6 APO. At univariate analysis, factors associated with pregnancy complications were acquired risk factors (p:0.008), non-criteria aPL manifestations (p:0.024), lupus-like manifestations (p:0.013), and triple positive aPL profile (p:0.001). At multivariate analysis, only the association with a triple aPL profile was confirmed (p:0.01, OR 21.3, CI 95% 1.84–247). Patients with triple aPL positivity had a higher rate of pregnancy complications, despite they were more frequently receiving combined treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) at prophylactic dose.\n\nConclusion: This study highlights the importance of risk stratification in pregnant aPL carriers, in terms of both immunologic and non-immunologic features. Combination treatment with LDA and LMWH did not prevent APO in some cases, especially in carriers of triple aPL positivity. Triple positive aPL carriers may deserve additional therapeutic strategies during pregnancy.\n\nantiphospholipid (aPL) antibodiespregnancy complicationadverse pregnancy outcomes (APO)thrombosisanticardiolipin (aCL)lupus anticoagulantanti-β2 glycoprotein I antibodiesantiphospholipid syndrome (APS)\n==== Body\nIntroduction\nAntiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies reacting against phospholipids, phospholipid-protein complexes and phospholipid-binding proteins, detected by different assays: lupus anticoagulant (LA), anticardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies.\n\nThe so called “aPL carriers” are individuals with persistent aPL positivity, in the absence of the clinical criteria of APS (pregnancy morbidity or thrombosis) (1). Sometimes aPL positivity is found in the presence of less specific features, defined as “non-criteria” manifestations (e.g., thrombocytopenia, valvulopathies, livaedo reticularis) (2) or the so called “lupus-like” manifestations; these patients are also included in the “aPL carriers” term.\n\nThe finding of the aPL positivity in a completely asymptomatic subject may happen during a laboratory work-up for non-autoimmune conditions. For example, aPL can be searched when a first-grade relative is affected by APS or as a second-level examination when a prolonged phospholipid-dependent coagulation time is found prior to surgery. Moreover, aPL are sometimes included in the diagnostic protocols to assess infertility causes performed before assisted reproduction procedures. Despite being asymptomatic, these subjects are theoretically at increased risk of vascular and obstetric events because they carry persistently positive aPL. In fact, aPL have been demonstrated to be pathogenic (3), therefore they should be considered as risk factors for thrombosis or pregnancy morbidity, with several other variables modulating the final clinical expression (4, 5).\n\nThe management of pregnant APS patients aims at preventing obstetric complications and maternal thrombotic events, tailoring a therapeutic strategy based on risk stratification. Risk stratification includes general factors (smoking, arterial hypertension, overweight, maternal age, diabetes mellitus, inherited thrombophilia) and disease-specific factors, particularly the so called “aPL profile.”\n\nIn most of the studies on APS patients, the “triple aPL profile” (3 positive aPL tests) is indicated as a major risk factor for thrombosis (6, 7) and pregnancy complications (8–12), while single aPL positivity seems to be generally associated with a favorable outcome (8).\n\nRegarding the single tests, there is no definitive conclusion: some authors indicated LA as the strongest factor associated with obstetric complications (13), while others found that anti-β2GPI antibodies could be the most relevant ones (9, 14). Concerning the isotype, IgG is historically considered as more significant than IgM (15), but according to data from the European Registry of obstetric APS (EUROAPS), IgM isotype still remains important for the classification and the diagnosis of APS (16). Whether the same considerations could be valid also in patients with no history of aPL-related clinical events, has still to be demonstrated.\n\nIn patients with an established diagnosis of obstetric APS, combination therapy of low-dose aspirin (LDA) and low molecular weight heparin (LMWH) is regarded as the conventional treatment (17). At this moment, EULAR recommendations are available for pregnant aPL positive patients and can help clinicians in everyday practice, although being based mainly on expert opinion (18).\n\nRegarding the specific subpopulation of pregnant women not fulfilling the APS criteria, and especially aPL carriers, LDA is usually part of the therapeutic strategy (19), even if the available studies failed to demonstrate its efficacy (20, 21). Possible limits of these studies seem to be mainly related to the heterogeneity of the patients included, regarding both the aPL profile or the associated risk factors. Importantly, the setting of aPL positivity in the context of an autoimmune disease should be considered as a completely different entity, as compared to the isolated aPL positivity in the absence of a definite autoimmune disease (22).\n\nIn a previous collaborative study, we retrospectively analyzed the pregnancy outcome of different clinical subgroups of aPL patients (11). Of note was that the outcome of aPL carriers was comparable to that of patients with a diagnosis of a definite thrombotic or obstetric APS.\n\nStarting from these observations, the present study aimed at identifying factors associated with pregnancy complications in aPL carriers in a multicenter Italian cohort of prospectively followed pregnancies.\n\nMaterials and Methods\nStudy Cohort and Inclusion Criteria\nMedical records of pregnant women regularly attending 3 Rheumatology centers with a Pregnancy Clinic from January 1994 to December 2015 were retrospectively evaluated.\n\nThe inclusion criteria were:\n- Persistent aPL positivity;\n\n- First prospectively followed pregnancy for each patient; if a patient had more than one prospectively-followed pregnancy, only the first was considered for the inclusion in the study.\n\n- Singleton pregnancies.\n\n\n\nExclusion Criteria\n- Organ-specific or systemic autoimmune diseases (according to the international classification criteria), apart from autoimmune thyroiditis;\n\n- History of thrombosis;\n\n- History of complicated pregnancies;\n\n- History of previous treated pregnancies (with or without complications);\n\n- Pregnancies complicated by concomitant conditions (i.e., anatomical abnormalities, cervix dilatation);\n\n- Pregnancies without any complications, but not prospectively followed in one of the 3 centers.\n\nAutoantibodies Detection\nAt the preconception visit or during the first trimester of pregnancy, a complete aPL profile composed by the three criteria assays, was available for each subject. The aPL were considered positive if confirmed at least 12 weeks apart. LA was detected by coagulation assay, according to the current guidelines of the International Society on Thrombosis and Hemostasis (23). The aCL IgG/IgM and anti-B2GPI IgG/IgM tests were performed with Enzyme-linked Immunosorbent assay (ELISA) technique, according to the current recommendations (24). The cut-off to determine positive aCL and anti-B2GPI was settled as the 99th percentile of healthy blood donors, and the levels of positivity were expressed as “low” and “medium-high titers” according to collaborative international consensus (25). “Non-criteria” aPL antibodies were not routinely tested.\n\nAntinuclear antibodies (ANA), antibodies to extractable nuclear antigens (anti-ENA), anti–double-stranded DNA antibodies (anti-dsDNA) and complement C3 and C4 fractions were detected as for clinical practice. The aPL and the other immunological tests were performed in each of the three participating centers, by certified laboratories fulfilling European quality standards.\n\n“Non-criteria APS” and “Lupus-Like” Manifestations\nThe clinical charts of the patients were reviewed for the presence of “non-criteria APS” and “lupus-like” features as reported by the clinicians. According to a recent international consensus (2), “non-criteria APS” manifestations were defined as the occurrence of at least one of the followings: superficial venous thrombosis, thrombocytopenia, microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis.\n\n“Lupus-like” manifestations were defined as the presence of one of the typical features of Systemic Lupus Erythematosus (SLE), including arthralgia, Raynaud's phenomenon, photosensitivity and alopecia, in the absence of a diagnosis of SLE (26) or undifferentiated connective tissue disease.\n\nAcquired Risk Factors\nAcquired risk factors were defined as one or more of the followings: obesity (body max index >30), current cigarette smoke, diabetes mellitus (fasting plasma glucose tests ≥126 mg/dl), dyslipidemia (total cholesterol blood levels ≥200 mg/dl and/or triglycerides >150 mg/dl), hyper-homocysteinemia (blood homocysteine ≥13 μmol/L), systemic arterial hypertension (≥140/90 mmHg), inherited thrombophilia [antithrombin or protein C or protein S deficiency, homozygous mutation of factor V Leiden or prothrombin or methylenetetrahydrofolate reductase mutation (MTHFR)].\n\nPregnancy Complications\nFor the purpose of this study, a wider spectrum of complications was considered beyond the classical clinical manifestations as defined by international APS criteria (1). In particular, the occurrence of either maternal thrombotic events (venous and/or arterial) during pregnancy or the occurrence of adverse pregnancy outcomes (APO) related to aPL. APO were defined as one of the following events: spontaneous abortion (<10th weeks of gestation); fetal death (≥10th weeks of gestation); neonatal death before hospital discharge due to complications of prematurity; preterm delivery before 36th weeks of gestation with or without pre-eclampsia and HELLP syndrome (Hemolysis, Elevated Liver Enzymes, Low Platelet Syndrome).\n\nStatistical Analysis\nContinuous variables were reported as mean value (± standard deviation), whereas categorical variables as proportion and/or percentage. Mann-Whitney test for continuous variables and Fisher's exact test or Chi-square test for categorical variables were applied as appropriate. Logistic regression was applied for multivariate analysis. P-values <0.05 were considered significant and Odds Ratio (OR) with 95% Confidence Interval (95% CI) was indicated.\n\nResults\nDescription of the Cohort\nThe Pregnancy Clinics' database of each center were reviewed and 62 women met the inclusion criteria during the period comprised between 1994 and 2015. These patients had 69 pregnancies during the study period, but only the first pregnancy followed at one of the 3 participating centers was considered for further analysis, according to the inclusion and exclusion criteria listed above. Therefore, we considered 62 pregnancies in 62 women. The number of patients enrolled for the 3 centers were n = 26 in Brescia, n = 29 in Padua, and n = 7 in Milano. The majority were Caucasian (n = 59, 95.2%) and the minority were African (n = 3, 4.8%). Autoimmune thyroiditis was present in 13 patients (21.7%). Nineteen patients (30.6%) had at least one acquired thrombophilic risk factor (12 current smoke, 3 hypercholesterolemia, 3 obesity, 3 hyper-homocysteinemia and 2 systemic arterial hypertension). While 14 had a single acquired risk factor, and 5 had 2 simultaneous risk factors, none had more than 2 acquired risk factors. Inherited thrombophilia was present in 5 of 36 patients in whom it was tested (13.9%).\n\nNon-criteria manifestations were observed in 6 out of 62 patients (9.7%): 2 livedo reticularis, 1 livedo reticularis with neurologic manifestations (migraine, seizures), 1 thrombocytopenia, 1 pulmonary arterial hypertension and 1 migraine recovered with anticoagulants.\n\nLupus-like manifestations were present in 5 out of 62 women (8.1%): 5 cases of photosensitivity, in 2 patients associated with mild arthralgias. Among these 5 patients, 2 had positive ANA, while none had positive anti-dsDNA. Globally, ANA were positive in 11 patients (17.7%), anti-ENA in 2 (3.2%) (anti-Ro/SSA in both patients) and anti-dsDNA in none.\n\nComplement levels (C3 and C4 fractions) were available in the preconception period or in the first trimester for 34 patients (55%) and were reduced in 11 cases (29%).\n\nDescription of the Pregnancy Complications\nMean maternal age at conception was 31.9 ± 5.1 years. Two pregnancies were induced by assisted reproduction techniques, both with in vitro fertilization (male infertility in one case, female infertility in the other case). A synthetic description of these complicated pregnancies is reported in Table 1.\n\nTable 1 Description of the 8 complicated pregnancies.\n\nTherapy\tCalendar year\tStart of therapy\tNon-criteria APS manifestations\tAcquired risk factors\tInherited thrombophilia\tLupus-like manifestations\taPL Profile*\tComplications\t\nLDA+\npLMWH\t2005\t12 w\tYES\n(livedo reticularis)\t2\tProtein S\nDeficiency\tNO\tTriple\tFetal death (14 w)\t\nLDA+\npLMWH\t2001\t6 w+\n11 w\tYES\n(livedo reticularis)\t2\tNot present\tYES\tTriple\tPE and Neonatal death (25 w)\t\nLDA+\ntLMWH\t2010\t7 w\tNO\t0\tNot present\tNO\tSingle (aCL IgM low titer)\tPopliteal vein thrombosis (7 w)\t\nLDA+\npLMWH\t2009\t8 w\tNO\t1\tNot present\tNO\tTriple\tIschemic stroke (37 w)\t\nLDA\t2006\tPre-conceptional\tNO\t1\tIncreased APCR\tYES\tTriple\tFetal death (22 w)\t\nLDA\t2002\t6 w\tNO\t0\tNot present\tNO\tSingle (aCL IgG medium titer, IgM low titer)\tSpontaneous abortion (9 w)\t\nLDA\t2003\t9 w\tNO\t2\tNot present\tNO\tTriple\tPE (35 w)\t\nNONE\t2013\t27 w (LDA+ pLMWH)\tYES\n(livedo reticularis)\t1\tNot present\tYES\tSingle (aCL IgG low titer)\tPE/HELLP syndrome (32 w)\t\nw, weeks; aCL, anti-cardiolipin; APCR, Activated protein C resistance; HELLP, Hemolysis, Elevated Liver Enzymes, Low Platelet Syndrome; LDA, low-dose aspirin; PE, preeclampsia; pLMWH, low molecular weight heparin at prophylactic dosage; tLMWH, low molecular weight heparin at therapeutic dosage.\n\n* Number of positive aPL tests.\n\nEight pregnancy complications in 8 patients were observed: 2 thrombotic events (3%) and 6 APO (9%). Thrombotic events were one deep venous thrombosis (7th week) and one ischemic stroke (37th week). APO recorded were: 1 spontaneous abortion, 2 fetal deaths and 3 pre-term deliveries before the 34th week with pre-eclampsia. In one patient with a severe preterm delivery (25th week), a neonatal death occurred.\n\nAnalysis According to the Immunologic Profile\nIn the preconception or first trimester complete aPL assays, the positivity for each test was distributed as follows:\n- LA in 10 (16.1%) (9 in the context of triple aPL positivity, 1 in the context of double aPL positivity)\n\n- aCL in 39 (62.9%), including 28 IgG and 23 IgM (45.2 and 37.1%)\n\n- anti-B2GPI in 44 (71.0%), including 27 IgG (43.5%) and 27 IgM (43.5%).\n\n\n\nA triple aPL positivity was present in 9 women (14.5%), double positivity in 13 (20.9%) and single positivity in 40 (64.5%). None of the single positive patients had isolated LA positivity.\n\nIn the triple aPL positive group, as compared to single plus double positive group (Table 2), there was a significantly higher frequency of APO (p:0.003), despite more frequently receiving the combination treatment of LDA and LMWH (p:0.001). This group had also an increased frequency of acquired risk factors (p:0.019) and non-criteria manifestations (p:0.035).\n\nTable 2 Analysis according to the type of aPL profile: comparison between triple aPL positive patients and the pool of single and double aPL positive patients.\n\n\tSingle aPL positive (n = 40)\tDouble aPL positive (n = 13)\tTriple aPL positive (n = 9)\tp-value*\t\nPATIENTS CHARACTERISTICS\t\nAge ≥35 years\t17/40 (42.5%)\t8/13 (61.5%)\t1/9 (11.1%)\t0.070\t\nAcquired risk factorsa\t10/40 (25.0%)\t3/13 (23.1%)\t6/9 (66.7%)\t0.019\t\nInherited thrombophiliab\t2/21 (9.5%)\t1/7 (14.2%)\t2/8 (25.0%)\t0.305\t\nNon-criteria aPL manifestationsc\t3/40 (7.5%)\t0/13 (0%)\t3/9 (33.3%)\t0.035\t\nLupus-like manifestationsd\t2/40 (5.0%)\t1/13 (7.7%)\t2/9 (22.2%)\t0.149\t\nPREGNANCY OUTCOME\t\nComplicated pregnancy\t3/40 (7.5%)\t0/13 (0%)\t5/9 (55.5%)\t0.001\t\nThrombosis\t1/40 (2.5%)\t0/13 (0%)\t1/9 (11.1%)\t0.271\t\nAdverse pregnancy outcome\t2/40 (5.0%)\t0/13 (0%)\t4/9 (44.4%)\t0.003\t\nTREATMENT DURING PREGNANCY\t\nNo treatment\t14/40 (35.0%)\t6/13 (46.1%)\t0/9 (0%)\t0.050\t\nLDAe\t25/40 (62.5%)\t5/13 (38.5%)\t4/9 (44.5%)\t0.719\t\nLDA+LMWHf\t1/40 (2.5%)\t2/13 (15.5%)\t5/9 (55.5%)\t0.001\t\n* p-value calculated comparing triple vs. single plus double aPL positive patients.\n\na Acquired risk factors: obesity; current smoke; any previous diagnosis of diabetes mellitus, dyslipidaemia, systemic arterial hypertension.\n\nb Inherited thrombophilia: antithrombin or protein C or protein S deficiency, homozygous factor V Leiden or prothrombin or methylenetetrahydrofolate reductase (MTHFR) mutation.\n\nc Non-criteria aPL manifestations: superficial venous thrombosis, thrombocytopenia, microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis.\n\nd Lupus-like manifestations: arthralgia, Raynaud's phenomenon, photosensitivity, alopecia.\n\ne LDA, low dose aspirin.\n\nf LMWH, low molecular weight heparin.\n\nMoreover, 3 of the 5 triple aPL positive patients taking the LDA plus LMWH, developed pregnancy complications.\n\nAnalysis of the Factors Associated With Pregnancy Complications\nThe comparison of clinical and laboratory features between patients with and without complicated pregnancies is illustrated in Table 3. At the univariate analysis, acquired risk factors (p:0.008), non-criteria aPL manifestations (p:0.024), lupus-like manifestations (p:0.013), triple positive aPL profile (p:0.001), were found to be associated with pregnancy complications. The combination treatment was also significantly more frequent in complicated pregnancies (p:0.007).\n\nTable 3 Comparison between complicated and non-complicated pregnancies: univariate and multivariate analysis.\n\n\tComplicated pregnancies (n = 8)\tNon-complicated pregnancies (n = 54)\tp-value (univariate analysis)\t\nAge (mean ± SD)\t28.3 ± 5.8\t32.4 ± 4.8\t0.028§\t\nNulliparity\t6/8 (75.0%)\t43/54 (79.6%)\t0.670\t\nAcquired risk factorsa\t6/8 (75.0%)\t13/54 (24.1%)\t0.008§\t\nInherited thrombophiliab\t2/8 (25.0%)\t3/28 (10.7%)\t0.305\t\nAutoimmune thyroiditis\t2/8 (25.0%)\t11/54 (20.4%)\t0.670\t\nNon-criteria APS manifestationsc\t3/8 (37.5%)\t3/54 (5.6%)\t0.024§\t\nLupus-like manifestationsd\t3/8 (37.5%)\t2/54 (3.7%)\t0.013§\t\nSingle aPL positivity\t3/8 (37.5%)\t37/54 (68.5%)\t0.119\t\n LAC\t0/3 (0%)\t0/37 (0%)\t\t\n aCL IgG/IgM\t3/3 (100%)\t13/37 (35.1%)\t\t\n aB2GPI IgG/IgM\t0/3 (0%)\t24/37 (64.9%)\t\t\nDouble aPL positivity\t0/8 (0%)\t13/54 (24.1%)\t0.186\t\n aCL + LAC\t0/0 (0%)\t1/12 (7.7%)\t\t\n aCL + aB2GPI\t0/0 (0%)\t12/13 (92.3%)\t\t\nTriple aPL positivity\t5/8 (62.5%)\t4/54 (7.4%)\t0.001§*\t\nNo treatment\t1/8 (12.5%)\t19/54 (35.2%)\t0.258\t\nLDAe\t3/8 (37.5%)\t31/54 (57.4%)\t0.450\t\nLDA+LMWHf\t4/8 (50.0%)\t4/54 (7.4%)\t0.007\t\na Acquired risk factors: obesity; current smoke; any previous diagnosis of diabetes mellitus, dyslipidemia, systemic arterial hypertension.\n\nb Inherited thrombophilia: antithrombin or protein C or protein S deficiency, homozygous factor V Leiden or prothrombin or methylenetetrahydrofolate reductase (MTHFR) mutation.\n\nc Non-criteria aPL manifestations: superficial venous thrombosis, thrombocytopenia, microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis.\n\nd Lupus-like manifestations: arthralgia, Raynaud's phenomenon, photosensitivity, alopecia.\n\ne LDA, low dose aspirin.\n\nf LMWH, low molecular weight heparin.\n\n§ Variables considered at the multivariate analysis;\n\n* p-value (multivariate analysis): 0.01, OR (95% CI): 21.3 (1.84–247).\n\nTriple aPL positivity was the only variable significantly associated with APO at the multivariate analysis (p:0.01, OR 21.3, CI 95% 1.84–247) (Table 3).\n\nAnalysis According to the Type of Therapy\nTwenty of the 62 patients (32.3%) received no treatment during pregnancy; 42 (67.7%) received LDA, in combination with LMWH in 8 cases (12.9%) (Table 4). In 36 out of 42 patients, LDA was started in the first trimester (85.7%), while in 6 (14.3%) in the pre-conception period. In 7 cases heparin was used at prophylactic dosage, while in one it was introduced at a therapeutic dosage because of a deep venous thrombosis occurred at the 7th gestational week. In 6 out of 7 patients, the prophylactic dosage was increased during the third trimester (a period in which the thrombophilic risk dramatically increases) or whether patient's weight was ≥70 Kg, according to local practice. Low dose prednisone (5 mg/day) was used in 2 patients (3.2%) for mild thrombocytopenia. No adverse events related to anti-thrombotic treatment were recorded; in particular, no major bleeding, no placental abruption or heparin-induced thrombocytopenia.\n\nTable 4 Analysis according to the type of treatment received during pregnancy.\n\n\tNone\n(n = 20)\tLDAe\n(n = 34)\tLDAe + LMWHf\n(n = 8)\t\nPATIENTS CHARACTERISTICS\t\nAge ≥ 35years\t8/20 (40.0%)\t16/34 (47.1%)\t2/8 (25.0%)\t\nAcquired risk factorsa\t5/20 (25.0%)\t11/34 (32.4%)\t3/8 (37.5%)\t\nInherited thrombophiliab\t2/10 (20.0%)\t2/19 (10.5%)\t1/7 (14.3%)\t\nNon-criteria aPL manifestationsc\t1/20 (5.0%)\t3/34 (8.8%)\t2/8 (25.0%)\t\nLupus-like manifestationsd\t2/20 (10.0%)\t2/34 (5.9%)\t1/8 (12.5%)\t\naPL PROFILE\t\nSingle aPL positivity\t14/20 (70.0%)\t25/34 (73.5%)\t1/8 (12.5%)\t\nDouble aPL positivity\t6/20 (30.0%)\t5/34 (14.7%)\t2/8 (25.0%)\t\nTriple aPL positivity\t0/20 (0%)\t4/34 (11.8%)\t5/8 (62.5%)\t\nPREGNANCY OUTCOME\t\nComplicated pregnancy\t1/20 (5.0%)\t3/34 (8.8%)\t4/8 (50.0%)\t\nThrombosis\t0/20 (0%)\t0/34 (0%)\t2/8 (25.0%)\t\nAdverse pregnancy outcome\t1/20 (5.0%)\t3/34 (8.8%)\t2/8 (25.0%)\t\na Acquired risk factors: obesity; current smoke; any previous diagnosis of diabetes mellitus, dyslipidemia, systemic arterial hypertension.\n\nb Inherited thrombophilia: antithrombin or protein C or protein S deficiency, homozygous factor V Leiden or prothrombin or methylenetetrahydrofolate reductase (MTHFR) mutation.\n\nc Non-criteria aPL manifestations: superficial venous thrombosis, thrombocytopenia, microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis.\n\nd Lupus-like manifestations: arthralgia, Raynaud's phenomenon, photosensitivity, alopecia.\n\ne LDA, low dose aspirin.\n\nf LMWH, low molecular weight heparin.\n\nDiscussion\nAntiphospholipid antibodies have a clear pathogenic role in APS and should be considered as risk factors for thrombosis and APO. Patients with persistently positive aPL without the clinical APS criteria, the so called “aPL carriers,” are increasingly recognized in different contexts, such as the “non-criteria” manifestations or activated partial thromboplastin time (aPTT) prolongation found before surgical procedures. The incidence of thrombotic and obstetric events and the therapeutic strategy to prevent them, especially during pregnancy, are still poorly defined.\n\nIn a previous collaborative study, we observed that the rate of APO was similar in aPL carriers and in patients with definite thrombotic or obstetric APS (11). Moreover, the treatment assigned in the aPL carriers patients was globally less intensive than in the other subgroups, probably based on the absence of clinical criteria.\n\nIn the present study, focused on aPL carriers women, triple aPL positivity emerged as the only independent factor associated with pregnancy complications. This profile was previously identified as a major risk factor for both thrombosis and APO in the long-term follow-up of patients with primary APS (7). In the large multicenter PREGNANTS cohort, triple aPL positivity was associated with a lower live birth rate and a higher incidence of IUGR, compared with double aPL positive and LA negative women (14). Conversely, the prospective PROMISSE study identified LA as the main predictor of APO in aPL women, independently from triple aPL positivity (27). In our cohort LA was present only in the context of triple or double aPL positivity, while none of the single aPL positive patients had isolated LA, therefore we cannot comment on this subgroup. However, it is known that isolated LA positivity might be misleading, as it is more frequently observed in patients with diseases different from APS (28). Moreover, isolated LA may define a distinct subgroup of patients positive for anti-prothrombin/phosphatidylserine (anti-PT/PS) (usually IgM isotype) at lower risk of thromboembolic events (29).\n\nIn the next future, the risk stratification of aPL carriers will probably include also the “non-criteria” aPL tests. In fact, anti-B2GPI domain I antibodies have been associated with late pregnancy morbidity and thrombosis and were more frequently detected in triple aPL positive patients (30). Moreover, anti-PT/PS have been identified as risk factors for IUGR and pre-eclampsia (31).\n\nInterestingly, at the univariate analysis, maternal age was significantly lower in the group of complicated pregnancies, conversely to what expected in the general population. We can assume that the presence of aPL, together with other risk factors, was able to elicit pregnancy complications at a younger age in these women.\n\nRegarding the therapeutic aspects, the combination of LDA plus LMWH is currently considered as the conventional strategy for APS pregnant women (18), while this approach is not routinely used in aPL carriers patients (20, 22, 32). In our cohort only 8 patients received this kind of therapy; 3 of them, all with triple aPL profile, developed pregnancy complications. Moreover, in the EUROAPS cohort the “non-criteria APS” patients less frequently received a treatment during pregnancy, compared to the “criteria APS” one, despite experiencing a similar rate of complications (33). Together, these data suggest that clinicians are more prone to prescribe a full treatment if in the context of a definite obstetric APS, giving much importance to a previous history of APO. Based on our study, the combination treatment may be considered as preventative treatment in those aPL carriers at higher risk of obstetric and maternal complications, particularly in those with triple aPL positivity. These women could be counseled to start LDA before conception, as it is current practice in APS patients (18). A joint management with the obstetrician is necessary for the adjustment of heparin dosage during pregnancy (increase in maternal body weight, signs of placental insufficiency, etc.). The multidisciplinary management before and during pregnancy should aim at tailoring the treatment and the intensity of surveillance, yielding to the minimization of the risk of fetal and maternal complications (18, 34).\n\nAnother therapeutic option could be the addition of an immunomodulatory treatment, such as hydroxychloroquine (HCQ). If benefits of HCQ in SLE pregnancy are well-established (18), they are now increasingly described also in APS pregnancy (35). Its beneficial effects have been demonstrated in pre-clinical studies on the placenta, particularly at the trophoblast level (36), and in retrospective clinical studies with a reduction of pregnancy complications in aPL positive patients with or without APS (37–39), including refractory APS (40). The ongoing clinical trials HYPATIA (HYdroxychloroquine to improve pregnancy outcome in women with AnTIphospholipid Antibodies) (41) and HYDROSAPL (42) will provide further insights on this topic.\n\nRegarding the potential side effects of treatments, we did not observe any case of major bleeding or heparin-induced thrombocytopenia. Our results are in line with those of a recent multicenter retrospective study, in which the occurrence of a bleeding complication in a cohort of pregnant APS patients was not increased by the anti-thrombotic treatment, including the combination of LDA plus LMWH (43). Therefore, the risk of bleeding should not prevent the physician from offering a combination treatment of anti-thrombotic agents to aPL carriers.\n\nFinally, aside from pregnancy, aPL carriers should be considered as a population at increased risk of thrombosis, as demonstrated in different studies (7, 44, 45). Considering data of the obstetric APS women in the APS ACTION cohort, acquired risk factors, non-criteria manifestations and younger age at pregnancy morbidity represented risk factors for the development of thrombosis (subsequently recorded in 63% of patients) (45). In the present study, the patients who experienced complications during pregnancy were significantly younger. Therefore, they should be regarded as patients at possible increased risk of developing subsequent thrombosis.\n\nOur study has some limitations, that include the relatively small sample size and the retrospective nature, even if all the pregnancies included were prospectively followed. Moreover, autoimmune thyroiditis was frequently recorded and a common reason for which aPL tests were requested, but data on thyroid function was not systematically collected. Future analysis should also consider thyroid-stimulating hormone (TSH) value, especially considering the recent endocrinology studies, in which TSH values at the upper limit of normal seems to be associated with early pregnancy losses (46).\n\nComplement fractions levels were not systematically assessed as well. The complement system may gain utility in pregnancy monitoring as it plays an important role in the pathogenesis of obstetric APS (47); several evidences support the link between variations in the levels of different complement fractions and pregnancy complications (48–50). This pathogenetic pathway should be adequately addressed in the future as a potential therapeutic target.\n\nIn conclusion, the analysis of pregnant aPL carriers allowed the identification of triple aPL profile as an independent factor associated with pregnancy complications. The risk stratification of pregnant aPL carriers should include the definition of aPL profile to offer the combination treatment of LDA and LMWH to the “high-risk” patients. The value of additional therapeutic strategies, such as HCQ, will be defined in the next future; at the moment they may be considered for aPL carriers patients with lupus-like and non-criteria manifestations.\n\nData Availability\nAll datasets generated for this study are avaialble upon request.\n\nEthics Statement\nThe study was performed according to the principles of the Declaration of Helsinki and was approved by all the Local Ethic Committees (approval number 1088 in the Promoting Center). All patients signed a written informed consent.\n\nAuthor Contributions\nM-GL, LA, AR, P-LM, VP, and AT designed the study. M-GL organized the database. M-GL, MF, LA, CC, TD, MG, AK, M-GR, AL, FR, SZ, LT, AR, P-LM, VP, and AT recruited and evaluated the patients and fulfilled the database. M-GL, MF, LA, and AT wrote the manuscript. All authors contributed reviewed the manuscript draft, read and approved the submitted version.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Miyakis S Lockshin MD Atsumi T Branch DW Brey RL Cervera R . International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (aps) . J Thromb Haemost . (2006 ) 4 :295 –306 . 10.1111/j.1538-7836.2006.01753.x 16420554 \n2. Abreu MM Danowski A Wahl DG Amigo M-C Tektonidou M Pacheco MS . The relevance of “non-criteria” clinical manifestations of antiphospholipid syndrome: 14th international congress on antiphospholipid antibodies technical task force report on antiphospholipid syndrome clinical features . Autoimmun Rev . (2015 )14 :401 –14 . 10.1016/j.autrev.2015.01.002 25641203 \n3. Meroni PL Borghi MO Grossi C Chighizola CB Durigutto P Tedesco F . Obstetric and vascular antiphospholipid syndrome: same antibodies but different diseases? \nNat Rev Rheumatol . (2018 ) 14 :433 –40 . 10.1038/s41584-018-0032-6 29891914 \n4. Ruffatti A Del Ross T Ciprian M Nuzzo M Rampudda M Bertero M . Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study . Ann Rheum Dis . (2009 ) 68 :397 –9 . 10.1136/ard.2008.096669 18812393 \n5. Andreoli L Tincani A . Beyond the “syndrome”: Antiphospholipid antibodies as risk factors . Arthritis Rheum . (2012 ) 64 :342 –5 . 10.1002/art.33341 21953446 \n6. Ruiz-Irastorza G Cuadrado M Ruiz-Arruza I Brey R Crowther M Derksen R . Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th international congress on antiphospholipid antibodies . Lupus . (2011 ) 20 :206 –18 . 10.1177/0961203310395803 21303837 \n7. Pengo V Ruffatti A Legnani C Testa S Fierro T Marongiu F . Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study . Blood . (2011 ) 118 :4714 –8 . 10.1182/blood-2011-03-340232 21765019 \n8. Ruffatti A Tonello M Visentin MS Bontadi A Hoxha A De Carolis S . Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case–control study . Rheumatology . (2011 ) 50 :1684 –9 . 10.1093/rheumatology/ker139 21652586 \n9. Rezk M Dawood R Badr H . Maternal and fetal outcome in women with antiphospholipid syndrome: a three-year observational study . J Matern Fetal Neonatal Med. (2016 ) 29 :4015 –9 . 10.3109/14767058.2016.1152254 26856354 \n10. De Jesus GR Agmon-Levin N Andrade CA Andreoli L Chighizola CB Porter TF . 14th international congress on antiphospholipid antibodies task force report on obstetric antiphospholipid syndrome . Autoimmun Rev . (2014 ) 13 :795 –813 . 10.1016/j.autrev.2014.02.003 24650941 \n11. Fredi M Andreoli L Bettiga E Aggoggeri E Lazzaroni MG Le Guern V . Risk factors for adverse maternal and fetal outcomes in women with confirmed apl positivity: results from a multicenter study of 283 pregnancies . Front Immunol . (2018 ) 9 :864 . 10.3389/fimmu.2018.00864 29867924 \n12. Latino J Udry S Aranda F Perés Wingeyer S Fernández Romero D de Larrañaga G . Pregnancy failure in patients with obstetric antiphospholipid syndrome with conventional treatment: the influence of a triple positive antibody profile . Lupus . (2017 ) 26 :983 –8 . 10.1177/0961203317692432 28173738 \n13. Lockshin MD Kim M Laskin CA Guerra M Branch DW Merrill J \nPrediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies . Arthritis Rheum . (2012 ) 64 :2311 –8 . 10.1002/art.34402 22275304 \n14. Saccone G Berghella V Maruotti GM Ghi T Rizzo G Simonazzi G . Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the pregnants study . Am J Obstet Gynecol . (2017 ) 216 :525. e1 –e12 . 10.1016/j.ajog.2017.01.026 28153662 \n15. Galli M Luciani D Bertolini G Barbui T . Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature . Blood . (2003 ) 101 :1827 –32 . 10.1182/blood-2002-02-0441 12393574 \n16. Alijotas-Reig J Ferrer-Oliveras R Ruffatti A Tincani A Lefkou E Bertero MT . The european registry on obstetric antiphospholipid syndrome (euroaps): a survey of 247 consecutive cases . Autoimmun Rev . (2015 ) 14 :387 –95 . 10.1016/j.autrev.2014.12.010 25555817 \n17. Empson MB Lassere M Craig JC Scott JR \nPrevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant . Cochrane Database Syst Rev . (2005 ) 18 :CD002859 \n10.1002/14651858.CD002859.pub2 \n18. Andreoli L Bertsias G Agmon-Levin N Brown S Cervera R Costedoat-Chalumeau N \nEular recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome . Ann Rheum Dis . (2017 ) 76 :476 –85 . 10.1136/annrheumdis-2016-209770 27457513 \n19. Amengual O Fujita D Ota E Carmona L Oku K Sugiura-Ogasawara M . Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review . Lupus . (2015 ) 24 :1135 –42 . 10.1177/0961203315578765 25813871 \n20. Del Ross T Ruffatti A Visentin MS Tonello M Calligaro A Favaro M \nTreatment of 139 pregnancies in antiphospholipid-positive women not fulfilling criteria for antiphospholipid syndrome: a retrospective study . J Rheumatol . (2013 ) 40 :425 –9 . 10.3899/jrheum.120576 23418380 \n21. Chauleur C Galanaud J-P Alonso S Cochery-Nouvellon E Balducchi J-P Marès P . Observational study of pregnant women with a previous spontaneous abortion before the 10th gestation week with and without antiphospholipid antibodies . J Thromb Haemost . (2010 ) 8 :699 –706 . 10.1111/j.1538-7836.2010.03747.x 20088936 \n22. Chighizola CB Andreoli L Gerosa M Tincani A Ruffatti A Meroni PL . The treatment of anti-phospholipid syndrome: a comprehensive clinical approach . J Autoimmun . (2018 ) 90 :1 –27 . 10.1016/j.jaut.2018.02.003 29449131 \n23. Brandt JT Triplett DA Alving B Scharrer I . Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the subcommittee on lupus anticoagulant/antiphospholipid antibody of the scientific and standardisation committee of the isth . Thromb Haemost . (1995 ) 74 :1185 –90 . 10.1055/s-0038-1649901 8560433 \n24. Bertolaccini ML Amengual O Andreoli L Atsumi T Chighizola CB Forastiero R . 14th international congress on antiphospholipid antibodies task force. Report on antiphospholipid syndrome laboratory diagnostics and trends . Autoimmun Rev . (2014 ) 13 :917 –30 . 10.1016/j.autrev.2014.05.001 24824074 \n25. Tincani A Allegri F Balestrieri G Reber G Sanmarco M Meroni P . Minimal requirements for antiphospholipid antibodies elisas proposed by the european forum on antiphospholipid antibodies . Thromb Res . (2004 ) 114 :553 –8 . 10.1016/j.thromres.2004.06.035 15507291 \n26. Asherson R \nA “primary” antiphospholipid syndrome? \nJ Rheumatol . (1988 ) 15 :1742 –6 .14552307 \n27. Yelnik CM Laskin CA Porter TF Branch DW Buyon JP Guerra MM . Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in apl-positive patients: validation of PROMISSE study results . Lupus Sci Med . (2016 ) 3 :e000131 . 10.1136/lupus-2015-000131 26835148 \n28. Mattia E Tonello M Del Ross T Zerbinati P Campello E Simioni P . Clinical and laboratory characteristics of isolated lupus anticoagulants . Thromb Res . (2018 ) 165 :51 –3 . 10.1016/j.thromres.2018.03.008 29567587 \n29. Pengo V Del Ross T Ruffatti A Bison E Cattini M Pontara E . Lupus anticoagulant identifies two distinct groups of patients with different antibody patterns . Thromb Res . (2018 ) 172 :172 –8 . 10.1016/j.thromres.2018.11.003 30466070 \n30. Chighizola CB Pregnolato F Andreoli L Bodio C Cesana L Comerio C . Beyond thrombosis: anti-β2gpi domain 1 antibodies identify late pregnancy morbidity in anti-phospholipid syndrome . J Autoimmun . (2018 ) 90 :76 –83 . 10.1016/j.jaut.2018.02.002 29454510 \n31. Canti V Del Rosso S Tonello M Lucianò R Hoxha A Coletto LA . Antiphosphatidylserine/prothrombin antibodies in antiphospholipid syndrome with intrauterine growth restriction and preeclampsia . J Rheumatol . (2018 ) 45 :1263 –72 . 10.3899/jrheum.170751 30008452 \n32. Soh MC Pasupathy D Gray G Nelson-Piercy C \nPersistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes . Rheumatology. (2013 ) 52 :1642 –7 . 10.1093/rheumatology/ket173 23681394 \n33. Alijotas-Reig J Esteve-Valverde E Ferrer-Oliveras R LLurba E Ruffatti A Tincani A . Comparative study between obstetric antiphospholipid syndrome and obstetric morbidity related with antiphospholipid antibodies . Med Clin. (2018 ) 151 :215 –22 . 10.1016/j.medcle.2017.11.052 29274674 \n34. Ruffatti A Gervasi M Favaro M Ruffatti A Hoxha A Punzi L . Adjusted prophylactic doses of nadroparin plus low dose aspirin therapy in obstetric antiphospholipid syndrome. A prospective cohort management study . Clin Exp Rheumatol . (2011 ) 29 :551 –4 . 21640048 \n35. Sciascia S Branch DW Levy RA Middeldorp S Pavord S Roccatello D . The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment . Thromb Haemost . (2016 ) 115 : 285 –90 . 10.1160/th15-06-0491 26421409 \n36. Albert CR Schlesinger WJ Viall CA Mulla MJ Brosens JJ Chamley LW . Effect of hydroxychloroquine on antiphospholipid antibody-induced changes in first trimester trophoblast function . Am J Reprod Immunol . (2014 ) 71 :154 –64 . 10.1111/aji.12184 24325143 \n37. Mekinian A Lazzaroni MG Kuzenko A Alijotas-Reig J Ruffatti A Levy P . The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: data from a european multicenter retrospective study . Autoimmun Rev . (2015 ) 14 :498 –502 . 10.1016/j.autrev.2015.01.012 25617818 \n38. Ruffatti A Tonello M Hoxha A Sciascia S Cuadrado MJ Latino JO . Effect of additional treatments combined with conventional therapies in pregnant patients with high-risk antiphospholipid syndrome: a multicentre study . Thromb Haemost . (2018 ) 118 :639 –46 . 10.1055/s-0038-1632388 29490410 \n39. Sciascia S Hunt B Talavera-Garcia E Lliso G Khamashta M Cuadrado M . The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies . Am J Obstet Gynecol . (2016 ) 214 :273.e1 –e8 . 10.1016/j.ajog.2015.09.078 26429521 \n40. Mekinian A Alijotas-Reig J Carrat F Costedoat-Chalumeau N Ruffatti A Lazzaroni MG . Refractory obstetrical antiphospholipid syndrome: features, treatment and outcome in a european multicenter retrospective study . Autoimmun Rev . (2017 ) 16 :730 –4 . 10.1016/j.autrev.2017.05.006 28478081 \n41. Schreiber K Breen K Cohen H Jacobsen S Middeldorp S Pavord S \nHydroxychloroquine to improve pregnancy outcome in women with antiphospholipid antibodies (HYPATIA) protocol: a multinational randomized controlled trial of hydroxychloroquine versus placebo in addition to standard treatment in pregnant women with antiphospholipid syndrome or antibodies . Semin Thromb Hemost . (2017 ) 43 :562 –71 . 10.1055/s-0037-1603359 28609801 \n42. Mekinian A Vicaut E Cohen J Bornes M Kayem G Fain O . Hydroxychloroquine to obtain pregnancy without adverse obstetrical events in primary antiphospholipid syndrome: french phase ii multicenter randomized trial, HYDROSAPL . Gynecol Obstet Fertil Senol . (2018 ) 46 :598 –604 . 10.1016/j.gofs.2018.06.008 30041771 \n43. Yelnik C Lambert M Drumez E Le Guern V Bacri J Guerra M . Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome . Lupus . (2018 ) 27 :1679 –86 . 10.1177/0961203318787032 30016929 \n44. Taraborelli M Reggia R Dall'Ara F Fredi M Andreoli L Gerosa M . Longterm outcome of patients with primary antiphospholipid syndrome: a retrospective multicenter study . J Rheumatol . (2017 ) 44 :1165 –72 . 10.3899/jrheum.161364 28572466 \n45. de Jesús GR Sciascia S Andrade D Barbhaiya M Tektonidou M Banzato A \nFactors associated with first thrombosis in patients presenting with obstetric antiphospholipid syndrome (aps) in the aps alliance for clinical trials and international networking clinical database and repository: a retrospective study . BJOG . (2019 ) 126 :656 –61 . 10.1111/1471-0528.15469 30222236 \n46. Moreno BT Carvajal GC Fernandez LV Lazaro VA Benfail L Carrera CT \nRelationship between tsh values in the first trimester of pregnancy and obstetric and neonatal complications. ECE 2018 . In Proceedings of the 20th European Congress of Endocrinology , Barcelona : Endocrine Abstracts (2018 ), p. 56 :OC1.2 .\n47. Tedesco F Borghi MO Gerosa M Chighizola CB Macor P Lonati PA \nPathogenic role of complement in anti-phospholipid syndrome and therapeutic implications . Front Immunol . (2018 ) 9 :1388 \n10.3389/fimmu.2018.01388 29971066 \n48. Reggia R Ziglioli T Andreoli L Bellisai F Iuliano A Gerosa M . Primary anti-phospholipid syndrome: Any role for serum complement levels in predicting pregnancy complications? \nRheumatology . (2012 ) 51 :2186 –90 . 10.1093/rheumatology/kes225 22923750 \n49. Kim MY Guerra MM Kaplowitz E Laskin CA Petri M Branch DW \nComplement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies . Ann Rheum Dis . (2018 ) 77 :549 –55 . 10.1136/annrheumdis-2017-212224 29371202 \n50. Buyon JP Kim MY Guerra MM Laskin CA Petri M Lockshin MD . Predictors of pregnancy outcomes in patients with lupus: a cohort study . Ann Intern Med . (2015 ) 163 :153 –63 . 10.7326/M14-2235 26098843\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "10()",
"journal": "Frontiers in immunology",
"keywords": "adverse pregnancy outcomes (APO); anti-β2 glycoprotein I antibodies; anticardiolipin (aCL); antiphospholipid (aPL) antibodies; antiphospholipid syndrome (APS); lupus anticoagulant; pregnancy complication; thrombosis",
"medline_ta": "Front Immunol",
"mesh_terms": "D000328:Adult; D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D001241:Aspirin; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D012307:Risk Factors; D013927:Thrombosis; D053482:beta 2-Glycoprotein I",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "1948",
"pmc": null,
"pmid": "31475009",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "12393574;14552307;15507291;15846641;16420554;18812393;20088936;21303837;21640048;21652586;21765019;21953446;22275304;22923750;23418380;23681394;24325143;24650941;24824074;25555817;25617818;25641203;25813871;26098843;26421409;26429521;26835148;26856354;27457513;28153662;28173738;28478081;28572466;28609801;29274674;29371202;29449131;29454510;29490410;29567587;29867924;29891914;29971066;30008452;30016929;30041771;30222236;30466070;8560433",
"title": "Triple Antiphospholipid (aPL) Antibodies Positivity Is Associated With Pregnancy Complications in aPL Carriers: A Multicenter Study on 62 Pregnancies.",
"title_normalized": "triple antiphospholipid apl antibodies positivity is associated with pregnancy complications in apl carriers a multicenter study on 62 pregnancies"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1007422",
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"activesubstancename": "ASPIRIN"
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{
"abstract": "A young patient with relapsed diffuse large B-cell lymphoma presented with new onset respiratory symptoms and hypereosinophilia in the early stage post high-dose therapy/autologous stem cell rescue. Here, we present a step-wise practical approach to this unexpected laboratory finding for a not uncommon infective complication in the immunosuppressed patient.",
"affiliations": "Hematology Department, Royal Free London NHS Foundation Trust, London, UK. g1ahmed@yahoo.co.uk.",
"authors": "Zakout|G A|GA|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "18(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Pneumocystis pneumonia; high-dose therapy/autologous stem cell rescue; hypereosinophilia",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002081:Buttocks; D003371:Cough; D003937:Diagnosis, Differential; D004417:Dyspnea; D004802:Eosinophilia; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D000072078:Positron Emission Tomography Computed Tomography; D014057:Tomography, X-Ray Computed; D014182:Transplantation, Autologous",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "765-767",
"pmc": null,
"pmid": "27422045",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Beware the \"red herring\".",
"title_normalized": "beware the red herring"
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{
"companynumb": "GB-TEVA-757916ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"actiondrug": "5",
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"activesubstancename": "METHYLPREDNISOLONE"
},
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{
"abstract": "BACKGROUND\n5-Aminosalicylate (5-ASA) is widely used as the first-line drug for ulcerative colitis (UC). 5-ASA is mostly a safe and effective drug, but it can bring about exacerbation due to 5-ASA intolerance. 5-ASA intolerance can be confusing and it can mislead physicians into considering unnecessary treatment escalation, including corticosteroid (CS), biologics, or even surgery. In spite of the clinical importance of 5-ASA intolerance, there have been few studies on its incidence, clinical features, and diagnosis.\n\n\nMETHODS\nIn order to evaluate the incidence, characteristic symptoms, disease course, and laboratory data of children with 5-ASA intolerance, we retrospectively reviewed the medical records of 80 children with UC.\n\n\nRESULTS\nEleven of 80 children (13.8%) with UC were diagnosed with 5-ASA intolerance. The median time between the initiation of 5-ASA and the onset of 5-ASA intolerance was 10 days (range, 4-20 days) in patients not receiving CS. Drug-induced lymphocyte stimulation test (DLST) was performed in 10 patients, and was positive in eight. C-reactive protein (CRP) increased significantly when exacerbation of colitis symptoms occurred.\n\n\nCONCLUSIONS\nThe incidence of 5-ASA intolerance was relatively high. Besides the challenge test, elevation of CRP and positive DLST appeared to support the diagnosis of 5-ASA intolerance.",
"affiliations": "Division of Gastroenterology, National Center for Child Health and Development, Setagaya, Tokyo, Japan.;Division of Gastroenterology, National Center for Child Health and Development, Setagaya, Tokyo, Japan.;Department of Education for Clinical Research, National Center for Child Health and Development, Setagaya, Tokyo, Japan.;Division of Gastroenterology, National Center for Child Health and Development, Setagaya, Tokyo, Japan.;Division of Gastroenterology, National Center for Child Health and Development, Setagaya, Tokyo, Japan.",
"authors": "Shimizu|Hirotaka|H|;Arai|Katsuhiro|K|;Tang|Julian|J|;Hosoi|Kenji|K|;Funayama|Rie|R|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.13235",
"fulltext": null,
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"issn_linking": "1328-8067",
"issue": "59(5)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "5-aminosalicylate intolerance; C-reactive protein; drug-induced lymphocyte stimulation test; pediatrics; ulcerative colitis",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002648:Child; D003093:Colitis, Ulcerative; D018450:Disease Progression; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D019804:Mesalamine; D012189:Retrospective Studies",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "583-587",
"pmc": null,
"pmid": "28063246",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "5-Aminosalicylate intolerance causing exacerbation in pediatric ulcerative colitis.",
"title_normalized": "5 aminosalicylate intolerance causing exacerbation in pediatric ulcerative colitis"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1038646",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy that originates from plasmacytoid dendritic cells. It can involve skin, bone marrow, and/or lymph nodes. There is no consensus recommendation regarding treatment especially in the relapsed setting. Tagraxofusp, a CD123 directed agent, was recently approved by the Food and Drug Administration to treat BPDCN. We report a case of an elderly patient with diagnosis of BPDCN who was treated initially with tagraxofusp followed by azacitidine and venetoclax combination on relapse.\n\n\nMETHODS\nA 79 year old male presented with violaceous skin lesions. He had no other symptoms. Biopsy of these lesions was consistent with a diagnosis of BPDCN. Further testing showed no extracutaneous involvement.Management and outcome: Tagraxofusp was started at full dose (12 mcg/kg). This dose was not tolerated well. Patient could only tolerate the lowest dose (5 mcg/kg). Toxicities included elevated liver function tests, hyperglycemia, capillary leak syndrome, and pancreatitis. Dose escalation on progression was not possible due to side effects. Treatment was switched to venetoclax and azacitidine. Combination treatment was tolerated very well and patient showed major cutaneous response after 5 cycles and continues to do well.\n\n\nCONCLUSIONS\nTagraxofusp is a novel therapy that needs more real-world experience. This case describes the clinical course of an elderly patient on tagraxofusp. We also review the literature of azacytidine/venetoclax combination as a potential yet tolerable treatment option for this rare disease entity. This is the fourth case in literature to be treated with this combination.",
"affiliations": "Division of Hematology and Cellular Therapy, Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA.;Division of Hematology and Cellular Therapy, Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA.;Division of Hematology and Cellular Therapy, Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA.;Department of Pathology and Laboratory Medicine, Allegheny Health Network, Pittsburgh, PA, USA.;Division of Hematology and Cellular Therapy, Allegheny Health Network Cancer Institute, Pittsburgh, PA, USA.",
"authors": "Samhouri|Yazan|Y|https://orcid.org/0000-0003-0271-4798;Ursu|Sorana|S|;Dutton|Nina|N|;Tanvi|Verma|V|;Fazal|Salman|S|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; C000592123:tagraxofusp; D001374:Azacitidine; C579720:venetoclax",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220951850",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Blastic plasmacytoid dendritic cell neoplasm; azacitidine; tagraxofusp; venetoclax",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003713:Dendritic Cells; D019337:Hematologic Neoplasms; D006801:Humans; D008297:Male; D011993:Recombinant Fusion Proteins; D012878:Skin Neoplasms; D013449:Sulfonamides",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "990-995",
"pmc": null,
"pmid": "32847479",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Tagraxofusp followed by combined azacitidine and venetoclax in blastic plasmacytoid dendritic cell neoplasm: A case report and literature review.",
"title_normalized": "tagraxofusp followed by combined azacitidine and venetoclax in blastic plasmacytoid dendritic cell neoplasm a case report and literature review"
} | [
{
"companynumb": "US-STEMLINE THERAPEUTICS, INC.-2020ST000054",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TAGRAXOFUSP-ERZS"
},
"druga... |
{
"abstract": "Homicidal poisonings remain rare and can be difficult to detect, especially in the elderly or in medical settings. In this atypical poisoning series, a young nursing assistant purposely poisoned thirteen residents of a nursing home and killed ten of them. The medications used were a mix of psychotropic medications (cyamemazine, loxapine, tiapride, risperidone, and mirtazapine), under liquid formulation, which were inducing malaise and coma. The forensic investigation included analysis of blood, urine, hair, and bone marrow and exhumations of seven corpses up to 3 years after the inhumation. Hair collected from a hairbrush of a cremated victim have been analyzed. Bone marrow sample preparation was based on a liquid/liquid triple extraction. Hair were incubated after decontamination overnight at 55 °C in methanol. Segmentation was possible for seven samples, except for delayed exhumation samples (n = 4) and hairbrush hair sample (n = 1). The extracts were then analyzed using gas chromatography coupled with mass spectrometry (GC-MS) for unknown screening and using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for a targeted screening and quantification. Screenings revealed the presence of the same mix of psychotropic medications. Cyamemazine, mirtazapine, loxapine, tiapride, and risperidone hair concentrations were 6-17,458 pg/mg, 74-1271 pg/mg, 9-1346 pg/mg, 13-148 pg/mg, and 3-5 pg/mg, respectively. Cyamemazine bone marrow concentrations were 229 and 681 ng/g and 152-717 ng/mL in blood. Patients' medications were also identified and quantified. This poisoning series provide analytical data that could support subsequent toxicological result interpretation in similar forensic cases.",
"affiliations": "Laboratory of Pharmacology, Pharmacogenetics and Toxicology, Grenoble Alpes University Hospital, Grenoble, France. twilleman@chu-grenoble.fr.;Forensic Laboratory, University Grenoble Alpes, Grenoble, France.;Clinical Forensic Medicine Department, Grenoble Alpes University Hospital, Grenoble, France.;Forensic Laboratory, University Grenoble Alpes, Grenoble, France.;Laboratory of Pharmacology, Pharmacogenetics and Toxicology, Grenoble Alpes University Hospital, Grenoble, France.;Clinical Forensic Medicine Department, Grenoble Alpes University Hospital, Grenoble, France.;Laboratory of Pharmacology, Pharmacogenetics and Toxicology, Grenoble Alpes University Hospital, Grenoble, France.;Clinical Forensic Medicine Department, Grenoble Alpes University Hospital, Grenoble, France.",
"authors": "Willeman|Théo|T|http://orcid.org/0000-0002-0348-7171;Allibe|Nathalie|N|;Sauerbach|Laura|L|;Barret|Anne|A|;Eysseric-Guerin|Hélène|H|;Paysant|François|F|;Stanke-Labesque|Françoise|F|;Scolan|Virgine|V|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00414-021-02703-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-9827",
"issue": null,
"journal": "International journal of legal medicine",
"keywords": "Bone marrow; Forensic toxicology; Hair analysis; Liquid chromatography-tandem mass spectrometry; Poisoning",
"medline_ta": "Int J Legal Med",
"mesh_terms": null,
"nlm_unique_id": "9101456",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34591183",
"pubdate": "2021-09-30",
"publication_types": "D016428:Journal Article",
"references": "23361068;17199622;32144480;21061013;28969544;15172074;17047795;32146303;29300918;20355195;25676714;15172073;16778731;8138227;21354729;28535979;33559900;29331713;16567235;21300991;29959837",
"title": "Homicidal poisoning series in a nursing home: retrospective toxicological investigations in bone marrow and hair.",
"title_normalized": "homicidal poisoning series in a nursing home retrospective toxicological investigations in bone marrow and hair"
} | [
{
"companynumb": "FR-ORGANON-O2110FRA002823",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MIRTAZAPINE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nPatient safety regulations and medical error reporting systems have been at the forefront of current health care legislature. In 2000, Florida mandated that all physicians report, to a central collecting agency, all adverse events occurring in an office setting.\n\n\nOBJECTIVE\nTo analyze the scope and incidence of adverse events and deaths resulting from office surgical procedures in Florida from 2000 to 2004.\n\n\nMETHODS\nWe reviewed all reported adverse incidents (the death of a patient, serious injury, and subsequent hospital transfer) occurring in an office setting from March 1, 2000, through March 1, 2004, from the Florida Agency for Health Care Administration. We determined physician board certification status, hospital privileges, and office accreditation via telephone follow-up and Internet searches.\n\n\nRESULTS\nOf 286 reported office adverse events, 77 occurred in association with an office surgical procedure (19 deaths and 58 hospital transfers). There were seven complications and five deaths associated with the use of intravenous sedation or general anesthesia. There were no adverse events associated with the use of dilute local (tumescent) anesthesia. Liposuction and/or abdominoplasty under general anesthesia or intravenous sedation were the most common surgical procedures associated with a death or complication. Fifty-three percent of offices reporting an adverse incident were accredited by the Joint Commission on Accreditation of Healthcare Organizations, American Association for Accreditation of Ambulatory Surgical Facilities, or American Association for Ambulatory Health Care. Ninety-four percent of the involved physicians were board certified, and 97% had hospital privileges. Forty-two percent of the reported deaths were delayed by several hours to weeks after uneventful discharge or after hospital transfer.\n\n\nCONCLUSIONS\nRequiring physician board certification, physician hospital privileges, or office accreditation is not likely to reduce office adverse events. Restrictions on dilute local (tumescent) anesthesia for liposuction would not reduce adverse events and could increase adverse events if patients are shifted to riskier approaches. State and/or national legislation establishing adverse event reporting systems should be supported and should require the reporting of delayed deaths.",
"affiliations": "The Skin Cancer Center, Cincinnati, Ohio, USA.",
"authors": "Coldiron|Brett|B|;Fisher|Ann Harriott|AH|;Adelman|Eric|E|;Yelverton|Christopher B|CB|;Balkrishnan|Rajesh|R|;Feldman|Marc A|MA|;Feldman|Steven R|SR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-0512",
"issue": "31(9 Pt 1)",
"journal": "Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]",
"keywords": null,
"medline_ta": "Dermatol Surg",
"mesh_terms": "D000556:Ambulatory Surgical Procedures; D000758:Anesthesia; D003406:Credentialing; D005431:Florida; D006801:Humans; D019221:Mandatory Reporting; D010824:Physicians' Offices; D011785:Quality Assurance, Health Care; D012189:Retrospective Studies; D017751:Safety Management",
"nlm_unique_id": "9504371",
"other_id": null,
"pages": "1079-92; discussion 1093",
"pmc": null,
"pmid": "16162309",
"pubdate": "2005-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adverse event reporting: lessons learned from 4 years of Florida office data.",
"title_normalized": "adverse event reporting lessons learned from 4 years of florida office data"
} | [
{
"companynumb": "US-PFIZER INC-2020094436",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "We present a rare case of pancreatic panniculitis in a 59-year-old male simultaneous pancreas-kidney (SPK) recipient with failed allografts. The patient presented with fever and painful erythematous nodules on his leg 1 month after stopping all immunosuppression. A thorough infectious and rheumatological workup was negative. He had pancreas rejection 4 years after SKP transplant and was restarted on dialysis after 14 years when his renal allograft failed due to chronic allograft nephropathy. His chronic immunosuppression (tacrolimus, azathioprine) was stopped and prednisone was weaned over 3 months at that time. A skin biopsy revealed saponification of the subcutaneous fat with inflammation pathognomonic of pancreatic panniculitis. Concurrent allograft pancreatitis confirmed with elevated lipase and a computed tomography scan finding of peripancreatic graft stranding and atrophic native pancreas. He was started on pulse steroid therapy for 3 days followed by oral taper. This resulted in dramatic resolution of all skin lesions and normalization of lipase levels within 1 week, followed by resumption of low-dose tacrolimus and azathioprine. This is an extremely rare occurrence of panniculitis in pancreas allograft after 10 years of pancreatic failure associated with stopping immunosuppression.",
"affiliations": "Department of Medicine-Division of Nephrology/Transplant, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Medicine-Division of Nephrology/Transplant, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Medicine-Division of Nephrology/Transplant, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Surgery-Transplant, Indiana University School of Medicine, Indianapolis, Indiana.;Department of Medicine-Division of Nephrology/Transplant, Indiana University School of Medicine, Indianapolis, Indiana.",
"authors": "Baig|Mirza M|MM|;Yaqub|Muhammad S|MS|;Taber|Tim E|TE|;Fridell|Jonathan|J|;Sharfuddin|Asif|A|0000-0001-5488-1956",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15485",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "19(10)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "acute; clinical research/ practice; complication; diabetes; immunosuppression/immune modulation; immunosuppressive regimens - maintenance; insulin/C-peptide; medical/metabolic; pancreas/simultaneous pancreas-kidney transplantation; pathology/histopathology; rejection; type 1",
"medline_ta": "Am J Transplant",
"mesh_terms": "D064591:Allografts; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D010182:Pancreatic Diseases; D015434:Panniculitis; D011183:Postoperative Complications; D011379:Prognosis",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2934-2938",
"pmc": null,
"pmid": "31152473",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late pancreatic panniculitis in a simultaneous pancreas kidney transplant patient with failed allografts.",
"title_normalized": "late pancreatic panniculitis in a simultaneous pancreas kidney transplant patient with failed allografts"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213952",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drug... |
{
"abstract": "Lymphomas, both within and outside the central nervous system, are uncommon among patients with systemic lupus erythematosus (SLE). We describe a 58-year old Korean woman with SLE who presented with acute headache and confusion in the setting of prednisone and mycophenolate mofetil (MMF) therapy used to treat focal proliferative and membranous lupus nephritis. Three-dimensional brain magnetic resonance imaging (MRI) showed two peripherally ('ring') enhancing lesions within the basal ganglia, bilaterally, with associated mass effect and subfalcine herniation. A brain biopsy revealed an Epstein-Barr virus (EBV)-positive diffuse large B cell lymphoma. This is the first description of CNS lymphoma in a patient treated with MMF for lupus nephritis. While intracerebral lymphoma in the immunocompromised patient with lupus is rare, this disorder should be considered in the differential diagnosis of new-onset neurological symptoms among such patients.",
"affiliations": "Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.",
"authors": "Dasgupta|N|N|;Gelber|A C|AC|;Racke|F|F|;Fine|D M|DM|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1191/0961203303lu2179cr",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "14(11)",
"journal": "Lupus",
"keywords": null,
"medline_ta": "Lupus",
"mesh_terms": "D001932:Brain Neoplasms; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008181:Lupus Nephritis; D016393:Lymphoma, B-Cell; D008875:Middle Aged; D009173:Mycophenolic Acid",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "910-3",
"pmc": null,
"pmid": "16335585",
"pubdate": "2005",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Central nervous system lymphoma associated with mycophenolate mofetil in lupus nephritis.",
"title_normalized": "central nervous system lymphoma associated with mycophenolate mofetil in lupus nephritis"
} | [
{
"companynumb": "NVSC2020US092584",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "This randomized, retrospective study evaluated the effect of thalidomide combined with bortezomib-dexamethasone (TBD) or vincristine-doxorubicin-dexamethasone (T-VAD) on 46 patients with multiple myeloma. Newly diagnosed patients were randomly allocated to receive TBD (n = 24) or T-VAD (n = 22). The high-quality response rate (complete response plus very good partial response) was 62.5% in the TBD group and 45.4% for T-VAD. The complete response rate was 29.2% for TBD and 13.6% for T-VAD. Overall survival at 2 and 3 years, respectively, was 91.7% and 62.5% for TBD versus 86.4% and 54.5% for T-VAD. Most of the toxic effects of treatment were well tolerated. Both regimens were effective in the treatment of newly diagnosed multiple myeloma patients. Further studies are required to determine the role of thalidomide in these two regimens.",
"affiliations": "Department of Haematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.",
"authors": "Chen|R A|RA|;Tu|Y|Y|;Cao|Y|Y|;Liu|L|L|;Liang|Y|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D013792:Thalidomide; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1177/147323001103900544",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-0605",
"issue": "39(5)",
"journal": "The Journal of international medical research",
"keywords": null,
"medline_ta": "J Int Med Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011719:Pyrazines; D012189:Retrospective Studies; D013792:Thalidomide; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "1975-84",
"pmc": null,
"pmid": "22118002",
"pubdate": "2011",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Bortezomib-dexamethasone or vincristine-doxorubicin-dexamethasone as induction therapy followed by thalidomide as maintenance therapy in untreated multiple myeloma patients.",
"title_normalized": "bortezomib dexamethasone or vincristine doxorubicin dexamethasone as induction therapy followed by thalidomide as maintenance therapy in untreated multiple myeloma patients"
} | [
{
"companynumb": "CN-JNJFOC-20160822070",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "While hypothyroidism has frequently been reported with the use of TKIs, the thyroid-stimulating hormone (TSH) suppressing effect of TKIs is rare, except for thyroiditis. We describe a case with progressive recurrent chordoma who initially became hyperthyroid in a context of autoimmunity under sorafenib treatment and later under imatinib treatment.\n\n\n\nA 57-year-old man with lumbar chordoma began daily treatment of 800 mg sorafenib. He did not have any other medication or recent iodinated-contrast exposure and his family history was negative for thyroid and autoimmune disease. There was no history of neck pain, irradiation or trauma, recent fever or viral illness. Pre-treatment TSH was normal. After 18 weeks of treatment, the patient presented hyperthyroidism with positive anti-TSH receptor antibodies. More surprisingly, Graves' disease recurred during treatment with imatinib.\n\n\n\nThe fact that Graves' disease occurred after two different TKIs suggests that it could be a rare but important class effect. Anti-TSH receptor antibodies should be systematically measured when TSH decreases in order to avoid the erroneous diagnosis of transient hyperthyroidism due to thyroiditis.",
"affiliations": "Department of Medicine, Division of endocrinology, APHM, Conception Hospital, Marseille, France. Juliette.EROUKHMANOFF@ap-hm.fr.;Department of Medicine, Division of endocrinology, APHM, Conception Hospital, Marseille, France.;Department of Medicine, Division of adult oncology, Oscar Lambret Institute, Lille, France.;Aix Marseille Univ, INSERM, U911, Marseille, France.",
"authors": "Eroukhmanoff|Juliette|J|;Castinetti|Frederic|F|;Penel|Nicolas|N|;Salas|Sebastien|S|",
"chemical_list": "D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-016-2705-3",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 270510.1186/s12885-016-2705-3Case ReportAuto-immune thyroid dysfunction induced by tyrosine kinase inhibitors in a patient with recurrent chordoma Eroukhmanoff Juliette 33 4 91 38 65 97Juliette.EROUKHMANOFF@ap-hm.fr 1Castinetti Frederic Frederic.CASTINETTI@ap-hm.fr 1Penel Nicolas n-penel@o-lambret.fr 2Salas Sebastien sebastien.salas@ap-hm.fr 341 Department of Medicine, Division of endocrinology, APHM, Conception Hospital, Marseille, France 2 Department of Medicine, Division of adult oncology, Oscar Lambret Institute, Lille, France 3 Aix Marseille Univ, INSERM, U911, Marseille, France 4 Department of Medicine, Division of adult oncology, APHM, Timone Hospital, Marseille, France 24 8 2016 24 8 2016 2016 16 1 67930 6 2015 10 8 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nWhile hypothyroidism has frequently been reported with the use of TKIs, the thyroid-stimulating hormone (TSH) suppressing effect of TKIs is rare, except for thyroiditis. We describe a case with progressive recurrent chordoma who initially became hyperthyroid in a context of autoimmunity under sorafenib treatment and later under imatinib treatment.\n\nCase presentation\nA 57-year-old man with lumbar chordoma began daily treatment of 800 mg sorafenib. He did not have any other medication or recent iodinated-contrast exposure and his family history was negative for thyroid and autoimmune disease. There was no history of neck pain, irradiation or trauma, recent fever or viral illness. Pre-treatment TSH was normal. After 18 weeks of treatment, the patient presented hyperthyroidism with positive anti-TSH receptor antibodies. More surprisingly, Graves’ disease recurred during treatment with imatinib.\n\nConclusion\nThe fact that Graves’ disease occurred after two different TKIs suggests that it could be a rare but important class effect. Anti-TSH receptor antibodies should be systematically measured when TSH decreases in order to avoid the erroneous diagnosis of transient hyperthyroidism due to thyroiditis.\n\nKeywords\nAuto-immune thyroid dysfunctionTyrosine kinase inhibitorsChordomaAssistance Publique - Hôpitaux de Marseilleissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nTyrosine kinase inhibitors (TKIs) are molecular targeted agents used in the treatment of various cancers. Treatment with TKIs has been associated with changes in thyroid hormone status. While hypothyroidism has frequently been reported with the use of TKIs, hyperthyroidism is less frequent, except with thyroiditis [1–3]. Here, we describe a case with progressive recurrent chordoma who initially became thyrotoxic in a context of autoimmunity under sorafenib treatment and later under imatinib treatment.\n\nCase presentation\nA 57-year-old man with lumbar chordoma was treated initially by two surgical interventions, radiotherapy and proton therapy. In 2011, he began a daily treatment of 800 mg sorafenib in a phase 2 Angionext clinical trial. This study is registered in the European Clinical Trials Register (EudraCT N° 2007-004651-10) and in the ClinicalTrial.gov site (Number: NCT 00874874). He did not have any other medication or recent iodinated-contrast exposure and his family history was negative for thyroid and autoimmune disease. There was no history of neck pain, irradiation or trauma, recent fever or viral illness. Pre-treatment TSH was normal.\n\nAfter 18 weeks of treatment, his general condition worsened with anorexia, abdominal pain and nausea, leading to a weight loss of 30 % compared to baseline (Grade 4 undernutrition). His test results were suggestive of overt hyperthyroidism [TSH < 0.005 IU/ml (0.27–4.20); free thyroxine (fT4): 34 ng/l (9.32–17.1) and free triiodothyronine (fT3): 10.1 ng/l (2.54–4.36)]. High titers of anti-TSH receptor antibodies were present [31.8 IU/l (N < 1 IU/l)] (Roche Diagnostics, Elecsys 2010, limit of quantification 0.9 U/L). Neck ultrasound showed a voluminous homogeneous gland moderately hypervascularized and without any nodule, and Tc-99 thyroid scintigraphy showed homogeneously increased absorption. These results were highly suggestive of Graves’ disease so the patient was treated with 40 mg carbimazole daily. At this time, sorafenib was discontinued. One month after starting carbimazole, thyroid hormone levels were suggestive of mild hypothyroidism (fT4, 5.7 ng/l; TSH, 6.3 IU/ml). Anti-TSH receptor antibodies were still positive (37.2 IU/l). Carbimazole was maintained at the same dose and L-thyroxin was initiated. Euthyroidism (normal TSH and T4 levels) was obtained one month later, while anti-TSH receptor antibodies were still present though largely decreased (9 IU/L).\n\nThe patient was then switched to imatinib 400 mg daily. One month after starting it and while still on fixed doses of carbimazole and L-thyroxin, the patient developed subclinical hyperthyroidism (TSH: 0.14 IU/ml, fT4: 14.9 ng/l, fT3: 6.7 ng/L). Surprisingly, anti-TSH receptor antibodies had risen sharply to 199 UI/l. No extra-thyroid sign of Grave’s disease was observed. Carbimazole was maintained at the same dose while L-thyroxin was rapidly decreased, hyperthyroidism continued to raise (TSH = 0.008 IU/l, fT4 = 30.9 ng/l, T3 = 10.6 ng/l) during the 3 months after beginning imatinib. A mild hypothyroidism at week 106 (TSH 10, fT4 6.6 ng/l, and fT3 3 ng/l) led us to decrease the carbimazole dose and moderately increase the L-thyroxin dose. Anti-TSH receptor antibodies decreased to 9.9 IU/l. Six months later, the patient was euthyroid with the same dose of carbimazole and L-thyroxin, while still on the same dose of imatinib. At the last follow-up 4 months later, anti-TSH receptor antibodies had increased to 37 IU/l and the L-thyroxin dose had to be decreased owing to the recurrence of hyperthyroidism (TSH 0.1 UI/L; fT4 24 ng/l; fT3 10.6 ng/l). Thereafter, the patient presented a tumor progression and imatinib was discontinued. He was euthyroid again one month later, and carbimazole and L-thyroxin doses were progressively decreased.\n\nConclusion\nTKI-induced hyperthyroidism has been mainly described as a preliminary step before hypothyroidism in some patients with a likely mechanism of destructive thyroiditis. In this setting, hyperthyroidism is always transient and does not necessarily require any treatment. [1, 2, 4]. Miyake et al. reported in a prospective observational trial that 23.9 % of patients with metastatic Renal Cell Carcinoma receiving sorafenib had decreased TSH levels before developing hypothyroidism, which suggested a drug-induced destructive thyroiditis causing thyroid hormone release [5]. The same evolution from hyper- to hypothyroidism was also reported in patients with hepatocarcinoma treated by sorafenib [2].\n\nWe report here a case of hyperthyroidism with positive anti-TSH receptor antibodies after treatment with two different successive TKI, sorafenib and imatinib. In our case, hyperthyroidism was due to Graves’ disease as proven by highly positive anti-TSH receptor antibodies, neck ultrasound and scintigraphy. The classical chronology of Graves’ disease is that positive anti-TSH receptor antibodies are detected shortly before the clinical signs. Our patient developed overt hyperthyroidism 18 weeks after starting a TKI. It is highly likely that these antibodies appeared because of the drug, and that the patient first presented sorafenib-induced Graves’ disease. Hyperthyroidism with positive anti-TSH receptor antibodies was also reported in a Turkish patient with a metastatic renal cell cancer treated by sorafenib [6].\n\nMore surprisingly, Graves’ disease appeared during treatment with imatinib at a time when the patient was still being treated by anti-thyroid drugs. The major increase in anti-TSH receptor antibodies (from 32 to 199 UI/l) suggests that this occurrence was not due to poor compliance. To our knowledge, this is the first description of such an event occurring with imatinib, which is known to induce hypothyroidism [7–9]. One hypothesis to explain the discrepancy between the large number of patients treated by imatinib and the few cases of Graves’ disease reported until now could be that imatinib is able to induce Graves’ disease only in patients with anti-TSH receptor antibodies, which was the case for our patient who still had positive antibodies when imatinib was initiated.\n\nFrom an endocrinological viewpoint, the dose needed to control Graves’ disease is also surprising. While the treatment of TKI-induced hypothyroidism can sometimes be challenging with the need for a rapid increase in the dose of L-thyroxin, the treatment of Graves’ disease in our patient seemed rather easy despite the fact that the anti-TSH receptor antibodies were particularly increased. A standard dose of carbimazole finally afforded rapid control of the hyperthyroidism (at its 1st and 2nd occurrences) that was still effective at the most recent follow-up. There is no clear explanation for the final increase in anti-TSH receptor antibodies despite unchanged doses of carbimazole, L-thyroxin and imatinib. One might argue that this easy response could be due to the fact that our patient was actually having thyroiditis rather than Grave’s disease: However, the method of TRAb measurement was highly specific, the scintigraphy showed increased trapping of the radionuclide, and the ultrasound revealed a mildly hypervascular goiter. T3 levels were not as high as expected during the first episode (but this might be due to the altered general condition of the patient), and this could be an evidence for thyroiditis; T3 levels were more consistant with Grave’s disease during the recurrence of thyrotoxicosis. In both cases, TRAb were highly positive, and they were measured in the same department of biology. All these evidence make it more likely the diagnosis of Grave’s disease than thyroiditis. From an oncological viewpoint, the fact that Graves’ disease occurred after two different TKIs suggests that it could be a rare but important class effect. As several studies have also demonstrated impaired thyroid function with sunitinib [10–14], axitinib [15, 16] and motesanib [17], our case report emphasizes the need for thyroid follow-up during any treatment with a TKI in order to screen for both hypothyroidism and hyperthyroidism. Systematically measuring anti-TSH receptor antibodies before TKI initiation is not realistic due to the low frequency of hyperthyroidism, unlike with hypothyroidism. However, anti-TSH receptor antibodies should be systematically assessed whenever TSH levels decrease in order to avoid the erroneous diagnosis of transient hyperthyroidism due to thyroiditis.\n\nEven though hyperthyroidism is rare, diagnosing Graves’ disease is of major importance as it requires prolonged treatment, unlike thyroiditis. Further studies on the mechanism of how TKIs lead to thyroid dysfunction and autoimmunity are needed in order to understand and predict the potential risks for patients on this therapy. There is evidence that various TKIs are able to modulate immune responses. In particular, TKIs might mediate both beneficial and harmful effects on immune cells, and trigger global auto-immunity system, by releasing new tumoral antigenes [18–20]. Moreover, a recent prospective observational cohort study of 27 patients showed novel appearance of antithyroid antibodies in one third of patients under Sunitinib, concluding that TKIs could be able to trigger/exacerbate thyroid autoimmunity [21]. Oncologists and endocrinologists should collaborate closely in the management of patients whenever endocrine side effects of a more and more frequently given treatment, namely TKI, become apparent.\n\nAbbreviations\nfT3Free triiodothyronine\n\nfT4Free thyroxine\n\nTKITyrosine kinase inhibitor\n\nTRAbAnti-thyroid-stimulating hormone antibodies\n\nTSHThyroid-stimulating hormone\n\nAcknowledgement\nWe thank Ray Cooke and Clara Eroukhmanoff for english correction.\n\nWe would like to thank Dr Elise Lombard for fruitful discussions about the TRAb method.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll relevant data are within the paper.\n\nAuthors’ contribution\nJE carried out acquisition of data, analysis and interpretation of data, conception and design, drafting the manuscript. FC participated in acquisition of data, analysis and interpretation of data, drafting manuscript. SS has been involved in conception and design, acquisition of data, analysis and interpretation of data, drafting manuscript, final approval of the version. NP’s role involved proofeading the last stages of the article. All authors have read and approved the manuscript.\n\nAuthors information\nJE : Medical Doctor in Endocrinology, Residency.\n\nSS : Medical Doctor in Oncology, Assistant Professor, PhD\n\nFC : Medical Doctor in Endocrinology, Assistant Professor, PhD\n\nNP : Physician in Oncology, PhD\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nEthics approval and consent to participate\nOral consent was obtained from the patient for participation and publication of this case report at the very beginning of drafting manuscript. Unfortunately the patient died recently so we are not able to obtain written consent from him. However, his brother’s written consent is available.\n==== Refs\nReferences\n1. Iavarone M Perrino M Vigano M Beck-Peccoz P Fugazzola L Sorafenib-induced destructive thyroiditis Thyroid 2010 20 9 1043 1044 10.1089/thy.2010.0070 20825302 \n2. van Doorn L Eskens FA Visser TJ van der Lugt A Mathijssen RH Peeters RP Sorafenib induced thyroiditis in two patients with hepatocellular carcinoma Thyroid 2011 21 2 197 202 10.1089/thy.2010.0234 21275767 \n3. Grossmann M Premaratne E Desai J Davis ID Thyrotoxicosis during sunitinib treatment for renal cell carcinoma Clin Endocrinol (Oxf) 2008 69 4 669 672 10.1111/j.1365-2265.2008.03253.x 18394019 \n4. Tamaskar I Bukowski R Elson P Ioachimescu AG Wood L Dreicer R Mekhail T Garcia J Rini BI Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib Ann Oncol 2008 19 2 265 268 10.1093/annonc/mdm483 17962201 \n5. Miyake H Kurahashi T Yamanaka K Kondo Y Muramaki M Takenaka A Inoue TA Fujisawa M Abnormalities of thyroid function in Japanese patients with metastatic renal cell carcinoma treated with sorafenib: a prospective evaluation Urol Oncol 2010 28 5 515 519 10.1016/j.urolonc.2009.08.011 19914105 \n6. Konca Degertekin C Coskun U Balos Toruner F Akturk M Demirci U Hyperthyroidism and thyroid autoimmunity induced by sorafenib in metastatic renal cell cancer Endocrine 2012 42 3 756 757 10.1007/s12020-012-9683-2 22562706 \n7. Kim TD Schwarz M Nogai H Grille P Westermann J Plockinger U Braun D Schweizer U Arnold R Dorken B Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia Thyroid 2010 20 11 1209 1214 10.1089/thy.2010.0251 20929406 \n8. de Groot JW Zonnenberg BA Plukker JT van Der Graaf WT Links TP Imatinib induces hypothyroidism in patients receiving levothyroxine Clin Pharmacol Ther 2005 78 4 433 438 10.1016/j.clpt.2005.06.010 16198662 \n9. de Groot JW Zonnenberg BA van Ufford-Mannesse PQ de Vries MM Links TP Lips CJ Voest EE A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma J Clin Endocrinol Metab 2007 92 9 3466 3469 10.1210/jc.2007-0649 17579194 \n10. Babacan T Sevinc A Akarsu E Balakan O Sunitinib-induced autoimmune thyroiditis in a patient with metastatic renal cell carcinoma: a case report Chemotherapy 2012 58 2 142 145 10.1159/000337086 22584361 \n11. Desai J Yassa L Marqusee E George S Frates MC Chen MH Morgan JA Dychter SS Larsen PR Demetri GD Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors Ann Intern Med 2006 145 9 660 664 10.7326/0003-4819-145-9-200611070-00008 17088579 \n12. Rini BI Tamaskar I Shaheen P Salas R Garcia J Wood L Reddy S Dreicer R Bukowski RM Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib J Natl Cancer Inst 2007 99 1 81 83 10.1093/jnci/djk008 17202116 \n13. Mannavola D Coco P Vannucchi G Bertuelli R Carletto M Casali PG Beck-Peccoz P Fugazzola L A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake J Clin Endocrinol Metab 2007 92 9 3531 3534 10.1210/jc.2007-0586 17595247 \n14. Illouz F Laboureau-Soares S Dubois S Rohmer V Rodien P Tyrosine kinase inhibitors and modifications of thyroid function tests: a review Eur J Endocrinol 2009 160 3 331 336 10.1530/EJE-08-0648 19103722 \n15. Ohba K Takayama T Matsunaga H Matsushita A Sasaki S Oki Y Ozono S Nakamura H Inappropriate elevation of serum thyrotropin levels in patients treated with axitinib Thyroid 2013 23 4 443 448 10.1089/thy.2012.0378 23157669 \n16. Daimon M Kato T Kaino W Takase K Karasawa S Wada K Kameda W Susa S Oizumi T Tomita Y Thyroid dysfunction in patients treated with tyrosine kinase inhibitors, sunitinib, sorafenib and axitinib, for metastatic renal cell carcinoma Jpn J Clin Oncol 2012 42 8 742 747 10.1093/jjco/hys076 22628612 \n17. Sherman SI Wirth LJ Droz JP Hofmann M Bastholt L Martins RG Licitra L Eschenberg MJ Sun YN Juan T Motesanib diphosphate in progressive differentiated thyroid cancer N Engl J Med 2008 359 1 31 42 10.1056/NEJMoa075853 18596272 \n18. Mohty M Blaise D Olive D Gaugler B Imatinib: the narrow line between immune tolerance and activation Trends Mol Med 2005 11 9 397 402 10.1016/j.molmed.2005.07.007 16087402 \n19. Seggewiss R Price DA Purbhoo MA Immunomodulatory effects of imatinib and second-generation tyrosine kinase inhibitors on T cells and dendritic cells: an update Cytotherapy 2008 10 6 633 641 10.1080/14653240802317639 18836918 \n20. Seliger B Massa C Rini B Ko J Finke J Antitumour and immune-adjuvant activities of protein-tyrosine kinase inhibitors Trends Mol Med 2010 16 4 184 192 10.1016/j.molmed.2010.02.001 20304705 \n21. Pani F Atzori F Baghino G Boi F Tanca L Ionta MT Mariotti S Thyroid Dysfunction in Patients with Metastatic Carcinoma Treated with Sunitinib: Is Thyroid Autoimmunity Involved? Thyroid 2015 25 11 10.1089/thy.2015.0170\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "16()",
"journal": "BMC cancer",
"keywords": "Auto-immune thyroid dysfunction; Chordoma; Tyrosine kinase inhibitors",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000970:Antineoplastic Agents; D002817:Chordoma; D006111:Graves Disease; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D000077157:Sorafenib",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "679",
"pmc": null,
"pmid": "27558389",
"pubdate": "2016-08-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23157669;16087402;16198662;20825302;19103722;20929406;22562706;17088579;22628612;20304705;17595247;18394019;22584361;21275767;17962201;17202116;26414109;18836918;18596272;19914105;17579194",
"title": "Auto-immune thyroid dysfunction induced by tyrosine kinase inhibitors in a patient with recurrent chordoma.",
"title_normalized": "auto immune thyroid dysfunction induced by tyrosine kinase inhibitors in a patient with recurrent chordoma"
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"activesubstancename": "IMATINIB"
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"abstract": "Prolintane is a sympathomimetic amine with pharmacologic properties similar to d-amphetamine. Side effects include insomnia, nervousness, and irritability. Overdoses of prolintane may cause hallucinations, psychosis, and death. The drug is commonly prescribed in Africa, Australia, and Europe but is not available in the United States. This manuscript reports the first medically documented cases of prolintane abuse in the United States. In the first, a 34-year-old male presented to the emergency department confused, agitated, and unable to follow commands. Initial drug and alcohol screens were negative, but analysis by gas chromatography-mass spectrometry (GC-MS) indicated the presence of amitriptyline, nortriptyline, nicotine, and prolintane. The second patient, a healthy 26-year-old female, presented to the emergency department after intrauterine fetal death and spontaneous delivery. GC-MS revealed the presence of multiple drugs, including cannabinoids, cocaine, nicotine, hydrocodone, and prolintane. The medical and scientific communities should be aware of the potential for prolintane abuse because it may cause symptoms similar to those of the amphetamines but is not likely to be detected by a routine urine drug screen.",
"affiliations": "Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA. pkyle@pathology.umsmed.edu",
"authors": "Kyle|Patrick B|PB|;Daley|William P|WP|",
"chemical_list": "D000697:Central Nervous System Stimulants; D011759:Pyrrolidines; C005598:prolintane",
"country": "England",
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"issue": "31(7)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D000697:Central Nervous System Stimulants; D062787:Drug Overdose; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D011759:Pyrrolidines; D011998:Recreation; D019966:Substance-Related Disorders; D014481:United States",
"nlm_unique_id": "7705085",
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"pages": "415-8",
"pmc": null,
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"pubdate": "2007-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Domestic abuse of the European rave drug prolintane.",
"title_normalized": "domestic abuse of the european rave drug prolintane"
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"abstract": "Retrobulbar hemorrhage is a vision-threatening emergency that may occur spontaneously or following facial trauma, orbital surgery, endoscopic sinus surgery, and retrobulbar injections. It may determine visual loss because of central retinal artery occlusion, optic neuropathy from direct compression, or compression of the circulation from mechanical tamponade. In addition to a deterioration in visual acuity with total blindness in the most severe cases, several symptoms and signs can be found, such as a sudden onset of severe pain, proptosis, and ophthalmoplegia.The knowledge of past medical history and underlying medical conditions is crucial in patients with retrobulbar hemorrhages. In fact, patients with blood dyscrasias have to be considered high-risk patients due to their increased propensity for uncontrolled bleeding.The aim of this article was to present and discuss the management of a case of double consecutive retrobulbar hemorrhage in a high-risk patient in treatment with aspirin and warfarin.",
"affiliations": "Division of Maxillofacial Surgery, Head and Neck Department, San Giovanni Battista Hospital, University of Turin, Turin, Italy.",
"authors": "Viterbo|Stefano|S|;Boffano|Paolo|P|;Guglielmi|Valeria|V|;Fasolis|Massimo|M|;Palumbo|Carlo|C|;Berrone|Sid|S|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D001241:Aspirin",
"country": "United States",
"delete": false,
"doi": "10.1097/SCS.0b013e31826701f0",
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"issn_linking": "1049-2275",
"issue": "23(6)",
"journal": "The Journal of craniofacial surgery",
"keywords": null,
"medline_ta": "J Craniofac Surg",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001241:Aspirin; D005131:Eye Injuries; D006801:Humans; D008297:Male; D019315:Retrobulbar Hemorrhage; D014057:Tomography, X-Ray Computed; D014859:Warfarin",
"nlm_unique_id": "9010410",
"other_id": null,
"pages": "1782-4",
"pmc": null,
"pmid": "23147322",
"pubdate": "2012-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Double consecutive retrobulbar hemorrhage in a high-risk patient in treatment with aspirin and warfarin.",
"title_normalized": "double consecutive retrobulbar hemorrhage in a high risk patient in treatment with aspirin and warfarin"
} | [
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"companynumb": "PHHY2014IT128309",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"abstract": "BACKGROUND\nIn patients with hepatitis C virus (HCV) and malignant lymphoma, hepatitis C flare during R-CHOP can result in discontinuation of treatment. However, appropriate therapeutic strategies for managing hepatitis C flare during R-CHOP have not been established, and this issue is complicated by conflicting results regarding the use of direct-acting antivirals in patients with uncontrolled malignancies.\n\n\nMETHODS\nWe report the first case of effective and safe treatment with on-demand 8-week glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in a patient with diffuse large B-cell lymphoma (DLBCL). The patient completed five additional courses of R-CHOP without hepatic toxicity. A complete response of DLBCL and a sustained virological response were observed at 24 weeks after glecaprevir and pibrentasvir completion.\n\n\nCONCLUSIONS\nOn-demand, direct-acting antivirals could be a novel strategy for managing hepatitis C flare during R-CHOP.",
"affiliations": "Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan. gsudgast@pop.med.hokudai.ac.jp.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.",
"authors": "Umemura|Machiko|M|;Suda|Goki|G|http://orcid.org/0000-0003-0098-9106;Tsukamoto|Shihori|S|;Ebata|Ko|K|;Takahash|Shinjiro|S|;Sasaki|Takashi|T|;Nakajima|Sae|S|;Hirata|Koji|K|;Ozasa|Mariko|M|;Takano|Masatoshi|M|;Katagiri|Masaki|M|;Sakamoto|Naoya|N|",
"chemical_list": "D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D001562:Benzimidazoles; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D011759:Pyrrolidines; D011810:Quinoxalines; C571759:R-CHOP protocol; D012367:RNA, Viral; D013449:Sulfonamides; C000622691:pibrentasvir; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011392:Proline; D007930:Leucine; C000612853:glecaprevir; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-021-06091-x",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6091\n10.1186/s12879-021-06091-x\nCase Report\nSuccessful treatment by on-demand glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in patients with diffuse large B-cell lymphoma: a case report\nUmemura Machiko 1\nhttp://orcid.org/0000-0003-0098-9106\nSuda Goki gsudgast@pop.med.hokudai.ac.jp\n\n12\nTsukamoto Shihori 1\nEbata Ko 1\nTakahash Shinjiro 1\nSasaki Takashi 1\nNakajima Sae 1\nHirata Koji 1\nOzasa Mariko 1\nTakano Masatoshi 1\nKatagiri Masaki 1\nSakamoto Naoya 2\n1 grid.415262.6 0000 0004 0642 244X Sapporo Hokuyu Hospital, Sapporo, Hokkaido Japan\n2 grid.39158.36 0000 0001 2173 7691 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido Japan\n27 4 2021\n27 4 2021\n2021\n21 38918 1 2021\n20 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/. 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\nIn patients with hepatitis C virus (HCV) and malignant lymphoma, hepatitis C flare during R-CHOP can result in discontinuation of treatment. However, appropriate therapeutic strategies for managing hepatitis C flare during R-CHOP have not been established, and this issue is complicated by conflicting results regarding the use of direct-acting antivirals in patients with uncontrolled malignancies.\n\nCase presentation\n\nWe report the first case of effective and safe treatment with on-demand 8-week glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in a patient with diffuse large B-cell lymphoma (DLBCL). The patient completed five additional courses of R-CHOP without hepatic toxicity. A complete response of DLBCL and a sustained virological response were observed at 24 weeks after glecaprevir and pibrentasvir completion.\n\nConclusion\n\nOn-demand, direct-acting antivirals could be a novel strategy for managing hepatitis C flare during R-CHOP.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12879-021-06091-x.\n\nKeywords\n\nGlecaprevir\nHepatitis C virus\nPibrentasvir\nDirect-acting antiviral, hepatitis C flare\nhttp://dx.doi.org/10.13039/100009619 Japan Agency for Medical Research and Development JP20fk0210072, JP20fk0210047 Suda Goki issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nGlobally, hepatitis C virus (HCV) remains a major cause of hepatocellular carcinoma and liver-related deaths. HCV infection can cause extrahepatic disorders, including lichen planus, diabetes mellitus, renal dysfunction, and lymphoma [1].\n\nRecently developed direct-acting antivirals (DAAs) have improved the efficacy and safety of anti-HCV therapy compared with interferon-based therapy. Several basic studies, clinical trials, and real-world studies have shown that DAA therapy is highly safe and effective, with minimal drug–drug interactions [2–4]. However, anti-HCV treatment for patients with advanced malignancies remains controversial. DAA treatment is contraindicated in HCV-infected patients with uncontrolled malignancies [5]. In addition, there are no guidelines for the timing of DAA administration with respect to the individual anti-tumor treatment schedule in patients with HCV and cancer. Further, the indications for DAA treatment with these cases remain unknown [5].\n\nHCV infection is associated with lymphoma, especially diffuse large B-cell non-Hodgkin lymphoma and HCV-associated indolent B-cell non-Hodgkin lymphomas [1, 6]. After HCV eradication by anti-HCV therapy, indolent B-cell non-Hodgkin lymphoma regression, especially in marginal zone lymphomas, is sometimes observed, suggesting a link between HCV and lymphoma progression [1, 6, 7]. Compared with non-HCV-positive diffuse large B-cell lymphoma (DLBCL) patients, HCV-positive DLBCL patients were reported to have different characteristics, including elevated LDH and old age [8, 9]. High HCV-RNA viral load is associated with a worse prognosis in patients with diffuse large B-cell lymphoma (DLBCL) [10] and HCV infection causes liver cirrhosis and hepatocellular carcinoma; thus, if possible, proper treatment is required. During standard therapies, including high rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) for DLBCL, a total of 14–28% of patients experienced grade 3–4 hepatic toxicity [9, 11]. Thus, patients with DLBCL and HCV infection administered with R-CHOP may require careful monitoring for hepatic toxicity, as well as proper management; however, to our best knowledge, no study has evaluated the more recent DAAs; glecaprevir and pibrentasvir for hepatitis C flares during R-CHOP.\n\nHere, we describe successful HCV treatment by on-demand gearlever and pivrentasvir, which is initiated only when hepatic C flare is observed during R-CHOP therapy, in an HCV-infected patient with DLBCL.\n\nCase presentation\n\nCase\n\nA 48-year-old man presented to our hospital for cervical lymph node swelling (Supplementary Fig. 1). Cervical lymph node biopsy showed diffuse large cells infiltration in lymphoid follicles. Immunohistochemical staining showed that the large atypical cells were positive for CD20 and CD79a and negative for CD3, bcl-2, bcl-6, and cyclinD1. Ki-67 LI values were graded as more than 90%. In situ hybridization for EBV RNA using the EBER probe showed positive labeling in almost all the atypical cells. Those findings led to the diagnosis of EBV-positive DLBCL, NOS, activated B-cell subtype. Systemic examination, including PET-CT, revealed that the Ann Arbor classification was stage IVA since the mass has spread in the lung and cervical and abdominal lymph nodes.\n\nTable 1 shows the results of blood tests and virological examinations. The International Prognostic Index (IPI), Revised IPI, and the National Comprehensive Cancer Network (NCCN) IPI showed low, good, and low–intermediate risk, respectively. The treatment regimen for the patient was first-line chemotherapy with six courses of R-CHOP. Table 1 Result of blood and urine tests performed before R-CHOP therapy\n\nParameter\tValue\tUnit\tReference value\tParameter\tValue\tUnit\tReference value\tParameter\tValue\tUnit\tReference value\t\nBlood cell count\tBiochemistry\tImmunology\t\nWBC\t4720\t× 103/μL\t\tTP\t9.0\tmg/dL\t6.5–8.2\tCRP\t0.79\tmg/dL\t< 0.30\t\nSt\t0\t%\t0.0–19.0\tAlb\t3.6\tmg/dL\t3.7–5.5\tIgG\t2532\tmg/dL\t820–1740\t\nSeg\t89\t%\t27.0–72.0\tα1\t3.6\t%\t1.7–2.9\tIgA\t457\tmg/dL\t90–4000\t\nLy\t6\t%\t18.0–50.0\tα2\t10.5\t%\t5.7–9.5\tIgM\t96\tmg/dL\t31–200\t\nMo\t5\t%\t1.0–8.0\tβ\t10.0\t%\t7.2–11.1\tHBsAb\t(−)\t\t(−)\t\nEo\t0\t%\t0.0–7.0\tγ\t29.5\t%\t10.2–20.4\tHBcAb\t(−)\t\t(−)\t\nBa\t0\t%\t0.0–2.0\tBUN\t13\tmg/ dl\t8.0–20.0\tHBV-DNA\t(−)\t\t(−)\t\nRBC\t5\t×106/μL\t4.38–5.77\tCre\t1\tmg/ dl\t0.65–1.09\tHCV Ab\t(+)\t\t(−)\t\nHb\t15\tg/dL\t13.6–18.3\tT-bil\t0.4\tmg/dL\t0.3–1.2\tHCV-RNA\t2.0\tLIU/ mL\t(−)\t\nHt\t\t%\t40.4–51.9\tD-bil\t0.1\tmg/dL\t< 0.4\tHCV serotype\tGroup2\t\t(−)\t\nPlt\t295\t×103/μL\t14.0–37.9\tAST\t23\tU/L\t10–40\tHIV Ab\t(−)\t\t(−)\t\n\t\t\t\tALT\t19\tU/L\t5–45\tHTLV-1 Ab\t(−)\t\t(−)\t\nCoagulation\tLDH\t211\tU/L\t120–245\t\t\t\t\t\nPT\t12\tsec\t10.0–13.0\tALP\t238\tU/L\t104–338\tTumor Marker\t\nPT%\t99\t%\t80.0–120.0\tγ-GTP\t104\tU/L\t< 79\tβ2MG\t2.5\tmg/ L\t0.9–1.9\t\nPT-INR\t1.01\tratio\t0.90–1.13\tChE\t305\tU/L\t245–495\tsIL-2R\t1753\tU/ mL\t\t\nAPTT\t28\tsec\t26.0–38.0\tCPK\t53\tU/L\t50–230\tSP-D\t169.3\tng/ mL\t< 110.0\t\nFib\t304\tmg/dL\t170–410\t\t\t\t\t\t\t\t\t\nAb antibody, Ag antigen, sIL-2R soluble IL-2 recepter, β2-MG β2-microglobulin\n\nThe patient was previously diagnosed with HCV infection, with no treatment history for the infection and a history of injecting drug use more than 10 years ago. As shown in Table 1, the HCV genotype was 2, and the HCV-RNA viral load was 2 log IU/mL. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, PT%, and albumin levels were all within normal ranges and ultrasound and computer tomography imaging did not show liver cirrhosis (Supplementary Fig. 1). In a previous study [12], HCV flare was defined as an increase in HCV-RNA of ≥1 log10 IU/mL compared with baseline values and hepatitis flare as an increase in ALT to ≥3 times the upper limit of the normal value.\n\nFig. 1 shows the clinical course for this patient after the initiation of R-CHOP. HCV-RNA levels increased rapidly from 2.0 log10 IU/mL at baseline to 5.0 log10 IU/mL 9 days after the initiation of the first course of R-CHOP. AST and ALT levels increased rapidly from normal baseline values to 146 U/L and 181 U/L 9 days after R-CHOP initiation and 162 U/L and 245 U/L (CATCAE v5.0, grade 3) at 12 days after R-CHOP initiation, respectively. Based on these findings, the patient was diagnosed with HCV flare and hepatitis flare due to R-CHOP. We initiated 8 weeks of glecaprevir and pibrentasvir for the HCV flare and hepatitis flare 13 days after R-CHOP initiation. As shown in Fig. 1, HCV-RNA decreased rapidly from 5.0 log10 IU/mL on day 9 to 2.5 log10 IU/mL on day 14. AST and ALT decreased rapidly from 162 U/L and 245 U/L on day 12 to 22 U/L and 96 U/L on day 17, respectively (Fig. 1). Fig. 1 Virologic response and clinical course of glecaprevir and pibrentasvir therapy for HCV and hepatitis flare during R-CHOP for DLBCL. Changes in the serum hepatitis C virus (HCV) titer, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) are shown. HCV, hepatitis C virus; ALT, alanine transaminase\n\nOn day 24, when the second course of R-CHOP was initiated, AST and ALT levels normalized and HCV-RNA became undetectable by RT-PCR. The patient completed the 8-week glecaprevir (300 mg/day) and pibrentasvir (120 mg/day) treatment and achieved a sustained virological response at 24 weeks after its completion, without remarkable adverse events.\n\nAfter the initiation of glecaprevir and pibrentasvir, the patient did not experience hepatic toxicity during the remaining five courses of R-CHOP. Enhanced computed tomography after six courses of R-CHOP revealed a complete response in DLBCL.\n\nDiscussion and conclusions\n\nRecently, several studies have reported the efficacy and safety of concurrent or subsequent anti-HCV therapy in immunochemotherapy (I-CT), including R-CHOP for patients with HCV and malignant lymphoma. Concurrent or upfront concomitant DAAs and I-CT are potential therapeutic approaches [12, 13]; however, a limited number of patients have been treated with I-CT and concurrent DAAs. In addition, anti-HCV treatment for patients with advanced malignancies remains controversial, and DAA treatment is contraindicated in patients with HCV and uncontrolled malignancies [5]. Thus, in general practice, R-CHOP is used without concurrent DAAs for HCV-infected patients with malignant lymphoma.\n\nAdministration of DAAs following I-CT—including R-CHOP—is highly safe and effective based on studies involving a relatively large number of patients [12, 13]. However, in the initial I-CT, 60% (23/38) and 18% (7/38) of patients experience any grade of hepatic toxicity and severe hepatic toxicity, respectively [13]. Similarly, Zaky et al. have reported that in HCV-infected patients with lymphoma, R-CHOP causes severe hepatic toxicity at a high rate of 28% (19/68) and that these hepatic toxicities lead to the modification and discontinuation of I-CT, resulting in poor responses to treatment [11]. Thus, the management of hepatic toxicity during R-CHOP in HCV-infected patients with malignant lymphoma is a crucial issue requiring clarification. To the best of our knowledge, the present case is the first evidence for the safety and efficacy of on-demand glecaprevir and pibrentasvir therapy for hepatitis C flare, thereby enabling further R-CHOP without hepatic toxicity. Thus, in addition to concurrent or upfront concomitant DAAs and I-CT, this “on demand” DAAs therapy might be promising approach.\n\nThere have been recent reports of HCV reactivation in patients receiving anti-malignancy therapy. In a prospective study, HCV reactivation occurred in 23% (23/100) of patients with HCV infection who were treated with anti-cancer therapy. In addition, of 23 patients with HCV reactivation, 10 patients experienced hepatitis flare, in some cases requiring the discontinuation of the anti-cancer treatment. A multivariate analysis revealed that rituximab and high-dose steroids are significantly associated with HCV reactivation [14]. Thus, R-CHOP, which involves rituximab and high-dose steroids, is considered a high-risk anti-cancer treatment. Moreover, Zaky et al. reported that in patients with DLBCL and HCV infection, R-CHOP is associated with severe hepatic toxicity and shows a high rate of discontinuation. In addition, significantly higher serum HCV-RNA levels after treatment initiation have been observed in patients treated with R-CHOP compared to those treated with CHOP [11].\n\nAs described previously, although Deming et al. proposed that DAA treatment is contraindicated in patients with HCV and uncontrolled malignancies, they recommended it in patients with stable cancers or those in remission for at least 3–6 months after cancer treatment [5]. Insufficient cancer therapy might cause poor outcomes; thus, to avoid discontinuation or dose reduction of cancer therapy, we hypothesized that on-demand glecaprevir and pibrentasvir are potential options. Recent favorable treatment outcomes of concurrent DAAs and I-CT for patients with malignant lymphoma and HCV infection [12, 13, 15] support this strategy. Glecaprevir and pibrentasvir are more recent DAAs and approved in many countries (Supplementary Table 1). In Japan, the combined administration of vincristine and glecaprevir and pivrentasvir is not a “precaution for co-administration” and “contraindication for concomitant use” refer to its package insert (https://aconnect.abbvie.co.jp//media/assets/pdf/products/maviret/Maviret_tmpDocument.pdf); however, vincristine is a substrate of P-glycoprotein (P-gp) and concentrations may increase due to inhibition of Pgp by glecaprevir and pivrentasvir and might cause adverse events. Additionally, there is no study regarding combined administration of vincristine and glecaprevir and pivrentasvir; thus, to ensure its safe use, further analysis is warranted. Merli et al. reported nine cases of concurrent administration of DAAs and I-CT. The DAAs regimen of the nine cases consisted of one case of sofobuvir and ribavirin, three cases of sofosbuvir and ledipasvir, and five cases of sofosbuvir and daclatasvir [13]. The safe use of sofosbuvir-based therapies has been reported; thus, these therapies could be used as alternatives for gelcaprevir and pibrentasvir. However, these therapies are adapted to limited HCV genotypes and required longer treatment duration than glecaprevir and pibrentasvir. Thus, further study is warranted.\n\nSeveral reports have shown that anti-HCV therapy with both IFN and DAAs could improve overall survival or disease-free survival in HCV-infected patients with malignant lymphoma, and HCV infection cause liver cirrhosis and hepatocellular carcinoma [15–17]. Thus, DAA therapy for HCV-infected patients with malignant lymphoma should be considered, with cost and insurance issues varying in each country.\n\nIn the present case, after one course of R-CHOP, increases in ALT and HCV-RNA were observed. HCV-RNA increased 1000-fold over baseline levels 9 days after treatment initiation. An immune response to virus-infected hepatocytes is a common cause of viral hepatitis. However, our previous in vitro and in vivo analyses had shown that rapid increases in HCV cause hepatic toxicity [18]. Thus, in this case, in addition to an immune response to virus-infected hepatocytes, as a potential hypothesis, a rapid increase in HCV might cause hepatic toxicity.\n\nAfter 2 days of glecaprevir and pibrentasvir administration, our patient’s HCV-RNA levels decreased rapidly (a nearly 2.5 decrease); thus, glecaprevir and pibrentasvir showed immediate suppressive effects on HCV replication. This might result in immediate attenuation of hepatic toxicity. Glecaprevir or pibrentasvir monotherapy could decrease HCV-RNA levels by nearly 3 log 24 h after treatment initiation [19]; thus, our patient’s clinical course might be reasonable. Glecaprevir and pibrentasvir have a highly potent anti-HCV ability and induce a shorter treatment duration than previous DAA treatments; this combination might be suitable in R-CHOP-induced HCV flare and subsequent hepatitis.\n\nThis case report has a few limitations. Some clinical data, including fibroscan data, were lacking. Additionally, the safety regarding drug-drug interaction between R-CHOP and glecaprevir and pibrentasvir remains unclear. Thus, these should be considered when interpreting the case report results, and a prospective study with a large sample is required to validate the findings.\n\nIn conclusion, on-demand glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in HCV-infected patients with malignant lymphoma might be safe and effective.\n\nSupplementary Information\n\nAdditional file 1: Supplementary Fig. 1. Imaging of Cervical lymph nodes and liver. Cervical lymph nodes (a) on CT and (b) on PET-CT. (c) Hepatic image on CT.\n\nAdditional file 2: Supplementary Table 1. Glecaprevir and piverentasvir approved countries (at March 2021)\n\nAbbreviations\n\nR-CHOP Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone\n\nALT Alanine aminotransferase\n\nAST Aspartate aminotransferase\n\nHCV Hepatitis C virus\n\nDAAs Direct-acting antivirals\n\nDLBCL Diffuse large B-cell lymphoma\n\nThis study was supported by the Japan Agency for Medical Research and Development (AMED; grant number JP20fk0210072, JP20fk0210047). The authors want to thank all the patients and their families, as well as the investigators and staff of the participating institutions and the NORTE study group.\n\nAuthors’ contributions\n\nMU and GS contributed equally to this work. MU and GS designed this case study and wrote the manuscript. TS, SN, KH, MO, MT, and MK collected the data. NS provided hepatological advice and edited the manuscript. ST, KE, ST, and NS revised the manuscript for important intellectual content. All authors have read and approved the manuscript\n\nFunding\n\nThis research was funded by the Platform Project for Supporting in Drug Discovery and Life Science Research from Japan Agency for Medical Research and Development (AMED) (grant number JP20fk0210072, JP20fk0210047). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nAvailability of data and materials\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent to publish this case report was obtained from the patient.\n\nCompeting interests\n\nProfessor Naoya Sakamoto received research grants from Gilead Sciences Inc. and AbbVie Inc. Dr. Goki Suda received research grants from Bristol Myers Squibb and MSD K.K.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nMachiko Umemura and Goki Suda contributed equally to this work.\n==== Refs\nReferences\n\n1. Gill K Ghazinian H Manch R Gish R Hepatitis C virus as a systemic disease: reaching beyond the liver Hepatol Int 2016 10 3 415 423 10.1007/s12072-015-9684-3 26660706\n2. Zeuzem S Foster GR Wang S Asatryan A Gane E Feld JJ Asselah T Bourliere M Ruane PJ Wedemeyer H Glecaprevir-Pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection N Engl J Med 2018 378 4 354 369 10.1056/NEJMoa1702417 29365309\n3. Kowdley KV Gordon SC Reddy KR Rossaro L Bernstein DE Lawitz E Shiffman ML Schiff E Ghalib R Ryan M Rustgi V Chojkier M Herring R di Bisceglie AM Pockros PJ Subramanian GM An D Svarovskaia E Hyland RH Pang PS Symonds WT McHutchison JG Muir AJ Pound D Fried MW Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis N Engl J Med 2014 370 20 1879 1888 10.1056/NEJMoa1402355 24720702\n4. Suda G Furusyo N Toyoda H Kawakami Y Ikeda H Suzuki M Arataki K Mori N Tsuji K Katamura Y Takaguchi K Ishikawa T Tsuji K Shimada N Hiraoka A Yamsaki S Nakai M Sho T Morikawa K Ogawa K Kudo M Nagasaka A Furuya K Yamamoto Y Kato K Ueno Y Iio E Tanaka Y Kurosaki M Kumada T Chayama K Sakamoto N Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan J Gastroenterol 2018 53 1 119 128 10.1007/s00535-017-1353-y 28560477\n5. Torres HA Pundhir P Mallet V Hepatitis C virus infection in patients with Cancer: impact on clinical trial enrollment, selection of therapy, and prognosis Gastroenterology 2019 157 4 909 916 10.1053/j.gastro.2019.01.271 30797794\n6. Arcaini L Besson C Frigeni M Fontaine H Goldaniga M Casato M Visentini M Torres HA Loustaud-Ratti V Peveling-Oberhag J Fabris P Rossotti R Zaja F Rigacci L Rattotti S Bruno R Merli M Dorival C Alric L Jaccard A Pol S Carrat F Ferretti VV Visco C Hermine O Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection Blood 2016 128 21 2527 2532 10.1182/blood-2016-05-714667 27605512\n7. Frigeni M Besson C Visco C Fontaine H Goldaniga M Visentini M Pulsoni A Torres HA Peveling-Oberhag J Rossotti R Zaja F Rigacci L Merli M Dorival C Alric C Piazza F Gentile M Ferrari A Pirisi M Nassi L Rattotti S Frustaci A Milella M Cencini E Defrancesco I Ferretti VV Bruno R Hermine O Arcaini L Interferon-free compared to interferon-based antiviral regimens as first-line therapy for B-cell lymphoproliferative disorders associated with hepatitis C virus infection Leukemia 2020 34 5 1462 1466 10.1038/s41375-019-0687-2 31836855\n8. Visco C Arcaini L Brusamolino E Burcheri S Ambrosetti A Merli M Bonoldi E Chilosi M Viglio A Lazzarino M Pizzolo G Rodeghiero F Distinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy Ann Oncol 2006 17 9 1434 1440 10.1093/annonc/mdl131 16766591\n9. Visco C Finotto S Hepatitis C virus and diffuse large B-cell lymphoma: pathogenesis, behavior and treatment World J Gastroenterol 2014 20 32 11054 11061 10.3748/wjg.v20.i32.11054 25170194\n10. Merli M Visco C Spina M Luminari S Ferretti VV Gotti M Rattotti S Fiaccadori V Rusconi C Targhetta C Stelitano C Levis A Ambrosetti A Rossi D Rigacci L D'Arco AM Musto P Chiappella A Baldini L Bonfichi M Arcaini L Outcome prediction of diffuse large B-cell lymphomas associated with hepatitis C virus infection: a study on behalf of the Fondazione Italiana Linfomi Haematologica 2014 99 3 489 496 10.3324/haematol.2013.094318 24270404\n11. Zaky AH Bakry R El-sayed MI Elwanis MA Nabih O Impact of treatment-related toxicity on outcome of HCV-positive diffuse large B-cell lymphoma in rituximab era Hematology 2014 19 7 412 416 10.1179/1607845413Y.0000000147 24620947\n12. 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Mishima K Sakamoto N Sekine-Osajima Y Nakagawa M Itsui Y Azuma S Kakinuma S Kiyohashi K Kitazume A Tsuchiya K Imamura M Hiraga N Chayama K Wakita T Watanabe M Cell culture and in vivo analyses of cytopathic hepatitis C virus mutants Virology 2010 405 2 361 369 10.1016/j.virol.2010.06.020 20609455\n19. Lawitz EJ O'Riordan WD Asatryan A Freilich BL Box TD Overcash JS Lovell S Ng TI Liu W Campbell A Lin CW Yao B Kort J Potent antiviral activities of the direct-acting antivirals ABT-493 and ABT-530 with three-day Monotherapy for hepatitis C virus genotype 1 infection Antimicrob Agents Chemother 2015 60 3 1546 1555 10.1128/AAC.02264-15 26711747\n\n",
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"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "Direct-acting antiviral, hepatitis C flare; Glecaprevir; Hepatitis C virus; Pibrentasvir",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000621:Aminoisobutyric Acids; D000971:Antineoplastic Combined Chemotherapy Protocols; D000998:Antiviral Agents; D001562:Benzimidazoles; D003520:Cyclophosphamide; D003521:Cyclopropanes; D004317:Doxorubicin; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D047029:Lactams, Macrocyclic; D007930:Leucine; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011392:Proline; D011759:Pyrrolidines; D011810:Quinoxalines; D012367:RNA, Viral; D000069283:Rituximab; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D014750:Vincristine; D019562:Viral Load",
"nlm_unique_id": "100968551",
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"pages": "389",
"pmc": null,
"pmid": "33906643",
"pubdate": "2021-04-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24270404;16766591;30552159;26712592;30797794;24720702;25170194;29365309;28653760;28560477;24620947;28714143;26660706;32343165;26711747;27605512;31836855;20609455;27501007",
"title": "Successful treatment by on-demand glecaprevir and pibrentasvir for hepatitis C flare during R-CHOP in patients with diffuse large B-cell lymphoma: a case report.",
"title_normalized": "successful treatment by on demand glecaprevir and pibrentasvir for hepatitis c flare during r chop in patients with diffuse large b cell lymphoma a case report"
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"abstract": "Linezolid is an oxazolidinone antibacterial agent indicated for serious gram-positive infections. Only minor adverse effects were seen in phase III trials. However, more serious adverse effects were reported after commercial release, including cases of lactic acidosis, peripheral and optic neuropathy, and serotonin syndrome. Peripheral and optic neuropathy was usually seen after several months of linezolid therapy (median 5 mo), lactic acidosis after several weeks (median 6 wks), and serotonin syndrome after several days (median 4 days). Death occurred in two of seven reported cases of lactic acidosis, and three of 15 reported cases of serotonin syndrome. Improvement or complete recovery occurred in all cases of optic neuropathy, whereas complete recovery failed to occur in any patient with peripheral neuropathy. Linezolid should be discontinued immediately in patients experiencing these adverse effects. Patients receiving linezolid for more than 28 days should be monitored for signs of peripheral and optic neuropathy.",
"affiliations": "Infectious Disease Section, University of Pittsburgh, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15240, USA.",
"authors": "Narita|Masashi|M|;Tsuji|Brian T|BT|;Yu|Victor L|VL|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D017367:Serotonin Uptake Inhibitors; D000069349:Linezolid",
"country": "United States",
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"doi": "10.1592/phco.27.8.1189",
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"issue": "27(8)",
"journal": "Pharmacotherapy",
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"abstract": "Antibody-mediated rejection (AMR) is not uncommon after renal transplantation and is harder to handle compared to cell-mediated rejection. When refractory to conventional therapies, rituximab is an attractive option. This study aims to examine the effectiveness of rituximab in refractory late acute AMR. This is a retrospective study involving nine renal transplant recipients. Four doses of rituximab were administered at weekly interval for 4 weeks, at a dose of 375 mg/m2. The mean age of patients was 35.3 ± 7.38 years. The median period between transplantation and graft dysfunction was 30 ± 20 months. Mean serum creatinine at the time of discharge after transplantation and at the time of acute AMR diagnosis was 1.14 ± 0.19 mg/dl and 2.26 ± 0.57 mg/dl, respectively. After standard therapy, it was 2.68 ± 0.62 mg/dl. One patient died of Pseudomonas sepsis and three patients progressed to end-stage renal disease (ESRD). Four biopsies showed significant plasma cell infiltrations. Mean serum creatinine among non-ESRD patients at the end of 1 year progressed from 2.3 ± 0.4 to 3.8 ± 1.2 mg/dl (P value 0.04). eGFR prior to therapy and at the end of 1 year were 34.4 ± 6.18 and 20.8 ± 7.69 ml/min (P value 0.04), respectively. Only one patient showed improvement in graft function in whom donor-specific antibody (DSA) titers showed significant improvement. Rituximab may not be effective in late acute AMR unlike in early acute AMR. Monitoring of DSA has a prognostic role in these patients and plasma cell rich rejection is associated with poor prognosis.",
"affiliations": "Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.;Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.;Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.;Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.;Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.;Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.",
"authors": "Surendra|M|M|;Raju|S B|SB|;Raju|N|N|;Chandragiri|S|S|;Mukku|K K|KK|;Uppin|M S|MS|",
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"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-26-31710.4103/0971-4065.177207Original ArticleRituximab in the treatment of refractory late acute antibody-mediated rejection: Our initial experience Surendra M. Raju S. B. Raju N. Chandragiri S. Mukku K. K. Uppin M. S. 1Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India1 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, IndiaAddress for correspondence: Dr. S. B. Raju, Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad - 500 082, Telangana, India. E-mail: sreebhushan@hotmail.com9 2016 26 5 317 321 Copyright: © Indian Journal of Nephrology2016This 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.Antibody-mediated rejection (AMR) is not uncommon after renal transplantation and is harder to handle compared to cell-mediated rejection. When refractory to conventional therapies, rituximab is an attractive option. This study aims to examine the effectiveness of rituximab in refractory late acute AMR. This is a retrospective study involving nine renal transplant recipients. Four doses of rituximab were administered at weekly interval for 4 weeks, at a dose of 375 mg/m2. The mean age of patients was 35.3 ± 7.38 years. The median period between transplantation and graft dysfunction was 30 ± 20 months. Mean serum creatinine at the time of discharge after transplantation and at the time of acute AMR diagnosis was 1.14 ± 0.19 mg/dl and 2.26 ± 0.57 mg/dl, respectively. After standard therapy, it was 2.68 ± 0.62 mg/dl. One patient died of Pseudomonas sepsis and three patients progressed to end-stage renal disease (ESRD). Four biopsies showed significant plasma cell infiltrations. Mean serum creatinine among non-ESRD patients at the end of 1 year progressed from 2.3 ± 0.4 to 3.8 ± 1.2 mg/dl (P value 0.04). eGFR prior to therapy and at the end of 1 year were 34.4 ± 6.18 and 20.8 ± 7.69 ml/min (P value 0.04), respectively. Only one patient showed improvement in graft function in whom donor-specific antibody (DSA) titers showed significant improvement. Rituximab may not be effective in late acute AMR unlike in early acute AMR. Monitoring of DSA has a prognostic role in these patients and plasma cell rich rejection is associated with poor prognosis.\n\nKey words\nDonor-specific antibodylate acute antibody mediated rejectionplasma cell rich rejectionrituximab\n==== Body\nIntroduction\nAcute antibody-mediated rejection (AMR) is characterized by acute graft dysfunction, histologic evidence of acute tissue injury, deposition of C4d in peritubular capillaries, and the presence of donor-specific antibodies (DSAs).[1234] Acute AMR can be arbitrarily divided into early (occurring within 6 months of renal transplantation) or late (occurring after 6 months of renal transplantation).[5]\n\nAn accurate diagnosis of AMR in allograft dysfunction is important since the management is different as compared to cell-mediated rejection and it needs to be treated aggressively. In the last decade, our knowledge about AMR, both acute and chronic, has greatly evolved[67] as a result of remarkable improvements in the technology of anti-human leukocyte antigen antibody detection. The concept of AMR is now well defined,[89] with specific diagnostic criteria laid down by the Banff group and with regular updates of the Banff classification.[24]\n\nInternational guidelines suggest the use of plasma exchange (PE), intravenous immunoglobulin (IVIG), rituximab, or lymphocyte-depleting antibodies for acute AMR.[10] Rituximab is an attractive option when it is refractory to conventional therapies such as pulse steroids, IVIGs, and PE. The effectiveness of rituximab in early AMR has been emphasized in literature.[11] Rituximab is a chimeric antibody recognizing the cell surface marker CD20, which is expressed at most stages of B-cell development except the very early stages but not on plasma cells.[12] However, its role in late acute antibody-mediated rejection is not well studied, especially in the Indian scenario. In this study, we put forward our experience in treating refractory late AMRs with rituximab.\n\nMaterials and Methods\nThis was a retrospective study involving 9 patients diagnosed with late acute AMR between 1st August 2013 and 31st July 2014, which were resistant to standard therapy (steroid/PE/IVIG). All these patients received rituximab as per protocol and the 1 year outcome of graft function; graft survival and patient survival were evaluated.\n\nInclusion criteria\nPatients who were diagnosed to have acute AMR according to the Banff 07 update[2] were included in the study.\n\n\nAMR was defined as a triad involving the presence of DSA, positive C4d-staining of the biopsy in peritubular capillaries and histopathological evidence of antibody-mediated injury (glomerulitis, peritubular capillaritis, and arteritis)\n\nAcute AMR of late onset (occurrence of AMR after 6 months of transplantation)\n\nAMR refractory to standard treatment, defined as the deterioration of graft function after receiving 1 gram of methyl prednisolone for 3 consecutive days followed by 7 sessions of PE and 7 doses of low dose IVIG on alternate days\n\nPatients who were willing to receive rituximab after ruling out contraindications for rituximab administration.\n\n\n\n\nDSA mean fluorescence intensity (MFI) values >500 were considered significant. We included only those biopsies with diffuse C4d in peritubular capillaries detected by immunohistochemistry and those showing features of glomerulitis plus endothelitis plus peritubular capillaritis without any evidence of chronicity.\n\nPE was done with 20% salt-poor albumin as replacement fluid and 1.5 times the plasma volume was replaced. Prothrombin time and activated partial thromboplastin time was monitored.\n\nEvery session of PE was followed by low dose IVIG (100 mg/kg/dose) on the next day. After administration of three doses of one gram of methyl Prednisolone for three consecutive days, oral Prednisolone was started at a dose of 20 mg/day that is tapered to 10 mg/day over 3 months. Mycophenolate mofetil sodium was increased to 720 mg twice daily and continued at the same dose in all patients, and it was discontinued at the time of initiation of dialysis in those patients who reached end-stage renal disease (ESRD). Tacrolimus dose was not changed as serum drug levels were within normal range and continued in all patients and it was discontinued at the time of initiation of dialysis in those patients who reached ESRD.\n\nA total of eleven patients met the diagnostic criteria for late acute AMR in the study period. Two patients were not willing to receive rituximab, after explaining the protocol and complications of rituximab and hence were not included in the study.\n\nAfter obtaining the informed consent, nine patients were initiated on the rituximab protocol. All the baseline characteristics were recorded, as shown in Table 1. Four doses of rituximab were administered at weekly intervals for 4 weeks at a dosage of 375 mg/m2. We evaluated the graft survival, patient survival and graft function at the end of 1 year along with other demographic features. Graft function and graft survival were monitored by serum creatinine and GFR measured by the MDRD formula.\n\nTable 1 Baseline characteristics of study population\n\nStatistical analysis\nAll results were expressed as mean ± standard deviation for continuous variables. Student's t-test was used to compare graft function before and after initiation of rituximab. P < 0.05 was considered significant.\n\nResults\nIn our study, the mean age of patients was 35.3 ± 7.38 years. Seven of nine patients were men. Average posttransplant duration prior to rejection was 30 ± 20 months. All were live related transplants, and none of the patients received induction therapy. Mean serum creatinine at the time of discharge after transplantation and at the time of acute AMR diagnosis was 1.14 ± 0.19 mg/dl and 2.26 ± 0. 57 mg/dl, respectively.\n\nAfter standard therapy, it was 2.68 ± 0.62 mg/dl (2.3 ± 0.4 mg/dl in patients who survived and did not reach ESRD at the end of 1 year). All the patients received rituximab according to the dose mentioned. Mean GFR measured by the MDRD formula before initiation of rituximab was 29.55 ± 7.76 ml/min (34.4 ± 6.18 ml/min in those patients who survived and did not reach ESRD at the end of 1 year). Five of these patients had a history of noncompliance and all to mycophenolate mofetil sodium. Renal biopsies of four patients showed rich plasma cell infiltrate in the interstitium and were classified as plasma cell rich-AMR.\n\nFollow-up\nThree patients progressed to ESRD at the end of 4 months, 6 months and 10 months and are on maintenance hemodialysis (MHD) [Table 2]. One patient died of Pseudomonas sepsis after 2 months of therapy. Serum creatinine prior to sepsis episode was 4.2 mg/dl and at the time of death was 5.1 mg/dl. Only one patient showed improvement in graft function, with a stable creatinine of 1.9 mg/dl, whereas, in the remaining patients graft function worsened over 1 year. Assessment of graft function in 5 patients who were alive and did not progress to ESRD also showed deterioration at the end of 1 year, which is statistically significant. The mean serum creatinine progressed from 2.3 ± 0.4 to 3.8 ± 1.2 mg/dl (P value 0.04). Mean GFR, measured by the MDRD formula before initiation of rituximab and, at the end of 1 year was 34.4 ± 6.18 ml/min and 20.8 ± 7.69 ml/min (P value 0.04). DSA Class I antibody was positive in one patient, Class II in six patients and both Class I and Class II were positive in two patients. At the end of 1 year, only one patient showed negative DSA titers and, this was the only patient who showed improvement in graft function (patient 1).\n\nTable 2 Follow-up data of patient population\n\nOf four patients who had plasma cell rich rejection, three had graft loss. Three patients developed complications related to rituximab such as pseudomonas sepsis (patient died), CMV disease, and cardiac dysfunction.\n\nDiscussion\nAcute AMR can be early (occurring within 6 months of renal transplantation) or late (occurring more than 6 months after renal transplantation). The beneficial role of rituximab is well documented in few case series/case reports. However, the majority of these studies are of early acute AMR. In the present study, we examined the role of rituximab in late acute AMR patients.\n\nBecker et al. used a single dose of rituximab to treat 27 patients with AMR.[13] At a mean of 605 days of follow-up, only three grafts were lost to rejection. However, the mean duration of onset of rejection after transplantation in this study was 127 days.\n\nFaguer et al. treated eight patients with four doses of rituximab along with PE and reported 81% graft survival at 20 months.[14] However, the mean duration of onset of rejection after transplantation in this study was 45 days.\n\nKaposztas et al. published their experience with the use of rituximab in combination with PE. Twenty-six patients were treated with rituximab plus PE and IVIG.[15] The graft outcomes were compared to historical controls who had received PE ± IVIG alone. The 2 years graft survival with rituximab plus PE was at 90%, which, is significantly better when compared to the 60% survival in the PE cohort. The mean duration of onset of rejection after transplantation in this study was 23 days.\n\nLefaucheur et al. compared the use of 2-week doses of rituximab along with high-dose IVIG and PE with historical controls, who received high-dose IVIG alone and reported a 91.7% graft survival but, it is 50% in high-dose IVIG alone group.[16] Mean duration of onset of rejection after transplantation in this study was 15 days. To the best of our knowledge, this is the first study where the role of rituximab in late acute AMR is assessed. In our study, the mean duration of onset of rejection was 30 months, which, is really high when compared to the other studies.\n\nContrary to the previous reports, our experience with rituximab showed no beneficial effect. This could be due to the delay in the detection of late acute AMR as patient monitoring was not as rigid as in early postoperative period, and all of them were asymptomatic.\n\nAt least five patients had a history of drug noncompliance. Morrissey et al. analyzed the importance of noncompliance in 87 cases of late acute AMR and concluded that noncompliance is a significant factor.[17] In our patients too, noncompliance was a significant contributing factor. We found that four patients had plasma cell rich rejection and three of them progressed to ESRD, which suggests that plasma cells may have a significant role in the rejection. This needs to be addressed in larger patient populations.\n\nIn our series, only one patient showed improvement in graft function, whereas, in all the remaining patients, graft function deteriorated; 3 of 8 patients reached ESRD and were put on MHD. DSA mean MFI decreased to <500 in the stable patient and in the remaining patients it is decreased but still MFI was more than 2000. This reflects that DSA monitoring has prognostic value. A study conducted by Lefaucheur et al. also showed that DSA monitoring is useful in monitoring of acute AMR.[16] When we analyzed the data with the Student's t-test in those five live patients who did not progress to the stage of ESRD, there is a statistically significant deterioration of graft function indicating that rituximab is not effective in this group of patients. Though application of Student's t-test for such a small sample size may not be appropriate, we believe that rituximab may not be effective as, out of nine patients, three patients progressed to ESRD and five patients showed deterioration of renal function.\n\nThree latest studies showed that the addition of rituximab to standard therapy was not associated with the superior graft function.\n\n1-year results were recently reported from a phase III, multicenter, randomized, placebo-controlled trial[18] (RITUX ERAH) that examined the effect of rituximab (combined with PE, IVIG, corticosteroids, tacrolimus and mycophenolate mofetil) on a composite measure of graft loss or absence of improvement of renal function at day 12, in 38 patients with biopsy-proven acute ABMR.\n\nIn this study, out of 38 patients, they administered a single dose of rituximab to 19 patients. 42% of cases have been of late acute AMR. A composite measure of graft loss or absence of improvement of renal function frequency at day 12 was 52.6% and 57.9% in the rituximab and placebo groups, respectively (P = 0.74) with no advantage of rituximab over control for the graft loss or renal function outcome. At the end of 1 year, both groups showed improvement in serum creatinine, histological parameters, and DSA levels; however, in the rituximab group, there is no additional benefit when compared to additional therapy and this trial concluded that the addition of rituximab to standard therapy of PE, IVIG, and steroids provides no additional benefit.\n\nGupta et al.[5] published their data in 23 cases of late acute AMR. Out of 23 patients, 18 patients received rituximab in addition to PE/IVIG and steroids and assessed serum creatinine, histologic improvement, and DSA titers. Initially, there was a marginal benefit observed with respect to serum creatinine but after follow-up of 71 days (43-802 days), worsening of serum creatinine, lack of histologic response and high DSA levels were observed and concluded that rituximab was not effective in late AMR.\n\nGulleroglu et al.[19] studied the effect of rituximab in 3 pediatric cases of refractory late acute AMR by administering 2–4 doses of rituximab (375 mg/m2). At the end of 1 year, two grafts were lost and concluded that addition of the rituximab to standard therapy was ineffective.\n\nHaving a small sample size in our study is definitely an important limitation along with a retrospective analysis of the data. A repeat biopsy at the end of the study would have been provided prognostic value which was not done in our study. We need randomized control trials with a larger sample size to confirm these results.\n\nConclusion\nRituximab may not be effective in late acute AMR unlike, in early acute AMR. Monitoring of DSA has a prognostic role in these patients and plasma cell rich rejection is associated with poor prognosis. These things should be confirmed by further studies involving larger sample size.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgements\nWe are thankful to Dr. Ch Ved Prakash Rao for helping in preparing this manuscript.\n==== Refs\nReferences\n1 Nankivell BJ Alexander SI Rejection of the kidney allograft N Engl J Med 2010 363 1451 62 20925547 \n2 Solez K Colvin RB Racusen LC Haas M Sis B Mengel M Banff 07 classification of renal allograft pathology: Updates and future directions Am J Transplant 2008 8 753 60 18294345 \n3 Sis B Mengel M Haas M Colvin RB Halloran PF Racusen LC Banff ’09 meeting report: Antibody mediated graft deterioration and implementation of Banff working groups Am J Transplant 2010 10 464 71 20121738 \n4 Solez K Racusen LC The Banff classification revisited Kidney Int 2013 83 201 6 23235566 \n5 Gupta G Abu Jawdeh BG Racusen LC Bhasin B Arend LJ Trollinger B Late antibody-mediated rejection in renal allografts: Outcome after conventional and novel therapies Transplantation 2014 97 1240 6 24937198 \n6 Racusen LC Haas M Antibody-mediated rejection in renal allografts: Lessons from pathology Clin J Am Soc Nephrol 2006 1 415 20 17699240 \n7 Gloor J Cosio F Lager DJ Stegall MD The spectrum of antibody-mediated renal allograft injury: Implications for treatment Am J Transplant 2008 8 1367 73 18510643 \n8 Racusen LC Colvin RB Solez K Mihatsch MJ Halloran PF Campbell PM Antibody-mediated rejection criteria – An addition to the Banff 97 classification of renal allograft rejection Am J Transplant 2003 3 708 14 12780562 \n9 Takemoto SK Zeevi A Feng S Colvin RB Jordan S Kobashigawa J National conference to assess antibody-mediated rejection in solid organ transplantation Am J Transplant 2004 4 1033 41 15196059 \n10 Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients Am J Transplant 2009 9 Suppl 3 S1 155 \n11 Puttarajappa C Shapiro R Tan HP Antibody-mediated rejection in kidney transplantation: A review J Transplant 2012 2012 193724 \n12 Barnett AN Hadjianastassiou VG Mamode N Rituximab in renal transplantation Transpl Int 2013 26 563 75 23414100 \n13 Becker YT Becker BN Pirsch JD Sollinger HW Rituximab as treatment for refractory kidney transplant rejection Am J Transplant 2004 4 996 1001 15147435 \n14 Faguer S Kamar N Guilbeaud-Frugier C Fort M Modesto A Mari A Rituximab therapy for acute humoral rejection after kidney transplantation Transplantation 2007 83 1277 80 17496547 \n15 Kaposztas Z Podder H Mauiyyedi S Illoh O Kerman R Reyes M Impact of rituximab therapy for treatment of acute humoral rejection Clin Transplant 2009 23 63 73 19200217 \n16 Lefaucheur C Nochy D Andrade J Verine J Gautreau C Charron D Comparison of combination plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection Am J Transplant 2009 9 1099 107 19422335 \n17 Morrissey PE Reinert S Yango A Gautam A Monaco A Gohh R Factors contributing to acute rejection in renal transplantation: The role of noncompliance Transplant Proc 2005 37 2044 7 15964334 \n18 Sautenet B Blancho G Büchler M Morelon E Toupance O One year results of the effects of rituximab on acute humoral rejection in renal transplantation: RITUX ERAH, a multicenter randomized placebo controlled trial Am J Transplant 2013 13 Suppl 5 1 9 [Abstract #266] \n19 Gulleroglu K Baskin E Bayrakci US Turan M Ozdemir BH Moray G Antibody-mediated rejection and treatment in pediatric patients: One center's experience Exp Clin Transplant 2013 11 404 7 24128133\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "26(5)",
"journal": "Indian journal of nephrology",
"keywords": "Donor-specific antibody; late acute antibody mediated rejection; plasma cell rich rejection; rituximab",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "317-321",
"pmc": null,
"pmid": "27795623",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": "15196059;20121738;12780562;18510643;17699240;19422335;15147435;23414100;15964334;19845597;26555944;24937198;17496547;23235566;24128133;22577514;19200217;20925547;18294345",
"title": "Rituximab in the treatment of refractory late acute antibody-mediated rejection: Our initial experience.",
"title_normalized": "rituximab in the treatment of refractory late acute antibody mediated rejection our initial experience"
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"abstract": "Dermatophytosis is one of the most common diseases worldwide and is difficult to treat due to its recalcitrant nature. Conventional treatment modalities are associated with frequent relapses due to the absence of a host immune interaction. Here, we present a case series of three patients with difficult-to-treat and recalcitrant dermatophytosis who were treated with homologous autoimplantation. Complete clearance of dermatophytosis was observed after three months in two of the patients and after two and a half months in one patient without the use of any antifungals. No relapses were observed within six months of follow-up. The outcomes of the three patients presented in this case series support homologous autoimplantation as a safe and effective procedure for the treatment of recalcitrant dermatophytosis. The procedure requires only a single visit that can be performed either alone or in combination with other modalities.",
"affiliations": "Drs. Kumar and A. Kaur are with the Department of Dermatology, Leprology and Venereology at Guru Gobind Singh Medical College in Faridkot, Punjab, India.;Drs. Kumar and A. Kaur are with the Department of Dermatology, Leprology and Venereology at Guru Gobind Singh Medical College in Faridkot, Punjab, India.;Drs. Kumar and A. Kaur are with the Department of Dermatology, Leprology and Venereology at Guru Gobind Singh Medical College in Faridkot, Punjab, India.",
"authors": "Kumar|Sumir|S|;Kaur|Amandeep|A|;Kaur|Sukhmani|S|",
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"country": "United States",
"delete": false,
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"issn_linking": "1941-2789",
"issue": "14(1)",
"journal": "The Journal of clinical and aesthetic dermatology",
"keywords": "Autoimplantation; dermatophytosis; immunotherapy; recalcitrant; relapse; resistant; tinea",
"medline_ta": "J Clin Aesthet Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101518173",
"other_id": null,
"pages": "34-37",
"pmc": null,
"pmid": "33584966",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports",
"references": "29644192;20952864;18783559;19915240;30041646;10847201;27057486;23372210;28584364",
"title": "Autoimplantation Therapy in Extensive and Recalcitrant Dermatophytosis: A Case Series.",
"title_normalized": "autoimplantation therapy in extensive and recalcitrant dermatophytosis a case series"
} | [
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"companynumb": "IN-SUNPHARMA-2022R1-323945AA",
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"abstract": "BACKGROUND\nThe search for mutations epidermal growth factor receptor (EGFR) has changed the therapeutic approach and prognosis of non-small cell lung cancer (NSCLC). The effectiveness of tyrosine kinase inhibitors (TKI) has been demonstrated orally in patients with EGFR mutation. We report the case of a patient for whom treatment with TKI was started effectively in a Critical Care Unit.\n\n\nMETHODS\nA patient of 59 years is followed for a stage IV lung adenocarcinoma with metastases in liver, brain, adrenal, lung and pleura. After a first course of chemotherapy (cisplatin-gemcitabine), the patient presents a multi-factorial acute respiratory distress. Due to an EGFR mutation, transfer to intensive care is decided then orotracheal intubation with mechanical ventilation. It is decided to initiate treatment with erlotinib via nasogastric tube. The evolution will be marked by a tumor response leading to a favorable issue.\n\n\nCONCLUSIONS\nThis case shows the value of initiate TKI despite hospitalization in Intensive Care Unit and highlights the question of the transfer in ICU patients with EGFR mutation.",
"affiliations": "Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de pneumologie, centre hospitalier de Saint-Quentin, 02100 Saint-Quentin, France.;Service de chirurgie thoracique, pneumologie et maladies respiratoires, boulevard Laennec, 02000 Saint-Quentin, France. Electronic address: Berna.pascal@chu-amiens.fr.",
"authors": "Dewolf|M|M|;Dayen|C|C|;Garoute|C|C|;Khamis|W|W|;Fourrier|M|M|;Rousselle|F|F|;Sadki|M|M|;Le Meunier|F|F|;Suguenot|R|R|;Lecuyer|E|E|;Bentayeb|H|H|;Douadi|Y|Y|;Berna|P|P|",
"chemical_list": "D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "France",
"delete": false,
"doi": "10.1016/j.pneumo.2017.03.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0761-8417",
"issue": "73(3)",
"journal": "Revue de pneumologie clinique",
"keywords": "Adénocarcinome bronchique; Bronchial adenocarcinoma; Critical care; EGFR mutation; Erlotinib; Mutation EGFR; Réanimation",
"medline_ta": "Rev Pneumol Clin",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D003422:Critical Care; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008175:Lung Neoplasms; D008875:Middle Aged; D009154:Mutation; D016896:Treatment Outcome",
"nlm_unique_id": "8406312",
"other_id": null,
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"abstract": "Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets.",
"affiliations": "Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK. g.j.inman@dundee.ac.uk.;Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK. j.a.wang@qmul.ac.uk.;Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.;Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.;Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.;Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK.;Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK.;Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.;Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.;Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK.;Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.;Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.;Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.;Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.;Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK.;Division of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK. i.m.leigh@dundee.ac.uk.",
"authors": "Inman|Gareth J|GJ|http://orcid.org/0000-0002-6264-4253;Wang|Jun|J|http://orcid.org/0000-0003-2509-9599;Nagano|Ai|A|;Alexandrov|Ludmil B|LB|http://orcid.org/0000-0003-3596-4515;Purdie|Karin J|KJ|;Taylor|Richard G|RG|;Sherwood|Victoria|V|;Thomson|Jason|J|;Hogan|Sarah|S|;Spender|Lindsay C|LC|;South|Andrew P|AP|;Stratton|Michael|M|;Chelala|Claude|C|;Harwood|Catherine A|CA|;Proby|Charlotte M|CM|;Leigh|Irene M|IM|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
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"doi": "10.1038/s41467-018-06027-1",
"fulltext": "\n==== Front\nNat CommunNat CommunNature Communications2041-1723Nature Publishing Group UK London 602710.1038/s41467-018-06027-1ArticleThe genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature http://orcid.org/0000-0002-6264-4253Inman Gareth J. g.j.inman@dundee.ac.uk 1http://orcid.org/0000-0003-2509-9599Wang Jun j.a.wang@qmul.ac.uk 2Nagano Ai 2http://orcid.org/0000-0003-3596-4515Alexandrov Ludmil B. 3Purdie Karin J. 4Taylor Richard G. 1Sherwood Victoria 1Thomson Jason 4Hogan Sarah 4Spender Lindsay C. 1South Andrew P. 5Stratton Michael 6Chelala Claude 2Harwood Catherine A. 4Proby Charlotte M. 1Leigh Irene M. i.m.leigh@dundee.ac.uk 11 0000 0004 0397 2876grid.8241.fDivision of Cancer Research, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, DD1 9SY UK 2 0000 0001 2171 1133grid.4868.2Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ UK 3 0000 0001 2107 4242grid.266100.3Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 USA 4 0000 0001 2171 1133grid.4868.2Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT UK 5 0000 0001 2166 5843grid.265008.9Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107 USA 6 0000 0004 0606 5382grid.10306.34Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA UK 10 9 2018 10 9 2018 2018 9 366731 7 2017 7 8 2018 © The Author(s) 2018Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets.\n\nIt is known cutaneous squamous cell carcinoma (cSCC) involves a high tumour mutation burden. Here the authors identify common cSCC mutated genes, copy number changes, altered pathways and report the presence of a novel mutation signature associated with chronic exposure to the immunosuppressive drug azathioprine.\n\nhttps://doi.org/10.13039/501100000289Cancer Research UK (CRUK)A13044Inman Gareth J. issue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nThe incidence of keratinocyte skin cancers in fair skinned populations currently exceeds that of all other cancers combined and is increasing year on year in our ageing population. More than one million new cases of cutaneous squamous cell carcinoma (cSCC) are diagnosed annually in the US, with significant health economic implications1. In contrast to most other epithelial malignancies, more than a third of patients develop multiple primary cSCC. This is especially true in immunosuppressed individuals with evidence in organ transplant recipients (OTR) of a more than 100-fold increased risk of developing cSCC2. Although many cSCC are effectively treated with surgery or radiotherapy, morbidity is significant, particularly as tumours frequently occur on cosmetically sensitive sites. Metastasis occurs in ~5% of cases and cSCC is responsible for approximately one-quarter of skin cancer-related deaths and estimates for annual mortality are similar to those for melanoma in parts of the USA3. There are few effective treatments for advanced cSCC, with five-year survival of less than 30% reported for metastatic disease4.\n\nCutaneous SCC is poorly understood at a molecular level and the drivers of disease progression have not been fully elucidated. Whole-exome sequencing (WES) has revealed a high mutation rate with on average 50 mutations per megabase pair DNA5. Additionally, gross chromosomal aberrations and numerous copy number alterations (CNA) indicative of genetic instability create a complex molecular landscape. Epidemiological and clinical evidence supports cumulative life time exposure to ultraviolet radiation (UVR) as the principle environmental carcinogen responsible for cSCC and the majority of mutations found in cSCC contain a ‘UV signature’. Our understanding of the genomic landscape of cSCC is further complicated by keratinocyte clones in apparently normal sun-exposed skin6 bearing mutations in cSCC tumour suppressor genes (TSGs) such as NOTCH1/2 and TP535,7–10. There is evidence that the mutational profile of cSCC harbours similarities to those of other epithelial tumours, including head and neck, lung and oesophageal SCCs (reviewed in ref. 11) and the squamous subtype of pancreatic SCC12, but comparisons are limited by small cSCC data sets.\n\nAnalyses of the patterns of mutations in cancer genomes has revealed the presence of distinct ‘mutational signatures’13,14. They are described using a simple classification based on the six classes of single base mutations in combination with the base 5' and 3' to each mutation and characteristic UVR-induced C > T mutations at pyrimidines appear to predominate in all cSCC studies to date (COSMIC signature 7).\n\nHere, we perform WES of 40 primary cSCC from both immunosuppressed (IS) and immunocompetent (IC) patients classified according to histological differentiation status (well-differentiated vs. moderately/poorly differentiated categories). We have taken an integrated bioinformatics approach with the intention of identifying a limited number of actionable pathways onto which this multiplicity of genetic events will converge. In addition to mutational, chromosomal and clonality analyses, a mutational signature analysis has been performed, revealing a novel mutational signature associated with patients who have been exposed to the immunosuppressive agent, azathioprine.\n\nFurthermore, we describe the molecular characterisation of 15 primary cSCC cell lines. These reflect the mutational signatures, mutational and genomic alteration profiles and gene expression changes of primary tumours and provide a resource for investigating the contribution of genes, pathways, and processes for cSCC progression.\n\nResults\nMutational burden and signatures\nForty cSCC samples from 37 patients (Supplementary Data 1) were analysed/reanalysed by WES (including 30 previously described)5,15. Twenty-nine patients were organ transplant recipients receiving immunosuppressive drugs and one was immunosuppressed for Crohn’s disease. This sample set contained equal numbers of well-differentiated (WD) vs. poorly/moderately differentiated (MD/PD) tumours (20 samples each). WES coverage averaged 54.3 × (range 25.8–79.1×) with 91% of bases covered > 10 × (range 73.5–97.8%) and 81.4% > 20 × (range 47.2–93%) (Supplementary Data 2). We identified 71,242 somatic mutations in the tumours (Supplementary Data 3). The number of nonsynonymous and synonymous mutations varied across each group averaging 1795 somatic variants in WD (range 23–6867) and 1793 somatic variants in MD/PD (range 13–5188) (Fig. 1a and Supplementary Data 3). Computational analysis of patterns of somatic mutations13 has enabled the identification of 30 distinct mutational signatures from more than 12,000 samples from a wide range of cancer types14,16,17 (for a complete set of currently known signatures see http://cancer.sanger.ac.uk/cosmic/signatures). Many of these signatures have been attributed to environmental exposure to mutagens14,16–18. Mutational signature analysis was performed on 37/40 of the cSCC whole-exome sequences (Fig. 1b and Supplementary Data 4). Signature 7 was observed in 33 samples (Fig. 1b), which reflected the C > T mutations of dipyrimidines and has previously been described as a ‘UVR signature’14 (Supplementary Fig. 1B). Twenty-one of these UVR signature positive tumours were from confirmed sun exposed sites (Fig. 1b; head and neck, wrist and hand, Supplementary Data 1) and the remaining 12 were from sites which included the leg, chest, shoulder and back, which may also have been sun exposed (Supplementary Data 1). MD07, which displays no evidence of UVR exposure, was isolated from the foot of the patient and was, therefore, unlikely to be sun exposed (Fig. 1b and Supplementary Data 1, 4).Fig. 1 Number of somatic mutations and mutation signatures across 40 cSCC samples in the moderate/poor and well-differentiated groups. a Number of nonsynonymous, synonymous and UTR mutations across 40 samples. b Mutation signature compositions across 37 of the 40 samples with sufficient mutation depth, in terms of moderate/poor and well-differentiated groups. IC immunocompetent, IS immunosuppressed, Aza confirmed azathioprine exposure, NC no confirmed azathioprine exposure, SE sun exposed site, U unknown if sun exposed site. c A novel signature, termed signature 32, predominately C > T mutations (75%) in combination with C > A, T > A, and T > C mutations, was identified as one of the dominant signatures. This signature is putatively associated with azathioprine treatment\n\n\n\nA previously undescribed mutational signature, termed signature 32 here-after, was found in 27 samples from both the WD and MD/PD tumours (Fig. 1b, orange bars). It is predominately C > T mutations (75%) in combination with C > A, T > A, and T > C mutations (Fig. 1c). There seems to be a clear presence for C > X at ApCpN and T > X at GpTpN. This novel mutational signature exhibits a very strong transcriptional strand bias potentially indicating an interplay with transcription coupled nucleotide excision repair (TC-NER) due to adducts on guanine and adenine (Supplementary Fig. 1A). The pattern of signature 32 is distinct from any of the previously known COSMIC mutational signatures, including signatures that have a pattern of mutations with predominately C > T transitions such as signature 7. Only two of the COSMIC mutational signatures exhibit a correlation > 0.5 between their respective patterns and that of signature 32. The pattern of signature 30 (attributed to mutations in the base excision repair gene NTHL119) has a correlation of 0.58 with signature 32 and that of signature 11 (attributed to exposure to alkylating agents13,14) has a correlation of 0.65 with signature 32. These correlations are lower than those of other distinct COSMIC signatures, for example COSMIC signatures 1 and 6 have a correlation of 0.8113,14. Further, signatures 11 and 30 do not exhibit the same transcriptional strand bias as signature 32. Thus, signature 32 is an entirely novel mutational signature.\n\nSignature 32 was prominent in many of the samples from immunosuppressed patients (Fig. 1b) indicating a potential association with exposure to immunosuppressant drugs. Most immunosuppressed patients received azathioprine (Fig. 1b) although this was usually part of a complex regimen involving at least one other immunosuppressive drug (Supplementary Data 1). However, three of the tumours with signature 32 were from patients who had received azathioprine alone (MD02, PD01, WD03) and both tumours analysed from immunosuppressed patients whom had not received azathioprine (MD08, WD15) did not exhibit mutational signature 32 (Fig. 1b and Supplementary Data 1, 4). There is a significant association only between a confirmed history of azathioprine exposure and the presence of signature 32 (Fisher’s exact test, p < 0.0001; Supplementary Fig. 2a) and not exposure to the other immunosuppressant drugs (Supplementary Fig. 2a). We did not identify any other significant associations between any of the mutational signatures and exposure to any of the immunosuppressant drugs (Supplementary Fig. 2b). Furthermore, analysis of treatment times revealed a strong positive correlation with the estimated time of azathioprine exposure and the prevalence of signature 32 (Spearman’s rank order correlation rs(26) = 0.679, p < 0.0001, Supplementary Fig. 3). Taken together these findings indicate that chronic exposure to azathioprine correlates with the presence of mutational signature 32. All tumours contained lower levels of signatures 1 and 5, which are found in most cancers and are attributed to so called ‘clock-like’ mutational processes20 (Fig. 1b and Supplementary Data 4). Four tumour samples also contained mutational signature contributions from Signatures 2 and 13 (MD06, MD07, WD02 and WD18; Fig. 1b and Supplementary Data 4), which are attributed to the activity of the AID/APOBEC family of cytidine deaminases converting cytosine to uracil14.\n\nSomatic copy number aberrations\nSomatic copy number aberrations (CNA) and loss of heterozygosity (LOH) events were identified across WD and MD/PD samples (Supplementary Data 5), with MD/PD samples having more large-scale genomic events than WD samples (Fig. 2a, b). 62.5% of the samples (25/40) had detectable copy number variations (CNVs) in at least 2 regions, which is consistent with previous observations21–24 with a significant positive correlation with previous studies for top frequent CNAs (Supplementary Fig. 4, Pearson’s correlation r = 0.37, p = 0.015). GISTIC25 analysis further identified significantly amplified and deleted regions (q < 0.1, Supplementary Data 6), including amplifications at 3q26, 5q22, 7q21, 11q22 and 15q11, and deletions at 3p12, 5q13 and 9q21. Amplifications at 3q21–24, 5q21, 7q24, and copy losses at 3p21–24 and 5q24 have also previously reported. Frequent gain of 9q and loss of 9p are also observed in this and previous studies of cSCC (Supplementary Data 7).Fig. 2 Somatic copy number aberrations (SCNA) and LOH events in 40 cSCC samples. a OncoPrint of copy gain, loss and copy-neutral (CN)-LOH segments across moderate/poor and well-differentiated groups. IS immunosuppressed, IC immunocompetent. b Box-and whisker plot indicating the percentage of the genome altered by CNA/LOH across the two groups. Individual values were shown by the blue dots. Moderate/poor differentiated group had significantly higher percentage of altered genome than well-differentiated group (Student’s t-test, two sided, p = 0.018)\n\n\n\nSignificantly mutated genes (SMGs) in cSCC\nWe employed three statistical mutational significance methods; MutsigCV26 (significance cutoff p < 0.05, Supplementary Data 8), Oncodrive-FM27 (significance cutoff q < 0.05, Supplementary Data 9) and Oncodrive-CLUST28 (significance cutoff q < 0.05, Supplementary Data 10). These identified 109, 97 and 171 SMGs respectively totalling 351 unique genes (Fig. 3a and Supplementary Data 8–10). We identified 22 SMGs by at least two methods (Fig. 3a, b). This revealed recurrent mutations in a number of genes previously implicated in human cSCC including NOTCH1/2, TP53 and CDKN2A (Fig. 3b and Supplementary Data 11, 12, Supplementary Fig. 5). The frequency and statistical significance of these potential driver genes are consistent with previous exome10 and targeted sequencing studies9 (Supplementary Data 13).Fig. 3 Twenty-two SMGs identified in 40 cSCC samples. a Venn diagram of overlap of significantly mutated genes as assessed by MutsigCV, OncodriveFM and OncodriveClust. b Mutation OncoPrint of the 22 SMGs identified by at least two of the three methods, with their aberrational frequencies also indicated with percentage bars. IS immunosuppressed, IC immunocompetent. c Pie chart of the mutational signature contribution to SMG mutations\n\n\n\nAdditional SMGs included HRAS, MAP3K9, PTEN, SF3B1, VPS41 and WHSC1 (Fig. 3b, Supplementary Fig. 6 and Supplementary Data 14) all of which have known genetic alterations in human malignancies29–38. We identified oncogenic activating mutations in HRAS in three tumours (Fig. 3b and Supplementary Fig. 6), which have previously been identified in 3–20% of cSCC9,10 (Supplementary Data 13) and keratoacanthomas (reviewed in ref. 4). Of note, 10% of the samples exhibit copy number loss of HRAS (Fig. 3b), which has been observed by others9, warranting a need for better understanding of the role of HRAS in cSCC. PTEN alterations have been previously described in cSCC9 (Supplementary Data 13), but the other SMGs including FLNB, GLIS3, CACNA1C, HERC6, TRAPPC9, MAPK1P1L (Fig. 3b, Supplementary Fig. 7 and Supplementary Data 15), GRHL2, CLCN3, TMEM51, ATP1A1, LCLAT1 and CRY1 (Fig. 3b, Supplementary Fig. 8 and Supplementary Data 16) are of unknown significance in cancer and present with no obvious hotspot mutations. Non-silent mutations in a few of these SMGs have also been observed in cSCC10 (Supplementary Data 13). Comparison of the frequency of alterations in the 22 SMGs between tumours isolated from immunosuppressed and immunocompetent patients revealed no significant difference in mutation frequencies indicating that tumours that arise in these patient groups have common drivers (Fig. 3b and Supplementary Data 17). Next, we assessed the probability for each mutational somatic substitution in the 22 SMGs to be caused by each of the operative mutational signatures. Overall the majority of the SMG gene mutations are caused by azathioprine signature 32 (66.2%): 24.4% are due to UVR driven signature 7; 7.8% are caused by clock-like mutational signatures20 (signatures 1 and 5) and the remaining 1.7% by APOBEC related signatures 2 and 13, suggesting the driving mutational processes responsible for the initiation and progression of the tumours in our sample set are due to a combination of UVR and azathioprine exposure (Fig. 3c and Supplementary Data 18).\n\nInference of clonal evolution and order of genetic changes\nNext, we performed clonal analysis, integrating somatic mutations (SNVs and indels) and CNAs using EXPANDs39, and SciClone40 which have been used to infer patterns of clonal evolution41,42. In 35 of 40 cSCC, WES data were sufficient for the identification of dominant clone and nested subpopulations in each sample, thus allowing for the differentiation between clonal and subclonal mutations. EXPANDS and SciClone had concordant estimates of tumour purity (Supplementary Fig. 9, Pearson’s correlation r = 0.9, p = 3.42e-13, Supplementary Data 19). There was no correlation between the number of somatic mutations identified in our samples and tumour purity (Pearson’s correlation r = 0.10, p = 0.57). Clonality analysis showed tumour heterogeneity across our samples, varying from 1 to 11 clones as estimated by EXPANDS (Fig. 4a) and 1 to 9 clones as estimated by SciClone (Fig. 4b) with some correlation in the number of clusters estimated by the two methods (Supplementary Fig. 10). 26/35 (74%) had at least two clones, 10/35 (29%) had at least three clones and 7/35 (20%) had at least five clones identified by both programmes (Fig. 4a, b and Supplementary Data 20) indicating a high degree of heterogeneity in cSCC.Fig. 4 Clonality analysis of cSCC tumour samples. Clonality analysis of 35 cSCC exomes using EXPANDS (a) and SciClone (b). Clonality analysis of 22 SMGs identifying clonal and subclonal nonsynonymous mutations using EXPANDS (c) and SciClone (d). The number of nonsynonymous mutations in each gene was also shown\n\n\n\nFor the 22 SMGs, we assessed the order of driver mutation acquisition inferred from the aggregate frequencies at which they were found to be clonal or subclonal43. We characterised the clonal and subclonal features of the nonsynonymous mutations for these 22 genes with 74% of all clonal mutations called by EXPANDS also identified as clonal by SciClone (Supplementary Fig. 10). Over 70% of mutations in CDKN2A, ATP1A1, HERC6, MAPK11P1L, GRHL2 and TP53 were clonal using both methods implying alterations in these genes tended to arise earlier during cSCC development (Fig. 4c, d). Rank order of clonality similarly indicated that mutations in these genes and also those in NOTCH1, TRAPPC9, FLNB and MAP3K9 may also be early events, whereas mutations in HRAS, VPS41, GLIS3, CACNA1C, NOTCH2, CLCN3, LCLAT1, TMEM51 and SF3B1 appeared to accumulate a higher proportion of subclonal nonsynonymous mutations (Fig. 4c, d and Supplementary Data 21), indicating that lesions in these genes are more likely to occur later.\n\nIntegration of genomic drivers and gene expression profiles\nTo investigate potential tumour suppressor or tumour promoter roles of our 22 SMGs and genes encoded within areas of significant CNAs, we analysed gene expression profiles (GEP) in five independent data sets comprising samples from normal skin, actinic keratoses (AK) and SCC. These included GSE4521644 coupled with additional samples described here as Data set 1 (Supplementary Data 22), GSE4267745, GSE250346, GSE842937 and GSE3262821. GLIS3 and LCLAT1 were determined to have a low level of expression in normal and/or lesional skin across samples and were excluded from this analysis (see Methods). The remaining 20 SMGs were clearly separated into two clusters in GSE42677 (Fig. 5a). One cluster was highly expressed in normal skin and became downregulated in AK and SCC, and the other cluster demonstrated the opposite trend (Fig. 5a). The down- and upregulated patterns for these genes were largely consistent between the five data sets (Fig. 5b). Among them, TP53 and NOTCH2 were downregulated in SCC compared to normal skin, while seven genes HERC6, CDKN2A, FLNB, MAP3K9, TMEM51, MAPK1IP1L and WHSC1 were upregulated in SCC relative to normal skin in at least 3 out of 5 data sets (Fig. 5b) suggesting respective potential tumour suppressing and tumour promoting roles in cSCC development.Fig. 5 Expression profiles of driver genes in five independent gene expression data sets. a Expression heatmap of 20 SMGs that were also expressed across normal, AK, in situ and invasive SCC samples from GSE42677. b Log2 fold changes (FC) of AK vs. normal and SCC vs. normal of 20 SMGs from GSE42677, Data set 1 (Lambert), GSE2503, GSE84293 and GSE32628. Normal normal skin, NSE non-sun exposed normal skin, SE Sun exposed skin, AK actinic keratosis. Significant genes in 3 out of 5 data sets were highlighted in green. Within the heatmap, red colour indicates the upregulation in AK or SCC compared to normal control, which blue colour indicates the downregulation in AK or SCC in relation to normal skin\n\n\n\nWithin the amplified regions identified by GISTIC analysis, the mRNA levels of 23 genes were upregulated in cSCC compared to normal skin in GSE42677 (Fig. 6a), 38 in Data Set 1, 78 in GSE32628, 7 in GSE2503 and 43 in GSE84293 (Fig. 6b, top Venn diagram). Overlap analysis revealed that 19 genes were encoded in amplified regions and upregulated at the mRNA level in at least three of these data sets (Fig. 6b, c) indicating that these genes may play tumour promoting roles in cSCC. Nine genes within deleted regions identified by GISTIC analysis were also downregulated at the mRNA level in cSCC compared to normal skin in GSE42677 (Fig. 6a), 11 in Data set 1, 24 in GSE3268,, 2 in GSE2503 and 5 in GSE84293 (Fig. 6b, bottom Venn diagram). Overlap analysis revealed that five genes were encoded in deleted regions and downregulated at the mRNA level in at least three of these data sets (Fig. 6b, c) indicating that these genes may play tumour suppressor roles in cSCC.Fig. 6 Expression profiles of genes significantly amplified or deleted in cSCC. a Expression heatmap of significantly amplified and upregulated genes (n = 23), and deleted and downregulated genes (n = 9) in the in situ vs. normal comparison that were also expressed across normal, AK, in situ and invasive SCC samples from GSE42677. b Venn diagrams of overlap across five gene expression data sets of significantly amplified genes and overexpressed (upper panel) and significantly deleted and downregulated genes (lower panel). c Log2 fold changes (FC) of pairwise comparisons of AK vs. normal and SCC vs. normal across the five data sets for 19 amplified/upregulated and 5 deleted/downregulated expressed genes shared across at least three data sets. Within the heatmap, red colour indicates the upregulation in AK or SCC compared to normal control and blue colour indicates the downregulation in AK or SCC in relation to normal skin\n\n\n\nIdentification of WD and MD/PD group-specific SMGs\nDifferentiation status is a prognostic marker in cSCC (reviewed in ref. 4). We developed a randomisation test strategy to identify WD and MD/PD group-specific SMGs based on the MutSigCV and OncodriveFM significance p-values (see Methods, Fig. 7a), and further selected those group-specific genes that were also regarded as expressed in the GEP data sets. This led to 16 MD/PD-specific and 6 WD-specific SMGs, respectively (Fig. 7b). The MD/PD-specific genes included TMEM51 and GRHL2 previously identified in the analysis of the whole 40 exomes but also identified additional MD/PD-specific genes ZZEF1, GMDS, NEDD4L, LRP1, PRB1, HECTD4, SOS2, ICAM1, VWF, ACVR2A, POLH, CNDP2, RPLP1 and PRMT3. Their significance has yet to be described in cSCC although non-silent mutations in some of these genes have been observed in cSCC10 (Supplementary Data 23). Interestingly, the expression of ACVR2A appeared to decline gradually with the disease progression, with the highest level of expression in the normal skin and the lowest in SCCs in all five GEP data sets (Supplementary Fig. 11), suggesting its potential tumour suppressing role in disease progression. The WD-specific genes included the previously identified ATP1A1 and additionally SULF1, ZNF528, NRCAM, FAT1 and SEMA5A. FAT1 has been identified as a significantly mutated putative driver gene in cSCC6,10 and in normal sun exposed skin6. None of these other WD-specific genes have been associated with cSCC although non-silent mutations in some of these genes have been observed in cSCC10 (Supplementary Data 23).Fig. 7 Comparison of significantly mutated genes and pathways between moderate/poor and well-differentiated groups. a Group-specific SMGs from the randomisation test based on MutSigCV and OncodriveFM p-values, respectively. Moderate/poor group-specific genes were marked with red circles, while well-differentiated group-specific genes were marked with blue circles. The size of the circle corresponds to its significance compared to that expected by chance. b Mutation OncoPrint of group-specific genes that were expressed across 40 cSCC samples in moderate/poor and well-differentiated groups. Significance level (-log10(p-value)) from the randomisation test was also shown for each gene as bar charts. Genes derived from the OncodriveFM statistics were shown in dark grey, while genes derived from MutSigCV statistics were in light grey. Genes at the top panel appeared to be more moderate/poor group specific, while genes at the bottom panel were more well-differentiated group specific. c Significantly mutated KEGG signalling pathways and d biological processes between moderate/poor and well-differentiated groups. Significant pathways and processes in moderate/poor group only were marked with a dotted square. Pathways and biological processes in the bar charts were sorted with terms significant in both groups at the top, and terms significant in moderate/poor group only at the bottom (indicated with red dashed boxes)\n\n\n\nMutational pathway analysis\nMutational pathway analysis revealed several KEGG signalling pathways that were more mutated in the MD/PD group, such as NOTCH, TGF-β, WNT, PI3K-AKT and neurotrophin signalling (Fig. 7c and Supplementary Data 24, 25). The MD/PD-specific mutated pathways also included those related to immune responses such as T-cell receptor, Fc epsilon RI, RIG-I-like receptor and chemokine signalling pathways (Fig. 7c). Furthermore, our mutational pathway analysis revealed that biological processes of ECM-receptor interaction, cell cycle, tight junction and glycolysis/gluconeogenesis were also more significantly mutated in the MD/PD group compared to WD group, whereas lysine degradation, regulation of the actin cytoskeleton, carbohydrate digestion and adsorption and basal transcription factors were among those specific to the WD group (Fig. 7d and Supplementary Data 25). Computational pathway analysis of mutated genes in cSCC has not previously been performed. Manual pathway assessment previously suggested involvement of the RAS/RTK/PI3K and cell cycle pathways in aggressive cSCC10 consistent with our observations (Fig. 7c, d). The findings that PI3K signalling is frequently altered in more aggressive SCCs such as HNSCC, lung and oesophageal SCC11 further supports our MD/PD pathway analysis implicating PI3K-AKT signalling in disease progression.\n\nPatient-derived cell lines reflect primary tumours\nTo facilitate future functional studies, tumour keratinocytes were cultured from multiple tumours and a panel of 15 cell lines was selected for full characterisation (Supplementary Data 26). Nine were derived from five OTR patients on immunosuppressive drugs including five from a single patient (PM1, MET1,2,4, T9)47. Six lines were derived from five immunocompetent patients (IC1, IC1MET, IC8, IC12, IC18 and IC19) with IC1/IC1MET being paired primary and metastatic lymph node derived lines, respectively.\n\nIn general, mutational profiles of patient-derived cell lines were comparable with those of the tumour sample set (Supplementary Data 27). Mutation signature analysis showed that signature 7 was present in all cell lines, and eight lines from four patients also contained signature 32, all of which were derived from tumours from immunosuppressed patients receiving azathioprine (Fig. 8a and Supplementary Data 28). Interestingly, PM1, MET1, 2, 4, and T9 from the same patient show very similar mutation signature compositions, except that MET4 also exhibited signature 26 associated with defective DNA mismatch repair14 in 32% of its total mutations (Fig. 8a and Supplementary Data 28). OncoPrint analysis indicated that many of the cell lines have alterations in mismatch repair genes (Supplementary Fig. 12) but this does not correlate with the presence of signature 26. Analysis of somatic CNA/LOH revealed many recurrently altered regions that were also present in patient tumours including amplification at 3q26, 7q21 and 11q22, and deletions at 5q13 and 3p12 (Fig. 8b). The cell lines exhibited a high degree of chromosome instability similar to the most genomically altered primary tumours. Mutations in the 22 SMGs from the primary tumour set also frequently occurred in cell lines, with TP53, NOTCH1/2 and CDKN2A the most recurrently altered with similar mutational profiles in primary tumour samples and cell lines (Fig. 8c, Supplementary Data 29 and Supplementary Fig. 13).Fig. 8 Mutation signatures, somatic CNA/LOH and mutation profiles for identified SMGs in cSCC tumour samples in SCC cell lines. a Mutation signatures across all SCC cell lines. Again, signature 7 and 32 were the most dominant signatures. IC immunocompetent, IS immunosuppressed, Aza confirmed azathioprine exposure, NC no confirmed azathioprine exposure, SE sun exposed site, U unknown if sun exposed site b OncoPrint of copy gain, loss and CN-LOH segments. c Mutation OncoPrint for 22 SMGs detected in cSCC tumour samples across cell lines, ordered by aberration frequency. d Mutation OncoPrint for WD/MD/PD driver genes detected in cSCC tumour samples across cell lines, ordered by frequency. MD/PD-specific genes found in cSCC samples are highlighted in orange\n\n\n\nWe also performed gene expression analysis of our cell lines and three separate isolates of primary normal human keratinocytes (NHKs) using Illumina Beadchip arrays (Supplementary Data 30). NOTCH2, a commonly downregulated SMG in the primary tumour data set, was also downregulated in cSCC cell lines in comparison to NHKs (Supplementary Fig. 14A). 2/7 commonly upregulated SMGs (CDKN2A and WHSC1) were also upregulated in cSCC cell lines compared to NHKs (Supplementary Fig. 14A). 3/19 commonly amplified and upregulated genes POLR2H, ALG3 and AP2M1, were also upregulated in the cell lines relative to NHKs and 2/5 of the commonly deleted and downregulated genes, SSBP2 and F2R, were also downregulated in cSCC relative to NHKs (Supplementary Fig. 14B). We further identified the mutational profiles for MD/PD and WD group-specific SMGs in cell lines, with MD/PD-specific SMGs ZZEF1, NEDD4L, LRP1, VWF, HECTD4, ICAM1 and ACVR2A being the most frequently altered, and WD-specific genes FAT1, NRCAM, SULF1 and ATP1A1 recurrently altered in SCC lines (Fig. 8d). Our cell lines thus represent a well characterised resource, which reflects the molecular landscape of primary cSCC.\n\nDiscussion\nHere, we present the largest analysis of cSCC WES so far performed and provide a unique data set with 20 samples from moderately/poorly differentiated tumours, 20 from well-differentiated tumours and 15 samples from cSCC cell lines. Thirty-three primary tumour samples and nine cell lines were derived from immunosuppressed patients. Patients who are iatrogenically immunosuppressed to prevent organ transplant rejection have been recognised as being at greatly increased risk of cSCC (100–250-fold) with a reversal of the normal BCC:cSCC ratio from 4:1 to 1:22,48.\n\nEach biological process causing mutations in somatic cells that may drive tumour formation leaves a mutational signature and deciphering these signatures is a unique opportunity to reveal the mutational processes operative in different cancer types13,14,16,17,49. We applied this approach to our data set and found five previously identified signatures in our tumours including signature 7, which has been associated with exposure to UVR a known potent skin cancer carcinogen. The UVR signature was found in 33/37 exomes examined and in all 15 cell lines. A novel signature, termed signature 32 was found in 27 of the tumour samples and 8 of the cell lines (Figs. 1, 8). Interrogation of the clinical history for each patient found that the presence of signature 32 correlated with immunosuppressive regimens including use of azathioprine. Although immunosuppressants such as mycophenolate mofetil, cyclophosphamide and cyclosporine A affect DNA damage mechanisms, including UV induced DNA excision repair50–52, three patients received azathioprine alone and analysis of treatment times revealed a strong positive correlation with exposure time to azathioprine and signature 32 prevalence (Supplementary Fig. 3). All of the signature 32 positive cell lines were also from immunosuppressed patients who received azathioprine (Fig. 8). Furthermore, only exposure to azathioprine and not the other immunosuppressive drugs correlated with the presence of signature 32 and the only significant correlation of immunosuppressive drug use and the presence of any of the mutational signatures was with azathioprine exposure and signature 32 (Supplementary Fig. 2). This signature is likely to be of biological relevance as mutational signature analysis of mutations in the putative driver genes identified in our study, revealed that over 65% of these were signature 32 (Fig. 3c). Azathioprine, an inhibitor of de novo purine synthesis, is associated with selective ultraviolet A (UVA) photosensitivity and mutagenic effects in the skin53. The azathioprine metabolite 6-thioguanine (6-TG) replaces a small proportion of DNA guanine and becomes a strong UVA chromophore, interacting with UVA to generate reactive oxygen species, which cause widespread DNA damage and protein oxidation; the latter damages the DNA repair proteome increasing UVB mutagenicity53,54. Azathioprine photosensitivity is clinically measurable, may be associated with a specific genetic signature in basal cell carcinoma55 and can be reduced by switching from azathioprine to mycophenolate mofetil (MMF), although azathioprine metabolites may persist in the skin for several years after withdrawal56. Given the photosensitising properties of azathioprine we postulate that the combined action of UVR and incorporation of azathioprine metabolites into DNA provide the biochemical basis for this novel signature. We propose that these azathioprine effects are associated with this new genetic signature (signature 32) that contributes to tumour progression. This has clinical significance for the many patients currently receiving azathioprine who should be counselled about their skin cancer risk and UVR photosensitivity.\n\nWe confirm the high mutational burden present in cSCC with an average of over 1700 mutations present in the primary tumour exomes (Fig. 1). WES data enabled us to assess clonality and revealed that most tumours are highly heterogenous containing 2–11 clones (Fig. 4). GISTIC analysis revealed common areas of copy number loss and gain in our samples with MD/PD tumours exhibiting higher levels of chromosomal instability compared to WD tumours (Fig. 2) further illustrating the genetic complexity of cSCC.\n\nWe employed three computational methods (MutSig, OncodriveClust, OncodriveFM) and identified 351 SMGs at the cutoffs we used. Twenty-two genes were found to be significant in two or more of these programmes enabling a further ranking of the potential driver genes (Fig. 3). Combination of these analyses with CNA/LOH analysis indicate that alteration of NOTCH1 and NOTCH2 genes are among the most common events in cSCC (Fig. 3) with only 3/20 MD/PD tumours and 5/20 WD tumours escaping alteration in either of these genes indicating that the NOTCH pathway is an almost universal tumour suppressor pathway in cSCC probably due to its role in promoting cell cycle exit and differentiation57. We also identify TP53 alterations in 70% of our tumours and CDKN2A changes in nearly 50% of cases. Clonality analysis revealed that CDKN2A mutations are clonal (Fig. 4c, d) indicating a likely early event in formation of the tumours in which they were identified. Strikingly, despite deep sequencing efforts, CDKN2A mutations in contrast to TP53 or FAT1 mutations have yet to be identified in sun-exposed ‘normal skin’6 suggesting a key gatekeeper role of p16INK4B in cSCC. Our findings also suggest that mutations in ATP1A1, HERC6, MAPK1P1L, GRHL2, TRAPPC9, FLNB, NOTCH1 and MAP3K9 represent early driving events in cSCC (Fig. 4c, d). Within these, alteration in ATP1A1 may pre-dispose to well-differentiated tumours, whereas alterations in GRHL2 may pre-dispose to more poorly differentiated and potentially poorer prognosis tumours (Fig. 7). GRHL2 mutations are associated with an autosomal-recessive ectodermal dysplasia58 and this transcription factor may drive a cancer stemness phenotype in oral SCC59. This gene clearly warrants further investigation in cSCC.\n\nTo further sift our list of somatically mutated genes and those that are encoded within regions of common amplification or loss we integrated our WES data with five independent gene expression data sets (Figs. 5, 6). Interestingly, despite the proposed tumour suppressor role of inactivating mutations in CDKN2A we consistently observed upregulation of CDKN2A gene expression in the GEP data sets and in our cell lines (Fig. 5 and Supplementary Fig. 14). Transcription factor motif analysis indicates that ERK signalling through ETS transcription factors may be operative during SCC progression7 and this may act to upregulate CDKN2A expression as part of a stress induced senescence programme60 possibly explaining this discrepancy. This analysis highlights potential oncogenic tumour promoting roles for the actin binding protein encoded by FLNB and the histone methyltransferase encoded by WHSC1, as expression of both of these genes are elevated during cSCC progression and they do not contain premature termination codon or splice site mutations (Fig. 5 and Supplementary Fig. 6, 7). We also identified genetic alteration of the arginine methyltransferase, PRMT3, specifically in the MD/PD tumours (Fig. 7B), further indicating that epigenetic modifiers may regulate cSCC progression. Genes that are amplified and upregulated during cSCC progression may act as oncogenic drivers of disease and we revealed 19 further genes with this potential role including the SKI like proto-oncogene SnoN encoded by the SKIL gene (Fig. 6). This transcription factor can modulate canonical TGF-β signalling61 and pathway analysis revealed that genomic alterations in TGF-β signalling are enriched in the MD/PD group of tumours (Fig. 7C). Consistent with this we also identify alterations in the ACVR2A gene that encodes for an activin/BMP receptor enriched in this tumour group, which is also downregulated during tumour progression (Fig. 7B and Supplementary Fig. 11) implying a tumour suppressor role for this gene. Our recent studies have confirmed that the TGF-β pathway acts as a potent tumour suppressor pathway in cSCC with mutational inactivation of TGFBR1 and/or TGFBR2 occurring in ~40% of cSCC tumours15.\n\nIntegration of gene expression data sets with GISTIC analysis of CNVs provides a powerful technique for identifying genes, which contribute to disease progression without the involvement of SNV alterations. This analysis implicates SEMA3C, STEAP4, MMP10, RAP2B and AP2M1 as a potential cSCC drivers (Fig. 6). These genes have been implicated in promoting tumour growth. SEMA3C can activate RTK signalling and drive prostate cancer growth62, STEAP4 may promote colorectal cancer development63, MMP10 may mediate c-Fos driven cSCC development64, RAP2B is a well described oncogenic activator65 and AP2M1 may participate in senescence escape66. These observations support the hypothesis that our integrated analysis approach has potentially revealed novel drivers of cSCC and provides further impetus for functional interrogation of the genes and pathways revealed in our study.\n\nIn summary, this study describes the complex molecular landscape of cSCC and identifies new potential driver genes, pathways and processes associated with both the development of well-differentiated and potentially poorer prognosis moderately/poorly differentiated tumours in both immunosuppressed and immunocompetent patients. Importantly we identify a novel mutational signature associated with chronic azathioprine exposure and describe the molecular landscape of 15 cSCC cell lines derived from both primary and metastatic lesions which reflect the complexity of tumours and provides a unique resource for determining the biological significance of the molecular events responsible for cSCC maintenance and progression.\n\nMethods\nCollection of patient samples\nThe study was approved by the East of Scotland Research Ethics Service (reference: 08/S1401/69) and the East London and City Health Authority Local Ethics Committee and conducted according to the Declaration of Helsinki Principles. All patients participating in the study provided written, informed consent. Punch biopsies of cSCC were collected in tissue culture transport medium comprising DMEM supplemented with 50 units/ml penicillin and 50 μg/ml streptomycin and 1x fungizone solution (all from Life Technologies, Paisley, UK) or snap-frozen in liquid nitrogen. Venous blood samples were taken from patients into EDTA tubes, aliquoted into cryovials and stored at −80 °C. Histology of patient samples were reviewed blind by two independent pathologists. Details of prescribed medications including drug, dose and duration were derived from two independent reviews of available clinical notes and transplant databases for all immunosuppressed patients. The estimated time of azathioprine therapy for all patients with a history of azathioprine use were calculated and rounded to the nearest month. Complete clinical notes spanning the entire patient journeys were not available for all patients and those without documentary evidence of azathioprine exposure were classified as no confirmed exposure.\n\nIsolation and culture of cSCC lines\nCultures were established according to a previously described method67. In brief, tumour tissue was cut into small pieces and dissociated by incubation at 37 °C in 0.25% trypsin-EDTA (Life Technologies, Paisley, UK) followed by physical disruption using needles. Residual tissue was removed by passing the cell suspension through a 100 μm cell strainer and SCC keratinocytes recovered by centrifugation and plated onto a mouse 3T3 feeder cell layer in keratinocyte culture medium comprising DMEM/Ham’s F12 (3:1; Life Technologies, Paisley, UK) supplemented with 10% fetal bovine serum (FBS; Biosera, Ringmer, UK) and a cocktail of mitogens67. Cultures were maintained in keratinocyte culture medium supplemented with 10 ng/ml EGF (Serotec, Oxford, UK) and passaged upon attaining 80% confluence. All cell lines were routinely screened for mycoplasma and were negative throughout the study.\n\nDNA extraction and genetic analysis\nDNA was extracted from snap-frozen tissue, cultured cells and blood using the Qiagen DNA Mini kit (Qiagen, Crawley, UK) according to the manufacturer’s instructions. Quantitation was performed using the double-stranded DNA-specific Qubit dsDNA BR assay kit in conjunction with the Qubit 2.0 fluorometer (both Life Technologies, Paisley, UK). Short tandem repeat (STR) genotyping was performed to authenticate the unique identity of each cell line. Sixteen loci distributed across the human genome were amplified using the AmpFLSTR Identifiler PCR Amplification Kit followed by capillary sequencing on the 3730xl DNA analyser (all reagents from Life Technologies, Paisley, UK). Microarray-based single-nucleotide polymorphism (SNP) analysis was performed by subjecting 500 ng DNA from each cell line and matched blood to the Genome-Wide Human SNP Nsp/Sty 6.0 assay (Affymetrix, Santa Clara, CA) according to the manufacturer’s instructions. Whole-exome sequencing (WES) was performed by Oxford Gene Technology (OGT) using Agilent SureSelect All Exon v5 for exome capture. Briefly, 1 μg of DNA from each sample were used to prepare the sequencing library through shearing of the DNA followed by ligation of sequencing adaptors. Sequencing was performed on the Illumina HiSeq platform. Paired-end sequencing (2 × 100 bp) was carried out using HiSeq sequencing instruments.\n\nWES data processing, somatic variant calling and annotation\nThirty previously published sporadic cSCC samples5,15 were included and reanalysed with our ten newprimary tumour samples and 15 cSCC cell lines. WES data of all samples (except the T2 cell line, see below) were analysed using our established pipeline68,69. The minimum coverage for identified variant sites was required to be as ten reads. For the cell line sample T2, the variant calling was performed using the VarScan2 somatic calling module70. There was around 22% of DNA in the corresponding normal sample that was tumour DNA, suggested by the variant allele frequency (VAF) density from the normal sample. Within VarScan2 somatic calling, allele frequencies from the T2 cancer cell line and the normal control sample were compared by Fisher’s Exact Test, and somatic p-values were derived. High-confidence somatic calls were subsequently extracted for T2 using the VarScan2 ‘process-Somatic’ module, with mutations with > 20% VAFs further selected. Identified somatic variants, including single-nucleotide variants (SNV) and indels, in 40 patient samples and 12 cell lines were further annotated using Oncotator71 and SNPnexus72. Mutation signatures across the 40 exomes were identified based on the non-negative matrix factorisation (NMF) approach previously described13. WES data of 40 cSCC samples have been deposited to the European Genome-phenome Archive (EGA) under the accession of EGAS00001002612.\n\nIdentification of mutational driver genes and pathways\nWe used three methods to identify different positive selection signals that occurred in driver mutations: OncodriveFM27, OncodriveCLUST28, both implemented in the IntoGen software73, and MutSigCV26. For OncodriveFM and OncodriveCLUST, we used corrected p-values (q < 0.05) for significance. For MutSigCV, due to the small sample size, p-values could not be adjusted, so raw p < 0.05 was applied. Overlapped genes that were identified being significant by at least two of the three methods were further selected. Significantly mutated pathways were also identified using OncodriveFM (q < 0.05).\n\nRandomisation test to identify MD/PD and WD-specific drivers\nTo identify moderate/poor and well-differentiated specific driver genes, we further applied OncodriveFM and MutSigCV on 20 moderate/poor and 20 well-differentiated cSCC samples separately. The significance p-values derived from the two methods were (-log10) transformed and compared between the two groups to highlight group-specific genes. In the MutSigCV test, we selected genes with p < 0.01 in one group but p > 0.1 in the other group. In the OncodriveFM test, we focused on genes with corrected p < 0.05 in one group but corrected p > 0.1 in the other. For these selected candidate genes, we further developed a randomisation test procedure where the pool of 40 SCC samples was randomly split into two groups of equal size (n = 20). We then applied MutSigCV and OncodriveFM on the two groups and recorded the significance values for our candidate genes. We repeated this randomisation procedure 100 times and the transformed p-values from MutSigCV or OncodriveFM generally followed a normal distribution for each gene. We next calculated the probability that the observed significance in moderate/poor or well-differentiated group was stronger than that expected by chance for each candidate. Significant genes from the randomisation test (two-tail p < 0.05) were further noted and regarded as the true moderate/poor or well-differentiated specific genes.\n\nIdentification of CNA and LOH using WES data\nAnalyses for CNA and LOH events from WES data were based on a combinational approach previously described69,74. We adopted two independent approaches (ASCAT75 and VarScan2/DNAcopy R packages) to analyse matched tumour and normal samples for copy number analyses. Using ASCAT, a gain (amplification) is called if (predicted total copy number – predicted ploidy) > 0.6 and a loss if (predicted total copy number – predicted ploidy) < −0.6. Using DNAcopy circular binary segmentation (CBS) segments, the logR ratio was used to discriminate copy number gains and losses (logR ratio > 0.15 = gain, logR < −0.15 = loss). We then selected only the consensus calls across the two methods. In addition, we visually inspected all CNA/LOH events using the logR and B-allele frequency (BAF) plots, and further included copy number gain and loss events when they were clearly supported by one method, but just below the cutoff threshold in the other. Genes targeted by copy gain, loss and copy-neutral LOH (cn-LOH) in each sample were further identified.\n\nIdentification of significantly amplified/deleted regions\nTo further identify significantly amplified and deleted regions in cSCC genomes, we applied GISTIC2.025 (q < 0.1) using the CNA segments and markers generated by VarScan variant calling and ASCAT R package75. Thirty-one of the 40 cSCC exomes that passed the ASCAT analysis were used. Regions that overlap with centromere and telomere were excluded. We further removed regions that were identified as both significantly amplified and deleted.\n\nTumour subpopulation identification and clonality analysis\nEXPANDS39 was used to estimate clonal expansions and cellular frequency of each clonal and subclonal population. Somatic SNVs, indels and CNA segments derived from DNAcopy CBS algorithm were used as input for each tumour. Tumour samples with less than 200 somatic mutations were excluded from this analysis, since stable results may not be solved for these samples, resulting in processing of 35 out of the 40 WES samples. Within each tumour sample, the largest clone was identified as the dominant clone and clones with lower cellular frequencies were regarded as sub-clones. Tumour purity was also estimated based on the cellular frequency of the dominant clone. All somatic variants were assigned to their nested clones. We also used SciClone40 to estimate mutational clusters and Infer clonal architecture for 35/40 cSCC exomes. Similar to EXPANDS, Somatic SNVs, indels with their VAFs along with CNA segments were used as input. The cluster with the largest number of mutations was regarded as the dominant clone for each sample, and subpopulations and tumour purity were subsequently derived. The clonality results and tumour purity from both methods were further compared and assessed.\n\nGene expression microarray data analysis and integration\nFive sets of expression microarray data of patient samples were selected and downloaded from Gene Expression Omnibus (GEO), GSE4267745, GSE4521644, GSE250346, GSE842937 and GSE3262821. The GSE42677 data set included 10 normal skin, 5 AK, 5 in situ and 5 invasive SCC samples, the GSE2503 data set included 6 normal skin, 4 AK and 5 SCC samples, the GSE84293 data set included 8 normal skin, 9 AK and 9 SCC samples and the GSE32628 data set included 13 normal skin, 14 AK and 15 SCC samples. The available normalised expression values in log2 scale were used. The GSE45216 data set had 10 AK and 30 SCC. For this set, we further included 16 non-sun-exposed (NSE), 20 sun-exposed (SE) normal skin and 18 AK samples profiled using the same platform, Affymetrix Human Genome U133 Plus 2.0 Array. All raw.CEL files of 94 samples were assembled and processed together. Quality control (QC) and normalisation were performed on our O-miner transcriptomics analysis platform76, where the RMA (robust multi-array average) approach was used. For all five data sets, differential expression (DE) analyses between different groups were performed using limma R package77. The DE genes were identified using the adjusted p-value < 0.05.\n\nFor SMGs, as well as significantly amplified and deleted genes identified above, we further investigated their expression profiles across normal skin, AK and SCC samples. Based on the normalised non-log2 transformed expression values, we regarded probes with the expression values <100 as not being expressed or expressed at a low level. Thus, we further identified genes that were expressed across normal skin, AK and SCC samples in the five data sets. We then categorised them as genes with an activating role in the tumour development if they were significantly upregulated, or genes with a suppressing role if they were significantly downregulated in SCC/AK samples compared to normal skin, in at least three out of the five data sets.\n\nFor patient-derived cell lines, gene expression data were obtained from Illumina HumanHT-12 v4 Expression BeadChip. Raw image files were first processed using Illumina GenomeStudio, and then normalised using the O-miner platform where lumi R bioconductor package78 was applied. The limma R package was used for the DE analysis. The raw and normalised data have been deposited at GEO under the accession number of GSE98780.\n\nElectronic supplementary material\n\nSupplementary Information\n\n \nDescription of Additional Supplementary Files\n\n \nSupplementary Data 1\n\n \nSupplementray Data 2\n\n \nSupplementary Data 3\n\n \nSupplementary Data 4\n\n \nSupplementary Data 5\n\n \nSupplementary Data 6\n\n \nSupplementary Data 7\n\n \nSupplementary Data 8\n\n \nSupplementary Data 9\n\n \nSupplementary Data 10\n\n \nSupplementary Data 11\n\n \nSupplementary Data 12\n\n \nSupplementary Data 13\n\n \nSupplementray Data 14\n\n \nSupplementary Data 15\n\n \nSupplementary Data 16\n\n \nSupplementary Data 17\n\n \nSupplementary Data 18\n\n \nSupplementary Data 19\n\n \nSupplementary Data 20\n\n \nSupplementary Data 21\n\n \nSupplementary Data 22\n\n \nSupplementary Data 23\n\n \nSupplementary Data 24\n\n \nSupplementary Data 25\n\n \nSupplementary Data 26\n\n \nSupplementary Data 27\n\n \nSupplementary Data 28\n\n \nSupplementary Data 29\n\n \nSupplementary Data 30\n\n \n\n\nPublisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Gareth J. Inman, Jun Wang, Ai Nagano, Catherine A. Harwood, Charlotte M. Proby, Irene M. Leigh.\n\nElectronic supplementary material\nSupplementary Information accompanies this paper at 10.1038/s41467-018-06027-1.\n\nAcknowledgements\nG.J.I., K.J.P., V.S., A.P.S., C.A.H, C.M.P., and I.M.L. acknowledge support from Cancer Research UK programme grant (A13044) and a European Research Council Grant (250170). R.G.T was supported by a Cancer Research UK (Clinical PhD Fellowship/Centre grant (A12976). L.C.S. was supported by Worldwide Cancer Research grant (11-0788). J.W., A.N. and C.C. acknowledge support from Cancer Research UK Centre of Excellence Award to Barts Cancer Centre [C16420/A18066]. We thank Alan Evans (NHS Tayside, Dundee) and Hasan Rizvi (Barts Health Trust, London) for dermatopathology expertise.\n\nAuthor contributions\nParticipated in research design: G.J.I., J.W., A.N., L.B.A., R.G.T., A.P.S., M.S., C.C., C.A.H., C.M.P., I.M.L. Conducted analysis: G.J.I., J.W., A.N., L.B.A., R.G.T. Collected/processed patient samples: K.J.P., C.A.H., C.M.P. Collated patient details: J.T., S.H., C.A.H., C.M.P. Wrote or contributed to the writing of the manuscript: G.J.I, J.W, A.N, R.G.T, V.S., L.C.S., C.A.H., C.M.P., I.M.L.\n\nData availability\nAll data is provided in Supplementary Data 1-30, in GSE98780 and EGAS00001002612.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Guy GP Jr Machlin SR Ekwueme DU Yabroff KR Prevalence and costs of skin cancer treatment in the U.S., 2002-2006 and 2007-2011 Am. J. Prev. Med. 2015 48 183 187 10.1016/j.amepre.2014.08.036 25442229 \n2. Harwood CA A surveillance model for skin cancer in organ transplant recipients: a 22-year prospective study in an ethnically diverse population Am. J. Transplant. 2013 13 119 129 10.1111/j.1600-6143.2012.04292.x 23072567 \n3. 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"fulltext_license": "CC BY",
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"keywords": null,
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"mesh_terms": "D016475:3T3 Cells; D000818:Animals; D001379:Azathioprine; D001706:Biopsy; D002294:Carcinoma, Squamous Cell; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004354:Drug Screening Assays, Antitumor; D059472:Exome; D018628:Gene Dosage; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007166:Immunosuppressive Agents; D008137:Longitudinal Studies; D051379:Mice; D009154:Mutation; D011379:Prognosis; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms",
"nlm_unique_id": "101528555",
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"pmid": "30202019",
"pubdate": "2018-09-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature.",
"title_normalized": "the genomic landscape of cutaneous scc reveals drivers and a novel azathioprine associated mutational signature"
} | [
{
"companynumb": "PHHY2019GB083125",
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"activesubstancename": "PREDNISOLONE"
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{
"abstract": "Over the past decade, spontaneous coronary artery dissection (SCAD) has emerged as an important cause of myocardial infarction, particularly among younger women. The pace of knowledge acquisition has been rapid, but ongoing challenges include accurately diagnosing SCAD and improving outcomes. Many SCAD patients experience substantial post-SCAD symptoms, recurrent SCAD, and psychosocial distress. Considerable uncertainty remains about optimal management of associated conditions, risk stratification and prevention of complications, recommendations for physical activity, reproductive planning, and the role of genetic evaluations. This review provides a clinical update on the diagnosis and management of patients with SCAD, including pregnancy-associated SCAD and pregnancy after SCAD, and highlight high-priority knowledge gaps that must be addressed.",
"affiliations": "Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: Hayes.Sharonne@mayo.edu.;Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.;Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, United Kingdom.;Division of Cardiology, Vanderbilt University Medical Center, Nashville, Tennessee.;Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.;Division of Cardiac Surgery, University of British Columbia, Vancouver, British Columbia, Canada.;Division of Maternal and Fetal Medicine, Mayo Clinic, Rochester, Minnesota.",
"authors": "Hayes|Sharonne N|SN|;Tweet|Marysia S|MS|;Adlam|David|D|;Kim|Esther S H|ESH|;Gulati|Rajiv|R|;Price|Joel E|JE|;Rose|Carl H|CH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacc.2020.05.084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1097",
"issue": "76(8)",
"journal": "Journal of the American College of Cardiology",
"keywords": "SCAD; fibromuscular dysplasia; genetics; myocardial infarction; pregnancy-associated; women",
"medline_ta": "J Am Coll Cardiol",
"mesh_terms": "D003330:Coronary Vessel Anomalies; D019468:Disease Management; D005260:Female; D006801:Humans; D009203:Myocardial Infarction; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011379:Prognosis; D018570:Risk Assessment; D012307:Risk Factors; D014652:Vascular Diseases",
"nlm_unique_id": "8301365",
"other_id": null,
"pages": "961-984",
"pmc": null,
"pmid": "32819471",
"pubdate": "2020-08-25",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Spontaneous Coronary Artery Dissection: JACC State-of-the-Art Review.",
"title_normalized": "spontaneous coronary artery dissection jacc state of the art review"
} | [
{
"companynumb": "US-BAYER-2020-210860",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
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"dr... |
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